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VOL 5 | <strong>ISSUE</strong> 7<br />
PAGES 100<br />
<strong>NOVEMBER</strong> <strong>2018</strong><br />
FUTUREMEDICINEINDIA.COM<br />
IMMUNOTHERAPY FOR<br />
LUNG<br />
CANCER<br />
WILL CHECKPOINT BLOCKERS ALTER<br />
WELL-ENTRENCHED TREATMENT ALGORITHMS?<br />
COPD REGULATORY DRUG RESISTANCE CASE REPORT<br />
EBV INTERVENTION<br />
IN EMPHYSEMA<br />
MCI IN DIRE<br />
STRAITS<br />
TACKLING<br />
EMERGING<br />
PATHOGENS<br />
ABERNETHY -<br />
AN UNUSUAL<br />
SUSPECT
editor’s note<br />
<strong>NOVEMBER</strong> AUGUST <strong>2018</strong> <strong>2018</strong> / Vol: / Vol. 5 5 / Issue: / Issue 4 7<br />
Founder & & Editor Editor<br />
CH Unnikrishnan<br />
Executive Editor Editor<br />
S Harachand<br />
Harachand<br />
Science Editor<br />
Science Editor<br />
Dr Rajanikant Vangala<br />
Dr Rajanikant Vangala<br />
Consulting Editors<br />
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Design Editor<br />
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Dear Doctor,<br />
Dear Doctor<br />
Oncology is again in focus for us, which should not come as a surprise given<br />
the<br />
We<br />
extent<br />
know you<br />
of the<br />
are<br />
problem.<br />
busy. It is<br />
When<br />
always<br />
the<br />
reassuring<br />
entire world<br />
that<br />
of<br />
the<br />
medical<br />
trust and<br />
research<br />
faith of<br />
is<br />
firefighting to counter this monster, it will remain in our focus till we can be<br />
hundreds of patients in your healing touch keeps you busy in this noble<br />
sure that we have brought you the very last bit of technological breakthrough<br />
profession. In the hectic practice, it’s quite natural that you might miss<br />
on this topic.<br />
out on some of the latest developments in emerging medicine. In this era<br />
After an in-depth cover on liquid biopsy — a new revolutionary tool in the<br />
of innovation, medical science is getting redefined almost by the day. Old<br />
hands of oncologists for cancer tracking — in August, we now bring you the<br />
technologies are being replaced by the new in the blink of an eye. Robots<br />
latest in lung cancer, the most complex cancer to deal with. Immunotherapy<br />
and artificial intelligence are taking over a good part of the procedures,<br />
and a few other novel techniques are here to break new ground in managing<br />
while genomics and molecular science unveil the mysteries of life further.<br />
lung cancer, which has otherwise proven to be difficult to tame.<br />
We are fortunate to have such breakthroughs as they help specialists like<br />
COPD has been another largely prevalent but difficult-to-treat disease in<br />
you rise above the expectations of today’s informed patient.<br />
India due to limitations in traditional treatments. We are also excited to tip<br />
you about the new hope in endobronchial valve treatment in patients with<br />
emphysema.<br />
Similarly, it is also a time when India is witnessing revolutionary growth in<br />
healthcare industry, especially in the private sector, wherein an increasing<br />
I am sure you are fully aware of the other healthcare crisis that India<br />
and<br />
number<br />
the world<br />
of doctors<br />
at large<br />
are<br />
are<br />
taking<br />
likely<br />
up<br />
to<br />
multiple<br />
face in the<br />
roles<br />
very<br />
of clinician,<br />
near future<br />
researcher<br />
— the fastemerging,<br />
and<br />
entrepreneur.<br />
antibiotic-resistant<br />
This requires expansion<br />
pathogens.<br />
of your<br />
Our science<br />
focus to<br />
editor<br />
a wider<br />
Dr Rajanikant<br />
canvas. In<br />
Vangala this context, sheds it becomes light on the important urgent need how to a busy stop professional irrational antibiotic like you use can at all<br />
four keep stages pace with of treatment these latest — diagnosis, developments prescription, in a quick dispensing and easy and way. patient<br />
adherence.<br />
At With Future a variety Medicine, of other which scientific is conceived as well and as crafted regulatory by a updates, team of including senior<br />
the journalists, hot Union scientists vs IMA and debate doctors, on the our proposed aim is to NMC help Bill, you we’ve do just ensured that. We that<br />
you are equipped have an exciting to bring and you well-packaged the latest from information the science tool of in care your from hands across this<br />
time. the world in an interesting and convenient way, supplemented by the best<br />
of Happy views and reading, analyses from the masters in each field. We present you this<br />
specialised knowledge vehicle that plugs you into the emerging world of<br />
care seamlessly. Come, let’s join hands in this information journey.<br />
CH Unnikrishnan<br />
editor@futuremedicineindia.com<br />
C H Unnikrishnan<br />
editor@futuremedicineindia.com<br />
www.futuremedicineindia.com futuremedicineindia FutureMedIndia<br />
AUGUST <strong>2018</strong>/ FUTURE MEDICINE / 3
Vol 5 Issue 7<br />
November <strong>2018</strong><br />
₹ 250.00<br />
VOL 5 | <strong>ISSUE</strong> 7<br />
PAGES 100<br />
<strong>NOVEMBER</strong> <strong>2018</strong><br />
FUTUREMEDICINEINDIA.COM<br />
IMMUNOTHERAPY FOR<br />
LUNG<br />
CANCER<br />
38<br />
WILL CHECKPOINT BLOCKERS ALTER<br />
WELL-ENTRENCHED TREATMENT ALGORITHMS?<br />
CASE REPORT DRUG RESISTANCE REGULATORY COPD<br />
ABERNETHY - TACKLING<br />
MCI IN DIRE EBV INTERVENTION<br />
AN UNUSUAL EMERGING<br />
STRAITS<br />
IN EMPHYSEMA<br />
SUSPECT<br />
PATHOGENS<br />
REGULAR FEATURES<br />
CASE REPORT<br />
GENE THERAPY<br />
FOR BLINDNESS<br />
06 Letters<br />
08 News updates<br />
12 Regulatory<br />
34 Drug approvals<br />
50 Education<br />
56 Research snippets<br />
66 Hospital news<br />
68 Insurance<br />
70 Public health<br />
76 Research<br />
78 Orthopaedics<br />
82 Devices<br />
88 Events<br />
94 Calendar<br />
95 Book review<br />
98 Holy grail<br />
Columns<br />
20 THE CATALYST<br />
Muralidharan Nair<br />
58 TRIALOMICS<br />
Dr Arun Bhatt<br />
60<br />
POLICY<br />
TAKING OUT<br />
THE STIGMA<br />
Notwithstanding the new<br />
mental health act, experts feel<br />
protecting the rights of the<br />
mentally ill will be<br />
an uphill task<br />
12<br />
REGULATORY<br />
MCI IN DIRE<br />
STRAITS<br />
The fate of the medical council<br />
hangs in balance as govt<br />
enforces a governing body<br />
through an ordinance<br />
14<br />
DRUG RESISTANCE<br />
TACKLING<br />
EMERGING<br />
PATHOGENS<br />
Stopping irrational antibiotic<br />
use in all the four stages of<br />
treatment cycle is the<br />
need of the hour
COPD<br />
64<br />
EBV INTERVENTION<br />
IN EMPHYSEMA<br />
Endoscopic<br />
lung volume<br />
reduction using<br />
endobronchial<br />
valves is an<br />
emerging<br />
option for COPD<br />
patients<br />
Cancer<br />
immunotherapy<br />
has been in the<br />
doghouse for<br />
decades.<br />
54<br />
STRAIGHT TALK<br />
“I AM IN FAVOUR OF<br />
OPEN ACCESS, IT’S<br />
A GOOD MODEL”<br />
Myles Axton<br />
Chief editor, Nature Genetics<br />
Dr Vishva M Dixit<br />
Vice President<br />
and Staff Scientist,<br />
Physiological<br />
Chemistry at<br />
Genentech, San<br />
Francisco, CA.<br />
22<br />
COVER STORY<br />
IMMUNO PATH TO<br />
LUNG CANCER<br />
Immunotherapy comes as a silver lining<br />
for the sufferers of a malignancy which<br />
has the highest incidence and the<br />
bleakest prognosis
REGULATORY DIAGNOSTICS HEAD & NECK CANCER CASE REPORT<br />
letters to the editor<br />
COMBO-DRUGS<br />
ON THEIR<br />
WAY OUT?<br />
MICRODELETION:<br />
LOST IN<br />
TRANSLATION<br />
EXCITING FRONTIERS<br />
KNOWING<br />
ORAL CANCER<br />
STAGING BY<br />
DEPTH OF INVASION<br />
Roll of ECG in<br />
epilepsy diagnosis<br />
₹ 250.00<br />
VOL 5 | <strong>ISSUE</strong> 6<br />
PAGES 100<br />
OCTOBER <strong>2018</strong><br />
FUTUREMEDICINEINDIA.COM<br />
NON-INVASIVE PRENATAL<br />
SCREENING ENTERS<br />
THE UNBORN<br />
HOW SHE<br />
REGAINED<br />
HER LOST TASTE<br />
The Editor<br />
We were pleased to read the<br />
article titled “Heart rhythm<br />
disorders mimicking epilepsy”<br />
by Dr. Shivanee Shah in Vol.<br />
5, Issue 5, bringing this issue<br />
to the notice of the readers.<br />
The article failed to mention<br />
that these patients have the<br />
“Long QT syndrome”. Such<br />
families have an abnormality<br />
in the ECG, which gives a clue<br />
to the presence of the Long<br />
QT syndrome. Prolongation<br />
of QTc more than 440ms<br />
(milli seconds) points to this<br />
diagnosis. We have seen<br />
more than 100 families of<br />
this syndrome at our Institute<br />
over a period of 7 years.<br />
The patients present with<br />
a history of sudden loss of<br />
consciousness, truly a syncopy,<br />
but often misdiagnosed as<br />
epilepsy. These defects arise<br />
due to defects in cardiac<br />
channels that control the<br />
rhythm of the heart. In cases<br />
with rhythm disturbances of<br />
the heart, ECG should always<br />
be done in patients and the<br />
parents. Commonly, Long<br />
QT and Brugada syndromes<br />
(BrS) show specific types of<br />
abnormalities on the ECG.<br />
They also have different<br />
triggers. For example,<br />
symptoms in patients with<br />
LQT1 occur due to exercise/<br />
stress, while in LQT2 patients<br />
due to sudden noises/<br />
emotions and patients with<br />
LQT3 and BrS have symptoms<br />
during sleep. Occasionally,<br />
these patients may have a<br />
normal QTc/ECG but still have<br />
defect in the gene. The most<br />
definite test for diagnosis in<br />
these patients is to sequence<br />
the channelopathy genes.<br />
Of 100 patients we studied,<br />
mutations were identified<br />
in 45. This not only helps to<br />
confirm the clinical diagnosis,<br />
but aids in detecting<br />
asymptomatic mutation<br />
carriers among relatives by<br />
cascade screening, counseling<br />
for prenatal diagnosis, and<br />
making effective treatment<br />
plan. We carried out cascade<br />
screening in 42 families, and<br />
mutations were identified<br />
in atleast one of the two<br />
parents, most (95%) of whom<br />
were asymptomatic. Of the<br />
nineteen siblings screened,<br />
sixteen were identified with<br />
mutations (84%) of which<br />
eleven were asymptomatic<br />
(69%). Majority of mutations<br />
identified were novel and<br />
different than those reported<br />
in the West. This was the first<br />
molecular cohort study of<br />
LQTS syndrome and Brugada<br />
syndrome patients of Indian<br />
origin. We have published<br />
our results [Vyas B, et al.<br />
Am J Med Genet A. 2016<br />
Jun;170(6):1510-9; Vyas B, et<br />
al. Indian Pacing Electrophysiol<br />
J. 2016 Jan-Feb;16(1):8-18].<br />
In conclusion, we would like<br />
to emphasize that ECG should<br />
be performed in all cases with<br />
sudden loss of consciousness<br />
before making the diagnosis<br />
of epilepsy.<br />
Bijal Vyas-Bhatia, Ratna Puri<br />
and Ishwar Verma<br />
Institute of Medical Genetics<br />
and Genomics.<br />
Sir Ganga Ram Hospital,<br />
New Delhi<br />
icverma@gmail.com<br />
Very relevant<br />
Sir<br />
The cover-story and the<br />
interview in the October<br />
<strong>edition</strong> made the reader<br />
really cognizant of the<br />
relevant ideas, information<br />
and existing chasms in the<br />
field. The contents in general<br />
provide a great informational<br />
platform for medical students,<br />
practitioners and basically any<br />
science readers.<br />
Arundhati<br />
Bangalore<br />
Exhilarating<br />
Hi<br />
Having read the previous<br />
<strong>edition</strong>s of Future Medicine,<br />
I feel privileged to mention it<br />
“exhilarating”. The magazine<br />
seems to be a pioneer<br />
project and gives a fresh<br />
feeling to the readers with<br />
well-explored themes. The<br />
authors offer great insight<br />
into issues related to the<br />
urgent medical needs and<br />
ongoing developments, with<br />
well outlined case-study and<br />
interviews. My best wishes to<br />
the future endeavors of the<br />
magazine.<br />
Dr Preeti Kamal<br />
Ghaziabad<br />
Cheap robotic surgery<br />
Dear Sir<br />
I would like to comment<br />
on Prof. Liselotte Mettler’s<br />
optimism that India is about<br />
to make the big revolution<br />
in cheaper robotic surgery.<br />
It’s really wonderful to hear<br />
this from one of the highly<br />
reputed experts in the field of<br />
gynaecology.<br />
Congrats on your initiative<br />
of Future Medicine, intended<br />
on converging relevant<br />
advancements and chasms in<br />
the medical field. Experienced<br />
a reader friendly approach,<br />
and appreciate the well<br />
written, precise quality of<br />
the contents put forward.<br />
Expecting more from the<br />
magazine in its subsequent<br />
<strong>edition</strong>. Best wishes.<br />
Sunesh Waghmare<br />
Pune<br />
Excellent work<br />
Hello<br />
It is a great magazine<br />
with well framed contents<br />
including exclusive interview<br />
with renowned doctors<br />
and latest news on the<br />
progressing fields of medical<br />
science. The magazine shows<br />
its excellence in being up-todate<br />
promoting the readers to<br />
be aware of the on goings in<br />
the field. Excellent work.<br />
Jina Bodhisatwa<br />
Raipur
A medical science and news magazine for every new-age<br />
clinician. It empowers doctors with the most relevant updates,<br />
trends, case studies, expert views, knowledge exchange,<br />
hospital management and latest breakthroughs in medical<br />
science. To be relevant in the future of care, subscribe today.<br />
AUGUST <strong>2018</strong>/ FUTURE MEDICINE / 59
news updates<br />
Labels on fluoroquinolones should<br />
alert on mental health risk: DCGI<br />
India’s drug regulator has<br />
directed safety labelling<br />
changes for antibiotics<br />
belonging to the class of<br />
fluoroquinolones to strengthen<br />
warnings about risks of mental<br />
health side effects and serious<br />
blood sugar disturbances.<br />
The Drugs Controller<br />
General of India (DCGI) made<br />
the labelling regulations for<br />
these antibiotics stricter after<br />
the recommendation of its<br />
Antimicrobial and Antiviral<br />
Subject Expert Committee.<br />
Through an order, the<br />
DCGI has directed all state<br />
drug controllers to ensure<br />
immediate implementation of<br />
the new labelling norms on<br />
all fluoroquinolone antibiotics<br />
such as levofloxacin,<br />
ciprofloxacin, moxifloxacin,<br />
ofloxacin and gemifloxacin.<br />
Apart from the cautionary<br />
note on the label saying<br />
the drug “may cause low<br />
blood sugar and mental<br />
health-related side effects”,<br />
the package insert and<br />
promotional literature<br />
should mention: “The drug<br />
may cause low blood sugar<br />
and mental health-related<br />
side effects. Low bloodsugar<br />
levels, also called<br />
hypoglycemia, can lead to<br />
coma. The mental health side<br />
effects are more prominent<br />
and more consistent across<br />
the systemic fluoroquinolone<br />
drug class”.<br />
In July, USFDA mandated<br />
a new class-wide labelling<br />
change requiring that mental<br />
health side effects be listed<br />
separately from other central<br />
nervous system side effects<br />
across fluoroquinolone<br />
antibiotics.<br />
Mental health side effects<br />
to be included in the labeling<br />
across all fluoroquinolones<br />
are disturbances in attention,<br />
disorientation, agitation,<br />
nervousness, memory<br />
impairment and delirium.<br />
Additionally, the FDA<br />
required new labelling for all<br />
systemic fluoroquinolones<br />
to explicitly reflect the<br />
potential risk of coma with<br />
hypoglycemia.<br />
LifeCell<br />
introduces DNA<br />
screening test<br />
for newborns<br />
LifeCell International, a stem<br />
cell bank and a mother &<br />
baby diagnostics company,<br />
launched RightStart - an<br />
integrated DNA test for<br />
newborns to detect over 50<br />
medical conditions.<br />
The technology has been<br />
found to drastically reduce<br />
false-positive reporting,<br />
thereby avoiding unnecessary<br />
follow-up tests, LifeCell said.<br />
The current process<br />
of newborn screening for<br />
abnormal metabolic profile<br />
warrant further testing for<br />
confirmation.<br />
RightStart newborn<br />
screening does not require<br />
an additional sample since<br />
Netmeds buys telemedicine portal JustDoc.com<br />
Netmeds.com, India’s leading online<br />
pharmacy, announced that the<br />
company has acquired telemedicine<br />
portal JustDoc.com in a cash and stock<br />
transaction.<br />
Founded in 2015, JustDoc.com is an<br />
online consulting portal that connects<br />
patients with clinicians via a technology<br />
platform. JustDoc has served thousands<br />
of patients throughout India through<br />
their website and app, according to the<br />
company.<br />
Netmeds.com provides prescription<br />
medicine and healthcare products to<br />
more than 3,000,000 patients across<br />
India and serves over 19,000 pin codes.<br />
JustDoc.com offers video medical<br />
consultation in the country by connecting<br />
users to doctors. Netmeds will leverage<br />
the combined strengths of both<br />
companies. JustDoc technology will be<br />
integrated with Netmeds.com.<br />
Netmeds.com’s e-pharma portal<br />
offers prescription and over-the-counter<br />
(OTC) medicine along with other health<br />
products.<br />
8 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
a portion of the sample<br />
collected initially can be used.<br />
Also, no additional costs<br />
would need to be incurred by<br />
the parents.<br />
LifeCell had tied up with<br />
Dr Mary Seeterlin, who has<br />
a decade of experience<br />
in newborn screening<br />
programme at Department<br />
of Public Health in Michigan<br />
and is the co-author of<br />
several guidelines and<br />
publications on the subject,<br />
to serve as a consultant to<br />
the programme.<br />
In India, adoption of<br />
newborn screening has been<br />
weak, largely due to low<br />
awareness and also due to<br />
the lack of reliability of test<br />
results, according to the<br />
company.<br />
iGenetic<br />
launches<br />
TruTest labs<br />
iGenetic Diagnostics, a<br />
pathology labs chain, has<br />
launched TruTest Laboratories<br />
with an aim to provide<br />
advanced diagnostics.<br />
TruTest Laboratories is<br />
operational pan-India, with<br />
centres located in Mumbai,<br />
Delhi, Bengaluru, Hyderabad,<br />
Indore, Nagpur, and Kochi.<br />
The lab network will offer<br />
tests ranging from routine<br />
biochemistry to molecular<br />
pathology.<br />
“There is a huge demand<br />
for accurate diagnostic<br />
solutions, which can provide<br />
faster results and are<br />
affordable for the masses.<br />
The growing threat of various<br />
communicable and noncommunicable<br />
diseases<br />
has made it mandatory for<br />
people to go for regular<br />
health check-ups,” said<br />
Arunima Patel, founder, and<br />
managing director, iGenetic<br />
Diagnostics.<br />
Many diseases are<br />
asymptomatic initially and<br />
show symptoms at later<br />
stages, while many infections<br />
share common or similar<br />
symptoms. Regular testing<br />
has become the need<br />
of the hour for early<br />
diagnosis and treatment, she<br />
added.<br />
Metropolis<br />
plans to enter<br />
capital market<br />
M<br />
etropolis Healthcare<br />
Ltd, one of the leading<br />
diagnostics companies in<br />
India, has filed an offer<br />
document with the SEBI,<br />
proposing an Initial<br />
Public Offering (IPO) of<br />
its equity shares.<br />
The Equity Shares<br />
offered through<br />
the Red Herring<br />
Prospectus are<br />
proposed to be listed<br />
on BSE and NSE.<br />
The company’s IPO<br />
comprises up to 15.3 mln<br />
equity shares, consisting<br />
of an Offer for Sale of up to<br />
Handbook on benefits<br />
of vitamin E launched<br />
Merck Consumer Health India has launched a<br />
handbook that highlights the benefits and<br />
widespread utility of vitamin E. Titled “Vitamin E:<br />
Clinical Applications and Evidences”, the book has<br />
been edited by Dr YK Gupta and Dr AC Anand, leading<br />
health experts.<br />
The book focuses on the manifold uses of vitamin E<br />
as a supplement.<br />
According to Merck, People in India are not entirely<br />
aware of the extensive benefits offered by vitamin E<br />
and the book is a step toward increasing awareness<br />
about the benefits of vitamin E, backed by scientific<br />
data and clinical evidence.<br />
More than 90 percent of India is unaware of<br />
vitamin E applications and advantages. Educational<br />
initiatives like these have become the need of the hour,<br />
the company said. Extensive knowledge about vitamin<br />
E in the book underlines Merck’s efforts towards<br />
keeping Indian medical practitioners abreast of latest<br />
medical knowledge, thus giving way to a healthier<br />
future for the general population, the company said.<br />
5 mln shares by promoter<br />
Dr. Sushil Kanubhai Shah<br />
and up to 10.3 mln equity<br />
shares by investor CA Lotus<br />
Investments. The offer<br />
includes a reservation of<br />
up to 3 lakh equity shares<br />
for subscription by eligible<br />
employees.<br />
The Book Running Lead<br />
Managers (BRLMs) are JM<br />
Financial Limited, Credit<br />
Suisse Securities (India)<br />
Private Limited, Goldman<br />
Sachs (India) Securities<br />
Private Limited, HDFC<br />
Bank Limited and Kotak<br />
Mahindra Capital Company<br />
Limited.<br />
Metropolis conducts<br />
operations through a<br />
laboratory and service<br />
network which covers<br />
173 cities in India. During<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 9
the financial year <strong>2018</strong>, it<br />
conducted approximately<br />
16 million tests from<br />
approximately 7.7 million<br />
patient visits, as per company<br />
data.<br />
MedGenome<br />
launches gene<br />
test for CLL<br />
MedGenome has<br />
introduced the IGHV<br />
(immunoglobulin heavy<br />
chain) gene mutation<br />
testing for chronic<br />
lymphocytic leukemia (CLL)<br />
diagnosis.<br />
Current guidelines for<br />
CLL management involves<br />
a comprehensive molecular<br />
workup that includes some<br />
genetic tests performed on<br />
the patient’s blood or bone<br />
marrow sample. The tests<br />
enable oncologists to assess<br />
the prognosis of the disease<br />
subtype and further manage<br />
the disease by personalized<br />
therapy.<br />
Four of the important<br />
biomarker tests includes<br />
those for somatic<br />
hypermutations (SHM) of the<br />
immunoglobulin heavy chain<br />
variable region genes (IGHV)<br />
and somatic mutations of<br />
genes such as TP53, NOTCH1<br />
and SF3B1.<br />
Based on the SHM value,<br />
the disease is classified<br />
Mutated CLL (M-CLL) and<br />
Unmutated CLL (U-CLL).<br />
The status of SHM has a<br />
clear influence on the median<br />
survival of CLL patients.<br />
Presence of SHM of the IGHV<br />
region is strongly predictive<br />
of a good prognosis, while a<br />
lack of SHM predicts a poorer<br />
prognosis. Patients with an<br />
unmutated IGHV gene<br />
usually have a more<br />
aggressive disease and<br />
shorter overall survival.<br />
Patients with a mutated<br />
IGHV gene usually have a<br />
less aggressive disease, with<br />
longer overall survival, said<br />
the company.<br />
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Cardiologist invests US$60 m<br />
in DEB device firm<br />
An Indian-American<br />
cardiologist and<br />
entrepreneur, Dr Kiran Patel,<br />
has invested $60 million<br />
in a medical company that<br />
develops sirolimus-coated<br />
balloons as an alternative<br />
to stents used in coronary<br />
angioplasty.<br />
Concept Medical Inc, a<br />
Florida-based medical device<br />
company, has approached<br />
USFDA for an Investigational<br />
Device Exemption (IDE) for the<br />
world’s first sirolimus-coated<br />
balloon.<br />
The company can<br />
commence clinical studies<br />
to determine the safety and<br />
efficacy of the device after<br />
obtaining IDE from the US<br />
drug regulatory agency.<br />
According to the company,<br />
the investment by Dr Kiran<br />
Patel will pave way for clinical<br />
studies using the device.<br />
The fund will be utilised<br />
to augment clinical data and<br />
clinical registries to qualify<br />
for re imbursement in the<br />
European markets, where the<br />
company has commercially<br />
launched the product, said<br />
Concept Medical Inc.<br />
MagicTouch-DEB, the<br />
sirolimus -coated balloon with<br />
application in coronary and<br />
peripheral artery disease, is<br />
currently available in many<br />
parts of the world.<br />
Extended applications<br />
of MagicTouch-DEB in renal<br />
transplant, erectile dysfunction<br />
and Arteriovenous Fistula/<br />
Arteriovenous Graft (AVG)<br />
for renal dialysis patients are<br />
under ongoing clinical trials.<br />
The company has initiated<br />
a series of global clinical<br />
programmes for MagicTouch-<br />
DEB including Nanolute,<br />
Eastbourne, Transform-I,<br />
Transform-II. They are also<br />
pursuing regulatory pathways<br />
in Japan and China.<br />
Concept Medical has a<br />
manufacturing subsidiary in<br />
India, Envision Scientific Pvt.<br />
Ltd., where all their products<br />
are made. A portion of the<br />
funds will also be utilized to<br />
bolster the manufacturing<br />
operations. The company’s<br />
global distribution and<br />
marketing network is operated<br />
from offices in India, Singapore,<br />
Netherlands and Brazil. ESPL<br />
also has an India-focused,<br />
marketing and distribution<br />
business.<br />
A Board-certified<br />
cardiologist, Dr. Patel<br />
completed his residency<br />
in Internal Medicine in<br />
New Jersey after obtaining<br />
a medical degree from<br />
Gujarat University in India<br />
and an internship in Africa.<br />
In 1982, he completed his<br />
fellowship in Cardiology from<br />
a Columbia University-affiliated<br />
programme.<br />
Dr. Patel subsequently<br />
entered the managed care<br />
industry and was the chairman<br />
of WellCare of Florida till 2002.<br />
Chan Zuckerberg and Gates<br />
Foundation partner to track<br />
infectious diseases<br />
The Chan Zuckerberg<br />
Biohub (Biohub) and<br />
the Chan Zuckerberg<br />
Initiative (CZI) have<br />
launched IDseq, an open<br />
source cloud-based<br />
analysis platform to detect<br />
and respond to infectious<br />
disease outbreaks around<br />
the world.<br />
The tool works by<br />
rapidly combing through<br />
terabytes of metagenomic<br />
data for pathogens<br />
in a given sample. By<br />
identifying diseasecausing<br />
pathogens,<br />
IDseq can provide an<br />
actionable report of what<br />
is happening on the<br />
ground in labs and clinics<br />
anywhere in the world.<br />
In a recent pilot<br />
project, IDseq has been<br />
employed to identify<br />
the presence of the<br />
mosquito-borne viral<br />
chikungunya disease in<br />
the spinal fluid of patients<br />
at Dhaka Shishu Hospital,<br />
the largest paediatric<br />
hospital in Bangladesh.<br />
Based on this information,<br />
follow-up testing<br />
identified additional<br />
cases of neuroinvasive<br />
chikungunya from the<br />
same time period that<br />
were previously labeled<br />
“mystery cases.”<br />
To enable broader<br />
access to IDseq and<br />
valuable on-the-ground<br />
feedback, the Bill &<br />
Melinda Gates Foundation<br />
announced a new<br />
funding opportunity for<br />
global health workers<br />
via the Bill & Melinda<br />
Gates Foundation Grand<br />
Challenges Explorations<br />
Initiative. Awardees will<br />
receive molecular biology<br />
and bioinformatics<br />
training and free access<br />
and compute on the<br />
IDseq platform supported<br />
by CZI, along with the<br />
necessary equipment<br />
and supplies immediately<br />
needed to begin work in<br />
their own countries.<br />
The Biohub and<br />
CZI plan to make IDseq<br />
available within the<br />
next year to partner<br />
organizations, and then<br />
more broadly afterward.<br />
The software itself is<br />
open-source and freely<br />
available.<br />
The CZ Biohub is<br />
a non-profit medical<br />
research organization<br />
collaborating with the<br />
University of California,<br />
Berkeley, Stanford<br />
University and the<br />
University of California,<br />
San Francisco.<br />
The Chan Zuckerberg<br />
Initiative, founded by Mark<br />
Zuckerberg and Priscilla<br />
Chan is a philanthropic<br />
organization.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 11
egulatory<br />
MCI IN DIRE STRAITS<br />
The fate of the medical council hangs in balance as govt enforces a governing<br />
body through an ordinance<br />
DR SUMIT GHOSHAL<br />
Nearly two months after the Union<br />
Government promulgated an<br />
ordinance replacing the existing<br />
Executive Committee of the Medical<br />
Council of India (MCI) with a nominated<br />
board of governors, nobody is sure what<br />
is going to happen next. The Sept 26<br />
notification, titled Indian Medical Council<br />
(Amendment) Ordinance <strong>2018</strong>, has<br />
effectively placed the MCI in suspended<br />
animation and blocked the process of<br />
election or nomination of its executive<br />
members until further notice.<br />
“Whereas Parliament is not in<br />
session and the President is satisfied<br />
that circumstances exist which render<br />
it necessary for him to take immediate<br />
action…” the text of the ordinance says<br />
by way of introduction. In addition, the<br />
ordinance mentions that the Board<br />
of Governors would be assisted by a<br />
Secretary General who may be deputed<br />
from among the government’s own<br />
cadres or appointed from outside on a<br />
one-year contract.<br />
While the ordinance does not spell<br />
out the ‘circumstances’ which impelled<br />
President Ramnath Kovind to take<br />
this decision, independent reports in<br />
the media suggest that an Oversight<br />
Committee appointed by the Supreme<br />
Court to look after the affairs of the MCI<br />
was being ignored by those in charge.<br />
The Supreme Court committee had been<br />
formed after repeated allegations of<br />
corruption against some members of the<br />
MCI Executive Committee.<br />
In the past few years, the MCI had<br />
come under stringent criticism from<br />
IN THE PAST FEW YEARS,<br />
THE MCI HAS COME UNDER<br />
STRINGENT CRITICISM<br />
FROM THE SUPREME<br />
COURT AS WELL AS THE<br />
PARLIAMENTARY STANDING<br />
COMMITTEE.<br />
the Supreme Court as well as the<br />
Parliamentary Standing Committee for<br />
Health and Family Welfare. In its 92nd<br />
report, the Standing Committee wrote<br />
in September 2015: “The situation<br />
has gone far beyond the point where<br />
incremental tweaking of the existing<br />
system or a piecemeal approach can<br />
give the contemplated dividends. That<br />
is why the committee is convinced that<br />
the MCI cannot be remedied according<br />
to the existing provisions of the Indian<br />
Medical Council Act, 1956 which is<br />
certainly outdated.”<br />
The latest ordinance has to be<br />
ratified through suitable legislation<br />
within six months from the date of<br />
promulgation, or by the end of March<br />
2019. Meanwhile it has evoked strong<br />
criticism from the Indian Medical<br />
Association (IMA) and other professional<br />
bodies.<br />
“My main point of opposition<br />
is that the Board of Governors is a<br />
nominated body which has replaced<br />
a democratically elected body; that<br />
is, the MCI Executive Committee,” says<br />
Dr K K Agrawal, IMA’s immediate past<br />
president and the president-elect of the<br />
Confederation of Medical Associations<br />
of Asia and Oceania as well as the<br />
president of the Heart Care Foundation<br />
of India. “Hence, by its very nature, the<br />
government action is undemocratic.”<br />
Besides, Dr Agrawal adds, the Board<br />
comprises entirely of doctors belonging<br />
to the government cadres, while private<br />
doctors are nowhere in the picture.<br />
“Who will deal with the problems of the<br />
private doctors?” he asks rhetorically.<br />
Also, there are no representatives from<br />
12 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
any of the universities, nor anybody to<br />
represent state-level issues.<br />
A larger issue which could render<br />
the latest ordinance unnecessary and<br />
obsolete is that of the National Medical<br />
Commission (NMC). The draft NMC bill<br />
has been pending since 2016, after<br />
undergoing several modifications during<br />
these two years, and is likely to come up<br />
for discussion in the winter session of<br />
Parliament which is scheduled to begin<br />
in late November or early December.<br />
It will most probably be the last<br />
opportunity for a discussion on the Bill in<br />
the current Lok Sabha, whose term ends<br />
in June 2019.<br />
Under the NMC Bill, which was<br />
cleared by the Union Cabinet as far back<br />
as August-September 2016, the Medical<br />
Council will be replaced by the NMC.<br />
The new body would comprise four<br />
subordinate bodies: the Undergraduate<br />
Medical Education Board, Postgraduate<br />
Medical Education Board, the Medical<br />
College Assessment and Ratings Board<br />
and the Board of Medical Registration.<br />
Thus the NMC would take over all the<br />
important functions of the MCI.<br />
Senior medical teachers also point<br />
out that the NMC Bill could transform<br />
the state of medical education in the<br />
country, perhaps for the better. One of its<br />
proposals is to introduce a common final<br />
MBBS examination for all the medical<br />
colleges in the entire country. This would<br />
surely be an unprecedented innovation<br />
for medical education. The problem of<br />
varying standards of medical training<br />
imparted in various parts of the country<br />
would thus become a thing of the past.<br />
The IMA has been conducting a<br />
fierce campaign against the NMC Bill<br />
ever since it was made public two years<br />
ago on the grounds that the new body<br />
would almost entirely be composed of<br />
bureaucrats and government doctors,<br />
with no elected representatives.<br />
In addition, the IMA website<br />
describes the NMC Bill as anti-poor<br />
and anti-people, while alleging that “all<br />
the state health universities have been<br />
marginalized into an advisory role.” Also,<br />
the Parliamentary Standing Committee,<br />
to which the Bill had been sent for<br />
consideration, had recommended as<br />
many as 24 amendments. Of these, the<br />
government has accepted just one in full,<br />
and three in part, IMA sources said.<br />
My main point of opposition is that the Board<br />
of Governors is a nominated body which<br />
has replaced a democratically elected body;<br />
that is, the MCI Executive Committee.<br />
Dr K K Agrawal,<br />
IMA’s immediate past president<br />
Sabotaging<br />
democratic<br />
process: IMA<br />
The Indian Medical Association<br />
(IMA) said in a statement that the<br />
“supersession” of the MCI is only a<br />
smokescreen and a ploy to prepare<br />
the ground for the NMC and sabotage<br />
the democratic process of the Council.<br />
The Board of Governors (BOG)<br />
should conform to the basic tenets<br />
of the IMC Act and refrain from<br />
tinkering with its fundamental<br />
structure, the IMA said. The Board<br />
should refrain from taking major<br />
policy decisions or passing any<br />
amendment changing the character<br />
of the IMC Act. The election process<br />
of the MCI should be allowed to<br />
continue, it added.<br />
Crosspathy, registration of nonmedical<br />
persons, bridge courses<br />
and the mixing of syllabi are core<br />
concerns of the outgoing team. 184<br />
private medical colleges are awaiting<br />
recognition due to the strict norms<br />
of the outgoing MCI team, it said. By<br />
removing the democratically elected<br />
MCI, checks and balances have been<br />
removed and the chances of arbitrary<br />
action have increased. A generation<br />
of substandard doctors will be the<br />
legacy of this action, according to the<br />
statement.<br />
Maintaining that the composition<br />
of the Board itself was unacceptable,<br />
the team pointed out that there is<br />
no representation to women and<br />
registered medical practitioners.<br />
Directors of major institutions would<br />
scarcely find time to administer more<br />
than 450 medical colleges and their<br />
undergraduate and postgraduate<br />
courses, it alleged.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 13
drug resistance<br />
TACKLING<br />
EMERGING<br />
Stopping irrational antibiotic use in all the four stages<br />
of treatment cycle is the need of the hour<br />
14 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
DR RAJANI KANTH VANGALA<br />
In India, the largest therapeutic<br />
group — which accounts for 15.7% of<br />
the drugs market — are antibiotics.<br />
This suggests not only that antibiotics<br />
are now available to a larger segment<br />
of needed people, but also irrational<br />
use, leading to antibiotic resistance<br />
in bugs. India and the world at large<br />
are on the verge of facing their worst<br />
healthcare crisis due to fast-emerging<br />
antibiotic-resistant pathogens. This<br />
multifaceted problem arises due to<br />
several aspects, such as non-prescription<br />
self-medication, unwarranted dosages<br />
to patients by clinics, and the lack of<br />
knowledge translation to the public.<br />
According to the World Health<br />
Organization (WHO) definition,<br />
medicines are used ‘rationally’ (i.e.,<br />
responsibly, appropriately, correctly and<br />
properly) when patients receive the<br />
medicines from responsible clinicians in<br />
appropriate doses for correct indications<br />
and meet the individual need for an<br />
adequate period of time with proper<br />
knowledge. However, these aspects<br />
are seldom practiced, leading to high<br />
expenditure on buying medicines and<br />
the ever-growing problem of resistant<br />
bacteria. The development and<br />
implementation of certain guidelines<br />
by regulatory authorities may, to some<br />
extent, help in curbing this problem.<br />
Due to patients’ demand for instant<br />
gratification and other market issues,<br />
clinicians are forced to prescribe more<br />
than the required amount of antibiotics.<br />
It is important to note that bacteria<br />
can develop resistance in different<br />
ways, like de novo gene mutations<br />
and the import of resistance-related<br />
genetic information from other bacteria<br />
due to selective pressure on them by<br />
an overdose of antibiotics. With less<br />
antibiotic use, antibiotic effectiveness<br />
is maintained for a longer period and<br />
the chances of developing resistant<br />
bacteria are reduced.<br />
EML for better outcomes<br />
The inappropriate use of antibiotics<br />
can start at any of the four stages of<br />
treatment cycle, namely diagnosis,<br />
prescribing, dispensing and patient<br />
adherence. In the first stage, a wrong<br />
diagnosis can lead to the use of drugs<br />
which will be ineffective. It is very<br />
important to practice proper diagnosis<br />
and look at the possibility of using nondrug<br />
based therapies that may relieve<br />
the patient before prescribing drugs.<br />
Every country has an Essential<br />
Medicines List (EML) based on the<br />
needs of the populations. The concept<br />
of the EML is based on the notion that<br />
limited use of well-known and cost-<br />
PATHOGENS<br />
ANTIBIOTICS<br />
FOUR STAGES OF TREATMENT CYCLE<br />
The inappropriate use of antibiotics<br />
can start at any of the four stages<br />
DIAGNOSIS PRESCRIPTION DISPENSING PATIENT<br />
ADHERENCE<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 15
Three million surgeries and cancer<br />
treatments may turn life-threatening<br />
Public Health England’s (PHE’s)<br />
English Surveillance Programme for<br />
Antimicrobial Utilisation and Resistance<br />
(ESPAUR) report published in October<br />
highlights how more than 3 million<br />
common procedures such as cesarean<br />
sections and hip replacements could<br />
become life-threatening without<br />
antibiotics.<br />
Without antibiotics, infections related<br />
to surgery could double, putting people at<br />
risk of dangerous complications. Cancer<br />
patients are also much more vulnerable<br />
if antibiotics don’t work; both cancer and<br />
the treatment (chemotherapy) reduce<br />
the ability of the immune system to fight<br />
infections. Antibiotics are critical to prevent<br />
and treat infections in these patients.<br />
The threat of antibiotic resistance<br />
continues to grow. Bloodstream infections<br />
have increased, and the report shows that<br />
antibiotic-resistant bloodstream infections<br />
rose by an estimated 35% between 2013<br />
and 2017.<br />
Despite the risks of antibiotic<br />
resistance, research shows that 38%<br />
of people still expect an antibiotic<br />
from a doctor’s surgery, NHS walk-in<br />
centre or ‘GP out-of-hours’ service when<br />
they visited with a cough, flu or a throat,<br />
ear, sinus or chest infection in 2017.<br />
The ‘Keep Antibiotics Working’<br />
campaign educates the public about the<br />
risks of antibiotic resistance, urging people<br />
to always take healthcare professionals’<br />
advice as to when they need antibiotics.<br />
The campaign also provides effective<br />
self-care advice to help individuals and<br />
their families to feel better if they are not<br />
prescribed antibiotics.<br />
The Ipsos MORI Capibus Survey,<br />
‘Attitudes towards antibiotics, 2017’ was<br />
conducted between 24 January to 5<br />
February 2017 with a representative<br />
sample size of 1,691 adults (aged 15+) in<br />
England only.<br />
effective medicines can result in better<br />
healthcare outcomes, enhanced longterm<br />
supply and sustainable access to<br />
medicines.<br />
Prescribing is a complex process for<br />
doctors and begins with establishing<br />
the goal(s) of the therapy. Meeting the<br />
patient expectation, arriving at benefitrisk<br />
balance, availability and cost are the<br />
important considerations for clinicians.<br />
This daunting process of prescribing<br />
needs openness in engaging with the<br />
patient, which is important as it is the<br />
patient who is the ultimate recipient of<br />
any benefits of taking the medication.<br />
For most patients, transitioning into<br />
a role of someone who has to take<br />
medicines is often difficult. This is more<br />
so in cases where the benefits of the<br />
medication are not immediate and the<br />
mere presentation of the diagnosis<br />
may not be a motivator. There is an<br />
urgent need to understand this and<br />
develop better methodologies in patient<br />
adherence and reduce the irrational use<br />
of antibiotics.<br />
Threat to progress<br />
In the event of no proper diagnosis,<br />
incorrect or general antibiotic<br />
prescription can lead to complex and<br />
unwanted clinical outcomes. In such<br />
cases, it is important to evaluate the<br />
patient’s co-existing medical, genetic<br />
and environmental conditions. Beyond<br />
the prescription, dispensing and patient<br />
adherence are even more difficult to<br />
follow and improve. Especially in rural<br />
areas, the pharmacists almost become<br />
non-prescribing doctors in giving<br />
medicines and advice, which may not<br />
be effective. This aspect also leads<br />
to patient non-adherence in taking<br />
medications. Essential cross-checks<br />
and patient knowledge translation,<br />
empowering them for better adherence<br />
to therapy protocols, are needed.<br />
Antibiotic development is now<br />
considered to be a global health<br />
emergency, with the average time<br />
needed to receive regulatory approvals<br />
16 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
eing 7.2 years, with a very low clinical<br />
success rate of 16%. There is a need<br />
for a national-level plan to combat<br />
antibiotic resistance by driving more<br />
inter-sectoral partnerships among<br />
scientists and medical, epidemiological<br />
and diagnostic personnel. Ever since<br />
penicillin ushered in the modern era<br />
of antibiotic development, they have<br />
become the cornerstone of human<br />
lives by changing the way we live. In<br />
this post-antibiotic era, evaluation of<br />
epidemiological aspects and tailoring<br />
the use of antibiotics by proper use of<br />
scientific methods can lower the threat<br />
THE EMERGENCE OF<br />
NEW PATHOGENS<br />
WITH ANTIMICROBIAL<br />
RESISTANCE CAN MAKE<br />
HUMANITY GO BACK TO<br />
THE PRE-ANTIBIOTIC ERA.<br />
of ever-growing, drug-resistant bacteria.<br />
The impact of the irrational use of<br />
antibiotics can be more far-reaching<br />
than perceived, as suggested by the<br />
Nobel Laureate Joshua Lederberg: “The<br />
future of humanity and microbes will<br />
evolve as episodes...of our wits versus<br />
their genes”. The emergence of new<br />
pathogens with antimicrobial resistance<br />
can not only be seen as a threat to the<br />
progress made in healthcare, but also<br />
as something that can make humanity<br />
go back to the pre-antibiotic era where<br />
the masses suffered and died due to<br />
untreatable infections. It is now in our<br />
hands to embrace the most logical step<br />
of stopping irrational antibiotic use at<br />
each and every step of therapy.<br />
PIL questions unchecked<br />
antibiotics sale<br />
public interest litigation (PIL) has<br />
A been registered in Bombay High<br />
Court demanding action to address<br />
unchecked sales of high potency<br />
antibiotics without prescriptions. It was<br />
filed by a city-based lawyer against<br />
the Union of India, Government of<br />
Maharashtra, Central Drugs Standard<br />
Control and the Drug Controller.<br />
The PIL outlined mainly four<br />
aspects, including the unchecked sale<br />
and consumption of antibiotics as an<br />
OTC product, drug resistance and the<br />
impact on disease-control measures,<br />
increased cost of healthcare, insurance<br />
and research, and the unchecked<br />
sale and access to H and H1 category<br />
antibiotics.<br />
The petition, filed by Bharat Kothari,<br />
a Mumbai-based lawyer, followed<br />
findings of a survey conducted across<br />
500 pharmacies in Maharashtra.<br />
In the survey, Bharat Sarge, an<br />
activist, discovered that antibiotics<br />
belonging to H and H1 categories were<br />
freely available across pharmacies.<br />
Listing the critical issues that surfaced<br />
due to unchecked consumption<br />
of high-potency antibiotics, such<br />
as serious drug resistance among<br />
infectious diseases and unauthorised<br />
sale, the lawyer felt there was great<br />
merit in a PIL.<br />
According to Kothari, over 118<br />
different antibiotic formulations are sold<br />
in India. Out of such a large number of<br />
antibiotic formulations — as against just<br />
five in the United Kingdom and the US<br />
— 64% are apparently not approved by<br />
the national drug regulator, the Central<br />
Drugs Standard Control Organisation.<br />
Presently, India is the largest consumer<br />
of antibiotics in the world, he added.<br />
“Temporary suspension of licenses<br />
of local pharmacies have failed to<br />
control rising concerns and medicines<br />
continue to be dispensed irresponsibly<br />
by shop owners. It’s about time there<br />
is a system in place to control these<br />
irregularities effectively, and severe<br />
punishment should be levied against<br />
such defaulters,” says Bharat Serge<br />
of Venkateshwar Seva Sanstha, which<br />
conducted the survey.<br />
The petition has outlined citizens’<br />
rights to health, stated to have been<br />
compromised due to the indiscriminate<br />
OTC sale and unchecked use of<br />
prescription medication. It draws<br />
attention to the duty of the state to<br />
assess and monitor any dependency<br />
or addiction to antibiotics and other<br />
high-potency drugs and ensure that<br />
there is no damage to the consumers’<br />
health by uncontrolled, unchecked selfmedication.<br />
Since it has been a strategic goal<br />
of WHO and many countries to limit<br />
antimicrobial resistance, most countries<br />
are taking brisk measures to prevent<br />
production and sale of illegal and<br />
unapproved medication.<br />
The author is medical<br />
scientist and former<br />
director of SGRF,<br />
Bangalore<br />
18 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
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column<br />
the catalyst<br />
Dichotomy of price<br />
control<br />
Unless fortified by quality standards, price control on<br />
medical products could prove counterproductive<br />
MURALIDHARAN NAIR<br />
India has followed a policy of price control<br />
of pharmaceutical products for long,<br />
and in recent times it has extended the<br />
ambit to include certain devices as well.<br />
Now, there is an imminent possibility of it<br />
expanding further to include more medical<br />
products and even medical services.<br />
The policy of price control on healthcare<br />
products and services has been a subject<br />
of debate for long. It has intensified in<br />
the recent past owing to the twin factors<br />
of India’s high dependence on private<br />
sector health care facilities (more than 60<br />
percent of the surrendered care is through<br />
the private sector) and the increasing<br />
unaffordability of the same.<br />
The proponents of price control have<br />
often to contend with stiff opposition<br />
from market players who argue that it<br />
impairs the industry’s ability to invest<br />
sufficiently in innovation, and as long as<br />
there are competitive forces at play in<br />
the form of multiple providers/vendors,<br />
prices will find a fair equilibrium. I have<br />
never been convinced by this argument<br />
of the opponents of price control, based<br />
on my observations of the realities in the<br />
market for more than two decades now.<br />
A careful analysis of the market prices will<br />
reveal that the burden of an inefficient<br />
research and development process and<br />
an aggressive commercialization agenda<br />
have contributed to market prices that are<br />
not fair to the consumer. This is further<br />
compounded by the fact that consumer<br />
choice is highly influenced by care providers,<br />
and as such, it is not a free market. Let me<br />
try and elucidate this through the events<br />
leading to, and following, the imposition of<br />
price control on cardiac stents more than<br />
a year back. The cardiac stent market in<br />
India is characterized by a mix of Indian<br />
(~15 players), MNC (5 players) and some<br />
emerging Chinese players. There are two<br />
types of stents prevalent in the market, viz.<br />
Drug Eluting (DES) and Bare Metal, with the<br />
DES having a share of ~ 90%.<br />
It is evident from the data that any<br />
claim of the MNC players seeking to<br />
justify the price to patient / MRP as a<br />
legitimate cost for sustaining research and<br />
innovation is untenable since the post<br />
manufacturer “value addition” far exceeds<br />
the manufacturer’s (innovator’s) margins.<br />
It is essentially the cost of aggressive<br />
commercialization that the poor customer<br />
is paying in the name of innovation<br />
and quality, despite the market having<br />
reasonable competitive intensity. What<br />
happened subsequent to the price control,<br />
which essentially equalized the MRPs of<br />
Indian and MNC innovator players, is a great<br />
example of how little control the customer<br />
exercises in making the choice of healthcare<br />
products. Despite the price equalization,<br />
which should have effectively given a fillip to<br />
20 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
PRICE CONTROL SCENARIO<br />
1,30,000+<br />
2016<br />
PRE-PRICE<br />
CONTROL<br />
2017<br />
POST-PRICE<br />
CONTROL<br />
2016<br />
PRE-PRICE<br />
CONTROL<br />
2017<br />
POST-PRICE<br />
CONTROL<br />
PRICE (INR)<br />
1,00,000+<br />
57% 43% 61%<br />
39%<br />
30%<br />
70%<br />
45% 55%<br />
2016 2017<br />
29,284<br />
MARKET SHARE<br />
(ENTIRE COUNTRY)<br />
MARKET SHARE<br />
(METRO CITIES)<br />
INDIAN MNC<br />
Prices inclusive of GST<br />
Marketshare by volume<br />
SOURCE: NPPA, EY ANALYSIS<br />
MNC<br />
INDIAN<br />
TRANSFER PRICE/MANUFACTURING COST<br />
15,000-17,500 2,500-5,000<br />
PATIENT CHARGING PRICE<br />
1,20,000 60,000-70,000<br />
MRP (PRE-PRICE CONTROL)<br />
1,30,000+ 1,00,000+<br />
DESPITE THE PRICE<br />
EQUALIZATION, WHICH<br />
SHOULD HAVE EFFECTIVELY<br />
GIVEN A FILLIP TO THE MNC<br />
SHARE WITH ITS PERCEIVED<br />
SUPERIORITY OF AN<br />
ORIGINATOR, MNC’S<br />
MARKET SHARE FELL.<br />
the MNC share with its perceived superiority<br />
of an originator, MNC’s market share fell.<br />
Even if the domestic players could offer little<br />
price advantage post price control, it was<br />
not material enough to affect a decision<br />
change by a consumer in the context of the<br />
overall cost of angioplasty and criticality<br />
of the product in the scheme of things.<br />
Importantly, despite the massive reduction<br />
in the price of stent, which was a critical<br />
cost driver for angioplasty, the procedure<br />
cost did not come down materially (less<br />
than 15 percent).<br />
No less than the Prime Minister himself<br />
has spoken of stent price rationalization<br />
as one of the major successes of his<br />
government. But in reality, the intended<br />
beneficiaries are not really better off.<br />
This exposes the complexity involved<br />
in matters of healthcare delivery. What<br />
may offer great optics from a political<br />
perspective is not necessarily a measure<br />
of the true effectiveness of the policy.<br />
It is imperative that the policy makers<br />
understand the complexity around the<br />
issues before formulating a policy, to<br />
ensure that the intended benefit reaches<br />
the last mile. This is another important<br />
lesson for us to learn: Price control is an<br />
important tool and is also an attractive<br />
proposition as a populist measure, but<br />
price control alone, without accompanying<br />
measures for fortifying quality standards,<br />
may be counterproductive in the long<br />
run. More on this in the subsequent<br />
columns.<br />
The author has long-standing association with<br />
EY India but the views are strictly personal.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 21
cover story<br />
IMMUNO<br />
TO<br />
LUNG CANCER<br />
Immunotherapy comes as a silver<br />
lining for the sufferers of a malignancy<br />
which has the highest incidence and<br />
the bleakest prognosis<br />
22 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
LUNG CARCINOMA:<br />
THE COMMONEST CANCER<br />
WORLD OVER<br />
Lung cancer is now the most common cancer<br />
worldwide, with 2·1 million people diagnosed<br />
in <strong>2018</strong> and 1·8 million deaths, influenced<br />
strongly by the tobacco epidemic.<br />
WORLD<br />
INDIA<br />
11.6%<br />
incidence of<br />
lung cancer<br />
among<br />
all new<br />
cancer cases<br />
18.4%<br />
lung cancer<br />
accounts for all<br />
cancer related incidence<br />
6.3%<br />
of lung<br />
deaths cancer among<br />
all new<br />
cancer cases<br />
9.1%<br />
PATH<br />
INCIDENCE OF NSCLC AS<br />
COMPARED TO SCLC<br />
Adenocarcinoma accounts for nearly 40% of lung<br />
cancers and is the most common form of cancer<br />
among smokers<br />
5%+<br />
Large Cell<br />
6.7%<br />
1.Carcinoma<br />
1.0%+<br />
15.7%<br />
lung cancer<br />
accounts for all<br />
cancer related<br />
deaths<br />
Squamous Cell Carcinoma<br />
S HARACHAND<br />
Immunotherapy stepped onto the hall of fame by winning<br />
the <strong>2018</strong> Nobel prize for medicine. Through their landmark<br />
discovery, Professor James P Allison from the US and<br />
Professor Tasuku Honjo from Japan have outlined how<br />
immune checkpoints can be effectively targeted to deal with<br />
the toughest of cancers.<br />
Their seminal work on cytotoxic T-lymphocyte associated<br />
protein 4 (CTLA-4) and programmed cell death receptor-1 (PD-<br />
1) mechanism led to a new class of therapeutics called immune<br />
checkpoint inhibitors. These drugs have brought remarkable<br />
outcomes by radically changing the treatment approach to<br />
38.9%<br />
Adenocarcinoma<br />
11.6%+<br />
Other or unspecified 0.4%<br />
Small Cell Carcinoma<br />
24.0%<br />
0.3%+<br />
Non-smoker<br />
Smoker<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 23
cancer and made immunotherapy one of the<br />
hottest areas of cancer research.<br />
“If you really want to do something<br />
paradigm shifting, then you really have to probe<br />
basic mechanisms,” says Dr Vishva M Dixit,<br />
Vice President and Staff Scientist, Physiological<br />
Chemistry at Genentech, San Francisco, CA,<br />
commenting on the Nobel-winning work in<br />
basic science.<br />
Unlike conventional therapeutic modalities<br />
that directly target cancer cells, these drugs<br />
block the checkpoints of the host immune<br />
systems to unleash an outright attack on cancer<br />
cells.<br />
Since the approval of ipilimumab, a CTLA-4<br />
blocker, for melanoma by the USFDA in 2011,<br />
checkpoint inhibitors have fundamentally<br />
changed the outcome for certain subsets of<br />
patients with advanced forms of cancers, which<br />
were hitherto considered largely untreatable.<br />
This paved the way for US regulatory approval<br />
of checkpoint inhibitors with a broader range -<br />
PD-1 and PD-L1 - to treat over a dozen cancers.<br />
Of the two treatment strategies, checkpoint<br />
therapy against PD-1 has proven to be more<br />
effective for the carcinoma of the lung. As<br />
a group of malignancies, lung cancer offers<br />
the lowest survival rates. Lung cancer has an<br />
incidence rate of 11.6% - the highest among all<br />
cancers — and a mortality rate of 18.4%, the<br />
highest of all cancer-specific deaths, according<br />
to the Globocan <strong>2018</strong> report.<br />
Immune checkpoint inhibitors that block<br />
the PD-1/PD-L1 pathway, such as nivolumab,<br />
pembrolizumab and atezolizumab, have been<br />
rapidly adopted into clinical practice as a<br />
We are continuing<br />
to explore<br />
the potential<br />
of nivolumab<br />
through our broad<br />
development<br />
programme<br />
in thoracic<br />
malignancies,<br />
including early<br />
and late-stage<br />
NSCLC, SCLC and<br />
malignant pleural<br />
mesothelioma.<br />
Sabine Maier,<br />
M D, Development Lead,<br />
Thoracic Cancers,<br />
Bristol-Myers Squibb.<br />
standard treatment option for patients with<br />
advanced non-small-cell lung cancer (NSCLC).<br />
Exploring PD-1/PD-L1 pathways<br />
Nivolumab, a fully human monoclonal<br />
immunoglobulin G4 antibody to PD-1 intended<br />
for the treatment of squamous cell lung cancer,<br />
won US FDA approval in March 2015. Marketed<br />
by Bristol-Myers Squibb under the brand name<br />
Opdivo, its efficacy to treat squamous NSCLC<br />
was established in a randomized trial of 272<br />
participants, 135 of whom received nivolumab<br />
and 137 received docetaxel.<br />
In October 2015, FDA expanded<br />
nivolumab’s approval to advanced (metastatic)<br />
nonsquamous non-small cell lung cancer<br />
patients whose disease progressed during or<br />
after platinum-based chemotherapy.<br />
“We are continuing to explore the potential<br />
of nivolumab through our broad development<br />
programme in thoracic malignancies, including<br />
early and late-stage NSCLC, SCLC and malignant<br />
pleural mesothelioma,” says Sabine Maier, M D,<br />
Development Lead, Thoracic Cancers at Bristol-<br />
Myers Squibb.<br />
Pembrolizumab is an alternative, highly<br />
selective IgG4-kappa humanized monoclonal<br />
antibody against PD-1 receptor.<br />
Pembrolizumab got approval from the US<br />
FDA on October 2015 for the treatment of<br />
metastatic NSCLC in patients whose tumours<br />
express PD-L1 and who have failed treatment<br />
with other chemotherapeutic agents.<br />
Merck sells the drug under the brand name<br />
Keytruda.<br />
Merck is evaluating pembrolizumab in<br />
LUNG CANCER<br />
THE WORLDWIDE SCENARIO<br />
Age standardized (World) incidence<br />
rates, lung, females, all ages<br />
≥ 18.0<br />
10.0–18.0<br />
6.3–10.0<br />
3.9–6.3<br />
1.9–3.9<br />
< 1.9<br />
24 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
oth neoadjuvant and adjuvant settings; for example, in<br />
Keynote-091 (adjuvant) and Keynote-671 (neoadjuvant and<br />
adjuvant), which are currently recruiting patients, said a Merck<br />
spokesperson.<br />
Cemiplimab (Libtayo) is another PD-1 blocker, developed by<br />
Regeneron and Sanofi. The drug is being investigated presently<br />
for NSCLC as a monotherapy and in combination in first-line<br />
patients in different trial settings.<br />
Atezolizumab, marketed as Tecentriq by F Hoffmann-La<br />
Roche/Genentech, works through the PD-L1 pathway. The drug<br />
is approved in Europe and the USA for second-line treatment<br />
of NSCLC following platinum-based chemotherapy.<br />
Currently, Roche has eight Phase III lung cancer studies<br />
underway, evaluating atezolizumab alone or in combination<br />
with other medicines.<br />
Other PD-L1 inhibitors in late-stage development for NSCLC<br />
include durvalumab (Imfinzi, AstraZeneca) and avelumab<br />
(Bavencio, EMD Serono and Pfizer).<br />
LUNG TOPS CHART<br />
IN INDIA<br />
Lung cancer remains the<br />
leading type of malignancy in<br />
men in India, according to a new<br />
study conducted on data from<br />
28 population-based cancer<br />
registries (PBCR) across the<br />
country.<br />
The highest incidence of<br />
cancer was seen in the East and<br />
the Northeast regions and the<br />
lowest was in rural areas for all<br />
age groups in both men and<br />
women.<br />
The lung topped as the<br />
leading site for all the registries.<br />
In the Bengaluru registry,<br />
the leading cancer sites<br />
were the stomach and the<br />
lung. In Bhopal, Mumbai and<br />
Aurangabad, they were the lung<br />
and the mouth and in Kolkata<br />
and Tripura, it was the lung.<br />
Prepared by researchers<br />
from the Indian Council of<br />
Medical Research and the Delhibased<br />
Dharamshila Narayana<br />
Superspecialty Hospital, the<br />
paper compared data for all<br />
registries and reviewed the<br />
change in cancer pattern among<br />
different age groups from 2005<br />
to 2014.<br />
Checkpoint concerns<br />
Checkpoint therapy has really worked wonders. It brought<br />
SOURCE: GLOBOCAN <strong>2018</strong><br />
54.1<br />
24.0<br />
52.0<br />
24.5<br />
49.3<br />
11.9<br />
ASR (World) per<br />
CARCINOMA OF LUNG<br />
MALE FEMALE RATIO<br />
Age standardized (World)<br />
incidence rates, lung, by sex<br />
Male<br />
Female<br />
Micronesia<br />
Polynesia<br />
Central and<br />
Eastern<br />
Europe<br />
Eastern<br />
Asia<br />
Western<br />
Europe<br />
Southern<br />
Europe<br />
North<br />
America<br />
Western<br />
Asia<br />
Northern<br />
Europe<br />
World<br />
Australia/<br />
New<br />
Zealand<br />
South-<br />
Eastern<br />
Asia<br />
Southern<br />
Africa<br />
Caribbean<br />
Melanesia<br />
Northern<br />
Africa<br />
South<br />
America<br />
South-<br />
Central Asia<br />
Central<br />
America<br />
Middle<br />
Africa<br />
Eastern<br />
Africa<br />
Western<br />
Africa<br />
47.2<br />
21.9<br />
43.3<br />
25.7<br />
43.1<br />
15.7<br />
39.1<br />
30.7<br />
38.8<br />
7.8<br />
34.0<br />
26.9<br />
31.5<br />
14.6<br />
28.4<br />
24.0<br />
26.3<br />
9.6<br />
100,000<br />
26.0<br />
8.9<br />
23.5<br />
14.2<br />
17.1<br />
8.9<br />
16.9<br />
3.4<br />
16.8<br />
10.2<br />
9.4<br />
3.4<br />
7.2<br />
4.5<br />
3.8<br />
2.3<br />
3.4<br />
2.2<br />
2.4<br />
1.2<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 25
IMMUNE CHECKPOINT<br />
BLOCKADE: THE NEW RAGE<br />
Drugs that inhibit PD-1/PD-L1 pathway have been<br />
rapidly getting adopted into clinical practice<br />
NSCLC tumours overexpress the<br />
immunosuppressive checkpoint<br />
protein programmed death ligand 1<br />
(PD-L1) to evade detection and attack<br />
by immune cells. Inhibiting the PD-1/<br />
PD-L1 axis with monoclonal antibodies<br />
has significantly changed the treatment<br />
approach in lung cancer during the last<br />
5 years.<br />
Immune checkpoint inhibitors that<br />
block the PD-1/PD-L1 pathway, such<br />
as nivolumab, pembrolizumab and<br />
atezolizumab, have become a standard<br />
treatment option for patients with<br />
advanced non-small-cell lung cancer<br />
(NSCLC).<br />
NIVOLUMAB<br />
Nivolumab is a fully human monoclonal<br />
immunoglobulin G4 antibody targetting<br />
PD-1. The treatment won US FDA<br />
approval in March 2015 for the treatment<br />
of squamous cell lung cancer. Marketed<br />
by Bristol-Myers Squibb under the<br />
brand name Opdivo, its efficacy to treat<br />
squamous NSCLC was established in a<br />
randomized trial of 272<br />
participants of whom<br />
135 received nivolumab<br />
and 137 received<br />
docetaxel.<br />
In October 2015,<br />
FDA expanded<br />
nivolumab's approval to<br />
advanced (metastatic)<br />
nonsquamous nonsmall<br />
cell lung cancer in<br />
cases where the disease<br />
progressed during or<br />
after platinum-based chemotherapy.<br />
Patients who received nivolumab<br />
lived longer than those who received<br />
docetaxel in the study. However, it was<br />
found that the level of PD-L1 expression<br />
in NSCLC tumours may help identify<br />
the patients who are more likely to<br />
live longer with the help of nivolumab<br />
treatment. Therefore, the FDA also<br />
approved the PD-L1 IHC 28-8 pharmDx<br />
test to detect PD-L1 protein expression<br />
levels and help physicians determine<br />
which patients may benefit most from<br />
treatment with nivolumab.<br />
Currently, several studies are<br />
underway to determine whether<br />
nivolumab, in combination with other<br />
therapies, is effective in patients with<br />
advanced NSCLC. Among them are<br />
Biomarker-Targeted Second-Line Therapy<br />
in Treating Patients with Recurrent Stage<br />
IV Squamous Cell Lung Cancer (The<br />
Lung-MAP Screening Trial) and Alchemist<br />
treatment trial. Studies using nivolumab<br />
in NSCLC patients are ongoing in India as<br />
well, according to ClinicalTrials.gov<br />
“We are continuing to<br />
explore the potential of<br />
Opdivo through our broad<br />
development programme in<br />
thoracic malignancies, including<br />
early- and late-stage NSCLC,<br />
SCLC and malignant pleural<br />
mesothelioma,'' says Sabine<br />
Maier, M D, Development<br />
Lead, Thoracic Cancers,<br />
Bristol-Myers Squibb.<br />
In October, BMS<br />
announced topline results<br />
from the Phase 3 CheckMate-331 study<br />
evaluating nivolumab versus the current<br />
standard of care, topotecan or amrubicin,<br />
in patients with SCLC who relapsed<br />
following platinum-based chemotherapy<br />
did not meet its primary endpoint of<br />
overall survival.<br />
Earlier, in 2016, BMS said nivolumab<br />
failed to achieve its endpoint in a study<br />
and was no better than traditional<br />
chemotherapy at treating newly<br />
diagnosed lung cancer.<br />
Nivolumab has been approved for<br />
second-line NSCLC in more than 65<br />
countries, including the US, Europe,<br />
Japan and China.<br />
PEMBROLIZUMAB<br />
Pembrolizumab is a highly selective IgG4-<br />
kappa humanized monoclonal antibody<br />
against PD-1 receptor.<br />
Pembrolizumab was approved<br />
by the US FDA on October 2015 for<br />
the treatment of metastatic NSCLC in<br />
patients whose tumours express PD-L1<br />
and who have failed treatment with<br />
other chemotherapeutic agents.<br />
Merck sells the drug under the brand<br />
name Keytruda.<br />
Following the results of Keynote<br />
024 trial, the initial approval of<br />
pembrolizumab as a second-line<br />
treatment was extended to first-line<br />
treatment in NSCLC patients with high<br />
PD-L1-expressing tumours (PD-L1 >50%)<br />
with no EGFR or ALK mutations.<br />
The study found treatment with<br />
pembrolizumab prolonged progressionfree<br />
survival (PFS) and overall survival<br />
(OS) and improved objective response<br />
remarkable results in patients who are deemed untreatable<br />
otherwise. It resulted in the complete remission of disease<br />
even in cases of melanoma which has metastasised. However,<br />
it fails to do the trick in all patients with the same condition.<br />
PD-1/PD-L1 inhibitors also share some of the debilitating<br />
adverse effects which are common to this class of<br />
immunotherapies.<br />
“There’s a substantial toxicity because when we remove<br />
the brakes, the immune system will also attack normal tissue.<br />
There is, especially with the anti-CTLA4 therapy, a tendency to<br />
get autoimmune diseases like thyroiditis and hypopituitarism,”<br />
points out Dr Dixit. But that, fortunately, has been largely<br />
managed by dose alterations and other supportive care, he<br />
adds.<br />
26 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
ates (45% vs 28%, respectively)<br />
compared with chemotherapy in a firstline<br />
setting.<br />
The drug was granted accelerated<br />
approval by the US regulator in May<br />
2017 as a first-line combination therapy<br />
for metastatic non-squamous NSCLC<br />
regardless of PD-L1 status, based on the<br />
results of the Keynote-021 Phase 1/2<br />
clinical trial.<br />
"With Keynote-407 and Keynote-042,<br />
there are now five Phase 3 studies<br />
in patients with advanced NSCLC<br />
across common histologies where<br />
pembrolizumab, in combination or as<br />
a monotherapy, has demonstrated an<br />
improved OS benefit over chemotherapy,''<br />
said a Merck spokesperson.<br />
In a first-line setting, pembrolizumab<br />
has shown an OS benefit in around 80%<br />
of all NSCLC patients. In Keynote-189,<br />
pembrolizumab in combination with<br />
pemetrexed and platinum chemotherapy<br />
reduced the risk of death by half<br />
compared to chemotherapy alone as<br />
a first-line treatment for metastatic<br />
nonsquamous NSCLC, regardless of PD-<br />
L1 expression.<br />
In Keynote-407, pembrolizumab, in<br />
combination with carboplatin-paclitaxel<br />
or nab-paclitaxel, significantly improved<br />
OS and PFS as a first-line treatment<br />
in patients with metastatic squamous<br />
NSCLC, regardless of PD-L1 expression.<br />
As a monotherapy, in Keynote-024,<br />
pembrolizumab more than doubled<br />
median OS compared to chemotherapy<br />
in first-line treatment of patients with<br />
metastatic NSCLC whose tumours<br />
expressed PD-L1 with a TPS =50%.<br />
Keynote-042 showed that<br />
pembrolizumab monotherapy<br />
significantly improved OS as the firstline<br />
treatment in patients with locally<br />
advanced or metastatic nonsquamous<br />
or squamous NSCLC whose tumors<br />
expressed PD-L1 (TPS =1%).<br />
In a second-line setting, in<br />
Keynote-010, pembrolizumab significantly<br />
improved OS compared to chemotherapy<br />
in patients whose tumours express PD-L1<br />
(TPS of one percent or more).<br />
According to the Merck spokesperson,<br />
the company has an extensive clinical<br />
development programme in lung cancer<br />
and is advancing multiple registrationenabling<br />
studies with pembrolizumab in<br />
combination with other treatments, as<br />
well as in the form of a monotherapy.<br />
The programme, which comprises nearly<br />
9,000 patients across 15 clinical studies,<br />
is evaluating pembrolizumab across<br />
multiple settings and stages of the<br />
disease. Some of the subsets include:<br />
Pembrolizumab in patients<br />
IN A FIRST-LINE SETTING,<br />
PEMBROLIZUMAB HAS<br />
SHOWN AN OS BENEFIT<br />
IN AROUND 80% OF ALL<br />
NSCLC PATIENTS.<br />
with EGFR mutations (Keynote-789)<br />
or ALK translocations; and<br />
pembrolizumab for the treatment of<br />
SCLC as monotherapy (Keynote-158)<br />
and in combination with chemotherapy<br />
(Keynote-604).<br />
"Merck has more than 20<br />
early phase molecules that we are<br />
exploring as monotherapy or for<br />
potential combination activity with<br />
pembrolizumab, including STING, LAG-<br />
3, TIGIT, RIG-I and an oncolytic virus<br />
CAVATAK. All these agents have the<br />
potential to add significantly<br />
to the effectiveness of<br />
pembrolizumab," she<br />
added.<br />
ATEZOLIZUMAB<br />
Atezolizumab,<br />
marketed as Tecentriq<br />
by F Hoffmann-La<br />
Roche/Genentech is<br />
approved in Europe<br />
and the USA for<br />
second-line treatment of NSCLC following<br />
platinum-based chemotherapy. A<br />
Phase 3 study compared atezolizumab<br />
with docetaxel in unselected patients<br />
who had received up to two previous<br />
chemotherapy regimens, including<br />
at least one platinum-based therapy.<br />
The data showed that the regimen<br />
significantly improved OS in the<br />
atezolizumab treatment group compared<br />
with the docetaxel group. This benefit<br />
was independent of the level of PD-L1<br />
expression, with the patients with low<br />
or undetectable PD-L1 expression also<br />
demonstrating a prolonged OS with<br />
atezolizumab versus docetaxel (12.6 vs<br />
8.9 months).<br />
In March <strong>2018</strong>, Phase III IMpower150<br />
study showed that atezolizumab and<br />
bevacizumab plus carboplatin and<br />
paclitaxel helped people with advanced<br />
lung cancer live longer compared to<br />
bevacizumab plus carboplatin and<br />
paclitaxel.<br />
Currently, Roche has eight Phase III<br />
lung cancer studies underway, evaluating<br />
atezolizumab alone or in combination<br />
with other medicines.<br />
DURVALUMAB, AVELUMAB<br />
Other PD-L1 inhibitors in late-stage<br />
development for NSCLC include<br />
durvalumab (Imfinzi, AstraZeneca) and<br />
avelumab (Bavencio, EMD Serona and<br />
Pfizer). Data for both have recently been<br />
reported.<br />
Data from Pacific Phase 3 trial<br />
involving durvalumab showed that<br />
the drug reduced the risk of death by<br />
32% for patients with unresectable,<br />
stage III NSCLC following chemoradiation<br />
therapy.<br />
Avelumab failed to outdo docetaxel in<br />
second-line NSCLC patients with PD-L1-<br />
positive tumours that cannot be removed<br />
surgically.<br />
Uncertainty about which patients with NSCLC are most<br />
likely to benefit from anti-PD-1/PD-L1 therapy, however,<br />
continues to be the biggest concern for oncologists treating<br />
lung carcinoma.<br />
Researchers point to the many limitations of using the<br />
PD-L1 expression as a biomarker. Anti-PD-1/PD-L1 drugs<br />
do not inhibit every co-inhibitory interaction that may play<br />
a role in anti-tumour T-cell responses. This could be a<br />
contributing factor to the failure of PD-L1 expression to fully<br />
differentiate responders and nonresponders, they opine. The<br />
anti-PD-1/PD-L1 drug is co-developed with its own PD-L1<br />
immunohistochemistry (IHC) diagnostic assay. The US FDA has<br />
mandated that pembrolizumab be used only in conjunction<br />
with its companion PD-L1 test, while the assays for nivolumab<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 27
"Immunotherapy<br />
is going to be<br />
routinely used<br />
in NSCLC"<br />
The tumour cells<br />
have a blanket<br />
to prevent the<br />
immune system<br />
from working.<br />
With the help<br />
of these drugs<br />
[immunotherapy],<br />
we can take out the<br />
blanket and make<br />
the immune system<br />
work.<br />
Dr K Govind Babu<br />
Professor of Medical<br />
Oncology, Kidwai<br />
Memorial Institute of<br />
Oncology, Bengaluru.<br />
and atezolizumab are considered complementary.<br />
Too many subsets<br />
Sub-typing is<br />
better because<br />
now oncologists<br />
can understand<br />
the biology and<br />
treat the patients<br />
accordingly. But, it<br />
is also bad because<br />
it gets the diagnosis<br />
complicated,<br />
requiring many<br />
different approaches<br />
and resources.<br />
Dr Kurt A Schalper,<br />
Assistant Professor of<br />
Pathology and Medicine<br />
(Medical Oncology), Yale<br />
School of Medicine, USA<br />
The carcinoma of the lung has high mutational burden.<br />
Mutations in EGFR and ALK genes are considered key to<br />
the development of NSCLC. These driver mutations are<br />
seen to occur in approximately 10%–35% and 3%–7% of<br />
patients respectively. KRAS mutations are found in around<br />
30% of NSCLC cases. They are more common in patients<br />
with adenocarcinomas and smokers. At present, there is no<br />
approved targeted treatment for KRAS mutant NSCLC. Trials<br />
are underway to determine the efficacy of anti-PD-1/PD-L1<br />
therapy according to KRAS mutation status in a subgroup.<br />
It has also been found that high-level MET (exon 14<br />
skipping mutations) amplification and BRAF and ROS1<br />
mutations are driving events in NSCLC. They occur in 1%–3%<br />
of lung cancers.<br />
Carcinoma of the lung, which appears as a single disease<br />
entity at the outset, is actually a composite of several<br />
pathologies, avers Dr K Govind Babu, Professor of Medical<br />
Oncology, Kidwai Memorial Institute of Oncology, Bengaluru.<br />
“If a cell has a very high number of mutations, we call it<br />
a hot tumour. These cells can initiate a response from our<br />
immune system. But the tumour cells have a blanket to<br />
prevent the immune system from working. With the help<br />
Dr Vishva M Dixit is Vice President and<br />
Staff Scientist, Physiological Chemistry at<br />
Genentech, San Francisco, CA. After heading<br />
Molecular Oncology for 10 years, Dr Dixit<br />
has now turned his efforts to basic research<br />
to study the biochemistry of components<br />
of signaling pathways that often go awry<br />
in disease. Author of over 166 publications<br />
in various journals, he is the winner of<br />
several awards and honours including AHA<br />
Investigatorship Award – 1989-1994; Dawson<br />
Prize in Genetics – 2015 and Gutenberg<br />
Research Award – 2016, among others.<br />
"My mission is to further our knowledge<br />
of disease-related cellular signaling and to<br />
develop novel, high-impact therapeutics,"<br />
says Dr Dixit. Edited excerpts from his<br />
conversation with <strong>FM</strong>.<br />
A discovery on cancer immunotherapy<br />
won this year's Nobel Prize for medicine.<br />
How exactly does the discovery help in<br />
understanding malignancies?<br />
Cancer immunotherapy has been in<br />
the doghouse for decades. The work of<br />
the two investigators, James P. Allison<br />
and Tasuku Honjo, resurrected it so that it<br />
plays a prominent role in the therapeutic<br />
armamentarium in future.<br />
Immunotherapy held a lot of promise.<br />
But there weren't any successes. The reason<br />
is that people were trying to activate the<br />
immune system. And a number of immune<br />
activators were tried and they invariably<br />
failed. The realization of Allison and Honjo<br />
was that the cells have a brake on them. You<br />
can put as much fuel in the system as you<br />
want, as much accelerator as you can press<br />
on: The car is not going to go. The cell is not<br />
going to proliferate or rejuvenate unless you<br />
remove the brakes. That was their realisation.<br />
They said, you have been trying to activate<br />
the immune system in a tumour without<br />
28 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
PHOTO: UMESH GOSWAMI<br />
Cancer immunotherapy has been in the doghouse for decades.<br />
The work of the two investigators, James P. Allison and Tasuku<br />
Honjo, resurrected it so that it plays a prominent role in the<br />
therapeutic armamentarium in future.<br />
Dr Vishva M Dixit<br />
realising the fact that a brake has been<br />
put on it in the tumour environment.<br />
And the immune system is sitting there<br />
paralysed. It can't do anything unless<br />
you remove the brakes. The molecules<br />
CTLA4 and CD-1 are essentially the<br />
brakes of the immune system. Now they<br />
have developed antibodies to neutralize<br />
the brakes and get the immune system<br />
work. Now the immune system is able to<br />
eradicate tumour cells in many cases.<br />
In what way is immunotherapy<br />
going to change the treatment<br />
paradigms in cancer?<br />
The potential of immunotherapy has<br />
already been validated in melanoma<br />
and NSCLC. Treatment with the immune<br />
activators — which activate the immune<br />
system against cancer cells — has proved<br />
to be immensely beneficial. In many<br />
cases, people who would have ordinarily<br />
been dead are still alive...<br />
Does immunotherapy work for<br />
all cancers?<br />
No. There are many cancers that<br />
don't respond to immunotherapy. That is<br />
an area of active research today. It works<br />
only for malignancies that have a very<br />
high mutational burden. NSCLC has the<br />
highest mutation because of smokers.<br />
Smoking generates a lot of mutagens.<br />
What are the possible adverse<br />
effects?<br />
There's substantial toxicity, because<br />
when we remove the brakes, the<br />
immune system will also start to attack<br />
normal tissue. There is, especially with<br />
the anti-CTLA4 therapy, a tendency<br />
to get autoimmune diseases like<br />
thyroiditis and hypopituitarism. But that,<br />
fortunately, has been, largely managed<br />
now by dose alterations and other<br />
supportive care.<br />
How do you compare the benefit of<br />
immunotherapy with other standard<br />
therapies?<br />
These drugs are used in combination.<br />
In melanoma, metastatic melanoma, I<br />
never thought, in my lifetime, the<br />
disease could be cured. Now, it has<br />
been cured: Cured in 10% of the patients<br />
with twelve years out. There's no relapse.<br />
It's a small fraction. But still, it has been<br />
cured. I think it is an amazing step<br />
forward.<br />
What is the potential of<br />
immunotherapy in lung cancer?<br />
Trials are going on. NSCLC has been<br />
a heterogeneously aggressive disease.<br />
Maybe in the adjuvant setting, one may<br />
see a substantial benefit. We may get to<br />
a day when we have targeted biologics,<br />
or we have an inhibitor for an oncogene<br />
like the EGF receptor inhibitor. Then, we<br />
won't need chemotherapy. We are not<br />
there yet.<br />
The future of immunotherapy?<br />
I think it is going to be bright. That's<br />
why they gave the Nobel. It is going to<br />
be routinely used in melanoma, NSCLC,<br />
renal cancer and subsets of prominent<br />
malignancies. But it is not effective in<br />
colon cancer unless you have something<br />
called a mutated phenotype, which is<br />
found only in a small percent of colon<br />
cancers. But it is going to open the door<br />
for more immunotherapies.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 29
RESPIRATION-GATED<br />
RADIATION THERAPY<br />
PHOTOS: UMESH GOSWAMI<br />
According to Dr Manish Chandra, Chief Radio<br />
Oncologist at Jupiter Hospital, Thane, gated radiation<br />
therapy is an exciting and comparatively new option for<br />
treating lung cancer.<br />
“Though the cost is almost 30% more compared to<br />
traditional radiation, the local control achieved through<br />
this method is much better,” he added.<br />
The higher cost is because of more time spent per<br />
patient on the machine for gated radiation. The machine<br />
tries to ensure that the tumour is always within the<br />
radiation beam even as the tumor moves constantly<br />
during the treatment. It takes longer as the procedure is<br />
done after preparing the patient using a kind of breath<br />
control technique.<br />
Radiation treatment for lung cancer has always been<br />
a challenge to radiation oncologists as the target tumour<br />
is usually on the move during the treatment as the lung<br />
is a constantly moving organ.<br />
Traditionally, a larger area of the lung than strictly<br />
required is irradiated to ensure that the tumour is within<br />
the radiation beam, affecting the nearby healthy cells.<br />
With the respiration-gated approach, the radiation<br />
beam is targeted to a specific point in real time in<br />
keeping with the cycle of respiration. Radiation gating<br />
helps to reduce the amount of healthy tissues in the<br />
lung receiving radiation. Thus a higher dose of radiation<br />
can be used at the targeted location. It can also reduce<br />
the length of the treatment from as many as six weeks<br />
to just two or four.<br />
Chandra added that this method, which is practised<br />
by many experienced radio-oncologists in India today,<br />
brings new hope to lung cancer patients who are<br />
untreatable through surgery or traditional radiation<br />
therapy.<br />
Respiration-gated radiation therapy is also being<br />
considered for treating other difficult areas such as<br />
pancreas cancer or tumours close to the kidneys etc..<br />
The studies for such expansion are underway.<br />
of these drugs [immunotherapy], we can take out the<br />
blanket and make the immune system work,” Dr Babu<br />
elaborates.<br />
Newer sub-types of lung cancer are getting identified<br />
as genomic information helps to reclassify tumours. “There<br />
are many [subsets in lung carcinoma], more than we can<br />
count,” says Dr Kurt A Schalper, Assistant Professor of<br />
Pathology and Medicine (Medical Oncology), Yale School<br />
of Medicine, USA. Even as sub-typing helps re-group<br />
tumours more specifically, the deluge of information can<br />
also complicate the diagnosis process at times.<br />
“It is better because now oncologists can understand<br />
the biology and treat the patients accordingly. But, it<br />
is also bad because it gets the diagnosis complicated,<br />
requiring many different approaches and resources,” says<br />
Schalper.<br />
What makes immunotherapy a better option for<br />
lung cancer are certain features characteristic of this<br />
carcinoma. Tumours in the lung tissue, as in case<br />
of melanoma, are very good at invading immunity.<br />
Therefore, the stimulation and the restoration of<br />
the body’s immunity generates a lot of anti-tumour<br />
effects. Conventional treatments, when combined with<br />
immunostimulatory agents, have been shown to be more<br />
effective than either used alone. For example, advanced<br />
carcinoma of the lung, which used to be treated with<br />
standard platinum-based chemotherapy, now depends<br />
on the expression of PD-1 marker. This can improve the<br />
outcome.<br />
Immunotherapy is very a dynamic field and it has a<br />
very well-established role in lung cancer. Investigations<br />
are going on to see the effect of PD-1/PD-L1 blockers<br />
in earlier stages as well as in second and third-degree<br />
lesions, informs Dr Schalper.<br />
Prolonging survival<br />
In personalised medicine, oncologists can select drugs<br />
which works best for the individual by assessing the<br />
genetic makeup of a particular tumour. This concept<br />
of personalised medicine has greater relevance to the<br />
treatment of lung cancer. Earlier, chemotherapy used to<br />
be the only option to kill cancer cells. Then came targeted<br />
therapy where the tumour tissue is first sequenced and<br />
then specifically targeted by drugs. Now, immunotherapy<br />
shows that it is possible to enhance immunity with the<br />
help of some medications so that the body itself can<br />
attack the cancer cells. Here, all one has to do is to check<br />
for relevant biomarkers. “For lung cancers, biomarkers like<br />
PD-1 are currently available. If it is strongly positive, we<br />
can avoid chemo and go ahead with immune therapy,”<br />
comments Dr Rejiv Rajendranath, Consultant Oncologist,<br />
Apollo Specialty Hospital, Chennai, India.<br />
The identification of the right kind of treatment is<br />
better than exposing patients to tedious chemo regimens<br />
without being sure of their efficacy.<br />
30 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
Oncologists, according to Dr Rajendranath, are trying to<br />
lessen the use of chemo and radiation in case of lung cancer<br />
and stratify the patients to check the feasibility of various<br />
therapeutic regimes like targeted therapy, immunotherapy<br />
or chemotherapy. “Only if all the targets fail, will we go<br />
back to chemotherapy, unlike earlier days where we treated<br />
everybody with chemo,” he says, explaining how targeted and<br />
immunotherapies have brought about a shift in treatment<br />
approaches.<br />
Clearly, NSCLC has a lot of druggable targets. But SCLC<br />
is a different story altogether. SCLC has, largely, been an<br />
orphan disease. Cisplatin chemotherapy for lung carcinoma<br />
is now almost 20-30 years old. Hardly any trials are taking<br />
place in this direction. Most recently, some breakthrough<br />
studies have come up with data showing that if we add an<br />
immunetherapy agent along with chemo in advanced stage<br />
SCLC, the survival of the patient can be improved. Survival<br />
rates are still modest. But such an advancement is really<br />
practice-changing, because clinicians now have one more<br />
drug to use on patients left with no option after all available<br />
drugs failed, contends Dr Rejindranath.<br />
Several oncologists in India, however, prefer a wait-andwatch<br />
approach to immunotherapy. They believe that the<br />
concept is still in its infancy. Moreover, immunotherapy it is<br />
not curative. “We always tell patients that immunotherapy<br />
is not curative. But it is a better option for elderly patients,<br />
who cannot stand chemo,” says Dr Arun Warrier, Consultant<br />
ADENOCARCINOMA:<br />
CHANGING PROFILE<br />
People change. Lifestyles<br />
change. So do disease<br />
profiles. Earlier, squamous<br />
cell carcinoma and small cell<br />
carcinoma were common in<br />
the Indian population because<br />
of smoking and high tobacco<br />
consumption. But interestingly,<br />
lung carcinoma has given way<br />
to adenocarcinoma of late.<br />
“Adenocarcinoma is something<br />
which is more common in the<br />
West. Maybe, because of the<br />
higher use of filter cigarettes<br />
and the western style of life,<br />
adenocarcinoma has become<br />
the most common lung cancer<br />
in India also, according to Dr<br />
Rejiv Rajendranath.<br />
Recent trends indicate that<br />
the incidence of SCLC is coming<br />
down in India. But the numbers<br />
related to NSCLC are going<br />
up. “This increase in NSCLC is<br />
due to genetic aberrations. All<br />
these existed earlier too, but<br />
we’ve started to identify them<br />
only now, that’s all,” says Dr<br />
Anand Babu, Consultant Medical<br />
Oncologist, HCG, Bangalore.<br />
For lung cancers,<br />
biomarkers like<br />
PD-1 are currently<br />
available. If it is<br />
strongly positive,<br />
we can avoid<br />
chemo and go<br />
ahead with immune<br />
therapy.<br />
Dr Rejiv<br />
Rajendranath,<br />
Consultant Oncologist,<br />
Apollo Specialty Hospital,<br />
Chennai.<br />
We always tell<br />
patients that<br />
immunotherapy is<br />
not curative. But it<br />
is a better option<br />
for elderly patients,<br />
who cannot stand<br />
chemo.<br />
Dr Arun Warrier,<br />
Consultant Oncologist at<br />
Aster Medcity, Cochin.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 31
Oncologist at Aster Medcity, Kochi,<br />
Kerala. Overall, immunotherapy benefits<br />
only 10%-15% of the patients with<br />
lung cancer, although it is easier on the<br />
patients. The survival benefits are also<br />
not quite significant vis-a-vis the cost,<br />
he adds.<br />
Immunotherapy, as a breakthrough<br />
treatment modality, comes with a<br />
hefty price tag. Most Indian patients<br />
consider it unaffordable. Now, the effort<br />
is to combine the benefits of different<br />
therapies with checkpoint drugs.<br />
“But all these come at a financial cost<br />
that we like to call financial toxicity,”<br />
comments Dr Govind Babu.<br />
Cost is an issue but it might also<br />
come down over time, believes Dr<br />
Rejindranath. But the survival rate in<br />
lung cancer, which otherwise has the<br />
poorest prognosis among malignancies,<br />
LUNG CANCER: TARG<br />
Immuno-oncology landscape has many<br />
promising vaccine candidates against NSCLC<br />
Efforts to develop vaccines<br />
against lung cancer always<br />
stalled in the face of<br />
challenges and several previous<br />
attempts have proved ineffective.<br />
It is now recognised that immunesuppressive<br />
factors exist in the<br />
microenvironment of tumour cells.<br />
The local immunosuppression arises<br />
from the interplay of cellular and<br />
metabolic functions to regulate<br />
inflammation. Understanding the<br />
fundamental basis of the cancerimmunity<br />
cycle has significantly<br />
boosted vaccine efforts.<br />
A recent analysis of the global<br />
immune-oncology landscape that<br />
appeared in Annals of Oncology<br />
shows that there are more cancer<br />
vaccines under clinical investigation<br />
than any other class of therapeutic<br />
agents. There are more than 340<br />
agents under clinical trials and<br />
another estimated 260 candidates<br />
SURVIVAL BENEFITS, FOR<br />
CERTAIN SUBSETS OF LUNG<br />
CANCER, ARE TEN TIMES<br />
HIGHER THAN THOSE OF<br />
DECADES PAST. MOST OF<br />
THE TIME, PATIENTS WITH<br />
LUNG CARCINOMA COME<br />
FOR DIAGNOSIS AT VERY<br />
LATE STAGES OF THEIR<br />
DISEASE.<br />
has changed dramatically with the<br />
targeted therapies. Survival benefits,<br />
for certain subsets of lung cancer, are<br />
ten times higher than those of decades<br />
past. Most of the time, patients with<br />
lung carcinoma come for diagnosis at<br />
very late stages of their disease. “Here<br />
we can only prolong their survival<br />
and give a meaningful quality of life;<br />
instead of 5-6 months to 24-28-40<br />
months, slowly but steadily,” opines Dr<br />
Rejindranath. Surely, it does make a<br />
difference, all the more.<br />
Divya Choyikutty from Kochi contributed<br />
reporting to this article<br />
32 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
ETED VACCINE THERAPY ON WAY<br />
in preclinical and discovery stages as of<br />
September 2017.<br />
CIMAVax-EGF: Combo trials<br />
CIMAvax-EGF is a therapeutic vaccine<br />
being tested against advanced NSCLC,<br />
developed by the Center of Molecular<br />
Immunology, Havana, Cuba. It is<br />
composed of recombinant human<br />
EGF chemically conjugated to a<br />
recombinant carrier protein, p64, from<br />
Neisseria meningitidis. Results from a<br />
randomized phase III trial conducted<br />
in Cuba between 2006 and 2012 on<br />
a total of 405 patients with advanced<br />
NSCLC showed that the overall survival<br />
(OS) was numerically higher in the<br />
vaccine arm (receiving at least 1 dose<br />
of vaccine) versus control. In the<br />
analysis of per-protocol population,<br />
consisting of patients who received at<br />
least 4 vaccine doses, median OS was<br />
12.4 months versus 9.4 months in the<br />
control group. The survival effect was<br />
even better for patients who had high<br />
EGF concentration (serum EGF >870<br />
pg/ml) at baseline: Median OS for<br />
vaccinated patients in this group was<br />
14.7 versus 8.6 months in the matched<br />
control group.<br />
A study (NCT02955290) to<br />
evaluate the efficacy of CIMAvax-EGF<br />
in combination with nivolumab as<br />
second-line therapy for advanced<br />
NSCLC commenced recruitment in<br />
December 2016.<br />
Another randomized international<br />
phase III study of CIMAvax-EGF in<br />
combination with first-line platinumbased<br />
chemotherapy for patients with<br />
stage IV NSCLC is ongoing.<br />
Vx-001 targeting TERT<br />
Vx-001, a peptide-based vaccine<br />
developed by Paris-based Vaxon<br />
Biotech, is currently in Phase II<br />
clinical studies. It is designed to elicit<br />
immunogenicity of the cryptic epitope<br />
A RANDOMIZED<br />
INTERNATIONAL PHASE III<br />
STUDY OF CIMAVAX-EGF<br />
IN COMBINATION WITH<br />
FIRST-LINE PLATINUM-<br />
BASED CHEMOTHERAPY FOR<br />
PATIENTS WITH STAGE IV<br />
NSCLC IS ONGOING.<br />
derived from telomerase reverse<br />
transcriptase (TERT), a universal<br />
tumour antigen, in order to bind human<br />
leukocyte antigen A2 (HLA-A2) positive<br />
T cells. Data from a randomized,<br />
double-blind, placebo-controlled,<br />
phase IIb clinical trial in about 190<br />
HLA-A2–positive patients with<br />
metastatic or recurrent NSCLC after<br />
platinum-based first-line chemotherapy<br />
found no significant differences in<br />
OS between the groups treated with<br />
Vx-001 and placebo. However, 29%<br />
of patients, who were able to develop<br />
a vaccine-specific immune response,<br />
demonstrated higher OS compared<br />
with non-responders (21 vs 13 months,<br />
P = .004). A subset analysis also found<br />
better OS with vaccine, among patients<br />
who were never-smokers or light<br />
smokers and had non-immunogenic<br />
tumours, with median OS of 20.2<br />
months versus 7.9 months. Vaxon<br />
has plans to investigate Vx-001 in<br />
combination with immune checkpoint<br />
inhibitors in the population of patients<br />
with non-immunogenic NSCLC.<br />
Racotumomab: Anti-idiotype mAb<br />
Racotumomab (Vaxira) is a therapeutic<br />
vaccine that is currently under clinical<br />
development by Recombio, an<br />
international public-private consortium,<br />
in association with the Center of<br />
Molecular Immunology at Havana, Cuba<br />
(CIM) and researchers from Buenos<br />
Aires University and the National<br />
University of Quilmes in Argentina.<br />
It is an anti-idiotype monoclonal<br />
antibody (mAb) against ganglioside<br />
containing NeuGcGM3, a Neu glycolyl<br />
(NeuGc). NeuGcGM3 ganglioside is<br />
expressed in NSCLC. Anti-idiotypic<br />
antibodies are capable of eliciting<br />
an immunogenic reaction against<br />
the original epitope of the selected<br />
antigen as they mimic the nominal<br />
antigen. Final results are awaited<br />
from a randomized phase III trial<br />
(NCT01460472) of racotumomab in<br />
about 1,080 patients carried out in<br />
South America and Southeast Asia.<br />
Tumour neoantigens approach<br />
An alternative vaccine approach gaining<br />
currency recently is the targeting of<br />
tumour neoantigens that arise from<br />
somatic mutations. These neoantigens<br />
are tumour-specific and highly<br />
immunogenic. They are individualized<br />
vaccines comprising multiple RNA or<br />
peptide-based neoepitopes identified<br />
after whole exome sequencing of the<br />
tumour tissue in each patient. Several<br />
clinical trials are underway pursuing the<br />
neoantigens approach in combination<br />
with anti-PD1/PD-L1 drugs. Studies<br />
such as NEO-PV-01, RO7198457,<br />
mRNA-4157, NCT02897765,<br />
NCT03289962 and NCT03313778 are<br />
among them.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 33
drug approvals<br />
Dupilumab for asthma in US<br />
The US Food and Drug<br />
Administration has<br />
approved dupilumab<br />
(Dupixent) as an add-on<br />
maintenance therapy in<br />
patients aged 12 years and<br />
older with moderate-to-severe<br />
asthma with an eosinophilic<br />
phenotype and those with<br />
oral corticosteroid-dependent<br />
asthma.<br />
Dupilumab inhibits<br />
the overactive signaling<br />
of interleukin-4 (IL-4) and<br />
interleukin-13 (IL-13), two key<br />
proteins that contribute to<br />
the Type 2 inflammation that<br />
may underlie moderate-tosevere<br />
asthma. This effect is<br />
associated with the reduction<br />
of inflammatory biomarkers,<br />
including fractional exhaled<br />
nitric oxide (FeNO),<br />
immunoglobulin E (IgE) and<br />
eotaxin-3 (CCL26).<br />
The pivotal trial<br />
programme evaluated 2,888<br />
adult and adolescent patients<br />
with moderate-to-severe<br />
asthma in three randomized,<br />
placebo-controlled,<br />
Talazoparib to<br />
treat gBRCAm<br />
breast cancer<br />
Talazoparib (Talzenna) has<br />
been cleared by US FDA<br />
for patients with deleterious<br />
germline BRCA-mutated<br />
(gBRCAm), HER2-negative<br />
metastatic breast cancer.<br />
Developed by Pfizer,<br />
talazoparib is a poly (ADPribose)<br />
polymerase (PARP)<br />
inhibitor.<br />
The approval was based<br />
on EMBRACA, an open-label<br />
trial randomizing 431 patients<br />
(2:1) with gBRCAm HER2-<br />
negative locally advanced<br />
or metastatic breast cancer<br />
to receive talazoparib (1<br />
mg) or physician’s choice of<br />
chemotherapy (capecitabine,<br />
eribulin, gemcitabine or<br />
multicentre trials for six<br />
months to one year.<br />
In Trial 2 (the largest<br />
trial), dupilumab reduced<br />
exacerbations and improved<br />
lung function in the overall<br />
population. Benefits in<br />
exacerbations were seen<br />
in patients with eosinophil<br />
counts greater than or equal<br />
to 150 cells/microliter, which<br />
represented 70% of the<br />
patients enrolled. Efficacy<br />
improved in patients with<br />
vinorelbine).<br />
The primary efficacy<br />
outcome was progression-free<br />
survival (PFS), according to<br />
Response Evaluation Criteria<br />
in Solid Tumours (RECIST)<br />
1.1, as assessed by a blinded<br />
independent central review.<br />
Estimated median PFS was<br />
8.6 months and 5.6<br />
months in the talazoparib<br />
higher eosinophil counts.<br />
In Trial 3, which evaluated<br />
severe, oral corticosteroiddependent<br />
patients,<br />
dupilumab reduced average<br />
daily oral corticosteroid use<br />
by 70% compared to 42%<br />
with placebo. More than<br />
half of patients treated<br />
with dupilumab completely<br />
eliminated the use of oral<br />
corticosteroids, announced<br />
Regeneron Pharmaceuticals,<br />
Inc and Sanofi.<br />
and chemotherapy arms,<br />
respectively (HR 0.54; 95%<br />
CI: 0.41, 0.71; p
showed that rivaroxaban<br />
vascular dose, 2.5 mg twice<br />
daily, plus aspirin 100 mg<br />
once daily reduced the<br />
risk of the composite<br />
of stroke, CV death and<br />
heart attack by 24 percent<br />
compared with aspirin 100<br />
mg once daily alone in<br />
patients with CAD or PAD.<br />
Rivaroxaban was<br />
discovered by Bayer, and<br />
is being jointly developed<br />
with Janssen Research &<br />
Development, LLC.<br />
Abemaciclib<br />
for HR+ breast<br />
cancer in EU<br />
EMA has cleared<br />
abemaciclib (Verzenio) to<br />
treat women with hormone<br />
receptor-positive (HR+),<br />
epidermal growth factor<br />
receptor 2 negative (HER2-)<br />
locally advanced or metastatic<br />
breast cancer.<br />
The treatment with<br />
CDK4/6inhibitor is approved<br />
as a first-line therapy<br />
in combination with an<br />
aromatase inhibitor or<br />
fulvestrant, and as a secondline<br />
treatment after earlier<br />
endocrine drugs.<br />
The approval of<br />
abemaciclib is based on the<br />
results of the Monarch 2<br />
and Monarch 3 as secondline<br />
and first-line studies. A<br />
phase III trial called Monarch<br />
E is currently underway to<br />
determine the efficacy of<br />
abemaciclibas adjuvant<br />
therapy in early breast cancer.<br />
Earlier, Eli Lilly suspended<br />
the Phase 3 Juniper<br />
programme to extend the use<br />
of abemaciclibinto pancreatic<br />
cancer as it failed to meet the<br />
endpoints<br />
Elapegademase<br />
for ADA-SCID<br />
US FDA has granted<br />
approval for<br />
elapegademase (Revcovi) for<br />
adenosine deaminase severe<br />
combined immune deficiency<br />
(ADA-SCID).<br />
Elapegademase is a longacting<br />
drug that replaces<br />
the missing ADA enzyme in<br />
patients with ADA-SCID with<br />
an engineered, recombinant<br />
form.<br />
The new drug comes as an<br />
alternative to current animalderived<br />
enzyme replacement<br />
therapy pegademase bovine<br />
by Leadiant.<br />
Also known as bubble boy<br />
disease, ADA-SCID is an ultrarare,<br />
inherited geneticdisorder<br />
that compromises patients’<br />
immune systems and leaves<br />
patients unprotected from<br />
infections, and is fatal if<br />
untreated.<br />
The disease is typically<br />
diagnosed within the first<br />
few months of life, and<br />
undiagnosed babies with<br />
ADA-SCID usually die before<br />
Breakthrough<br />
designation for<br />
20-valent vac<br />
Pfizer’s 20-valent<br />
pneumococcal<br />
conjugate vaccine<br />
(20vPnC) candidate,<br />
PF-06482077, received<br />
breakthrough therapy<br />
designation from the US<br />
FDA for the prevention<br />
of pneumonia caused by<br />
Streptococcus pneumoniae<br />
serotypes in the vaccine in<br />
adults.<br />
The FDA decision is<br />
informed by the results<br />
of the 20vPnC Phase 2<br />
randomized, double-blind<br />
trial to evaluate the safety<br />
and immunogenicity of a<br />
multivalent pneumococcal<br />
conjugate vaccine in adults<br />
60 through 64 years of<br />
age.<br />
Anti-depressant vortioxetine<br />
launched in India<br />
Lundbeck launched vortioxetine<br />
(Brintellix) in India for the<br />
treatment of patients suffering<br />
from major depressive disorder<br />
(MDD), following approval from<br />
Drug Controller General of India<br />
(DCGI).<br />
Vortioxetine is a novel<br />
multimodal antidepressant which<br />
has been specifically designed<br />
to inhibit serotonin reuptake and<br />
modulate serotonergic receptor<br />
activity of the neurons in the brain<br />
of affected patients.<br />
It has demonstrated significant<br />
efficacy in reducing the mood<br />
symptoms in adult patients with<br />
depression as measured by<br />
traditional scales like MADRS or<br />
HAMD.<br />
The drug also improves<br />
cognitive performance in adult<br />
patients with depression, as<br />
measured with neuropsychological<br />
tests. Cognitive symptoms are<br />
part of the diagnostic criteria<br />
for depression and include the<br />
ability to concentrate, make<br />
decisions and the ability to<br />
remember, said Lundbeck.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 35
they reach age two due to<br />
infections.<br />
Elapegademase approval<br />
is based on two open-label<br />
trials demonstrating the drug<br />
increases ADA activity, reduces<br />
concentrations of toxic<br />
metabolites and improves<br />
total lymphocyte counts in<br />
ADA-SCID patients.<br />
Cemiplimab for<br />
skin cancer in US<br />
Inotersen to address polyneuropathy<br />
The US Food and Drug<br />
Administration has<br />
approved inotersen (Tegsedi)<br />
for the treatment of<br />
polyneuropathy of hereditary<br />
transthyretin-mediated<br />
amyloidosis in adults.<br />
Inotersenis an RNAtargeting<br />
therapeutic that<br />
reduces the production<br />
of TTR protein through a<br />
once-weekly subcutaneous<br />
injection offering a treatment<br />
for people living with<br />
polyneuropathy caused by<br />
hATTR amyloidosis.<br />
In hATTRamyloidosis,<br />
transthyretin (TTR) protein<br />
misfolds and accumulates as<br />
amyloid deposits throughout<br />
the body. Inotersen targets<br />
the disease at its source by<br />
reducing the production of<br />
TTR protein.<br />
The FDA looked at results<br />
from the Phase 3 NEURO-<br />
TTR study in patients with<br />
hATTRamyloidosis with<br />
symptoms of polyneuropathy.<br />
Results from that study<br />
demonstrated that patients<br />
treated with inotersen<br />
experienced significant benefit<br />
compared to patients treated<br />
with placebo across both coprimary<br />
endpoints: the Norfolk<br />
Quality of Life Questionnaire-<br />
Diabetic Neuropathy (Norfolk<br />
QoL-DN) and modified<br />
Neuropathy Impairment<br />
Score +7 (mNIS+7), a<br />
measure of neuropathic<br />
disease progression, Akcea<br />
Therapeutics, Inc and<br />
Ionis Pharmaceuticals, Inc,<br />
announced.<br />
Cemiplimab-rwlc(Libtayo)<br />
injection for the treatment<br />
of patients with metastatic<br />
cutaneous squamous cell<br />
carcinoma (CSCC) has been<br />
granted approval by USFDA.<br />
Cemiplimab works by<br />
targeting the cellular<br />
pathway known as PD-1. By<br />
blocking this pathway, the<br />
drug may help the body’s<br />
immune system fight the<br />
cancer cells.<br />
The safety and efficacy<br />
of Libtayo were studied in<br />
two open-label clinical trials.<br />
A total of 108 patients (75<br />
with metastatic disease and<br />
33 with the locally-advanced<br />
disease) were included in the<br />
efficacy evaluation.<br />
The study’s primary<br />
endpoint was objective<br />
response rate or the<br />
percentage of patients who<br />
experienced partial shrinkage<br />
or complete disappearance of<br />
their tumor(s) after treatment.<br />
Results showed that 47.2<br />
per centof all patients treated<br />
with cemiplimabhad their<br />
tumoursshrink or disappear.<br />
Cemiplimab is<br />
developed by Regeneron<br />
Pharmaceuticals, Inc.<br />
Emicizumab for<br />
haemophilia<br />
without FVIII<br />
The US FDA has<br />
approved emicizumabkxwh(Hemlibra)<br />
for routine<br />
prophylaxis to reduce the<br />
frequency of bleeding<br />
episodes in adults and<br />
children with haemophiliaA<br />
without factor VIII inhibitors.<br />
Emicizumab is now the<br />
only prophylactic treatment<br />
for people with haemophilia<br />
A with and without factor<br />
VIII inhibitors that can be<br />
administered subcutaneously<br />
and at multiple dosing<br />
options, Roche said.<br />
This approval is based<br />
on positive results from<br />
the phase III Haven 3 and<br />
Haven 4 studies. Emicizumab<br />
prophylaxis led to statistically<br />
significant and clinically<br />
meaningful reductions in<br />
treated bleeds compared to<br />
no prophylaxis and across all<br />
other bleed-related endpoints<br />
in the Haven 3 study, and<br />
showed control of bleeding in<br />
the Haven 4 study.<br />
Haven 3 is a randomised,<br />
multicentre, open-label, phase<br />
III study evaluating the efficacy,<br />
safety andpharmacokinetics of<br />
emicizumabprophylaxis versus<br />
no prophylaxis in people<br />
with haemophilia A without<br />
factor VIII inhibitors. The<br />
study included 152 patients<br />
with haemophiliaA who were<br />
previously treated with factor<br />
VIII therapy.<br />
Dacomitinib to<br />
treat metastatic<br />
NSCLC<br />
P<br />
fizer Inc said the USFDA<br />
has approved dacomitinib<br />
(Vizimpro) to treat non-small<br />
cell lung cancer (NSCLC) that<br />
has spread to other parts of<br />
the body.<br />
Dacomitinib is a kinase<br />
inhibitor indicated for firstline<br />
treatment of patients<br />
with metastatic NSCLC with<br />
epidermal growth factor<br />
receptor (EGFR) exon 19<br />
deletion or exon 21 L858R<br />
substitution mutations as<br />
detected by an FDA-approved<br />
test.<br />
The safety and efficacy of<br />
dacomitinib wasdemonstrated<br />
in Archer 1050, a randomized,<br />
multicenter, multinational,<br />
open-label study. A total of<br />
452 patients were randomized<br />
36 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
1:1 to dacomitinib or gefitinib.<br />
A statistically significant<br />
improvement in PFS, as<br />
determined by the IRC, was<br />
demonstrated for patients<br />
randomized to dacomitinib<br />
compared with gefitinib (HR<br />
= 0.59 [95% CI: 0.47, 0.74],<br />
p months (95% CI: 11.1, 16.6)<br />
compared with 9.2 months<br />
(95% CI: 9.1, 11.0) in the<br />
gefitinib arm.<br />
Vonicog to<br />
treat bleeding<br />
disorder in EU<br />
T<br />
he European Commission<br />
(EC) has granted Marketing<br />
Authorization for vonicogalfa<br />
(Veyvondi) for the treatment<br />
of bleeding events and<br />
treatment of surgical bleeding<br />
in adults with von Willebrand<br />
disease (VWD).<br />
Vonicog alfa is the first<br />
and only recombinant von<br />
Willebrand Factor (rVWF)<br />
treatment in the EU for VWD<br />
that specifically addresses the<br />
primary deficiency, Shire Plc<br />
said.<br />
EC has reviewed the<br />
outcomes from three clinical<br />
trials of a total80 patients with<br />
VWD exposed to vonicogalfa.<br />
These include a Phase 1<br />
multicentre, controlled,<br />
randomized, single-blind,<br />
dose-escalation study of<br />
the safety, tolerability, and<br />
pharmacokinectics(PK) of<br />
rVWF:rFVIII in subjects 18 to<br />
60 years of age with severe<br />
VWD.<br />
VWD is caused by a<br />
deficiency or dysfunction of<br />
VWF, one of several types of<br />
proteins in the blood that<br />
are needed to facilitate<br />
proper blood clotting.<br />
Only a minor proportion of<br />
Fremanezumab to<br />
prevent migraine<br />
The USFDA has approved<br />
fremanezumabvfrm(Ajovy)<br />
injection<br />
for the preventive<br />
treatment of migraine in<br />
adults,announced Teva<br />
Pharmaceuticals.<br />
Fremanezumabis a<br />
humanized monoclonal<br />
antibody that binds to<br />
calcitonin gene-related<br />
peptide (CGRP) ligand and<br />
blocks its binding to the<br />
receptor. It is the first and<br />
only anti-CGRP treatment<br />
for the prevention of<br />
migrainewith quarterly<br />
affected individuals have the<br />
severe form of the disease<br />
and are in need of VWF<br />
replacement.<br />
Vonicog alfa is indicated<br />
in adults with VWD, when<br />
(675 mg) and monthly (225<br />
mg) dosing options, Teva<br />
said.<br />
Fremanezumab was<br />
evaluated in two Phase<br />
III, placebo-controlled<br />
clinical trials that enrolled<br />
patients with disabling<br />
migraine and was studied<br />
as both a stand-alone<br />
preventive treatment and<br />
in combination with oral<br />
preventive treatments.<br />
In these trials, patients<br />
experienced a reduction<br />
in monthly migraine days<br />
during a 12-week period.<br />
desmopressin (DDAVP)<br />
treatment alone is ineffective.<br />
Axicabtagene<br />
gets orphan drug<br />
status in Japan<br />
Axicabtagene ciloleucel<br />
has been granted Orphan<br />
Drug designation by the Japan<br />
Ministry of Health, Labour<br />
and Welfare (MHLW) for the<br />
treatment of diffuse large<br />
B-cell lymphoma (DLBCL),<br />
primary mediastinal large<br />
B-cell lymphoma (PMBCL),<br />
high-grade B-cell lymphoma<br />
(HGBL) and transformed<br />
follicular lymphoma (TFL),<br />
which are aggressive forms<br />
of non-Hodgkin lymphoma<br />
(NHL).<br />
Axicabtagene ciloleucel is<br />
a chimeric antigen receptor T<br />
cell (CAR T) therapy directed<br />
against CD19, which harnesses<br />
a patient’s own immune<br />
system to fight certain types<br />
of B-cell lymphoma.<br />
Based on the results of<br />
a phase 1/2 study (ZUMA-1),<br />
axicabtagene ciloleucelhas<br />
been approved in the US<br />
and Europe. A phase 2 study<br />
similar to the ZUMA-1 study<br />
is currently being planned in<br />
Japan.<br />
The Japan MHLW Orphan<br />
Drug designation system is<br />
designed to promote research<br />
activities and support the<br />
development of orphan drugs<br />
for serious, difficult-to-treat<br />
diseases that affect fewer than<br />
50,000 patients in Japan, and<br />
for which significant unmet<br />
medical need exists.<br />
Baloxavir to<br />
treat acute flu<br />
The US FDA has granted<br />
approval to baloxavir<br />
marboxil for the treatment of<br />
acute uncomplicated influenza.<br />
The oral antiviral drug has<br />
been approved for all patients<br />
12 years of age and older who<br />
have been symptomatic for no<br />
more than 48 hours.<br />
The safety and efficacy of<br />
baloxavir were demonstrated<br />
in two randomized controlled<br />
clinical trials of 1,832 patients<br />
where participants were<br />
assigned to receive either<br />
baloxavir, a placebo, or another<br />
antiviral flu treatment within<br />
48 hours of experiencing<br />
flu symptoms. In both<br />
trials, patients treated with<br />
baloxavir had a shorter time<br />
to alleviation of symptoms<br />
compared with patients who<br />
took the placebo.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 37
case reports<br />
GENE THERAPY<br />
FOR BLINDNESS<br />
LCA - a congenital eye defect that<br />
continues to defy remedy<br />
A<br />
four-month old male child was brought to Lilawati<br />
Hospital in Mumbai with complaints of blindness and<br />
frequent rubbing of eyes. The child had an uneventful<br />
birth history and was active, with no other clinical symptoms<br />
other than roving, or searching, movements of the eyes.<br />
His family history indicated that four out of his father’s<br />
six first cousins had congenital blindness. Brain MRI was<br />
normal, as was the fundoscopy done by an ophthalmologist.<br />
Electroretinogram (ERG), which measures the activity in the<br />
retina, showed a reduction in photoreception function in<br />
the entire retina including both rods and cones. There was<br />
also a poor response to cone stimulation as seen by visual<br />
evoked potential (VEP). Keeping the family history and clinical<br />
observations in mind, the working diagnosis was that of<br />
Leber’s congenital amaurosis (LCA).<br />
LCA is a rare autosomal recessive genetic eye disease that<br />
appears at birth or during the first few months thereafter, and<br />
can affect males and females with an equal probability. While<br />
it affects 1-3 newborns in 1,000,000, it is one of the most<br />
common causes of blindness in children. This eye disease<br />
affects the retina that detects both light and colour, resulting<br />
in severe visual impairment early in the infancy. A common<br />
sign associated with LCA is the Franceschetti’s oculo-<strong>digital</strong><br />
sign, characterized by the poking, rubbing, and/or pressing of<br />
the eyes.<br />
LCA can be caused due to<br />
mutations in the genes necessary<br />
for normal vision. There are<br />
over 26 known genes that<br />
are implicated in LCA, and the<br />
list is still growing. LCA genes<br />
encode proteins important in a<br />
wide variety of retinal functions;<br />
for example, CRB1 and CRX are<br />
important for photoreceptor<br />
morphogenesis, GUCY2D and<br />
AIPL1 for phototransduction,<br />
LRAT, RDH12 and RPE65 for<br />
vitamin A cycling, etc. The<br />
mutations in some of the genes such<br />
as CEP290, CRB1, GUCY2D, or RPE65<br />
are the most commonly associated with<br />
LCA, though 20-30% of the children<br />
with LCA have no identifiable cause.<br />
Treatment for LCA is still primarily at<br />
the clinical trials stage, with only one FDA<br />
approved treatment for the RPE65 mutation<br />
THE AAV2 VECTOR DOES NOT<br />
CAUSE ANY DISEASE AND IS<br />
AN ATTRACTIVE VIRAL VECTOR<br />
FOR GENE THERAPY.<br />
so far. The current gene therapy involves<br />
delivering the RPE65 gene via sub-retinal<br />
injection, which allows for normal RPE65<br />
protein to be expressed and the consequent<br />
restoration of the visual cycle. Voretigene<br />
neparvovec (Luxturna) is a novel gene<br />
therapy developed by Spark Therapeutics<br />
and Children’s Hospital of Philadelphia, USA,<br />
and is the first in vivo gene therapy approved<br />
by the FDA. Voretigene consists of the<br />
Adeno-associated virus serotype 2 (AAV2)<br />
vector containing the RPE65 cDNA. The AAV2<br />
vector does not cause any disease and is<br />
an attractive viral vector for gene therapy.<br />
Vortigene treatment comes with its own<br />
hurdles; the cost of treatment for one eye<br />
is estimated to be a whopping $425,000!<br />
However, this is a one-time therapy, where<br />
the treatment is expected to have long-term<br />
benfits.<br />
38 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
While Voretigene has<br />
passed clinical trials and<br />
is now an FDA-approved THE CHILD’S BLOOD<br />
therapy, several other genetic SAMPLE WAS SENT<br />
therapy options for other FOR GENETIC TESTING.<br />
gene mutations for LCA are THE PANEL INCLUDED<br />
currently being researched in<br />
20 POTENTIAL GENES<br />
mouse models and cell lines.<br />
GUC2YD cDNA constructs IN WHICH A MUTATION<br />
in AAV vector, when subretinally<br />
injected in the BLINDNESS. THE RESULTS<br />
IS KNOWN TO CAUSE<br />
eyes of Gucy2e-/-Gucy2f-/- INDICATED A MUTATION<br />
knockout (GCdKO) mice, IN THE GUCY2D GENE.<br />
have been shown to evoke<br />
scoptopic and photopic<br />
ERG responses. In a slightly<br />
different approach, researchers are also attempting to use<br />
Antisense Oligonucleotide-Based Splicing Correction to allow<br />
normal protein expression in case of CEP290 gene mutations.<br />
Results have been promising so far for human cell lines and<br />
in CEP290 mutant mouse models. However, these studies<br />
still need to undergo clinical trials and obtain<br />
human use approvals, and are currently far<br />
from reaching the patient’s bedside.<br />
To confirm the diagnosis of LCA and to<br />
identify the genetic mutation in the fourmonth<br />
old baby, paediatric neurologist Dr.<br />
K. N. Shah sent the child’s blood sample for<br />
genetic testing using the LCA panel. This<br />
panel included 20 potential genes in which<br />
a mutation is known to cause blindness. The<br />
results indicated a mutation in the GUCY2D<br />
gene. Since, currently there is no therapy<br />
for the GUCT2D mutations, no treatment<br />
is possible for this baby. However, there<br />
is a large potential for the evolution of a<br />
treatment for the condition in the future, and<br />
it is likely that therapeutic options will start<br />
becoming available going forward.<br />
DR SHIVANEE SHAH<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 39
case reports<br />
A RARE SYNDROMIC<br />
ASSOCIATION<br />
A case of jaw tumour with hyper-parathyroidism, which posed several<br />
challenges in resection and reconstruction<br />
DR KRISHNAKUMAR THANKAPPAN &<br />
DR SUBRAMANIA IYER<br />
A<br />
19-year old male from Jharkhand presented with a<br />
10-year history of left sided swelling on the face. It<br />
was insidious in its onset, with a rapid increase in<br />
size during last three years. He had difficulties in breathing<br />
as well as taking his diet orally. The swelling had pushed<br />
his eyes outwards and upwards causing visual problems.<br />
He could only perceive light with his left eye. Clinical<br />
examination showed 15x15 cm swelling on the left side of<br />
face, (Figure 1) extending from the supraorbital ridge to<br />
the angle of the mandible. The swelling was distorting the<br />
external osseocartilaginous framework of the nose. Ala of<br />
the right nostril was preserved. There was also a separate<br />
swelling on the right nasolabial region. Intraoral examination<br />
showed a bulge on the right side, distorting the maxillary<br />
alveolar ridge. Imaging with a CT scan showed a fibroosseous<br />
lesion with a ‘soap-bubble’ appearance. A threedimensional<br />
reconstruction was also done to aid in planning.<br />
Biopsy was suggestive of a fibro-osseous<br />
pathology.<br />
Challenges in resection: The challenges<br />
were to remove the tumour completely<br />
with the preservation of normal structures.<br />
The preservation of the distorted eye<br />
anatomically and functionally was a major<br />
issue. Preserving the oral aperture with<br />
the intact musculature was also important.<br />
The skin was expanded by the tumour and<br />
hence could be preserved if not involved by<br />
the tumour.<br />
Challenges in reconstruction: The principle<br />
was to mirror the normal side and to follow<br />
the anatomical landmarks for fixation. All the<br />
bones were grossly expanded, preventing<br />
fixation. Hence there was no anatomical<br />
reference point. A computer-based planning<br />
was done on the three-dimensional images.<br />
40 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
1 2<br />
3 4<br />
The tumour was subtracted<br />
<strong>digital</strong>ly and the remnant<br />
bones on right were mirrored<br />
to the left. Plates were<br />
prebent as a frame to which<br />
free fibula bone flap was to<br />
be contoured and placed<br />
(Figure 2).<br />
THE CASE DEMONSTRATED<br />
THE IMPORTANCE<br />
OF METICULOUS<br />
MULTIDISCIPLINARY<br />
PLANNING AND<br />
SUCCESSFUL EXECUTION.<br />
Surgical procedure: The<br />
tumour was resected<br />
completely through an<br />
incision placed on the swelling. Much of the skin, the left oral<br />
commissure and the left eye could be preserved structurally. A<br />
left total maxillectomy and right partial maxillectomy was done.<br />
The defect was mainly left maxillary and total hard palate.<br />
There was also a loss of dorsal nasal support. A free fibula<br />
osteocutaneous flap was taken from the left leg of the patient.<br />
Three osteotomies were done to make four bone segments.<br />
Contouring was done on the prebent plate. Three segments<br />
were used to reconstruct the upper jaw; the last segment<br />
was placed vertically for malar eminence and orbital support.<br />
Fixation was done with plate and screws. The nasal deformity<br />
was corrected with dorsal augmentation from the remaining<br />
free fibula graft. Another piece was also used as a columellar<br />
strut. The flap was anastomosed to the facial artery and vein.<br />
The surgery lasted for about 14 hours.<br />
A week later, the pathology was reported as juvenile<br />
ossifying fibroma, psammomatoid type. Juvenile ossifying<br />
fibroma can be rarely associated with<br />
hyperparathyroidism. The patient was<br />
seen by an endocrinologist. Investigations<br />
for hyperparathyroid related syndromes<br />
were done. Serum Calcium (14.6 mg/<br />
dl) and parathyroid hormone (426 ng/L)<br />
were elevated. A Technitium Sestamibi scan<br />
showed increased uptake in the left inferior<br />
parathyroid. Ultrasonogram of the abdomen<br />
showed hamartoma of both kidneys. Left<br />
inferior parathyroidectomy was done as a<br />
second surgery. The PTH level dropped<br />
to 92 ng/L intraoperatively. The post-operative<br />
serum calcium was 8.5 mg//dl). The patient<br />
recovered well from the surgeries and was<br />
discharged. The visual acuity in the left eye<br />
remained the same. He may also require some<br />
additional corrective cosmetic procedures for<br />
the left eye later (Figure 3, 4).<br />
Hyperparathyroidism jaw tumour<br />
syndrome is a rare entity. It is inherited as an<br />
autosomal dominant pattern with incomplete<br />
penetrance. The syndromic associations are<br />
parathyroid adenomas, ossifying fibroma<br />
of the jaw, renal lesions, polycystic kidney<br />
disease, hamartomas and Wilm’s tumour.<br />
Absolute treatment is the removal of the<br />
jaw tumour and the offending parathyroid<br />
adenoma.<br />
It is important to look for the association<br />
of hyperparathyroidism in juvenile ossifying<br />
fibroma of the jaw. Treatment is complete only<br />
if parathyroidectomy is done. There is a 24%<br />
chance of the adenoma to turn malignant.<br />
The case demonstrated the importance of<br />
meticulous multidisciplinary planning and<br />
successful execution. Head and neck surgeons,<br />
plastic surgeons, craniomaxillofacial surgeons,<br />
radiologists, nuclear medicine specialists,<br />
ophthalmologists and pathologists were<br />
involved. The nursing and technical staff also<br />
helped immensely.<br />
Dr Krishnakumar Thankappan is Professor,<br />
Department of Head & Neck Surgery and Oncology<br />
and Dr Subramania Iyer is Professor and Head,<br />
Department of Head and Neck and Plastic Surgery,<br />
Amrita Institute of Medical Sciences, Kochi.<br />
drkrishnakumart@gmail.com<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 41
case reports<br />
ABERNETHY -<br />
AN UNUSUAL<br />
SUSPECT<br />
When the cause of breathlessness in a child<br />
turned out to be a very rare congenital<br />
venous system anomaly<br />
An eight-year-old boy was presented to his<br />
paediatrician with breathlessness. Upon regular<br />
examination, the pediatrician identified a murmur and<br />
referred the child to Dr. Shine Kumar, Paediatric Cardiologist<br />
at Amrita Institute of Medical Sciences, Kochi, for further<br />
evaluation. The child underwent ECG, X-ray, and echo. ECG<br />
and X-ray were nonconclusive. However, echo identified<br />
high pressure in the lung arteries, indicative of pulmonary<br />
hypertension.<br />
Pulmonary hypertension is a type of elevated blood<br />
pressure, but one that involves the arteries of the lung and<br />
the right side of the heart. Symptoms include breathlessness,<br />
fatigue, dizziness, as well as fast heart beats. There are<br />
several causes of pulmonary hypertension like congenital<br />
heart conditions, left-sided heart disease, lung disease, blood<br />
clots in the lungs, other conditions such as blood disorders or<br />
tumours pressing against pulmonary arteries etc. Treatment<br />
is dependent on the cause of pulmonary hypertension and<br />
majority of the time, it is not curable, and only supportive<br />
treatment is available. Doctors can at best help manage<br />
the condition; often having to change and improvise on the<br />
medication or treatment options.<br />
For an effective treatment, it was important to<br />
accurately diagnose the cause of pulmonary hypertension<br />
in this patient. Dr. Kumar’s team therefore carried out<br />
further investigative testing that included an abdominal<br />
ultrasound. The abdominal ultrasound identified an<br />
Abernethy malformation in the liver. Abernethy malformation<br />
is a congenital condition in which there is abnormal<br />
communication between the portal vein and the inferior<br />
vena cava, which causes elevated lung pressures. These<br />
are very rare vascular anomalies of the venous system of<br />
the abdominal region. Normally, de-oxygenated blood from<br />
the abdominal organs is drained by the portal vein into the<br />
liver and then circulated to the heart via the inferior vena<br />
cava. However, in case of Abernathy malformation, the<br />
liver is bypassed due to an extrahepatic<br />
portosystemic shunt and the blood is<br />
diverted directly to the systemic circulation<br />
via the inferior vena cava to reach the<br />
heart. These malformations are remnants<br />
of embryonic vessels and are typically<br />
congenital. There are two types of Abernathy<br />
malformations. Type I is predominantly found<br />
in females in whom there is a congenital<br />
absence of blood flow from the portal vein<br />
to the liver. Type II patients have an end-toend<br />
shunt or an extrahepatic communication<br />
that allows for a complete diversion of the<br />
portal blood into the systemic veins. Type II<br />
on the other hand is predominant in males<br />
where the portal vein is hypoplastic and the<br />
blood gets partially diverted from the portal<br />
vein to the inferior vena cava via a side-toside<br />
shunt or extrahepatic communication.<br />
Abernathy malformations are rare,<br />
42 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
occurring in less than 1%<br />
of the general population.<br />
They are generally detected<br />
incidentally in the paediatric<br />
population, during an<br />
investigation of associated<br />
liver or cardiac anomalies.<br />
It is much more challenging<br />
to identify in older patients<br />
especially in those with other<br />
chronic liver diseases and<br />
with no early diagnosis of<br />
congenital portosystemic<br />
shunts. Once identified,<br />
treatment is dependent on<br />
TYPE I MALFORMATIONS<br />
TYPICALLY REQUIRE A<br />
LIVER TRANSPLANTATION,<br />
WHEREAS TYPE II<br />
MALFORMATIONS ARE<br />
COMPLETELY CURABLE<br />
WITH EITHER<br />
SURGICAL LIGATION OR<br />
ENDOVASCULAR OCCLUSION.<br />
the type of malformation. Type I malformations typically<br />
require a liver transplantation, whereas type II malformations<br />
are completely curable in a simpler manner with either<br />
surgical ligation or endovascular occlusion.<br />
Within 2 weeks of diagnosing a type II Abernathy<br />
malformation, the 8-year-old boy underwent<br />
a keyhole surgery through a vein in the leg,<br />
and the abnormal extrahepatic channel<br />
was occluded using a metallic plug. Regular<br />
follow ups showed that the treatment<br />
was successful, and the child did not have<br />
pulmonary hypertension. It has been 2 years<br />
since the procedure and the patient is doing<br />
well.<br />
“Pulmonary hypertension can be caused<br />
due to many conditions, most of them are<br />
not curable. The ultrasound identified a type<br />
II Abernathy malformation in our patient,<br />
which was a very fortunate diagnosis as it<br />
is one of the few treatable conditions that<br />
causes pulmonary hypertension,” says Dr.<br />
Kumar.<br />
DR SHIVANEE SHAH<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 43
case reports<br />
PROBE ON CULTURE-NEGATIVE<br />
LESIONS<br />
Why it is important to pin down non-tuberculous mycobacteria species rapidly<br />
A<br />
72-year-old woman presented with multiple painful<br />
lesions on the abdomen to the dermatology<br />
department at Amrita Institute of Medical Science,<br />
Kochi. The consulting dermatologist, Dr. Soumya Jagadeesan,<br />
noted that the lesions were purulent and the patient had<br />
previously undergone surgical drainage multiple times<br />
without any benefit. Gram staining of smears and routine<br />
cultures were negative and the patient had been treated<br />
with multiple courses of broad spectrum antibiotics, with<br />
no response even after several weeks. A skin biopsy had<br />
revealed a granulomatous inflammation and the patient was<br />
started on anti-tuberculosis treatment on the presumption<br />
that it might be an extra-pulmonary<br />
tuberculosis infection, as the chest X-ray was<br />
normal. At the time of her presentation to<br />
the centre, the patient had not responded<br />
to even anti-tuberculosis treatment. An<br />
atypical (non-tuberculous) mycobacterial<br />
infection was then suspected. While there<br />
was no history of trauma or surgery, the<br />
patient was taking insulin injections at the<br />
same site and admitted that she was not<br />
taking efforts to take these injections in an<br />
aseptic manner. Further testing including<br />
44 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
Ziehl–Neelsen staining of smears and mycobacterial cultures<br />
were done. Staining showed acid-fast bacilli. Nonpigmented<br />
colonies were observed on the 6th day in the cultures.<br />
Multiplex PCR was done and confirmed the presence of M.<br />
chelonae. The patient was then started on doxycycline and<br />
clarithromycin. Clarithromycin<br />
had to be substituted with<br />
linezolid as the patient had<br />
severe diarrhea due to the<br />
medication. The lesions<br />
healed within 4 weeks of<br />
starting this treatment and<br />
the treatment was continued<br />
for an additional 6 weeks. No<br />
recurrence was observed at<br />
the sixth-month follow up.<br />
Incidence of nontuberculous<br />
mycobacteria is<br />
on the rise. Non-tuberculous<br />
mycobacteria include<br />
mycobacterial species other<br />
INCIDENCE OF<br />
NON-TUBERCULOUS<br />
MYCOBACTERIA IS ON THE<br />
RISE. NON-TUBERCULOUS<br />
MYCOBACTERIA INCLUDE<br />
MYCOBACTERIAL<br />
SPECIES OTHER THAN<br />
MYCOBACTERIUM<br />
TUBERCULOSIS.<br />
than Mycobacterium tuberculosis, and contribute to causing<br />
infections in the lungs, lymph nodes, bone, brain, kidneys,<br />
genital tract as well as skin tissue. Different mycobacterial<br />
species respond to different treatment regimens and<br />
therefore rapid identification of the correct species is<br />
extremely important for appropriate treatment. Further,<br />
many non-tuberculous mycobacteria are resistant to typical<br />
M. tuberculosis treatments, making it essential to accurately<br />
determine the causative species. In India, the most prevalent<br />
non-tuberculous mycobacterial species include M. abscessus,<br />
M. fortuitum and M. chelonae in extrapulmonary tissue<br />
samples.<br />
While rapid and accurate identification of these species<br />
is extremely important, diagnosis is challenging as they may<br />
not be identified via routine culture techniques. Recently,<br />
high performance liquid chromatography (HPLC) analysis of<br />
mycolic acids, probe-based tests and DNA sequencing have<br />
been used. However, they come with their own limitations.<br />
HPLC requires special expertise in interpreting the data<br />
generated and needs expensive equipment. Kit-based<br />
probe assays are costly and may not be readily available,<br />
while DNA sequencing is time consuming. Multiplex PCR<br />
options are also now available for accurate identification of<br />
rapid grower mycobacterium. It can differentially diagnose<br />
between M. abscessus, M. fortuitum,and M. chelonae, and is<br />
a useful diagnostic test in case rapid grower mycobacterium<br />
is suspected. Rapid identification is critical, since the<br />
treatment will depend on the species. For instance, M.<br />
chelonae responds well to medical management, however,<br />
M. abscessus may not and may require surgical management<br />
such as drainage of pus and removal of necrotic tissue to<br />
augment the treatment.<br />
This case was one of four M.chelonae infected cases<br />
that came to Dr. Jagadeesan’s attention in the past one<br />
and a half years, and she advises that<br />
“a high index of suspicion is necessary if<br />
a patient presents with lesions that are<br />
culture negative and has a history of injury<br />
or surgical treatment.” She advocates that<br />
since these infections often occur at surgical<br />
sites, especially following laparoscopic<br />
procedures, inadequate sterilization<br />
practices at the hospitals maybe a source of<br />
the infection and doctors may need to be<br />
ready to inform the source sites to prevent<br />
further cases.<br />
Dr. Jagadeesan is now quick to consider<br />
M. chelonaein case of culture-negative<br />
cases and is prompt in carrying out the<br />
multiplex PCR to confirm her working<br />
diagnosis. Recently, a 42-year old lady<br />
presented with lesions on the abdomen.<br />
These lesions were at the site of a recent<br />
laparoscopic sterilization procedure.<br />
Multiplex PCR was done and M. chelonae<br />
was identified fairly quickly. The patient<br />
was started on clarithromycin and ofloxacin<br />
tablets and recovered within 4 weeks. The<br />
treatment was however continued up to<br />
12 weeks to prevent any recurrence. Thus,<br />
accurate early identification can substantially<br />
reduce the lag time in correct diagnosis<br />
and avoid inappropriate antibiotic use and<br />
anti-tuberculosis therapy that can result in<br />
adverse side effects and undue toxicity.<br />
DR SHIVANEE SHAH<br />
46 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
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case reports<br />
BRACHYTHERAPY FOR<br />
BRAIN CANCER<br />
An instance where localised internal radiation therapy has been successfully<br />
used to control tumour growth<br />
Brachytherapy is an age-old method that is effective for<br />
irradiating cancer cells, especially in cervical, prostate,<br />
breast and skin cancers. This radiotherapy technique<br />
involves the introduction of a sealed source of radiation close<br />
to the area requiring treatment. Because of the proximity to<br />
the cancer cells, there is reduced probability of unnecessary<br />
damage to the neighbouring healthy cells. It is therefore<br />
relatively less harmful, even though high doses of localized<br />
radiation are delivered.<br />
Brachytherapy is a minimally invasive technique that<br />
reduces the treatment duration for certain<br />
types of cancer and is often considered to<br />
be an alternative treatment for challenging<br />
cases. Due to the simplicity of the technique,<br />
it offers the ease of an outpatient treatment<br />
regimen with a quicker recovery time. It<br />
has also been proposed that the short<br />
treatment duration of brachytherapy may<br />
also be of potential benefit in preventing<br />
cancer recurrence. With all these benefits, it<br />
48 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
could well have been the treatment of choice in such cases.<br />
However, it is effective only in cases when the tumour is<br />
accessible. Moreover, the survival rates are not consistently<br />
superior to other radiation oncology techniques.<br />
In India, brachytherapy is widely used for treating<br />
gynecological cancers. Some of the other types of cancer<br />
where it is used are those affecting the skin, prostate,<br />
head and neck, breast and even eyes. Despite its overall<br />
acceptability, this form of irradiation has not been reported<br />
for the treatment of brain tumours in India. In perhaps one of<br />
the first brachytherapy treatment cases for brain cancer, Dr.<br />
Manish Chandra, a Radiation Oncologist at Jupiter Hospital,<br />
Thane, successfully used this method on a patient recently.<br />
A 40-year old man, who had high grade glioblastoma<br />
(WHO Grade IV), had previously undergone tumour resection<br />
surgery, followed by radiation therapy. By the end of 18<br />
months post treatment, the cancer recurred and the patient<br />
had to undergo a second surgical procedure, followed by<br />
chemotherapy. Unfortunately, within a span of 2 months<br />
after the second surgery, the tumour was found to have<br />
recurred again. Since the tumour was recurring and repeated<br />
brain surgery has adverse effects, the patient was referred<br />
to Dr. Chandra for further treatment and follow-up. After<br />
carefully considering the patient’s previous history, age, the<br />
accessibility of the tumour, and most importantly, the fact<br />
that the patient was otherwise healthy, Dr. Chandra proposed<br />
brachytherapy as the best choice to go forward. The patient<br />
was also explained the reasons behind the proposed choice,<br />
and was willing to undergo<br />
the procedure. One of the<br />
challenges of this technique<br />
is the need to anticipate<br />
possible brain damage as<br />
the needles go through<br />
the brain tissue to reach<br />
the tumour. This procedure<br />
was performed in local<br />
anaesthesia and patient<br />
was conscious during the<br />
procedure.<br />
Pre-procedure planning<br />
was quite elaborate as the<br />
exact location of the tumour<br />
needed to be mapped. A<br />
team of doctors, including<br />
Dr. Chandra, Neurosurgeon<br />
Dr. Harshad Purandare and<br />
technical person Mr Devarsh<br />
(3D – Rendering), first set<br />
about preparing a grid-based<br />
model using 3D images from<br />
MRI scans to determine the<br />
location at which the holes<br />
would need to be drilled in<br />
the skull for needle insertion<br />
ONE OF THE CHALLENGES<br />
OF THIS TECHNIQUE IS<br />
THE NEED TO ANTICIPATE<br />
POSSIBLE BRAIN DAMAGE<br />
AS THE NEEDLES GO<br />
THROUGH THE BRAIN<br />
T<strong>ISSUE</strong> TO REACH THE<br />
TUMOUR.<br />
and the length of the individual needles. At<br />
the time of the procedure, the pre-designed<br />
grid was marked on the skull of the patient<br />
such that the specific points within the grid<br />
were identified with a label and each label<br />
corresponded to the depth of the hole that<br />
was to be drilled. The process of pre-fixing<br />
the depth of the needle insertion to deliver<br />
the radiation is a very delicate and complex<br />
process and must be done keeping in mind<br />
not just the location of the tumour, but also<br />
the positioning of underlying blood vessels<br />
and the surrounding healthy tissue. Dr.<br />
Purandare then drilled 17 holes in the skull<br />
for needle insertion. The entire procedure<br />
was carried out under local anaesthesia<br />
and the patient was able to communicate<br />
with the operating surgeons throughout<br />
the surgery. Once the needles were fixed,<br />
confirmatory MRI and CT scans were done.<br />
After computerized treatment planning,<br />
the radiation therapy was delivered.<br />
Approximately 36 Gy was delivered in six<br />
fractions over three days.<br />
The needles were then removed in the<br />
operation theatre on the 3rd day, as some<br />
blood/fluid leakage was expected. However,<br />
anaesthesia was not required for the needle<br />
removal process. The patient was kept in<br />
the ICU, where he was closely monitored<br />
over the next two days. A CT scan was done<br />
immediately after the removal of the needles<br />
and was found to be normal. By 24 hours,<br />
the CT showed minor bleeding, which was<br />
expected, and by 48 hours, the condition<br />
was stable. The patient was discharged and<br />
advised to come for regular follow-ups every<br />
three months. In his latest follow-up at six<br />
months, the MRI showed that the tumour<br />
size was stable. The patient had been<br />
relieved of his pre-brachytherapy symptoms<br />
of nausea, vomiting, and headache.<br />
Many patients and their families have<br />
approached Dr. Chandra since the success<br />
of this treatment procedure. However, Dr.<br />
Chandra is very careful in selecting only<br />
those cases that are likely to benefit from<br />
this treatment. He further cautions that this<br />
therapy only prolongs life by 6-9 months on<br />
average and is not a cure for brain tumour,<br />
but just another way of managing the<br />
condition.<br />
DR SHIVANEE SHAH<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 49
education<br />
NEUBERG-ANAND TO OFFER<br />
POST-MD FELLOWSHIP COURSE<br />
NAALM aims to create awarenness on nextgen diagnostics by education and research<br />
PHOTO: DEEPAK PAWAR<br />
As advances in genomics and<br />
bioinformatics revolutionize the<br />
field of diagnostics, the medical<br />
fraternity in India is forced to play<br />
catch up. This is the idea behind the<br />
creation of Neuberg Anand Academy<br />
of Laboratory Medicine (NAALM), a<br />
new school for pathologists and other<br />
specialists. The aim behind this firstof-its<br />
kind project is to create a unique<br />
platform for academics and encourage<br />
research in this field.<br />
Neuberg founder and managing<br />
director GSK Velu is unambiguous<br />
about his objective. “Low awareness<br />
about next generation diagnostics is<br />
a key challenge in Indian healthcare<br />
today. This is true across healthcare<br />
providers as well as seekers. So, we<br />
want to first create awareness among<br />
the decision makers, which is the<br />
medical fraternity, by giving them a<br />
live exposure to the new tests and<br />
processes.”<br />
The potential for the clinical<br />
application of genomic technologies,<br />
despite their relative novelty, is<br />
vast. They offer a wide range of<br />
opportunities across medical specialities<br />
to ensure a more accurate diagnosis<br />
and treatment. But these benefits<br />
will not reach the needy unless<br />
the clinician is familiar with these<br />
possibilities.<br />
While many new-generation<br />
clinicians are already exposed to such<br />
technologies and are quick to adopt the<br />
new methods, especially in the metros<br />
and urban areas, awareness is still very<br />
low among old-school practitioners,<br />
particularly in semi urban and rural<br />
areas. Similarly, there is also a severe<br />
shortage of technicians who can handle<br />
these new technologies.<br />
The diagnostics education and<br />
research initiative under NAALM is<br />
expected to not only help fill the gap<br />
to a certain extent, but also trigger<br />
more such initiatives in the industry<br />
to address the need. Large-scale<br />
awareness will automatically lead to<br />
50 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
etter availability and affordability,<br />
which are the other big challenges<br />
in the adoption of these new<br />
technologies in India.<br />
NAALM is a not-for-profit<br />
foundation set up by Neuberg<br />
Diagnostics, an international diagnostic<br />
alliance, to provide fellowship<br />
programmes in the fields of laboratory<br />
medicine and laboratory management<br />
to MD/DNBs in the specialties of<br />
pathology, microbiology, biochemistry<br />
and transfusion medicine. DCPs with<br />
one year experience can also apply for<br />
this programme, which will start from<br />
this year.<br />
Neuberg, an alliance of established<br />
diagnostic chains from India, Sri Lanka,<br />
South Africa and UAE, has a proven<br />
NAALM IS A NOT-FOR-<br />
PROFIT FOUNDATION SET UP<br />
BY NEUBERG DIAGNOSTICS,<br />
TO PROVIDE FELLOWSHIP<br />
PROGRAMMES IN THE<br />
FIELDS OF LABORATORY<br />
MEDICINE AND<br />
LABORATORY MANAGEMENT<br />
TO MD/DNBS.<br />
skill-set and experienced resources in<br />
different areas of diagnostics. It claims<br />
to have at least three world class<br />
global reference laboratories located<br />
in Bangalore, Ahmedabad<br />
and Durban (South Africa), carrying<br />
out an advanced range of testing<br />
using new generation in vitro<br />
diagnostic techniques, total lab<br />
automation and big data analytics<br />
supported by a robust laboratory<br />
information system.<br />
The NAALM Foundation has<br />
already tied up with Sri Devraj Urs<br />
Academy of Higher Education &<br />
Research, Karnataka, and is also<br />
talking to other universities and<br />
research and education institutions<br />
in different regions to get its<br />
programmes affiliated with them.<br />
“We will reinvest revenue<br />
from NAALM back to<br />
education and research”<br />
What was the inspiration<br />
behind NAALM?<br />
Neuberg Diagnostics was formed<br />
with a strategic vision that it will<br />
be in the top league of diagnostic<br />
industry in terms of technology,<br />
experience and volume, as it is an<br />
alliance of five leading and most<br />
reputed diagnostic chains from India<br />
and other countries. We wanted<br />
to pursue the same vision by<br />
developing the overall sector as well<br />
as the market by creating awareness<br />
about the benefits of these modern<br />
technologies. We also want to<br />
encouraging research in this field for<br />
future growth in technology.<br />
Why did you start this<br />
programme under a non-profit<br />
entity?<br />
With this, we wanted to create<br />
a platform that will contribute<br />
immensely to the growth of the<br />
sector; by building awareness<br />
through education. So, it cannot<br />
be mixed with business. Since we<br />
won’t have any external investors, at<br />
least for the next 3-4 years, we are<br />
free to invest in such activities that<br />
GSK Velu<br />
won’t result in revenue and profit<br />
immediately. In the future too, we<br />
would like to continue to invest in it<br />
by putting back the income from this<br />
venture into education and research.<br />
How do you want to take<br />
Neuberg forward in the emerging<br />
healthcare trend?<br />
Neuberg Diagnostics, which has<br />
a combined diagnostic expertise of<br />
over 250 years, brings advanced<br />
diagnostics that is affordable to<br />
people across the globe. It is an<br />
alliance of top laboratories like<br />
Anand Diagnostic Laboratory,<br />
Supratech Micropath, Ehrlich Lab,<br />
Global Labs and Minerva Labs, which<br />
have already made their presence<br />
felt in their respective markets such<br />
as Karnataka, Gujarat, Tamil Nadu,<br />
South Africa and UAE. It will have<br />
three global reference laboratories<br />
located in Bangalore, Ahmedabad<br />
and Durban (South Africa), carrying<br />
out an advanced range of testing<br />
using new-generation in vitro<br />
diagnostic techniques along with<br />
total lab automation and big data<br />
analytics tools. Currently, there are<br />
10 labs and 40 satellite centres for<br />
all the five companies put together<br />
in southern and western India.<br />
The plan is to increase it to 100 in<br />
the next two years. About ₹450<br />
crore has been already invested<br />
in acquiring major sharesand<br />
upgrading the labs. The plan is<br />
to invest another ₹300 crore for<br />
expansion in coming years to bring<br />
in, and develop, new technologies,<br />
which include acquisitions in the US<br />
and Europe.<br />
PHOTO: PRASHANTH KADAM<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 51
education<br />
BRIDGE COURSE AT<br />
CROSSROADS<br />
IMA questions Gujarat govt’s move to implement six-month `bridge course’ for<br />
Ayush practitioners in court<br />
BANO SARKAR<br />
Even though a Union Cabinet<br />
meeting chaired by Prime<br />
Minister Narendra Modi removed<br />
a provision from the National Medical<br />
Commission (NMC) Bill for a bridge<br />
course for AYUSH practitioners to<br />
practice modern medicine in March,<br />
allopathic medical practitioners under<br />
the Indian Medical Association (IMA)<br />
have approached the Gujarat High<br />
Court questioning a similar move by<br />
the state government.<br />
Gujarat government issued an<br />
advertisement calling for applications<br />
for a six-month-long bridge course to<br />
permit those who completed Bachelor<br />
of Science (Nursing), Bachelor of<br />
Ayurvedic Medicine and Surgery (BAMS)<br />
and General Nursing and Midwifery<br />
(GNM) courses to practice modern<br />
medicine.<br />
The court, observing that the same<br />
plea is pending before the State Health<br />
Department, asked the department to<br />
consider the IMA’s arguments on the<br />
matter.<br />
IMA has been opposing the idea<br />
of replacing the Medical Council of<br />
India (MCI) from the time when the<br />
suggestion was made in the NMC<br />
Bill. It has also been raising an alarm<br />
on the potential dangers of allowing<br />
bridge courses for alternative medicine<br />
practitioners.<br />
IMA’s stand against the practitioners<br />
of other systems of medicine<br />
practising allopathic medicine has<br />
been there for many years. “It is<br />
estimated that about 10 lakh<br />
quacks are practising allopathic<br />
medicine, out of which 4 lakh belong<br />
to practitioners of Indian Medicine<br />
(Ayurvedic, Siddha, Tibb and Unani),”<br />
states its anti-quackery wing on its<br />
website.<br />
With doctors under the leadership<br />
of IMA announcing a strike against<br />
these decisions, the Union Cabinet had<br />
IMA HAS BEEN RAISING AN<br />
ALARM ON THE POTENTIAL<br />
DANGERS OF ALLOWING<br />
BRIDGE COURSES FOR<br />
ALTERNATIVE MEDICINE<br />
PRACTITIONERS.<br />
removed the provision dealing with<br />
bridge courses for AYUSH practitioners.<br />
However, it had also said that it was<br />
“leaving it to state governments to take<br />
necessary measures for addressing and<br />
promoting primary health care in rural<br />
areas.”<br />
The idea behind the decision go<br />
offer bridge courses was, in a way,<br />
to address the acute shortage of<br />
qualified allopathic doctors to attend<br />
to the underserved population,<br />
especially in rural areas.<br />
Infrastructure and<br />
availability of<br />
medical practitioners are crucial to the<br />
success of government’s prestigious<br />
national health scheme Ayushman<br />
Bharat Yojana.<br />
According to a recent report by<br />
IndiaSpend, a public interest data<br />
journalism initiative, public health<br />
centres need 25,650 doctors to attend<br />
to a minimum of 40 patients per doctor<br />
per day for outpatient care across the<br />
country. But there is a shortage of 3,027<br />
doctors, leaving 1,974 PHCs without<br />
doctors, which means almost 1,21,080<br />
patients cannot meet a doctor for their<br />
health requirement every day.<br />
While a section of allopathic<br />
medicine practitioners oppose bridge<br />
courses tooth and nail, another section<br />
from the same fraternity are of the<br />
view that making qualified healthcare<br />
professionals in the rural areas would<br />
help to address the healthcare need<br />
of the country and can also relieve<br />
doctors from undergoing compulsory<br />
rural practice. It could also address the<br />
issue of quacks and practitioners of<br />
other systems of medicines practising<br />
allopathic medicine and putting<br />
the lives of people in rural<br />
areas at risk.<br />
52 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
straight talk<br />
“I AM IN FAVOUR OF OPEN<br />
ACCESS, IT’S A GOOD MODEL”<br />
MYLES AXTON, chief editor,<br />
Nature Genetics, believes that open<br />
access is a good model for online<br />
publications, though it doesn’t have<br />
the same reader responsiveness<br />
as the subscription model. But the<br />
bigger challenge for the publishers<br />
of the world’s most read<br />
peer-reviewed journals is still<br />
the large overhead costs,<br />
especially for the ones which<br />
do not charge article processing<br />
charges, says Axton in Straight Talk<br />
with CH UNNIKRISHNAN.<br />
Edited excerpts:<br />
One of the key concerns of scientists and medical<br />
researchers, who dream of getting their research papers<br />
published in reputed peer-reviewed journals like yours, is<br />
the fear of rejection. How would you react to this?<br />
It is important to make sure that scientists have access to<br />
the best advice so that they can get their research published<br />
quickly and in a robust form that can be used as a research<br />
tool by other people. Any research, which meets the basic<br />
and the strong elements of novelty and conceptual advance<br />
shouldn’t ideally face any such issue.<br />
I don’t have much respect for the concept of symbolic<br />
publication. The idea is that if there is a breakthrough or<br />
something big that needs to be known by everyone, it is<br />
more important that scientists should know this first as a tool<br />
to move the field forward. And at the end, when you look<br />
at one’s career, you should be able to say that you made a<br />
lot of good scientific decisions and some clever experiments<br />
with dedication to solve a particular set of problems. This is<br />
what makes you a great scientist.<br />
Often a great scientist is somebody on the ground close<br />
to the problem and who realises that this is a problem and<br />
therefore it has a technical solution. Often, this solution is<br />
not very difficult. But it requires new resources, knowledge<br />
and years of dedication. Finally you may find that it was<br />
essentially a simple solution.<br />
How do you prioritise the papers for publishing from the<br />
large number of submissions by authors?<br />
It is the same, like novelty and conceptual advance,<br />
like any other journal. And of course, a voice in your head<br />
saying how many labs would do their projects differently<br />
after reading this paper is another key consideration.<br />
The interesting insights that we get on the research from<br />
the authors and the paper about how significant was the<br />
knowledge gap that they tried to fill in while bringing up the<br />
point for conclusion, whether it led to positive or negative<br />
result, also contributes to the decision. Ideally, the best paper<br />
to publish is the one that helps in moving the field forward.<br />
In terms of interviewing authors, it is quite satisfying for<br />
my team of managers as they ask questions to know the<br />
story behind the story. And they will tell you what happened<br />
in the lab and so on and so forth, which helps the editor to<br />
really take a much better view of the paper, which is often<br />
appreciated by the authors as well as readers. That way, as<br />
an editor of a peer-reviewed science journal, it is nice to get<br />
54 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
to start the communication with a question<br />
to which they wanted answers and reward<br />
them with an answer to know more on<br />
what they are looking for. For example,<br />
in your case, the doctors would be more<br />
interested in science if that has a direct<br />
clinical application.<br />
Similarly, it will be difficult to<br />
communicate to a clinical researcher unless<br />
you are close to clinical research. In clinical<br />
research, the doctor is always curious to<br />
know why the condition of one group of<br />
patients improves while it worsens for the<br />
other. He also wants to know if he can<br />
have a marker or the patients need to be<br />
put on a different course of treatment.<br />
As an editor of a peer-reviewed science<br />
magazine, I have to always think in the<br />
perspective of a peer reviewer asking a<br />
question to the author in the language of a<br />
scientist. But for science editors who cater<br />
to the information needs of a public or<br />
professional audience, they need to think<br />
in users’ perspective.<br />
paid as a professional appreciator.<br />
As far as communicating the science is<br />
concerned, how is it different in a magazine<br />
like Nature Genetics, which is read by a<br />
scientific audience, compared to journals<br />
that are aimed at a translational audience?<br />
The mistake in communicating science<br />
to translational or non-scientific audience is<br />
often that the scientists or the communicator<br />
approach them thinking that they<br />
understand science. It will never work unless<br />
the audience finds it connected to their<br />
area of work or interest. The translational<br />
audience will get interested or try to<br />
understand the subject only if it answers<br />
their questions or they find some direct<br />
applications of the same in their field. It<br />
is true across professions whether it is an<br />
agriculturist or a doctor. So it is always better<br />
PHOTO: UMESH GOSWAMI<br />
Translational<br />
audience will<br />
get interested<br />
or try to<br />
understand the<br />
subject only<br />
if it answers<br />
their questions<br />
or they find<br />
some direct<br />
applications<br />
of the same in<br />
their field.<br />
What about an open access policy for<br />
journals like Nature?<br />
I am in favour of open access, I<br />
think it’s a good model. But it doesn’t<br />
have the same reader responsiveness<br />
as subscription model, except the fact<br />
that it can be read by everybody. In the<br />
subscription model, the readers take it<br />
as valuable and place it in the library<br />
of research, but on the contrary, in the<br />
open access model, one can say that it<br />
is valuable as even the students who are<br />
not affiliated with wealthy institutions can<br />
be inspired by the research. So, the draw<br />
aspect of the open access is very attractive<br />
indeed. Certainly, we can get 50% more<br />
readership for Nature Genetics if we make<br />
every article open access and that would<br />
be appealing.<br />
Nature is a big open access publisher.<br />
We have got Nature Communications with<br />
nearly 70 editors and making a big effort<br />
with open access. We publish Reference<br />
Genomes under open access because the<br />
community demands it. But we don’t take<br />
any article processing charge as we don’t<br />
have any business model to accept that.<br />
So there is no prospect of making all of the<br />
journals open access as that’s not the way<br />
the journal was set up.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 55
esearch snippets<br />
eLiquid biopsy detects<br />
early lung cancer<br />
Wei et al demonstrate electric fieldinduced<br />
release and measurement<br />
(EFIRM) as a novel platform for liquid<br />
biopsy (LB) which enables the diagnosis<br />
of early-stage non-small-cell lung<br />
cancer (NSCLC) when surgical cure is<br />
still possible. The EFIRM-liquid biopsy<br />
(eLB) accurately detects two actionable<br />
epidermal growth factor receptor<br />
(EGFR) mutations seen in the blood of<br />
patients with early-stage NSCLC. The<br />
study showed specific detection of two<br />
specific EGFR mutations- p.L858R and<br />
Exon 19del. The scientists collected<br />
plasma samples from 248 patients with<br />
suspected lung cancer, of which 44<br />
were diagnosed with Stage I or Stage<br />
II NSCLC. EFIRM was able to detect the<br />
p.L858R mutation in 11 of 12 samples<br />
and the Exon 19del mutation in seven of<br />
nine samples, resulting in greater than<br />
90 percent sensitivity and 80 percent<br />
specificity. The clinical sensitivity of<br />
EFIRM to detect patients with early-stage<br />
NSCLC is limited by the percentage of<br />
tumours containing either or both of the<br />
two variants, which is estimated at 27<br />
percent of NSCLC tumours. The research<br />
suggests more studies to be performed<br />
to optimize the technical and clinical<br />
performance of the assay which once<br />
validated can be useful in screening<br />
and for many other high-throughput<br />
applications.<br />
The Journal of Molecular Diagnostics, November<br />
<strong>2018</strong>, Volume 20, Issue 6, Pages 738–742 /<br />
https://doi.org/10.1016/j.jmoldx.<strong>2018</strong>.06.008/<br />
ctDNA shows promise<br />
for monitoring<br />
paediatric glioma<br />
Panditharatna E. et al shows early<br />
evidence in proper monitoring of<br />
EGF receptors drive hair cell<br />
formation in mice cochlea<br />
paediatric diffuse midline gliomas (DMGs)<br />
using liquid biopsy. The researchers<br />
indicate the study to be the first to<br />
focus on the clinical utility of circulating<br />
tumour DNA (ctDNA) for longitudinal<br />
surveillance of DMGs in children. The<br />
assay quantified the levels of a mutation,<br />
H3K27M, which is known to be present<br />
in over 70 percent of patients with DMG<br />
correlating with a poorer clinical outcome.<br />
The study reported the identification of<br />
H3K27M in pre-treatment samples from<br />
42 of the 48 patients, a frequency that<br />
is comparable to what is seen in tissue<br />
samples showing cerebral spinal fluid to<br />
exhibit the presence of more mutated<br />
DNA, overall, than blood. Researchers<br />
observed a significant decrease in ctDNA<br />
in a subset of children with Diffuse<br />
Intrinsic Pontine Glioma (DIPG) who had<br />
liquid biopsy testing before and after<br />
radiation treatment in a clinical trial.<br />
Researchers also reported an agreement<br />
Zhang et al outlined a new approach<br />
in restoring hearing loss by activating<br />
ERBB2 pathway, which could enable the<br />
regeneration of sensory hair cells found<br />
in the cochlea of the inner ear. Their<br />
research was based on the hypothesis<br />
that signaling from epidermal growth<br />
factor receptor (EGF) family of receptors<br />
could play a role in cochlear regeneration<br />
in mammals. Thus, the study focused on<br />
activating a specific receptor ERBB2 of<br />
the EGF family by constitutively activating<br />
the receptor in neonatal mouse cochlear<br />
supporting cells using viruses, transgenic<br />
expression and also by using certain<br />
drugs which are known to activate<br />
ERBB2 signalling. The researchers<br />
found that activating the ERBB2<br />
pathway triggered a cascading<br />
series of cellular events by which<br />
cochlear support cells began to<br />
proliferate and activate the neighbouring<br />
stem cells to become new sensory<br />
hair cells. The study thus suggests a<br />
new model where the interplay of cell<br />
signalling regulates regeneration by<br />
endogenous stem-like cells.<br />
European Journal of Neuroscience 30<br />
September <strong>2018</strong> doi: 10.1111ejn.14183/<br />
of 75 percent between ctDNA response<br />
(a 50 percent decrease or more) and MRI<br />
tumour volume measurements (at least<br />
10 percent decrease). The liquid biopsy<br />
approach thus provides a molecularly<br />
based tool for tumour characterization<br />
helping doctors to monitor how well<br />
treatments are working in children with<br />
DMGs.<br />
Source: American Association for Cancer Research,<br />
October 15, <strong>2018</strong>/ DOI: 10.1158/1078-0432.CCR-<br />
18-1345 /<br />
Editing of mtDNA<br />
may correct genetic<br />
disorder<br />
Payam A. Gammage et al reported the<br />
first in vivo successes in using zinc<br />
finger nucleases (ZFN) for selectively<br />
editing away pathogenic mitochondrial<br />
56 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
DNA (mtDNAs) in a heteroplasmic<br />
mammalian mitochondrial population.<br />
They demonstrated the correction of a<br />
cardiac-specific mitochondrial disorder<br />
with the concomitant therapeutic<br />
restoration of molecular and biochemical<br />
hallmarks to an undiseased state by<br />
exploiting a recently developed mouse<br />
model that recapitulates common<br />
molecular features of heteroplasmic<br />
mtDNA disease in cardiac tissue.<br />
Each of the two ZFN proteins used<br />
was systemically delivered to the<br />
mouse via a cardiotropic version of<br />
the adenovirus. The research offers a<br />
potential therapeutic route for treatment<br />
of heteroplasmic mitochondrial disease<br />
using programmable nucleases, where<br />
amelioration or halting of disease<br />
progression could be expected. Though<br />
the development has the potential<br />
to transform the prospects of many<br />
patients with mitochondrial disease, the<br />
researchers suggest for further work to<br />
be executed to enable the translation of<br />
these tools into effective medicines.<br />
Nature Medicine (<strong>2018</strong>)/ https://www.nature.com/<br />
articles/s41591-018-0165-9 /24 September <strong>2018</strong><br />
CRISPR-mediated<br />
prenatal metabolic<br />
gene editing<br />
C. Rossidis et al performed the first<br />
A. prenatal gene editing to prevent a<br />
lethal metabolic disorder in mice models,<br />
offering the potential to treat human<br />
congenital diseases before birth. The<br />
scientists used CRISPR-Cas9 and base<br />
editor 3 (BE3) gene editing tools in utero<br />
to reduce cholesterol levels in a wildtype<br />
mice. They also used prenatal gene<br />
editing to improve liver function and<br />
prevent neonatal death in a subgroup<br />
of mice that had been engineered<br />
with a mutation causing the lethal liver<br />
disease hereditary tyrosinemia type 1<br />
(HT1). Adenovirus vectors were used<br />
for the delivery of CRISPR-Cas9 and<br />
BE3. Scientists observed a long-term<br />
postnatal persistence of edited cells in<br />
both models with reduced cholesterol<br />
levels and rescue of the lethal phenotype<br />
of HT1 following in utero gene targeting<br />
in respective mice models. Thus the<br />
research offers proof-of-concept for the<br />
prenatal use of a sophisticated, lowtoxicity<br />
tool in efficient gene editing<br />
that helps point to a potential new<br />
therapeutic approach in treating selected<br />
congenital genetic disorders.<br />
Nature Medicine, Volume 24, pages1513–1518<br />
(<strong>2018</strong>) https://www.nature.com/articles/s41591-<br />
018-0184-6/ 8th October <strong>2018</strong><br />
Protein marker<br />
indicates breast<br />
cancer recurrence<br />
Borgen et al identified a protein<br />
E. marker that can indicate the<br />
chances of reoccurrence and lethality<br />
of metastatic cancer in breast cancer<br />
patients. The researchers found a<br />
correlation between the low amounts<br />
of a protein NR2F1 (COUP-TF1) in bone<br />
marrow (BM) aspirations of patients<br />
whose breast cancer tumour had<br />
metastasized to BM and had led to<br />
sudden demise. Patients who had high<br />
concentrations of NR2F1 in the cancer<br />
cells in their bone marrow, however,<br />
did not frequently develop this type of<br />
metastatic cancer and survived longer.<br />
The presence of high concentration of<br />
NR2F1 was found related to dormancy<br />
of the disseminated tumour cells (DTC).<br />
Thus NR2F1 detection in BM DTCs may<br />
be a promising tool to determine the<br />
phenotype of DTCs and the prognosis of<br />
breast cancer patients. The study<br />
paves the way for testing new<br />
treatments that prevent metastasis<br />
by inducing dormancy or eradicating<br />
the dormant disseminated cancer cells<br />
that have not yet initiated metastatic<br />
growth. The researchers suggest that<br />
markers such as NR2F1 coupled with<br />
DTC genetics and other host-derived<br />
indicators may provide a breakthrough<br />
in the management of minimal<br />
residual disease (MRD) and metastasis<br />
prevention.<br />
Breast Cancer Research<strong>2018</strong> https://doi.<br />
org/10.1186/s13058-018-1049 /16 October <strong>2018</strong><br />
Metarrestin slows<br />
spread of ovarian<br />
cancer<br />
novel anti-cancer drug, ML246<br />
A (metarrestin), reveals its ability to<br />
attenuate the growth and progression<br />
of ovarian cancer. The study conducted<br />
by Kanis et al reports for the first time<br />
on the effects of ML246, an inhibitor of<br />
the perinucleolar compartment (PNC),<br />
in ovarian cancer cells. PNCs were<br />
detected in the human ovarian cancer<br />
cell lines, SKOV3 and OVCAR3, which<br />
were treated with ML246 for its invasive<br />
activity in vitro and was tested for its<br />
efficacy on tumour growth and spread<br />
in xenograft mice models in vivo. The<br />
results showed a remarkable decrease<br />
in the invasive ability of ovarian cancer<br />
cell lines and attenuated the growth of<br />
tumour in human xenografts of ovarian<br />
cancer which reduced the abdominal<br />
spread of the xenografts. The study<br />
data demonstrate ML246 is as effective<br />
as cisplatin in inhibiting ovarian cancer<br />
growth and thus suggests its utility in<br />
platinum-resistant disease. These data<br />
warrant additional investigation into<br />
the therapeutic potential of ML246 for<br />
ovarian cancer as well as its mode of<br />
action while showing PNC structure as<br />
a potential reliable target in treating<br />
ovarian cancer.<br />
Source: Gynecologic Oncology Research and<br />
Practice<strong>2018</strong>5:7 2nd October <strong>2018</strong> https://doi.<br />
org/10.1186/s40661-018-0064-2 /<br />
—Compiled by Divya Choyikutty<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 57
column<br />
trialomics<br />
Medical devices as<br />
healthcare tools<br />
Diagnostic devices are required to generate robust clinical<br />
evidence to stand scientific scrutiny<br />
DR ARUN BHATT<br />
Writer is a consultant<br />
on clinical research &<br />
development from<br />
Mumbai.<br />
arun_dbhatt@hotmail.com<br />
Today, medicine has become highly<br />
specialised and technology-driven,<br />
leading to the widespread use of<br />
medical devices as diagnostic and therapeutic<br />
healthcare tools. This has led to the rapid<br />
growth of the medical device industry. A<br />
medical device is different from a drug,<br />
as it acts by physical interaction with body/<br />
body part and the outcome depends on<br />
the skill or experience of the clinician or<br />
the technician. Hence, there are separate<br />
international and Indian regulations for<br />
medical devices.<br />
A medical device is any instrument,<br />
apparatus, appliance, software, material or<br />
any other article used in human beings for a)<br />
diagnosis, prevention, monitoring, treatment<br />
or alleviation of disease or alleviation of or<br />
compensation for an injury or handicap, b)<br />
investigation, replacement or modification of<br />
the anatomy or of a physiological process, or<br />
c) control of conception.<br />
For regulatory approval purpose, medical<br />
devices are classified by risk assessment<br />
based on:<br />
• Intended purpose<br />
• Duration of continuous use<br />
• Transient - less than 60 minutes<br />
• Short term - not more than 30 days<br />
• Long-term - more than 30 days<br />
• Invasiveness<br />
• Critical anatomical locations - central<br />
circulatory system, central nervous system<br />
• Active medical devices<br />
As such, medical devices could be<br />
1) non-invasive - stethoscopes, syringes,<br />
wound dressings, hemodialyser; 2) invasive<br />
- lancets, tracheal tubes, cardiac catheters,<br />
coronary stents, contraceptive devices, joint<br />
replacement prosthesis; 3) active - hearing<br />
aids, MRI, nebulizers dental implants; 4)<br />
special category - drug-eluting stents,<br />
contraceptive intrauterine devices, biological<br />
heart valves, blood bags; 5) In vitro diagnostic<br />
medical devices for detecting transmissible<br />
agents - HIV , blood grouping or tissue typing,<br />
and self-testing – glucometer.<br />
A device which is invasive or for long-term<br />
continuous use or used in critical anatomic<br />
location or is active carries a higher risk.<br />
The risk categories are:<br />
• Class A Low Risk: e.g. surgical gauze, sterile<br />
plasters<br />
• Class B Low-Moderate: e.g. hearing aids,<br />
ultrasonic diagnostic equipment<br />
• Class C Moderate-High: e.g. infusion<br />
pumps, ventilators, surgical lasers, dental<br />
implant<br />
• Class D High: e.g. many implants,<br />
replacement heart valves, pacemakers<br />
Classification of the device provides a<br />
practical, economic, and feasible approach<br />
to decide which category requires rigorous<br />
regulatory evaluation. Indian medical devices<br />
rule 2017 mandate regulatory approval<br />
requirements for all device categories.<br />
These requirements describe submission<br />
requirements for technical information, quality<br />
documentation and clinical evidence. Clinical<br />
evidence studies include those that look at 1)<br />
Pilot Preliminary Safety and Performance in<br />
a few patients; 2) Pivotal Efficacy and Safety/<br />
Adverse Effects in a larger number, and 3)<br />
Postmarketing long-term safety. The higher<br />
the risk category, the greater the regulatory<br />
requirement for data and clinical evidence.<br />
The development and marketing of a<br />
medical device or a diagnostic medical device<br />
require critical attention to technology, quality<br />
and the scientific challenges of generating<br />
robust clinical evidence.<br />
58 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
policy<br />
MENTAL HEALTH CARE ACT 2017<br />
TAKING OUT<br />
THE STIGMA<br />
Notwithstanding the<br />
new law, experts feel<br />
protecting the rights of<br />
the mentally ill will be<br />
an uphill task<br />
The Mental Health Care Act<br />
2017, which came into force in<br />
May this year, is set to make<br />
drastic changes in the treatment of<br />
psychological disorders. The Act, hailed<br />
as one of the most progressive pieces<br />
of legislation on mental health care in<br />
the world, entitles mentally ill patients<br />
to humane treatment and assures<br />
them the right to access mental health<br />
care. As per the Act, every person<br />
shall have the right to access mental<br />
health care and treatment from mental<br />
health services run or funded by the<br />
government. It entitles patients to<br />
access affordable and quality mental<br />
60 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
health services without any kind<br />
of discrimination. The Act has also<br />
decriminalised suicide attempts by<br />
mentally ill people.<br />
“The Act is a phenomenal, rightsbased<br />
approach, a game-changer in<br />
mental health care and one of the<br />
best health legislations in the world. It<br />
is an ideal and aspirational legislation,”<br />
observed Dr. Suresh Bada Math,<br />
Professor of Psychiatry at the National<br />
Institute of Mental Health and Neuro<br />
Sciences (NIMHANS)<br />
Upholding the legislation,<br />
Dr. Mala Kapur Shankardass,<br />
Sociologist, Gerontologist, Health and<br />
Development Social Scientist and<br />
Associate Professor, Dept. of Sociology<br />
at Delhi’s Maitreyi College, said: “The<br />
Mental Healthcare Act is a good<br />
legislation which is very much required<br />
in the country for better outreach to<br />
affected people”.<br />
Upholding rights<br />
The Act directs the government<br />
to make sufficient provision for<br />
providing a range of services required<br />
by persons with mental illness. It<br />
directs the government to ensure<br />
the availability of minimum mental<br />
health services run or funded by the<br />
government in each district. Patients<br />
should not be made to travel long<br />
distances to access mental health. If<br />
it is not available in the district where<br />
a person with mental illness resides,<br />
the person is entitled to access any<br />
other mental health service in the<br />
district and the cost of treatment will<br />
be borne by the government. It directs<br />
the government to make necessary<br />
budgetary provision for the effective<br />
implementation of the Act.<br />
“It is a rights-based legislation.<br />
Hence it is the responsibility of the<br />
state to provide mental health care.<br />
But do all the states have the political<br />
will and the financial commitment<br />
to implement the Act? Considering<br />
various constraints like poor human<br />
resources, it may take time to set<br />
up and receive the funds that are<br />
warranted to ensure its effectiveness<br />
– which is why the impAct of the law<br />
INDIA’S MENTAL DISEASE BURDEN<br />
Despite increasing incidence of mental disorders the<br />
economic impact of it is yet to be quantified<br />
38<br />
million<br />
have anxiety<br />
disorders<br />
IT IS A RIGHTS-BASED<br />
LEGISLATION. HENCE IT IS<br />
THE RESPONSIBILITY OF<br />
THE STATE TO PROVIDE<br />
MENTAL HEALTH CARE.<br />
BUT DO ALL THE STATES<br />
HAVE THE POLITICAL<br />
WILL AND THE FINANCIAL<br />
COMMITMENT TO<br />
IMPLEMENT THE ACT?<br />
may not be immediate and may not be<br />
seen in the near future,” said Dr. Math.<br />
The Act also stipulates the criteria<br />
for the admission, treatment and<br />
discharge of mentally ill people. An<br />
adult patient can be admitted only<br />
if the patient has mental illness of a<br />
severity requiring admission, is likely<br />
to benefit from the admission and<br />
has the capacity to make decisions<br />
regarding admission and treatment.<br />
All admissions in the mental health<br />
establishment shall, as far as possible,<br />
56<br />
million<br />
Indians suffer<br />
from depression<br />
7.5%<br />
Indians suffer from<br />
major or minor<br />
mental disorders<br />
that require expert<br />
intervention<br />
}<br />
A mental health<br />
survey found that<br />
the incidence of<br />
depression is roughly<br />
1 20 in<br />
Indians<br />
SOURCE: WHO AND NIMHANS<br />
be independent admissions except<br />
when such conditions exist as to make<br />
supported admission unavoidable.<br />
An independent patient shall not be<br />
given treatment without his informed<br />
consent. The independent patient<br />
can discharge themselves without<br />
the consent of the medical officer.<br />
However, the patient can be made to<br />
stay in the hospital for 24 hours if the<br />
mental health professional feels that<br />
the patient has impaired decisionmaking<br />
capacity, poses a risk to self or<br />
others and is incapable of self-care.<br />
Disorder criteria: A drawback?<br />
Though the Act focuses on the rights<br />
of patients, it is comes with lots<br />
of regulations and related control.<br />
“The rights of the mentally ill should<br />
be protected, but the numerous<br />
mechanisms involved may create<br />
more stigma to the patients. The<br />
main drawback of the Act is that the<br />
patients who do not meet the criteria<br />
of ‘substantial disorder with gross<br />
impairments’ for mental illness cannot<br />
be admitted even if they are keen to<br />
do so and their doctor is willing to<br />
provide treatment. It poses a violation<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 61
of the right of individual to seek<br />
treatment in the most appropriate<br />
setting. Even though the criteria<br />
for admission are described, the<br />
mental health review board does<br />
not have the power to review such<br />
admissions,” said Dr. John C. J., Senior<br />
Consultant, Psychiatrist, Medical Trust<br />
Hospital.<br />
In case of the admission of minors,<br />
the nominated representative of a<br />
minor, usually the legal guardian,<br />
needs to apply for admission. Two<br />
professionals — two psychiatrists or<br />
one psychiatrist and one mental health<br />
professional — need to independently<br />
assess and conclude that the minor<br />
has a mental illness of the severity<br />
requiring admission, that it is in the<br />
best interest of the minor and that<br />
all community-based interventions<br />
are unsuitable or have failed. The<br />
admission of a minor should be<br />
reported to the mental health review<br />
FOR SUPPORTED<br />
ADMISSION UNDER THE<br />
ACT, TWO PROFESSIONALS<br />
SHOULD INDEPENDENTLY<br />
EXAMINE THE PATIENT IN<br />
THE PRECEDING SEVEN<br />
DAYS.<br />
board within seven days and if the<br />
minor remains in the hospital for<br />
more than 30 days, the mental health<br />
review board should be informed<br />
immediately. When the board is<br />
informed about the hospital stay of<br />
a minor exceeding 30 days, it must<br />
review the concerned minor within<br />
seven days.<br />
For supported admission under<br />
the Act, two professionals — one<br />
psychiatrist and one mental health<br />
professional — should independently<br />
examine the patient in the preceding<br />
seven days and independently<br />
conclude that the mental illness is<br />
severe. Both professionals must certify<br />
that admission is the least restrictive<br />
option available and the patient’s<br />
capacity to make mental health care<br />
treatment decisions is impaired. If<br />
the patient requires hospital stay in<br />
excess of 30 days, the patient must<br />
be independently examined by two<br />
psychiatrists at any time during the<br />
preceding seven days. They should<br />
independently conclude that the<br />
patient meets severity criteria, and<br />
that admission is the least restrictive<br />
option and that the patient’s capacity<br />
to make decisions about mental health<br />
treatment is impaired.<br />
Dearth of resources<br />
Even as the Act gives utmost<br />
62 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
importance to the right of patients,<br />
the implementation of the Act poses<br />
a challenge for the authorities. “The<br />
challenges exist in trying to reach<br />
out to rural and illiterate populations<br />
and and those residing in areas<br />
where mental health care services are<br />
limited. The problem is about raising<br />
awareness regarding the Act and how<br />
it is an empowering tool. It has to be<br />
implemented properly and people<br />
must understand its uses,” said Dr.<br />
Mala Kapur Shankardass.<br />
Dr. Suresh Bada Math observed<br />
that the main challenge is the abysmal<br />
number of trained mental health<br />
human resources when compared with<br />
the prevalence of mental disorders,<br />
which are mind-boggling in numbers.<br />
“Though approximately 10 crore<br />
people require mental health, only<br />
7,000 (approximately) psychiatrists are<br />
available. The mental health human<br />
resources numbers in the public health<br />
sector are very meager, considering<br />
the rights-based mental health care<br />
[approach] and the number of people<br />
requiring attention. To fill this human<br />
resources gap, we may require 20<br />
years or more,” he said<br />
Dr Math said the current mental<br />
health budget is very minimal, while<br />
the required budget is at least Rs<br />
3,000 crore per month just for<br />
treatment. “At present, there are only<br />
a few rehabilitation centers in the<br />
public sector. The non-availability of<br />
halfway homes, long-stay homes,<br />
supported accommodation, sheltered<br />
accommodation, vocational rehab<br />
centers and the lack of daycare<br />
centers are the uphill tasks faced by<br />
governments in implementing the<br />
Act,” he said . He added that the<br />
government has been proactive and<br />
has taken a number of initiatives, such<br />
as <strong>digital</strong> academies at NIMHANS, CIP<br />
Ranchi and at LGB institute, Tezpur.<br />
The aim of these academies is to<br />
exponentially increase human resources<br />
for mental health care. Dr. Math<br />
emphasized that, considering the large<br />
treatment gap, all stakeholders need to<br />
work for a long time before the dream<br />
of the Act can be fully realized.<br />
MHA 2017 pledges right<br />
to live with dignity<br />
The long-awaited legislation<br />
empowers a person with<br />
mental illness and his nominated<br />
representative to access information<br />
on the provisions of the Act, the<br />
nature of mental illness, the proposed<br />
treatment plan and the known side<br />
effects of the proposed treatment<br />
plan in a language he can understand.<br />
The Act also extends the right<br />
to confidentiality, access to medical<br />
records, legal aid and the right to<br />
make complaints about deficiencies in<br />
the provision of services.<br />
The Act pledges the right to<br />
community living for the patients and<br />
to not put them in a mental health<br />
establishment merely because the<br />
patient does not have a family, is not<br />
accepted by his family or is homeless,<br />
or due to the absence of communitybased<br />
facilities.<br />
It promises the right to live with<br />
dignity and protection from cruel,<br />
inhuman and degrading treatment<br />
in any mental health establishment<br />
and the right to equality and nondiscrimination.<br />
As per the provisions<br />
of the Act, every person with mental<br />
illness shall be treated as equal to<br />
persons with physical illness.<br />
It directs every insurer to make<br />
provision for medical insurance for<br />
treatment of mental illness on the<br />
same basis as is available for<br />
treatment of physical illness.<br />
The Act directs the<br />
government to plan, design<br />
and implement programmes<br />
for the promotion of mental<br />
health and the prevention<br />
of mental illness in the<br />
country. The Act puts the<br />
onus on the government to<br />
take appropriate steps to<br />
address the human resource<br />
requirements of mental health<br />
services in the country.<br />
The Act proposes setting up a<br />
Central Mental Health Authority and<br />
State Mental Health Authorities in<br />
each state. The central authority shall<br />
be responsible for the registration of<br />
all mental health establishments under<br />
the control of the central government<br />
and shall maintain a register of all<br />
the mental health establishments in<br />
the country. It will also be responsible<br />
for training all persons, including<br />
law enforcement officials, mental<br />
health professionals and other health<br />
professionals, on the provisions and<br />
the implementation of the Act. The<br />
state authority will perform similar<br />
duties at the state level. The Act also<br />
proposes the constitution of a Central<br />
Mental Health Authority Fund and<br />
State Mental Health Authority Funds.<br />
According to the Act, no person<br />
or organization shall establish or run a<br />
mental health establishment unless it<br />
has been registered with the authority<br />
under the provisions of the Act.<br />
Another major highlight of<br />
the Act is the provision for the<br />
constitution of Mental Health Review<br />
Boards. Each board shall consist<br />
of a district judge or retired district<br />
judge, a representative of the district<br />
collector, persons with mental illness<br />
or caregivers or persons representing<br />
organisations of persons with<br />
mental illness or caregivers or nongovernmental<br />
organisations working in<br />
the field of mental health.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 63
COPD<br />
technology<br />
EBV INTERVENTION<br />
IN EMPHYSEMA<br />
Endoscopic lung volume reduction using endobronchial valves is an emerging<br />
option for COPD patients<br />
DR GEORGE MOTHI JUSTIN<br />
Chronic obstructive pulmonary<br />
disease (COPD) is characterised<br />
by the presence of bronchitis<br />
and emphysema. The latter process,<br />
due to breakdown of elastic alveolar<br />
tissue, leads to increased lung<br />
compliance and gas trapping. Lung<br />
hyperinflation worsens with exercise,<br />
leading to breathlessness and is<br />
associated with reduced physical<br />
activity and reduced survival. Inhaled<br />
bronchodilator medications have only<br />
modest impact on the symptoms and<br />
do not alter the natural history of the<br />
disease. In selected patients with a<br />
heterogeneous pattern of emphysema,<br />
surgical resection can be targeted at<br />
the worst affected areas of lung tissue<br />
which contribute disproportionately<br />
to gas trapping and hyperinflation,<br />
and improve respiratory mechanics.<br />
Lung volume reduction surgery (LVRS)<br />
improves symptoms and prolongs<br />
survival, but can be associated with<br />
significant morbidity and a risk of<br />
death, with a cost per quality adjusted<br />
life year (QALY).<br />
A more recent approach has<br />
been to instead use endobronchial<br />
valves to occlude the airways<br />
supplying the worst affected part of<br />
the lung. This is intended to cause<br />
a collapse in the target lobe, with<br />
a similar impact on the function of<br />
the rest of the lung as seen in LVRS.<br />
However, atelectasis will only occur in<br />
the absence of significant collateral<br />
ventilation between the<br />
target lobe and the adjacent one.<br />
Because of this, the success rate<br />
of valve placement in early studies<br />
was low, impacting the value of<br />
endobronchial valves as a therapeutic<br />
intervention.<br />
Case series and single-centre<br />
trials have demonstrated that<br />
endobronchial valve treatment in<br />
patients with emphysema can lead<br />
to improvements in symptoms,<br />
lung function and exercise capacity,<br />
reduction in dynamic hyperinflation<br />
and improvements in oxygen<br />
kinetics and chest-wall synchrony.<br />
Moreover, where target lobe<br />
volume loss is seen on CT, a<br />
substantial survival benefit has<br />
been observed, compared with cases<br />
where valve treatment has been<br />
ineffective.<br />
During a bronchoscopic procedure,<br />
endobronchial valves are placed in the<br />
airways to occlude a diseased part of<br />
SINGLE-CENTRE TRIALS<br />
HAVE DEMONSTRATED THAT<br />
ENDOBRONCHIAL VALVE<br />
TREATMENT IN PATIENTS<br />
WITH EMPHYSEMA CAN<br />
LEAD TO IMPROVEMENTS<br />
IN SYMPTOMS.<br />
64 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
ENDOBRONCHIAL<br />
VALVES FOR<br />
LUNG VOLUME<br />
REDUCTION<br />
Endobronchial valves (EBV)<br />
are small implantable<br />
devices. These one-way<br />
valves are implanted in an<br />
airway in the pulmonary<br />
system using a flexible<br />
delivery catheter through a<br />
bronchoscope. This minimally<br />
invasive procedure is used<br />
to treat emphysema and<br />
several other lung conditions.<br />
ZEPHYR<br />
Developed by Pulmonx, the Zephyr device<br />
is an implantable bronchial valve intended<br />
to decrease the volume of targeted regions<br />
of the lung. It is indicated for the treatment<br />
of patients with severe emphysema. The<br />
EBV are placed in the diseased region of the<br />
lung using bronchoscopy. Once implanted,<br />
the one-way valve prevents airflow into the<br />
diseased region, while allowing trapped air<br />
and fluids to escape. Reducing the volume<br />
of the diseased region may allow healthier<br />
regions to expand and function more<br />
efficiently. The Zephyr valve is removable if<br />
found to be not working properly.<br />
The Chartis System and the StratX Lung<br />
Analysis Platform are diagnostic companion<br />
products developed by Pulmonx. They are<br />
designed to identify likely responders and<br />
non-responders to Zephyr valve therapy.<br />
The US FDA granted approval for Zephyr<br />
endobronchial valve in June <strong>2018</strong> based<br />
on positive clinical data from the pivotal<br />
LIBERATE Study and two other multicenter<br />
randomized control trials. The LIBERATE<br />
study found Zephyr EBV provides clinically<br />
meaningful benefits for lung function, exercise<br />
tolerance, dyspnea and quality of life out to<br />
at least 12-months, with an acceptable safety<br />
profile in patients with little or no collateral<br />
ventilation in the target lobe.<br />
According to Pulmonx data, since 2007, more<br />
than 14,000 patients have been treated<br />
with the Zephyr Valve worldwide. Zephyr<br />
Valve treatment is included in emphysema<br />
treatment guidance issued by leading health<br />
organizations, including the Global Initiative<br />
for Chronic Obstructive Lung Disease (GOLD)<br />
and the UK’s National Institute for Health and<br />
Care Excellence (NICE).<br />
SPIRATION<br />
The Spiration Valve blocks incoming breath<br />
from entering damaged portions of the lung,<br />
while it permits trapped air and mucous to<br />
escape the damaged and potentially hyperinflated<br />
lung. That air is redirected to healthier<br />
portions of the lung through the valve without<br />
a pressure fit, allowing secretions to escape<br />
naturally along the bronchial wall. The valve<br />
has an anchoring system and an umbrellashaped<br />
design with 0% migration and<br />
expectoration even in complex airways.<br />
Marketed by Olympus, Spiration valves have<br />
also received the CE mark.<br />
EPIDEMIOLOGY<br />
OF ASTHMA<br />
The disease in adults pose an<br />
enormous health care burden<br />
Estimated the<br />
prevalence of<br />
asthma in India<br />
to be<br />
2.05%<br />
adults aged ≥15 years<br />
National<br />
burden of<br />
asthmatics<br />
18,000,000<br />
SOURCE: Lung India<br />
the lungs and reduce hyperinflation,<br />
allowing the healthier parts of the<br />
lungs to take in more air and work<br />
more effectively. The valves are<br />
designed to be permanent, but can be<br />
removed if necessary.<br />
The most common side effect<br />
associated Zephyr valve treatment<br />
was pneumothorax, which occurred<br />
in roughly one third of the patients.<br />
No intervention was required in about<br />
20% of the incidents; the majority of<br />
the rest of such cases were addressed<br />
with standard medical management.<br />
Other side effects, which occurred<br />
less frequently, included COPD<br />
exacerbation, pneumonia, respiratory<br />
failure and death.<br />
The Zephyr valve is contraindicated<br />
in patients with active lung infections;<br />
those who are allergic to nitinol,<br />
nickel, titanium or silicone; active<br />
smokers; and those who are not<br />
able to tolerate the bronchoscopic<br />
procedure.<br />
The author is Head,<br />
Department of Respiratory<br />
Medicine, Medical Trust<br />
Hospitals, Cochin<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 65
hospital news<br />
Continental Hospital<br />
starts heart failure<br />
clinic in Hyderabad<br />
Hyderabad-based Continental Hospital<br />
has launched a Heart Failure Clinic at<br />
its premises in the city.<br />
The clinic aims to provide advanced<br />
cardiac services to the people suffering<br />
from severe heart-related diseases. The<br />
number of heart failure cases are rising<br />
at an alarming rate in Hyderabad, with<br />
an estimated 15,000 new cases being<br />
registered every year.<br />
The Heart Failure Clinic offers<br />
comprehensive cardiac care services<br />
under one roof. Treatment decisions are<br />
made in a team approach, based on the<br />
medical details of each patient.<br />
The Hospital is equipped with<br />
state-of-the-art technology, including<br />
the implantation of artificial pumps to<br />
support the heart’s functions. Continental<br />
Hospitals is planning to extend the<br />
services with a dedicated outpatient<br />
department and a 24x7 helpline.<br />
Facility for children with<br />
multiple disabilities at Wadia<br />
Boehringer Ingelheim, one of the<br />
world’s leading pharmaceutical<br />
companies, inaugurated a facility for<br />
children with multiple disabilities at Bai<br />
Jerbai Wadia Hospital, Mumbai.<br />
Started in association with Muskan<br />
Foundation, the facility is designed with<br />
the aim of training visually impaired<br />
children who have additional disabilities.<br />
At the Facility, children are trained<br />
to manage their disabilities under a<br />
multi-disciplinary approach. The facility<br />
also focuses on educating parents, who<br />
will receive comprehensive training for<br />
effective management of these children<br />
at home.<br />
A part of the social entrepreneurial<br />
initiative at Boehringer Ingelheim (BI),<br />
the programme in Mumbai intends<br />
to help such children communicate<br />
effectively and develop modification to<br />
their behaviour essential for their daily<br />
routine.<br />
In India, there are 20.42 lakh<br />
disabled children who are aged<br />
between 0 and 6 years. Out of this,<br />
14.52 lakh and 5.9 lakh children live in<br />
rural and urban areas respectively. Of<br />
them, 11.04 lakh are male and 9.38 lakh<br />
female. Among them, 1.49 lakh<br />
children have multiple disabilities,<br />
according to BI.<br />
Jaslok Hospital launches clinic for elderly<br />
Jaslok Hospital and Research Centre<br />
has launched a geriatric clinic at<br />
Peddar Road in Mumbai.<br />
Planned as a one-stop elderly<br />
care centre, the dedicated geriatric<br />
care department will have outpatient<br />
care, in-patient care, emergency care<br />
and home health care. It will offer<br />
physical, cognitive and psychosocial<br />
assessment, a personal care plan,<br />
recommendations to improve health<br />
and functional ability, rehabilitation,<br />
the safe use of medicines and will<br />
address home and emergency care<br />
for the elderly.<br />
According to the Indian<br />
Ageing Report 2017, based on the<br />
2011 Census, the overall old-age<br />
dependency ratio shows that there<br />
are over 14 elderly per 100 working<br />
age persons, out of which 7 are<br />
termed as a dependent.<br />
The proportion of the elderly<br />
is expected to increase from 10.5<br />
percent to 22.4 percent during 2012–<br />
2050, according to estimates.<br />
66 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
insurance<br />
MORE ILLNESSES TO COME<br />
UNDER INSURANCE COVER<br />
The process is on to limit the number of exclusions on<br />
the current list of health policies<br />
Health insurance policies will<br />
soon cover more diseases, with<br />
the Insurance and Regulatory<br />
Authority of India (IRDAI) initiating<br />
the process to minimise the number<br />
of diseases that are not covered<br />
under the health insurance policies at<br />
present.<br />
In order to examine the matter,<br />
the regulator has constituted a tenmember<br />
working committee headed<br />
by Suresh Mathur, Executive Director,<br />
Health, IRDAI. The committee will<br />
examine the exclusions that are<br />
prevalent in health insurance policies<br />
and rationalize the exclusions by<br />
minimizing the number, so as to<br />
enhance the scope of health insurance<br />
coverage<br />
The terms of reference (ToR)<br />
of the working committee include<br />
rationalising the exclusions that<br />
disallow coverage with respect to<br />
new modalities of treatments and<br />
technologically advanced medical<br />
treatments and identifying the type of<br />
THE MOVE WILL BENEFIT<br />
POLICYHOLDERS IN A<br />
GREAT WAY AS THE SCOPE<br />
OF COVER AVAILABLE<br />
UNDER HEALTH INSURANCE<br />
POLICY WILL BE EXPANDED.<br />
exclusions which shall not be allowed.<br />
The committee has also been asked<br />
to study the wordings/language of<br />
the exclusions and standardize the<br />
wordings of exclusions in simple and<br />
easily understandable language, study<br />
the scope for allowing individual<br />
specific and/or ailment/disease specific<br />
permanent exclusions at the time of<br />
underwriting so that policyholders are<br />
not denied health insurance claims<br />
unrelated to the exclusions, and any<br />
other matter relevant to the subject of<br />
exclusions.<br />
Welcoming the move,<br />
Subramanyam Brahmajosyula,<br />
Head of Underwriting and Reinsurance<br />
at SBI General Insurance, said: “We are<br />
broadly supportive of the regulator’s<br />
move to expand the<br />
ambit of health insurance coverage,<br />
both in terms of increasing the<br />
number of people covered, as well as<br />
the various illnesses/diseases for<br />
which coverage is granted under<br />
health insurance policies. This needs to<br />
be viewed as a national priority,<br />
and not purely from the narrow<br />
perspective of any challenges<br />
it might pose to the insurance<br />
industry.”<br />
He added that the move will<br />
benefit policyholders in a great<br />
way as the scope of cover available<br />
under health insurance policy will be<br />
expanded.<br />
Improve penetration;<br />
increase rates<br />
The insurers feel that an enhancement<br />
68 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
in insurance coverage will lead to<br />
greater penetration. “The order<br />
will have implications for both<br />
the consumer and the industry. It<br />
will be beneficial to consumers,<br />
because less exclusion will mean<br />
more coverage for diseases. From<br />
the industry perspective, it will lead<br />
to a higher degree of insurance<br />
penetration, thus more sales,”<br />
said Vaidyanathan Ramani,<br />
Head, Product andInnovation,<br />
Policybazaar.com.<br />
Brahmajosyula also<br />
agreed that the move<br />
will lead to greater awareness of<br />
insurance and improve the penetration<br />
of health insurance in the country.<br />
However, insurance companies<br />
hinted at the possibility of an increase<br />
in policy rates. They said that some<br />
of the conditions which are proposed<br />
to be covered are either partially or<br />
completely excluded under the current<br />
health insurance policy coverage.<br />
“With the enhancement of coverage,<br />
it will be necessary for the insurance<br />
companies to relook at their pricing<br />
in order to cater to the expected<br />
claims from allowing coverage of such<br />
conditions,” said Brahmajosyula.<br />
“The premium may go up<br />
marginally in the long run, because<br />
enhanced coverage will lead to more<br />
claims and hence, the premium will<br />
THE CHALLENGES WOULD<br />
BE TO DEFINE, IN PRECISE<br />
TERMS, WHAT CONSTITUTES<br />
MENTAL ILLNESS TO AVOID<br />
DISPUTES IN THE EVENT<br />
OF CLAIMS, AS WELL AS<br />
COMPILING SUFFICIENT<br />
AND ACCURATE DATA TO<br />
DECIDE THE APPROPRIATE<br />
PREMIUM TO BE CHARGED.<br />
also go up. In spite of this, the order<br />
will impact positively for all those<br />
involved in the insurance business –<br />
the buyer and the seller,” according to<br />
Ramani.<br />
Cover for mental illness?<br />
Meanwhile, in another significant<br />
development, the IRDAI has asked<br />
insurers to make provision for medical<br />
insurance for the treatment of<br />
mental illness on the same basis as is<br />
available for the treatment of physical<br />
illness. The move is set to benefit a<br />
large number of people. The regulator<br />
has issued a circular in this direction<br />
after The Mental Healthcare Act 2017<br />
came into force in May <strong>2018</strong>. The act<br />
has stipulated that every insurer shall<br />
make provisions for the treatment<br />
of mental illness. “The insurance<br />
companies will have to re-price the<br />
products to cater to the coverage<br />
of mental illness. Other associated<br />
challenges would be to define, in<br />
precise terms, what constitutes mental<br />
illness to avoid disputes in the event of<br />
claims, as well as compiling sufficient<br />
and accurate data to decide the<br />
appropriate premium to be charged,”<br />
said Brahmajosyula.<br />
Ramani also welcomed the<br />
decision to cover the treatment of<br />
mental illness under health insurance<br />
policies. “This is a great step for the<br />
country as, with this move, we have<br />
started to accept that mental illness is<br />
a serious affair and needs treatment.<br />
Therefore, medical insurance covering<br />
the same is a great step. Mental<br />
illness will probably be a much<br />
higher risk than physical illness in<br />
the future,” he said. However, he<br />
added, there are a few issues which<br />
are still in the grey, like what are<br />
considered mental illnesses and what<br />
are the degrees of those, with the<br />
recommended treatments attributed to<br />
them. He added that it will be easier<br />
to define fair expenses and procedures<br />
for such treatments if some light was<br />
thrown over these issues, as mental<br />
illness is a very vague and big topic<br />
in itself.<br />
DISEASES PRESENTLY<br />
NOT COVERED*<br />
HIV/AIDS<br />
Infertility<br />
Genetic disorders<br />
Tobacco use and related<br />
complications<br />
Cosmetic surgery<br />
Cataract<br />
Hernia etc.<br />
Mental health<br />
*The list is incomplete. The rules and<br />
regulations vary with different players.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 69
public healh<br />
NOISE<br />
HAZARDS<br />
WHO guidelines for the EU region<br />
provide strong evidence that noise<br />
is one of the top environmental<br />
hazards to both physical and<br />
mental health<br />
70 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
Environmental noise is an<br />
important public health issue,<br />
featuring among the top<br />
environmental risks to health. It has<br />
negative impacts on human health and<br />
well-being and is a growing concern<br />
among both the general public and<br />
policy-makers in Europe.<br />
The WHO Regional Office for<br />
Europe has developed environmental<br />
noise guidelines for the European<br />
Region, proposing an updated set of<br />
public health recommendations on<br />
exposure to environmental noise.<br />
Objectives<br />
The main purpose of these guidelines<br />
is to provide recommendations<br />
for protecting human health from<br />
exposure to environmental noise<br />
originating from various sources:<br />
transportation (road traffic, railway,<br />
and aircraft) noise, wind turbine noise<br />
and leisure noise. Leisure noise in this<br />
context refers to all noise sources<br />
that people are exposed to due to<br />
leisure activities, such as attending<br />
nightclubs, pubs, fitness classes, live<br />
sporting events, concerts or live music<br />
venues and listening to loud music<br />
through personal listening devices.<br />
The following two key questions<br />
identify the issues addressed by the<br />
guidelines.<br />
• In the general population<br />
exposed to environmental noise, what<br />
is the exposure-response relationship<br />
between exposure to environmental<br />
noise (reported as various indicators)<br />
and the proportion of people with a<br />
validated measure of health outcome,<br />
when adjusted for confounders?<br />
• In the general population<br />
exposed to environmental noise, are<br />
interventions effective in reducing<br />
exposure to and/or health outcomes<br />
from environmental noise?<br />
In light of these questions,<br />
the guidelines set out to define<br />
recommended exposure levels for<br />
environmental noise in order to protect<br />
population health.<br />
Methods used<br />
The process of developing the<br />
WHO GUIDELINES<br />
FOLLOWED A RIGOROUS<br />
METHODOLOGY<br />
INVOLVING SEVERAL<br />
GROUPS WITH<br />
SEPARATE ROLES AND<br />
RESPONSIBILITIES.<br />
WHO guidelines followed a rigorous<br />
methodology involving several<br />
groups with separate roles and<br />
responsibilities. Throughout<br />
the process, the Grading of<br />
Recommendations Assessment,<br />
Development and Evaluation (GRADE)<br />
approach was followed. In particular,<br />
the different steps in the development<br />
of the guidelines include:<br />
• formulation of the scope and key<br />
questions of the guidelines;<br />
• review of the pertinent literature;<br />
•selection of priority health<br />
outcome measures;<br />
• a systematic review of the<br />
evidence;<br />
• assessment of certainty of the<br />
bodies of evidence resulting from<br />
systematic reviews;<br />
• identification of guideline<br />
exposure levels; and<br />
• setting of the strength of<br />
recommendations.<br />
Based on the defined scope<br />
and key questions, these guidelines<br />
reviewed the pertinent literature<br />
in order to incorporate significant<br />
research undertaken in the area of<br />
environmental noise and health since<br />
the community noise guidelines and<br />
night noise guidelines for Europe were<br />
issued ..<br />
In total, eight systematic reviews<br />
of evidence were conducted to<br />
assess the relationship between<br />
environmental noise and the following<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 71
health outcomes: cardiovascular and<br />
metabolic effects; annoyance; effects<br />
on sleep; cognitive impairment;<br />
hearing impairment and tinnitus;<br />
adverse birth outcomes; and<br />
quality of life, mental health and<br />
well-being.<br />
A separate systematic review of the<br />
evidence was conducted to assess the<br />
effectiveness of environmental noise<br />
interventions in reducing exposure<br />
and associated impacts on health.<br />
Once identified and synthesized,<br />
EIGHT SYSTEMATIC<br />
REVIEWS OF EVIDENCE<br />
WERE CONDUCTED TO<br />
ASSESS THE RELATIONSHIP<br />
BETWEEN ENVIRONMENTAL<br />
NOISE.<br />
the quality of the evidence of the<br />
systematic reviews was assessed<br />
by the Systematic Review Team.<br />
Subsequently, the Guideline<br />
Development Group (GDG) formulated<br />
recommendations, guided by the<br />
Systematic Review<br />
Team’s assessment and informed<br />
by of a number of additional<br />
contextual parameters. To facilitate<br />
the formulation of recommendations,<br />
WHO RECOMMENDATIONS ON ENVIRONMENTAL NOISE SOURCE<br />
ROAD TRAFFIC NOISE<br />
For average noise exposure, the<br />
GDG strongly recommends reducing<br />
noise levels produced by road traffic<br />
below 53 decibels (dB) L den , as<br />
road traffic noise above this level<br />
is associated with adverse health<br />
effects.<br />
For night noise exposure, the GDG<br />
strongly recommends reducing<br />
noise levels produced by road<br />
traffic during night time below 45<br />
dB L night , as night-time road traffic<br />
noise above this level is associated<br />
with adverse effects on sleep.<br />
To reduce health effects, the<br />
GDG strongly recommends that<br />
policy-makers implement suitable<br />
measures to reduce noise exposure<br />
from road traffic in the population<br />
exposed to levels above the<br />
guideline values for average and<br />
night noise exposure. For specific<br />
interventions, the GDG recommends<br />
reducing noise both at the source<br />
and on the route between the<br />
source and the affected population<br />
by changes in infrastructure.<br />
Strong<br />
RAILWAY NOISE<br />
For average noise exposure, the<br />
GDG strongly recommends reducing<br />
noise levels produced by railway<br />
traffic below 54 dB L den , as railway<br />
noise above this level is associated<br />
with adverse health effects.<br />
For night noise exposure, the GDG<br />
strongly recommends reducing<br />
noise levels produced by railway<br />
traffic during night time below 44<br />
dB L night , as night-time railway noise<br />
above this level is associated with<br />
adverse effects on sleep.<br />
To reduce health effects, the<br />
GDG strongly recommends that<br />
policy-makers implement suitable<br />
measures to reduce noise exposure<br />
from railways in the population<br />
exposed to levels above the<br />
guideline values for average and<br />
night noise exposure. There is,<br />
however, insufficient evidence<br />
to recommend one type of<br />
intervention over another.<br />
Strong<br />
AIRCRAFT NOISE<br />
For average noise exposure, the<br />
GDG strongly recommends reducing<br />
noise levels produced by aircraft<br />
below 45 dB L den ., as aircraft noise<br />
above this level is associated with<br />
adverse health effects.<br />
For night noise exposure, the GDG<br />
strongly recommends reducing<br />
noise levels produced by aircraft<br />
during night time below 40 dB<br />
L night ., as night-time aircraft noise<br />
above this level is associated with<br />
adverse effects on sleep.<br />
72 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
BY SOURCE<br />
To reduce health effects, the<br />
GDG strongly recommends that<br />
policy-makers implement suitable<br />
measures to reduce noise exposure<br />
from aircraft in the population<br />
exposed to levels above the<br />
guideline values for average and<br />
night noise exposure. For specific<br />
interventions, the GDG recommends<br />
implementing suitable changes in<br />
infrastructure.<br />
WIND TURBINE NOISE<br />
For average noise exposure, the<br />
GDG conditionally recommends<br />
reducing noise levels produced by<br />
wind turbines below 45 dB L den , as<br />
wind turbine noise above this level<br />
is associated with adverse health<br />
effects.<br />
No recommendation is made for<br />
average night noise exposure<br />
Lnight of wind turbines. The quality<br />
of evidence of night-time exposure<br />
to wind turbine noise is too low to<br />
allow a recommendation.<br />
To reduce health effects, the<br />
GDG conditionally recommends<br />
that policy-makers implement<br />
suitable measures to reduce noise<br />
exposure from wind turbines in the<br />
population exposed to levels above<br />
the guideline values for average<br />
noise exposure. No evidence is<br />
available, however, to facilitate the<br />
recommendation of one particular<br />
type of intervention over another.<br />
LEISURE NOISE<br />
For average noise exposure, the<br />
GDG conditionally recommends<br />
reducing the yearly average from<br />
all leisure noise sources combined<br />
to 70 dB L Aeq,24h as leisure noise<br />
above this level is associated<br />
with adverse health effects. The<br />
equal energy principle can be<br />
used to derive exposure limits for<br />
other time averages, which might<br />
be more practical in regulatory<br />
processes.<br />
For single-event and impulse noise<br />
exposures, the GDG conditionally<br />
recommends following existing<br />
guidelines and legal regulations to<br />
limit the risk of increases in hearing<br />
impairment from leisure noise in<br />
both children and adults.<br />
Following a precautionary approach,<br />
to reduce possible health effects,<br />
the GDG strongly recommends that<br />
policy-makers take action to prevent<br />
exposure above the guideline<br />
values for average noise and singleevent<br />
and impulse noise exposures.<br />
This is particularly relevant as a<br />
large number of people may be<br />
exposed to and at risk of hearing<br />
impairment through the use of<br />
personal listening devices. There<br />
is insufficient evidence, however,<br />
to recommend one type of<br />
intervention over another.<br />
strong<br />
conditional<br />
the GDG first defined priority health<br />
outcomes and then selected the<br />
most relevant health outcome<br />
measures for the outcomes.<br />
Consecutively, a process was<br />
developed to identify the guideline<br />
exposure levels with the help of<br />
the exposure-response functions<br />
provided by the systematic<br />
reviews. To reflect the nature of the<br />
research (observational studies)<br />
underpinning the relationship between<br />
environmental noise and health, the<br />
GRADE procedures were adapted to<br />
the requirements of environmental<br />
exposure studies where needed.<br />
Noise indicators<br />
From a scientific point of view,<br />
the best noise indicator is the one<br />
that performs best in predicting<br />
the effect of interest. There are,<br />
however, a number of additional<br />
criteria that may influence the<br />
choice of indicator. For example,<br />
various indicators might be suitable<br />
for different health end-points. Some<br />
considerations of a more political<br />
nature can be found in the European<br />
Commission’s Position paper on EU<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 73
slug<br />
NOISE POLLUTION:<br />
RISK OF ADVERSE<br />
HEALTH EFFECTS<br />
The guideline document identifies four<br />
priority health outcome measures<br />
and<br />
CARDIOVASCULAR<br />
DISEASE: IHD AND<br />
HYPERTENSION<br />
High-quality epidemiological<br />
evidence described in<br />
the systematic review on<br />
cardiovascular and metabolic<br />
effects of environmental noise<br />
indicates that exposure to road<br />
traffic noise increases the risk<br />
of IHD. The GDG was confident<br />
that health risks resulting from<br />
exposure at an RR increase<br />
in the order of 5–10% in the<br />
incidence of IHD. This is similar<br />
to the reasoning in the WHO<br />
air quality guidelines for fine<br />
particulate matter (PM2.5).<br />
To determine a relevant<br />
risk increase for IHD, the GDG<br />
took as a starting-point the<br />
relative risk (RR) increase<br />
of 5% measured in<br />
epidemiological<br />
studies of<br />
environmental noise<br />
or air pollution.<br />
Taking into account the<br />
incidence of IHD and the<br />
seriousness of the disease,<br />
it considered lowering the<br />
RR increase for IHD to 1%,<br />
as a 5% RR increase might<br />
imply a comparatively high<br />
absolute risk from a population<br />
perspective. To decide on<br />
the final benchmark value<br />
for IHD, several aspects were<br />
considered: the number of<br />
people in a population affected<br />
by IHD; whether health<br />
risks caused by noise would<br />
make up a large part of the<br />
incidence of the disease; other<br />
examples of health risks of<br />
similar magnitude leading to<br />
preventive action. For IHD, in<br />
an average EU country with<br />
20 million inhabitants, an RR<br />
increase of 5% for IHD would<br />
lead to several thousand extra<br />
cases attributable to noise<br />
yearly. This corresponds to<br />
a proportion of cases of IHD<br />
attributable to noise exposure<br />
of less than 10%, which is still<br />
relatively small. After extensive<br />
discussion at the very end of<br />
the guideline development<br />
process, the GDG decided to<br />
adhere to 5% as the relevant<br />
risk increase.<br />
noise indicators (EC, 2000).<br />
The current guidelines are intended<br />
to be suitable for policy-making in<br />
the WHO European Region. They,<br />
therefore, focus on the most used<br />
noise indicators L den and/or L night .<br />
They can be constructed using their<br />
components (L day , L evening , L night<br />
and the duration in hours of L night ),<br />
and are provided for exposure<br />
at the most exposed façade, outdoors.<br />
The L den and L night indicators are<br />
those generally reported by<br />
authorities and are widely used for<br />
exposure assessment in health effect<br />
studies.<br />
Recommendations<br />
Specific recommendations have<br />
been formulated for road traffic<br />
noise, railway noise, aircraft noise,<br />
SPECIFIC<br />
RECOMMENDATIONS HAVE<br />
BEEN FORMULATED FOR<br />
ROAD TRAFFIC NOISE,<br />
RAILWAY NOISE, AIRCRAFT<br />
NOISE, WIND TURBINE<br />
NOISE AND LEISURE NOISE.<br />
wind turbine noise and leisure noise.<br />
Recommendations are rated as either<br />
strong or conditional.<br />
Strength of recommendation<br />
• A strong recommendation can be<br />
adopted as a policy in most situations.<br />
The guideline is based on the<br />
74 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
Hypertension is a common<br />
condition and is an important<br />
risk indicator for IHD and other<br />
cardiovascular diseases. Thus,<br />
the hypertension risk increase<br />
can be transformed into a risk<br />
increase for cardiovascular<br />
disease. To derive a relevant<br />
risk increase, the GDG<br />
focused on the incidence<br />
of hypertension, owing to<br />
the nature and quality of<br />
epidemiological evidence. Since<br />
hypertension is less serious<br />
than IHD, and not all people<br />
with hypertension will progress<br />
to cardiovascular disease, the<br />
relevant risk increase in the<br />
incidence of hypertension<br />
needed to be higher than that<br />
for IHD. Therefore, the GDG<br />
agreed on an RR increase of<br />
10% for hypertension.<br />
SLEEP DISTURBANCE<br />
AND ANNOYANCE<br />
The GDG initially considered<br />
5%HSD and 10%HA due to<br />
noise as relevant absolute<br />
risks, not be exceeded at<br />
the guideline level. After<br />
discussion, however, members<br />
agreed that these absolute<br />
risks were too large since a<br />
considerable proportion of<br />
the population would still<br />
be affected; they decided<br />
to lower the relevant risk<br />
from 5% being highly sleepdisturbed<br />
to 3%. In doing so,<br />
the GDG referred to the WHO<br />
night noise guidelines (WHO,<br />
2009), which concluded that<br />
while there was insufficient<br />
evidence that physiological<br />
effects at noise levels below<br />
40 dB Lnight are harmful to<br />
health,<br />
there were observed<br />
adverse health effects at<br />
levels starting from 40 dB<br />
Lnight. At 40 dB, about 3–4%<br />
(depending on the noise<br />
source) of the population still<br />
reported being highly sleepdisturbed<br />
due to noise, which<br />
was considered relevant to<br />
health. The GDG considered<br />
it important that this level is<br />
consistent with the previous<br />
health-based approach<br />
adopted by the WHO<br />
night noise guidelines, and<br />
agreed that the absolute risk<br />
associated with the guideline<br />
value selected should not<br />
exceed 3%HSD to be health<br />
protective.<br />
For annoyance, which<br />
is considered a less serious<br />
health effect than self-reported<br />
sleep disturbance (as indicated<br />
by the respective DWs),<br />
the relevant risk remained<br />
at 10%HA. This means the<br />
absolute risk associated with<br />
the guideline value selected<br />
should be closest to, but not<br />
above 10%HA, to be health<br />
protective.<br />
COGNITIVE<br />
IMPAIRMENT<br />
Acquiring skills in reading and<br />
oral comprehension at a young<br />
age is important for further<br />
development: a delay in<br />
acquiring these skills can have<br />
an impact later in life. This<br />
impact cannot be predicted<br />
very accurately, but the GDG<br />
considered a delay of one<br />
month a relevant absolute risk.<br />
PERMANENT HEARING<br />
IMPAIRMENT<br />
The literature on hearing<br />
impairment as a result of<br />
occupational noise exposure<br />
is extensive. A noise exposure<br />
level beyond 80 dB during<br />
40 years of working a 40<br />
hour work week can give<br />
rise to permanent hearing<br />
impairment. Given that<br />
environmental exposure to<br />
noise is much lower than these<br />
levels and that noise-related<br />
hearing impairments are not<br />
reversible, the GDG considered<br />
that there should be no risk<br />
of hearing impairment due<br />
to environmental noise and<br />
considered any increased<br />
risk of hearing impairment<br />
relevant.<br />
confidence that the desirable effects<br />
of adherence to the recommendation<br />
outweigh the undesirable<br />
consequences. The quality of evidence<br />
for a net benefit – combined with<br />
information about the values,<br />
preferences and resources – inform<br />
this recommendation, which should be<br />
implemented in most circumstances.<br />
• A conditional recommendation<br />
requires a policy-making process with<br />
substantial debate and involvement<br />
of various stakeholders. There is<br />
less certainty of its efficacy owing<br />
to the lower quality of evidence<br />
of a net benefit, opposing values<br />
and preferences of individuals<br />
and populations affected or the<br />
high resource implications of the<br />
recommendation, meaning there may<br />
be circumstances or settings in which<br />
it will not apply.<br />
Alongside specific<br />
recommendations, several guiding<br />
principles were developed to provide<br />
generic advice and support for the<br />
incorporation of recommendations into<br />
a policy framework. They apply to the<br />
implementation of all of the specific<br />
recommendations.<br />
Guiding principles: reduce,<br />
promote, coordinate and involve<br />
• Reduce exposure to noise, while<br />
conserving quiet areas.<br />
• Promote interventions to reduce<br />
exposure to noise and improve health.<br />
• Coordinate approaches to control<br />
noise sources and other environmental<br />
health risks.<br />
• Inform and involve communities<br />
potentially affected by a change in<br />
noise exposure.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 75
esearch<br />
SEPSIS: PATHOGEN AND<br />
HOST BATTLE<br />
Researchers found that in the onset and progression of sepsis, a protective<br />
mechanism normally present in the host was disabled<br />
SONIA FERNANDEZ<br />
A<br />
major cause of human disability<br />
and death throughout the<br />
world, sepsis is a condition that<br />
begins with an infection, progresses<br />
rapidly and can set off a chain of<br />
effects that result in multiple organ<br />
failure and irreparable damage to the<br />
body.<br />
Because of the condition’s rapid<br />
onset, physicians must respond<br />
immediately to the symptoms<br />
with broad-spectrum antibiotics<br />
for infection, drugs to combat<br />
inflammation and, in the more critical<br />
cases, vasopressors to manage shock.<br />
Because sepsis is so difficult to<br />
detect in its early stages, however,<br />
little has been known about how it<br />
develops. This may explain why no<br />
new effective drugs to treat sepsis<br />
have been developed in decades,<br />
while it remains one of the leading<br />
causes of hospital deaths. Sepsis also<br />
can result in serious disabilities for<br />
those who survive.<br />
Now, researchers at UC Santa<br />
Barbara, Sanford Prebys Medical<br />
Discovery Institute (SBP) in La Jolla,<br />
California, and UC San Diego have<br />
developed a method for tracking, on<br />
a molecular level, the development<br />
of sepsis. Their resulting discoveries<br />
could, in turn, lead to more advanced<br />
76 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
therapies for sepsis that reduce its<br />
mortality, minimise the lifelong effects<br />
for survivors or even prevent the<br />
cascade of life-threatening effects<br />
before it begins, while reducing the<br />
billions of dollars spent every year to<br />
treat the condition.<br />
Their paper, “Accelerated Aging and<br />
Clearance of Host Anti-inflammatory<br />
Enzymes by Discrete Pathogens Fuels<br />
Sepsis” is published in the journal Cell<br />
Host & Microbe.<br />
“Sepsis is generally thought of as<br />
one singular disease, especially as<br />
it enters late stages,” said UC Santa<br />
Barbara biology professor Jamey<br />
Marth, who is the director of the<br />
campus’s Center for Nanomedicine,<br />
in addition to being a professor at<br />
SBP. “At this point, inflammation,<br />
and coagulopathy have caused the<br />
vascular and organ damage common<br />
to severe sepsis and septic shock. Our<br />
comparative approach to monitor the<br />
onset and progression of sepsis at the<br />
molecular level supports the view that<br />
there are different molecular pathways<br />
in sepsis depending on host responses<br />
to different pathogens.”<br />
New sepsis model<br />
In contrast to previous experimental<br />
models of sepsis, which typically<br />
release multiple and incompletely<br />
identified pathogens into the<br />
bloodstream, Marth and his team<br />
developed a more quantitative<br />
method that tracked the pathogen<br />
and host over time, beginning with<br />
infection. This method generated a<br />
reproducible protocol that allowed<br />
the scientists to map host responses,<br />
in this case to five different human<br />
pathogens representing common<br />
strains and isolates from different<br />
patients.<br />
In the study, Marth’s team found<br />
that in the onset and progression of<br />
sepsis caused by Salmonella or E. coli,<br />
a protective mechanism<br />
normally present in the host was<br />
disabled. The mechanism that the<br />
bacteria used included a means to<br />
accelerate the molecular aging and<br />
clearance of two anti-inflammatory<br />
alkaline phosphatase (AP) enzymes,<br />
called TNAP and IAP, which are<br />
normally present in the host<br />
bloodstream.<br />
This was achieved through<br />
pathogen activation of the host’s own<br />
Toll-like receptor-4 (TLR-4), and both<br />
pathogens were thus able to induce<br />
inflammatory compounds and reduce<br />
the likelihood of host survival. The<br />
scientists found that boosting the<br />
level of protective anti-inflammatory<br />
AP activity or using neuraminidase<br />
inhibitors to block the downstream<br />
IT’S POSSIBLE THAT SEPSIS<br />
IS SIMILAR TO CANCER, IN<br />
THAT WE NOW KNOW THAT<br />
CANCER IS A NOT A SINGLE<br />
DISEASE BUT REPRESENTS<br />
HUNDREDS OF DISEASES AT<br />
THE MOLECULAR LEVEL.<br />
effect of TLR-4 activation on NEU1<br />
and NEU3 induction were both<br />
highly therapeutic approaches as<br />
inflammatory markers were reduced<br />
and host survival increased —<br />
indicating a potential direction for drug<br />
development.<br />
“It has been known that AP<br />
isozymes can reduce inflammation<br />
in the context of some diseases and<br />
pathogens — indeed AP is currently in<br />
clinical trials focused on inflammatory<br />
diseases, including colitis and sepsis,”<br />
said Won Ho Yang, Ph.D., lead author<br />
and a senior scientist in the Marth<br />
laboratory at both UCSB and SBP.<br />
“This study shows that the pathogen is<br />
interacting with the host to disable a<br />
protective response. The findings also<br />
demonstrate how both pathogen and<br />
host battle each other by altering the<br />
rates of protein aging and clearance<br />
— which itself is a newly discovered<br />
regulatory mechanism we recently<br />
reported that controls the half-lives of<br />
proteins in the blood.”<br />
In contrast, these responses<br />
weren’t seen in infections caused<br />
by other bacteria tested, including<br />
methicillin-resistant Staphylococcus<br />
aureus (MRSA) and Streptococcus<br />
pneumoniae. The different host<br />
responses, in this case, appeared<br />
divided between Gram-positive<br />
and Gram-negative bacteria, which<br />
describes the existence or the absence<br />
of an inflammatory compound found<br />
on Gram-negative strains.<br />
“We are continuing to map and<br />
compare host responses to different<br />
pathogens in sepsis, using state-ofthe-art<br />
technical approaches, and<br />
hope to ultimately stratify the<br />
disease,” said Marth, who is the<br />
Professor of Biochemistry and<br />
Molecular Biology at UC Santa Barbara,<br />
as well as the Mellichamp Chair of<br />
Systems Biology.<br />
“It’s possible that sepsis is similar<br />
to cancer, in that we now know that<br />
cancer is a not a single disease but<br />
represents hundreds of diseases at the<br />
molecular level.”<br />
Research on this project was also<br />
conducted by Douglas M. Heithoff,<br />
Peter V. Aziz, Benjamin Haslund-<br />
Gourley and Michael J. Mahan, SBP<br />
and UC Santa Barbara; Julia S.<br />
Westman, Sonoko Narisawa, Anthony<br />
B. Pinkerton and José Luis Millán, SBP;<br />
and Victor Nizet, M.D., UC San Diego.<br />
The research was supported by<br />
National Institutes of Health (NIH)<br />
Heart, Lung, and Blood Institute (HLBI)<br />
grants HL125352 and HL131474.<br />
Additional support was provided<br />
by the Swedish Research Council<br />
2017-00192 and the Wille Family<br />
Foundation.<br />
—Reproduced with permission<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 77
orthopaedics<br />
REPAIRING<br />
ROTATOR CUFF<br />
Rotator cuff tear should be treated<br />
aggressively to prevent its return<br />
DR. ADITYA SAI KADAVKOLAN<br />
The shoulder is a ball and socket<br />
joint formed between the upper<br />
end of the arm bone and the<br />
shoulder blade. It is surrounded by<br />
a group of muscles called the<br />
rotator cuff; there are in all four<br />
muscles that constitute the<br />
rotator cuff group. The muscles<br />
form fibrous structures called<br />
tendons, which insert into the<br />
bone. The muscle has a very<br />
good blood supply whereas<br />
the tendons have a poor<br />
blood supply and that<br />
has implications in injury healing.<br />
The function of the rotator cuff<br />
muscles is two fold:<br />
Movement of the shoulder joint<br />
Stabilization of the shoulder joint<br />
The rotator cuff muscles glide<br />
under a bone called the acromion,<br />
which is an extension of your shoulder<br />
blade. In any population, there are<br />
broadly three variants of the acromion:<br />
a) Flat b) Curved c) Congenitally<br />
abnormal or hooked.<br />
Abnormal acromion morphology or<br />
conditions called scapular dyskinesia<br />
can cause increased contact between<br />
the acromion and the rotator cuff,<br />
leading to tendinitis or tear.<br />
Injuries like a fall on an<br />
outstretched hand or a fall on the<br />
shoulder can also lead to rotator cuff<br />
tears.<br />
Symptoms<br />
• Pain<br />
• Pain in the night<br />
• Difficulty in reaching behind the back<br />
or reaching for the top shelf<br />
Stiffness<br />
Many a time, shoulder pain due to<br />
rotator cuff tears is misdiagnosed as a<br />
frozen shoulder. A frozen shoulder, per<br />
se, is an entity where there is a global<br />
restriction in shoulder movement in<br />
spite of the absence of any muscle<br />
tear or any cartilage related issues.<br />
A rotator cuff tear has a poor<br />
tendency to heal as discussed<br />
previously because of a poor blood<br />
supply to the tendon.<br />
Treatment<br />
Surgical repair of acute / post-injury<br />
78 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
otator cuff tears has been shown<br />
to have excellent results and is the<br />
preferred line of treatment. Due<br />
to advances in technology, these<br />
procedures can be done through<br />
arthroscopic surgery, which restores<br />
the normal biomechanical function<br />
of the shoulder joint. With good<br />
physiotherapy and rehabilitation,<br />
individuals are able to get back to<br />
normal levels of function at the end of<br />
a certain period of time.<br />
For rotator cuff tears that are a<br />
result of impingement or abnormal<br />
morphology of the acromion or caused<br />
by an abnormal shoulder posture,<br />
an initial trial of a non-operative<br />
treatment can be given, with careful<br />
observation of shoulder function over<br />
a period of 3 months. If there is no<br />
improvement in symptoms over a<br />
period of time, then surgical treatment<br />
is a better option.<br />
Non-surgical treatment essentially<br />
consists of physiotherapy and<br />
rehabilitation; there is no role for<br />
medicines in rotator cuff tears other<br />
than to control the pain. Physiotherapy<br />
and rehabilitation improve the<br />
shoulder biomechanics and the intact<br />
tendons compensate for the deficient<br />
rotator cuff. However, it does not<br />
lead to a healing of rotator cuff tears.<br />
Physiotherapy and rehabilitation<br />
can improve shoulder function to a<br />
percentage of normal, but cannot<br />
entirely restore normal function and<br />
also need periodic follow up. Moreover,<br />
there’s a risk of the disease worsening<br />
in the future. Rotator cuff tears can<br />
become bigger and tendon/muscle<br />
quality can deteriorate, precluding a<br />
surgical repair.<br />
Neglected rotator cuff tears can<br />
lead to an increase in the size of<br />
the muscle tear and destabilize the<br />
shoulder joint over a period of time<br />
in what is called cuff tear arthropathy.<br />
Individuals with these issues are not<br />
able to lift the arm above the shoulder<br />
level. Some individuals develop what<br />
is termed a pseudoparalysis where,<br />
although no paralysis is present, they<br />
are not able to move the shoulder due<br />
to deficient muscle function.<br />
SUPERIOR RECONSTRUCTION<br />
TORN<br />
IRREPARABLE<br />
CUFF<br />
NEGLECTED ROTATOR CUFF<br />
TEARS OVER A PERIOD<br />
OF TIME CAN LEAD TO AN<br />
INCREASE IN THE SIZE OF<br />
THE MUSCLE TEAR AND<br />
DESTABILIZE THE SHOULDER<br />
JOINT, WHAT IS CALLED<br />
CUFF TEAR ARTHROPATHY.<br />
This is a very problematic issue<br />
with regard to the shoulder joint and<br />
hence some surgeons suggest a more<br />
aggressive approach in the treatment<br />
of rotator cuff tears to prevent<br />
advanced disease.<br />
In case of massive rotator cuff<br />
tears, which are not repairable, we<br />
have two options:<br />
In younger individuals or patients<br />
less than 60 years of age, two options<br />
are generally employed to preserve<br />
the shoulder joint:<br />
a) Muscle transfers: Other<br />
functioning muscles around the<br />
shoulder girdle are substituted to aid<br />
the rotator cuff function.<br />
b) Superior reconstruction, in which<br />
the patient’s tissue from thigh/allograft<br />
tissue is introduced into the joint to<br />
stabilize the shoulder and create a<br />
new rotator cuff.<br />
These procedures can be done on<br />
SUPERIOR<br />
CAPSULAR<br />
RECONSTRUCTION<br />
WITH GRAFT<br />
selected individuals who are willing<br />
to participate in the postoperative<br />
rehabilitation programme.<br />
In individuals above 60 years of<br />
age who have massive rotator cuff<br />
tears and presence of what is known<br />
as cuff tear arthropathy, the only<br />
surgical option that gives fair result<br />
is inverse shoulder replacement. It is<br />
called inverse because the relationship<br />
between the ball and socket part of<br />
the shoulder joint is reversed; this<br />
negates the need for a functioning<br />
rotator cuff to move the shoulder.<br />
There are several treatment options<br />
available for management of rotator<br />
cuff tears, ranging from physiotherapy<br />
to rotator cuff repair to a shoulder<br />
replacement. The most important takehome<br />
message for these problematic<br />
issues is that neglecting a rotator cuff<br />
tear may come back to haunt you<br />
later; so it is better to be watchful<br />
and to be more aggressive with the<br />
treatment and participate<br />
in the rehabilitation programme<br />
actively. If treated surgically at an<br />
early stage, these interventions yield<br />
excellent results.<br />
The author is Consultant,<br />
Arthroscopy, Sports<br />
Medicine & Shoulder<br />
Surgery at Dr. LH<br />
Hiranandani Hospital,<br />
Powai, Maharashtra<br />
80 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
devices&gadgets<br />
Leica introduces<br />
microsurgery microscope<br />
Leica Microsystems has launched<br />
Provido, a multidisciplinary microsurgery<br />
microscope.<br />
Provido features FusionOptics<br />
technology that gives depth of field and<br />
detail perception at the same<br />
time. The illumination technology<br />
brings light even to deep and narrow<br />
cavities. Having the full surgical field<br />
visible at once allows for better decision<br />
making and limits interruptions from<br />
readjusting the microscope. The surgeon<br />
can focus on progressing smoothly<br />
through the procedure, according to the<br />
company.<br />
Deep and narrow channels are a daily<br />
challenge in many surgical disciplines,<br />
particularly spine and otolaryngology. The<br />
microscope integrates concentrated 300<br />
W xenon light and specially-designed<br />
Small Angle Illumination that helps limit<br />
peripheral shadows. As a result, surgeons<br />
are able to see more of the surgical field<br />
without constantly refocusing or adjusting<br />
the light. In addition, there is no longer any<br />
limitation when longer surgical instruments<br />
are required as Provido offers 600 mm of<br />
free working space.<br />
The electromagnetic brakes and<br />
balancing system enables the Provido to be<br />
positioned at the required angle with the<br />
lightest touch. For even greater precision,<br />
micro adjustments can be achieved with<br />
the XY joystick control.<br />
SpineEX lateral<br />
lumbar device for<br />
disc disease<br />
S<br />
pineEX, Inc, a medical<br />
device company has<br />
received 510(k) clearance<br />
from the US Food and Drug<br />
Administration (FDA) for<br />
its Sagittae lateral lumbar<br />
interbody fusion (LLIF) device.<br />
The LLIF procedure<br />
uses minimally invasive<br />
techniques that approach<br />
the spine from the side of<br />
the patient, allowing for a<br />
larger implant footprint, and<br />
less disruption to lower back<br />
muscles as compared to other<br />
approaches.<br />
This personalized,<br />
expandable device is<br />
designed to minimize<br />
impaction, maximize indirect<br />
decompression, and provide<br />
a large graft space optimal<br />
for lumbar fusion procedures.<br />
It provides up to 8mm of<br />
continuous in situ expansion,<br />
with up to 30° of continuous<br />
in situ lordotic adjustment.<br />
Available in five<br />
sizes,Sagittae provides<br />
several options for surgeons<br />
to address optimal sagittal<br />
balance, while minimizing<br />
burdensome implant inventory<br />
traditionally required for each<br />
procedure.<br />
LLIF devices are indicated<br />
for interbody fusion in<br />
patients with degenerative<br />
disc disease (DDD) at one or<br />
two contiguous levels from<br />
L2 to S1. DDD is defined as<br />
back pain of discogenic origin<br />
with degeneration of the disc<br />
confirmed by history and<br />
radiographic studies. These<br />
DDD patients may also have<br />
up to Grade I spondylolisthesis<br />
or retrolisthesis at the involved<br />
82 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
Zeiss laser tech to treat astigmatism<br />
Carl Zeiss Meditec’s<br />
expanding myopia<br />
treatment for patients<br />
with astigmatism received<br />
premarket approval from the<br />
USFDA.<br />
ReLEx Smile utilises a highprecision<br />
femtosecond laser<br />
to create a lenticule inside the<br />
cornea and access incision<br />
in a single treatment step.<br />
Incisions are made through<br />
microscopic-photodisruptions<br />
of tissue, created by ultrashort<br />
pulses. VisuMax laser is the<br />
first femtosecond laser to<br />
receive FDA PMA approval for<br />
the treatment of a refractive<br />
indication in addition to 510k<br />
clearances for LASIK flap,<br />
keratoplasty, and ICR.<br />
The technology behind<br />
Smile was recently featured<br />
in the scientific background<br />
on the Nobel Prize in Physics<br />
<strong>2018</strong>. Dr. Gérard Mourou and<br />
Dr. Donna Strickland were<br />
awarded the Nobel Prize<br />
for his method to generate<br />
high-intensity ultrashort<br />
optical pulses. Their invention<br />
of so-called chirped pulse<br />
amplification is essential to<br />
generate the ultrashort laser<br />
pulses of the Zeiss VisuMax<br />
femtosecond laser system,<br />
according to the company.<br />
Carl Zeiss Meditec AG<br />
is the Medical Technology<br />
Business Group of Zeiss.<br />
level(s). These patients should<br />
be skeletally mature and have<br />
completed six months of<br />
non-operative treatment, the<br />
company said.<br />
Fujifilm launches<br />
endoscopes to<br />
detect GI cancers<br />
Fujifilm India Private Limited<br />
launched a range of novel<br />
image-enhanced endoscopy<br />
products for the detection of<br />
gastro cancers.<br />
Eluxeo 7000 Series<br />
endoscopes have Blue Light<br />
Imaging (BLI)/Linked Colour<br />
Imaging (LCI) technology to<br />
aid early detection of all types<br />
of stomach cancers.<br />
Stomach cancer is the<br />
second-most common cancer<br />
among men and third-most<br />
among females in Asia. The<br />
symptoms and sign of the<br />
stomach cancer are often<br />
reported late when the<br />
disease is already in advanced<br />
stages, and the 5-year survival<br />
rate is less than 30 percent<br />
in developed countries<br />
and around 20 percent in<br />
developing countries.<br />
The company said the<br />
Eluxeo 7000 is targeted for<br />
biopsy and early alarm by<br />
helping obtain high-resolution<br />
images to detect cancers at a<br />
very early stage.<br />
Drug-eluting<br />
stent approved<br />
for PAD<br />
Boston Scientific<br />
Corporation’s drugeluting<br />
vascular stent system,<br />
specifically developed for the<br />
treatment of peripheral<br />
artery disease (PAD), has<br />
been approved by the<br />
US FDA.<br />
The Eluvia stent<br />
utilizes a drug-polymer<br />
combination to provide<br />
sustained release of<br />
the drug paclitaxel for a<br />
one-year timeframe. It is<br />
designed to prevent tissue<br />
regrowth that might otherwise<br />
block the stented artery.<br />
The approval was based<br />
on findings from the IMPERIAL<br />
trial, the first superficial<br />
femoral artery head-tohead<br />
drug-eluting stent trial<br />
evaluating the safety and<br />
efficacy of Eluvia vs Zilver PTX<br />
in 465 patients.<br />
The results of the trial<br />
showed that patients<br />
treated with the Eluvia stent<br />
experienced a significantly<br />
greater 12-month primary<br />
patency of 88.5 percent,<br />
compared to 79.5 percent in<br />
patients treated with Zilver<br />
PTX.<br />
The Eluvia stent system<br />
is built on the Innova<br />
Stent System platform,<br />
a self-expanding nitinol<br />
stent that has been designed<br />
for use in the superficial<br />
femoral and proximal popliteal<br />
arteries, the main arteries that<br />
supply blood to the legs.<br />
Self-fitting OTC<br />
hearing aid<br />
gets nod<br />
The USFDA has cleared<br />
the Bose Hearing Aid,<br />
a self-fitting hearing aid<br />
for individuals 18 years or<br />
older with perceived mild to<br />
moderate hearing impairment.<br />
This hearing aid enables<br />
users to fit, programme and<br />
control the hearing aid on<br />
their own, without assistance<br />
from a health care provider.<br />
The Bose Hearing Aid<br />
is a user-fitted wireless air<br />
conduction hearing aid. Air<br />
conduction hearing aids<br />
work by capturing sound<br />
vibrations through one or<br />
more microphones. The<br />
signal is processed, amplified,<br />
and played back through an<br />
earphone placed in the ear<br />
canal.<br />
Patients can adjust the<br />
hearing aid through a mobile<br />
application on their phone.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 83
This technology enables users<br />
to fit the hearing aid settings<br />
themselves, in real-time and<br />
in real-world environments<br />
without the assistance of a<br />
healthcare professional.<br />
In authorizing marketing<br />
of the Bose device, the FDA<br />
reviewed data from clinical<br />
studies of 125 patients, which<br />
demonstrated that outcomes<br />
with self-fitting of the Bose<br />
Hearing Aid are comparable<br />
on average to those with<br />
professional fitting of the<br />
same device with respect to<br />
the amount of amplification<br />
selected, speech in noise<br />
testing and overall benefit,<br />
the regulatory agency said<br />
announcing the approval.<br />
Neuro imaging<br />
system gets<br />
clearance in US<br />
The US Food and Drug<br />
Administration has<br />
okayed a new imaging<br />
modality augmented reality<br />
(AR) GLOW800 surgical<br />
fluorescence for vascular<br />
neurosurgery.<br />
GLOW800 allows<br />
surgeons to observe<br />
cerebral anatomy in natural<br />
colour, in combination with<br />
ICG (Indocyanine Green),<br />
augmented by real-time<br />
vascular flow in a single image,<br />
with full depth perception.<br />
It provides the surgeon<br />
with a complete view of<br />
anatomy and physiology to<br />
support crucial decisions<br />
and actions during vascular<br />
neurosurgery.<br />
GLOW800 AR<br />
fluorescence is the first of<br />
many imaging modalities that<br />
will be based on the GLOW<br />
AR platform. GLOW AR<br />
modalities can be fully<br />
integrated into the ARveo<br />
<strong>digital</strong> augmented reality<br />
microscope, according to<br />
Leica Microsystems, the<br />
maker of the device.<br />
Certara cloudbased<br />
platform<br />
to help HCPs<br />
Certara has launched<br />
BaseCase Portal cloudbased<br />
platform that allows for<br />
the rapid creation of fullycustomizable<br />
mobile apps that<br />
connect live to mathematical<br />
models and algorithms, and<br />
help HCPs optimize treatment<br />
for individual patients.<br />
BaseCase Portal<br />
enables clinicians to use<br />
Boston Scientific launches kidney stone<br />
retrieval device<br />
Boston Scientific Corporation has<br />
launched LithoVue Empower Retrieval<br />
Deployment Device, designed to be used<br />
with the ureteroscope.<br />
The device comes with a compatible<br />
nitinol retrieval basket to enable urologists<br />
to operate a ureteroscope and basket<br />
simultaneously when retrieving kidney<br />
stones via flexible ureteroscopy (URS).<br />
According to Boston Scientific, until<br />
now, urologists have traditionally relied<br />
on another person to operate the basket<br />
used to collect kidney stones during kidney<br />
complex scientific models<br />
and algorithms that were<br />
previously only available in<br />
research settings, to guide<br />
therapeutic decision-making.<br />
The platform keeps a strict<br />
separation between the user<br />
interface and the underlying<br />
mathematical model. This<br />
offers many benefits over<br />
the old way of doing things<br />
in which algorithms typically<br />
were hardwired into a<br />
website. On BaseCase Portal,<br />
algorithms and models can be<br />
validated and updated much<br />
more easily.<br />
BaseCase Portal also<br />
features embedded version<br />
control and release workflows,<br />
and provides an audit trail,<br />
allowing a new version of an<br />
app to be uploaded as soon<br />
as it receives the requisite<br />
stone retrieval. Turning a two-person<br />
stone basketing procedure into a singleperson<br />
procedure provides greater control<br />
for the surgeon, decreasing the risk of<br />
miscommunication during stone basketing<br />
without compromising time.<br />
Retrieving kidney stones is one of<br />
the most time-consuming steps during<br />
ureteroscopy procedures, making this<br />
an opportune area to improve physician<br />
control, address communication/<br />
coordination challenges and identify time<br />
savings, says Boston Scientific.<br />
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AUGUST <strong>2018</strong>/ FUTURE MEDICINE / 85
legal and regulatory approvals.<br />
Besides precision dosing<br />
apps, BaseCase Portal can also<br />
be used for diverse purposes<br />
such as providing education<br />
and facilitating collaboration.<br />
Examples include apps that<br />
provide product information,<br />
inform on guidelines and<br />
treatment pathways, and track<br />
the progress of global studies.<br />
As BaseCase Portal is a<br />
white label solution, it can be<br />
tailored to reflect each clients’<br />
brand identity, Certara informs.<br />
BTG launches<br />
cryoablation<br />
system<br />
BTG plc has announced the<br />
global launch of the ICEfx<br />
Cryoablation System. ICEfx,is<br />
an updated version of the<br />
existing Visual ICE system is<br />
designed for interventional<br />
radiologists who want to<br />
offer their patients minimally<br />
invasive treatment options.<br />
It allows physicians to<br />
provide safe and efficient<br />
cryoablation procedures,<br />
facilitating precise and<br />
effective treatment without<br />
the need for surgery or<br />
repeated radiation treatments.<br />
The advanced cryoablation<br />
technology is currently<br />
supporting a number of active<br />
clinical research studies in<br />
bone, kidney, lung, pain, and<br />
prostate, the company said.<br />
BTG Interventional<br />
Oncology delivers IO ablation<br />
solutions across multiple<br />
physician specialties.<br />
Stent to seal<br />
coronary artery<br />
tears cleared<br />
The US FDA has cleared PK<br />
Papyrus Covered Coronary<br />
Stent System, a device to<br />
treat acute coronary artery<br />
perforations or tears in the<br />
blood vessels of the heart.<br />
A coronary artery<br />
perforation can occur during<br />
Percutaneous Coronary<br />
Guide XT system for<br />
visualization of DBS<br />
Guide XT System for<br />
visualization of deep<br />
brain stimulation (DBS)<br />
was launched in Europe,<br />
said Boston Scientific<br />
Corporation.<br />
The Guide XT System<br />
is built for directionality<br />
that utilizes patientspecific<br />
anatomy and<br />
stimulation field modeling.<br />
This technology provides<br />
physicians with 3-D image<br />
planning capability and<br />
when used in conjunction<br />
with the Vercise DBS<br />
Systems, enables physicians<br />
to personalise and optimise<br />
DBS treatment.<br />
DBS treats movement<br />
disorder symptoms in<br />
patients with Parkinson’s<br />
disease, dystonia or essential<br />
tremor. The procedure<br />
stimulates a targeted<br />
Intervention (PCI) procedures.<br />
The PK Papyrus Stent<br />
System is a balloonexpandable<br />
covered coronary<br />
stent and delivery system.<br />
The device is advanced into<br />
the perforated coronary<br />
artery vessel using a balloon<br />
catheter, similar to the<br />
one used during the PCI<br />
procedure. Once the PK<br />
Papyrus stent is implanted,<br />
it provides a physical barrier<br />
to seal the tear in the artery<br />
wall while still allowing<br />
region of the brain through<br />
implanted leads that are<br />
powered by a device called<br />
an implantable pulse<br />
generator (IPG).<br />
The Guide XT System<br />
automatically detects<br />
the location of the<br />
leads, implanted by a<br />
neurosurgeon, in the<br />
imaging of the brain.<br />
Following the implant, a<br />
clinician programmes a<br />
patient’s device and the<br />
Guide XT System can be<br />
used to help visualize<br />
the stimulation field and<br />
efficiently determine the<br />
most appropriate settings for<br />
each patient.<br />
Guide XT was developed<br />
in partnership with<br />
Brainlab AG, a softwaredriven<br />
medical technology<br />
company.<br />
blood to flow through the<br />
device to the heart muscle.<br />
Successful sealing of a<br />
coronary perforation with the<br />
PK Papyrus Covered Coronary<br />
Stent System can be a lifesaving<br />
procedure without the<br />
need for open-heart surgery.<br />
The FDA reviewed realworld<br />
survey data from<br />
80 patients who received<br />
PK Papyrus stents to treat<br />
coronary artery perforations.<br />
PK Papyrus stents were<br />
successfully delivered to the<br />
perforation site in 76 of the<br />
80 patients (95 percent), and<br />
the device successfully sealed<br />
the perforation in 73 patients<br />
(91.3 percent), according to<br />
US FDA.<br />
Micro pump for<br />
Parkinson’s gets<br />
CE mark<br />
Sensile Medical AG, a<br />
Swiss medical technology<br />
company, said its wearable<br />
micro pump has received CE<br />
certification from EU.<br />
The micro pump is<br />
designed to be used in<br />
the treatment of advanced<br />
Parkinson’s disease. The<br />
handy-sized, discreet<br />
pump has got easy to use<br />
features such as automatic<br />
filling with liquid medicine.<br />
Technologies such as colour<br />
display, charging unit and data<br />
storage help enhance therapy<br />
management.<br />
A personally<br />
programmable basal profile<br />
enables treatment to be<br />
optimized for Parkinson’s<br />
patients and ensures that they<br />
receive the precise dosage<br />
they need. Likewise for the<br />
bolus rate: A patient can<br />
cause the device to deliver<br />
a bolus at just one touch of<br />
a button. Sensile’s patented<br />
SenseCore micro rotary<br />
piston pump in the device<br />
ensures safe, precise drug<br />
delivery, eliminating flow rate<br />
calculations.<br />
86 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
events<br />
MVR CANCON<strong>2018</strong> debates transition<br />
in cancer diagnosis and treatment<br />
Leading oncologists thrash out advances in GI, lung, breast and gynaec cancers<br />
DIVYA CHOYIKUTTY<br />
The first <strong>edition</strong> of International<br />
Oncology Conference-MVR CANCON<br />
<strong>2018</strong> — organized by MVR Cancer<br />
Care and Research Institute with the<br />
theme “Consensus and Controversies<br />
in Oncology” — highlighted the<br />
latest therapeutic advances such as<br />
immunotherapy.<br />
The three-day CME, which concluded<br />
at MVRCCRI Campus at Kozhikode on<br />
30thSeptember <strong>2018</strong>, was held with the<br />
support of expert faculty from Cleveland<br />
Clinic, USA. The conference involved<br />
interactive sessions on current and<br />
emerging treatment options and research<br />
in oncology, with special emphasis on<br />
gastrointestinal tract, breast, lung and<br />
gynaec-oncological tumours.<br />
“Our main aim behind organizing this<br />
conference was to give clinical updates<br />
on various cancers through specialists<br />
and scientists from around the world and<br />
to make them cognizant of and be able<br />
to implement the knowledge through<br />
their practice,” said Dr. Narayanankutty<br />
Warrier, Medical Director and organizing<br />
chairperson at MVR Cancer Research<br />
Center.<br />
PHOTO: SHIJITH<br />
Our aim was to give clinical<br />
updates on various cancers<br />
to help clinicians implement<br />
the knowledge through their<br />
practice.<br />
Dr. Narayanankutty Warrier,<br />
Organising chairperson, CANCON<br />
and Medical Director at MVR Cancer<br />
Research Center.<br />
Oncology experts from various<br />
disciplines shared their views on how<br />
the recent advances in genomics and<br />
molecular genetics are transforming<br />
cancer diagnosis and treatment<br />
approaches .<br />
“Until a decade or so ago, when a<br />
patient got cancer at a particular location,<br />
he got treated for that cancer, while<br />
now we have moved on to treating<br />
that cancer based on the mutation<br />
in a particular receptor. So essentially,<br />
we have moved from an anatomical<br />
definition of the disease to a biological<br />
definition,” said Dr. Kurt A Schalper,<br />
Pathologist at Yale University, while<br />
discussing the advancements that<br />
precision medicine has brought about in<br />
the landscape of cancer treatment.<br />
Breast cancer is historically<br />
considered to be immunologically silent.<br />
However, several preclinical and clinical<br />
studies suggest that immunotherapy<br />
has the potential to improve clinical<br />
outcomes for patients with breast cancer.<br />
“We haven’t seen all the data yet,<br />
but it appears that the first approval for<br />
immunotherapy in breast cancer will<br />
be in combination with chemotherapy.<br />
Whether this is the best way to use<br />
immunotherapy remains to be seen. It<br />
may be active by itself or in combination<br />
with other classes of drugs as well,” says<br />
Dr. Thomas Budd, Professor of Medicine,<br />
Cleveland Clinic.<br />
Talking about the lack of mandatory<br />
screening procedures that can lead to<br />
advanced-stage lung cancer consultation<br />
scenario, Dr. Rejiv Rajendranath,<br />
Consultant Oncologist at Apollo Medical<br />
Center, indicated the necessity of<br />
incorporating low-dose CT scan as an<br />
opportunistic screening technique among<br />
the high-risk individuals to help diagnose<br />
lung cancer at an early stage.<br />
A proffered paper session, an annual<br />
quiz test, a workshop coordinated by<br />
radiation therapy technologists and a<br />
palliative care programme were other<br />
highlights of the symposium. Two young<br />
doctors, who were adjudged to have<br />
come up with the best oral and poster<br />
presentation, were given the opportunity<br />
for a one-month observership at<br />
Cleveland Clinic, USA.<br />
88 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
events<br />
8th NGBT calls for greater awareness<br />
on genomics amongst clinicians<br />
Over 800 delegates from India and abroad attend the three-day meet at Jaipur<br />
The 8th annual NGBT Conference<br />
held at Jaipur emphasised the<br />
urgent need for bringing greater<br />
awareness on genomics among Indian<br />
medical and healthcare fraternity.<br />
Genetic science, which holds a critical<br />
role in the emerging healthcare<br />
scenario, is still nascent in the<br />
country, and the key reason is a lack<br />
of awareness among the healthcare<br />
providers and seekers.<br />
“Genomics is clearly the future in<br />
the healthcare space, especially when<br />
we need precision care to manage lifethreatening<br />
disorders,” said Dr Sekar<br />
Seshagiri, chair of NGBT Conference,<br />
at the inaugural meet of the three-day<br />
science event held from September<br />
30 to October 2, <strong>2018</strong>. “The science<br />
directly impacts the cost of healthcare<br />
positively by providing insights to<br />
deliver personalized care to patients.”<br />
NextGen Genomics, Biology,<br />
Bioinformatics and Technologies<br />
(NGBT), organised by SciGenom<br />
Research Foundation, a not-for-profit<br />
organization dedicated to promoting<br />
PHOTOS: UMESH GOSWAMI<br />
Snakebite<br />
cure<br />
-A revisit<br />
One of the key highlights of <strong>2018</strong><br />
Conference was the "Live and Let<br />
Live: Snakebite Cure Symposia" that<br />
brought together experts on snakes and<br />
snake bite with a mission to find better<br />
treatments for snake bites.<br />
Dr. Manjunatha Kini, NUS, Singapore,<br />
organised a special symposium with the<br />
theme ‘Live and Let Live’.<br />
“Snake venoms are complex mixtures<br />
of lethal and pharmacologicallyactive<br />
proteins and polypeptides that<br />
contribute to both immobilization and<br />
digestion of prey. The study of venom<br />
proteins has expanded not just our<br />
understanding of venom toxicity, but also<br />
the knowledge of normal and disease<br />
states in human physiology,” said Kini,<br />
while presenting a paper “From Toxins<br />
to Therapeutics: Contradictory Roles of<br />
Snake Venom Toxins that Destroy Life on<br />
One Hand and Gives Life on the Other”<br />
In many cases, the study of snake<br />
venom has led to the development<br />
of powerful research tools, diagnostic<br />
techniques and pharmaceutical<br />
drugs. In the talk, he highlighted the<br />
contribution of snake venom toxins in the<br />
development of life-saving cardiovascular<br />
drugs.<br />
90 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
science in India through research and<br />
education, was attended by over 800<br />
delegates.<br />
One of the marquee life sciences<br />
conferences organised in India, NGBT<br />
this time had 12 keynote lectures and<br />
80 talks by speakers representing<br />
various scientific organisations from<br />
across the world. It showcased<br />
applications of NextGen sequencing<br />
and genomic technologies for basic<br />
and translational science in various<br />
areas of biology — including human<br />
genetics, drug discovery, clinical<br />
medicine, biomarkers, diagnostics and<br />
animal, plant and agricultural sciences.<br />
It also covered basic biology, cellular<br />
signalling, cancer and plant biology.<br />
“The genomics industry is still at a<br />
nascent stage in India. While genomic<br />
profiling is the way forward for<br />
healthcare, we need to create ample<br />
awareness in the medical community<br />
to leverage its potential,” said Sam<br />
Santhosh, Trustee, SGRF and Founder<br />
& Chairman, MedGenome, a leading<br />
US-India genomic research and<br />
diagnostics organisation.<br />
According to Sam Santhosh, NGBT<br />
conference provides a platform that<br />
brings together accomplished national<br />
and international speakers, thinkers<br />
and thought leaders who shape the<br />
course of scientific discovery, research<br />
and innovation. India, with its huge<br />
biodiversity and genetic pool, can<br />
contribute much more to the world’s<br />
Genomics industry is still<br />
at a nascent stage in India.<br />
While genomic profiling<br />
is the way forward for<br />
healthcare, we need to<br />
create ample awareness<br />
amongst medical community<br />
to leverage its potential.<br />
Sam Santhosh<br />
Trustee, SGRF<br />
genomic database and to the growth<br />
of future medicine.<br />
“The Conference also provides an<br />
environment of exchange of ideas<br />
and provides opportunities for people<br />
to form collaborations, and is an<br />
ideal platform to share knowledge<br />
and find out about the new and<br />
emerging technologies in biology and<br />
biology-enabling technology areas<br />
like genomics. Such forums help in<br />
understanding the real-life challenges<br />
and the ways to address them by<br />
engaging renowned experts from<br />
across the globe,” he added.<br />
NGBT Jaipur was hosted<br />
in collaboration with Toronto<br />
Recombinant Antibody Centre (TRAC),<br />
Canada; Birla Institute of Scientific<br />
Research (BISR), Jaipur; Rajasthan<br />
University of Health Sciences (RUHS),<br />
Jaipur; Eternal Heart Care Centre &<br />
Research Institute (EHCC), Jaipur; SMS<br />
Medical College Hospital (SMSMC),<br />
Jaipur; and Institute of Bioinformatics<br />
(IOB), Bengaluru.<br />
It also featured technology<br />
leaders from institutions like National<br />
University of Singapore, University of<br />
Toronto, University of Montreal, Pacific<br />
Biosciences, MedGenome, Genentech,<br />
Indian Institute of Science, BGI, Centre<br />
for Cellular & Molecular Biology<br />
(CCMB), Johns Hopkins University, 10X<br />
Genomics, Nature Genetics, National<br />
Institute of Biomedical Genomics,<br />
REVOLUTION Medicines and others<br />
from across the world.<br />
Dr. Kuldeep Singh, Director ICAR-<br />
National Bureau of Plant Genetic<br />
Resources, New Delhi, has been<br />
awarded the <strong>2018</strong> SGRF Excellence in<br />
Science Award.<br />
SGRF had also announced over<br />
100 “meeting scholarships” for<br />
students pursuing scientific research.<br />
The recipients of the scholarship were<br />
selected based on abstracts submitted<br />
for the conference.<br />
Using a combined toxicovenomics<br />
and phage display approach, scientist<br />
from the Technical University of<br />
Denmark could develop an experimental<br />
recombinant antivenom based<br />
on a cocktail of fully human antiimmunoglobulin<br />
G (IgG) monoclonal<br />
antibodies that are capable of<br />
neutralising the dendrotoxin mediated<br />
neurotoxicity of Black Mamba whole<br />
venom in a rodent model, said Dr<br />
Andreas H Laustsen of Denmark.<br />
This is the first report on the<br />
development of a fully-human<br />
monoclonal IgGs against animal toxins as<br />
well as the first use of oligoclonal human<br />
IgG mixture experimental snakebite<br />
envenoming,” according to Laustesen of<br />
Technical University of Denmark<br />
Other participants at the symposium<br />
included Kristen Wiley from Kentucky<br />
Reptile Zoo, US; Priyanka Kadam,<br />
Snakebite Healing and Education Society<br />
Maharashtra, India; Ajay Kartik, Madras<br />
Crocodile Bank Trust; Sadanand Raut,<br />
Vighnahar Foundation, Narayangaon,<br />
Maharashtra; Dr. Sekhar Seshagiri,<br />
Genentech, San Fransisco, USA; Dr. Jay<br />
Fox, University of Virginia, Charlottesville,<br />
USA; Dr. Robin Doley, Tezpur University,<br />
Assam; Dr. Viswanath BS, Mysore<br />
University, Karnataka; Dr. Kemparaju K,<br />
Mysore University, Karnataka; Dr. Dev<br />
Sidhu, University of Toronto, Canada;<br />
Dr. Gopi Kadiyala, Kyntox Biotech India<br />
Pvt. Ltd, Banglore and Dr. Omesh Bharti,<br />
Indira Gandhi Medical College, Shimla.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 91
essay<br />
CRISPR/CAS 9- A<br />
POWERFUL GENE<br />
EDITING TOOL<br />
Genome editing represents a potentially effective<br />
means of eliminating the genetic cause of several<br />
diseases<br />
CONFERENCE<br />
<strong>2018</strong><br />
competition<br />
Binata is pursuing Ph.D<br />
from All India Institute of<br />
Medical Sciences (AIIMS),<br />
New Delhi)<br />
binata.marik@gmail.com<br />
BINATA MARIK<br />
CRISPR (Clustered regularly<br />
interspaced short palindromic<br />
repeats)/Cas9 (CRISPR associated<br />
protein 9) mediated genome editing<br />
has emerged as a promising tool for<br />
the correction of genetic disorders.<br />
CRISPR-Cas9 is a part of the adaptive<br />
immune system in bacterial species,<br />
which recognizes foreign DNA and<br />
destroys it. There are various types of<br />
CRISPR-Cas systems in prokaryotes but<br />
only components of type II CRISPR are<br />
employed in genome editing. A CRISPR<br />
array is composed of a series of repeats<br />
interspaced by spacer DNA sequences<br />
derived from invading viral genomes.<br />
The CRISPR immune system protects<br />
bacteria from repeated viral attack via<br />
three basic steps: (a) adaptation, (b)<br />
production of CRISPR RNA (crRNA)<br />
and (c) targeting viral genome. During<br />
this immune response, following the<br />
exposure to invading genetic material<br />
from phages, short fragments of the<br />
foreign DNA are integrated into the<br />
CRISPR repeat-spacer array in the host<br />
chromosome as new spacers, thereby<br />
providing a genetic record of the<br />
previous infection that allows the host<br />
to prevent future invasion by the same<br />
species. Subsequent transcription of the<br />
CRISPR array and enzymatic processing<br />
of precursor-CRISPR transcripts through<br />
endonucleolytic cleavage produce<br />
short mature CRISPR RNAs (crRNAs).<br />
At the 5’ end, the crRNA contains the<br />
spacer, a short segment of RNA that is<br />
complementary to a sequence from the<br />
foreign DNA, and the 3’ end contains a<br />
piece of the CRISPR repeat sequence.<br />
Endonucleolytic cleavage<br />
Upon second or consecutive infections,<br />
the hybridization of crRNA spacer and<br />
complementary foreign DNA sequence<br />
occurs, which triggers sequence-specific<br />
destruction of the foreign DNA or RNA<br />
by Cas nucleases. Cas9, which cleaves<br />
the foreign genetic material, is a large<br />
(1,368-amino-acid) DNA endonuclease. It<br />
is composed of:<br />
1. Two distinct nuclease domains:<br />
HNH and RuvC,<br />
2. Single guide RNA sequence<br />
(sgRNA): A dual RNA sequence made up<br />
of CRISPR-RNA (crRNA) and transcribed<br />
crRNA (tracrRNA).<br />
Cas9 cuts double-stranded DNA<br />
(dsDNA) complementary to 20<br />
nucleotides of guide RNA sequence after<br />
recognizing Protospacer Adjacent Motif<br />
(PAM) sequence. PAM is a component of<br />
viral DNA and is usually composed of 3<br />
base pair (bp) sequence (NAG or NGG).<br />
The PAM sequence of the invading<br />
bacteriophage that Streptococcus<br />
pyogenes Cas9 recognizes as NAG or<br />
NGG, also corresponds to the universal<br />
splice acceptor sequence (AG) and<br />
donor sequences (GG). Therefore,<br />
directing Cas9 to the splice sites which<br />
92 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
will make a double strand break of<br />
DNA can allow deletion of an exon of a<br />
gene containing mutations and thereby<br />
restoring the function of the gene. Thus,<br />
Genome editing with CRISPR/Cas9 has<br />
become a popular genome-editing tool<br />
for correcting or mitigating diseasecausing<br />
mutations. It works by taking the<br />
advantage of the introduction of doublestrand<br />
breaks in DNA at a desired site<br />
in the genome. The DNA break is useful<br />
because it activates the cell’s natural<br />
DNA repair machinery, which significantly<br />
improves the efficiency of introducing<br />
alterations into the genome. Thus,<br />
genome editing makes it simpler to<br />
develop animal models of disease and<br />
possible clinical applications in patients<br />
with genetic disorders. The cell has two<br />
important ways of repairing DNA breaks.<br />
The first method is nonhomologous end<br />
joining (NHEJ), in which the free ends<br />
from the DNA break are simply rejoined.<br />
This method is the default repair<br />
pathway operating in all cells at all the<br />
time. But, NHEJ is an error-prone process<br />
and it can result in the random addition<br />
or deletion of DNA base pairs. Therefore,<br />
NHEJ can introduce frameshift mutations<br />
(deletions and insertions which disrupt<br />
the open reading frame of a gene) into<br />
a targeted gene, thereby disrupting (i.e<br />
knocking out) the function of the gene.<br />
Alternatively, the introduction of 2 DNA<br />
breaks on the same chromosome will<br />
often result in the deletion of entire DNA<br />
base pairs between the DNA breaks. This<br />
principle can be used to delete part of<br />
a gene, a whole gene, or a portion of<br />
a chromosome with many genes. The<br />
second method by which the cell can<br />
repair a DNA break is homology-directed<br />
repair (HDR), which takes place only in<br />
proliferating cells. Homology-directed<br />
repair requires a repair template that<br />
has sequences that is complementary<br />
to the DNA sequence near the site<br />
of the DNA break. If one introduces a<br />
custom-made DNA repair template into<br />
the cell that has matching sequences<br />
but also has the desired alteration, HDR<br />
can use the custom-made template to<br />
stably introduce the alteration into the<br />
genome. But, homology-directed repair<br />
has 3 disadvantages in comparison to<br />
NHEJ. First, HDR requires the delivery of<br />
an extra custom- made template into<br />
the target cells, whereas NHEJ does not.<br />
Second, HDR generally occurs in less<br />
frequently than NHEJ in proliferating<br />
cells. Third, HDR does not occur in nonproliferating<br />
cells, such as postnatal<br />
cardiomyocytes and neurons.<br />
DMD correction<br />
CRISPR-Cas9 has created a revolution<br />
in which researchers around the world<br />
are using the technology for studying<br />
genomic rearrangements and the<br />
progression of cancers or other diseases<br />
and potentially correcting genetic<br />
mutations responsible for inherited<br />
THE LARGE SIZE AND<br />
COMPLICATED STRUCTURE OF<br />
THE DMD GENE CONTRIBUTE<br />
TO ITS HIGH RATE OF<br />
SPONTANEOUS MUTATION.<br />
disorders such as Duchenne Muscular<br />
Dystrophy. This disorder is caused due<br />
to mutations in dystrophin (DMD) gene<br />
and people with this disorder rarely live<br />
past their 20s because they die due to<br />
heart failure. The DMD gene is the largest<br />
known gene in the human genome,<br />
encompassing approximately 2.6 million<br />
base pairs and encoding 79 exons. The<br />
large size and complicated structure<br />
of the DMD gene contribute to its high<br />
rate of spontaneous mutation. There<br />
are ~3000 reported DMD mutations in<br />
humans, which include large deletions<br />
or duplications (~77%), small indels<br />
(~12%), and point mutations (~9%).<br />
Ousterout et al, 2015 deleted the entire<br />
336-kb genomic region flanking exons<br />
45 to 55 in human DMD myoblasts by<br />
guide RNAs targeting introns 44 and 55<br />
to correct multiple hotspot mutations in<br />
the human genome. Young et al, 2016<br />
deleted 725-kb from introns 44 to 55<br />
to restore the dystrophin open reading<br />
frame in multiple DMD patient-derived<br />
induced pluripotent stem cells (iPSCs),<br />
which contain mutations in this region.<br />
To simplify the correction of diverse<br />
DMD mutations by CRISPR/Cas9 gene<br />
editing, Long et al, <strong>2018</strong> identified guide<br />
RNAs capable of skipping the top 12<br />
exons (hotspots), which account for<br />
~60% of DMD patients. They have used<br />
human iPSCs derived three dimensional<br />
engineered heart muscles (3D-EHM) to<br />
check whether the function of patientderived<br />
induced cardiomyocytes (iCMs)<br />
(i.e the contraction of the heart muscle)<br />
has restored after genome editing.<br />
They observed that correcting only a<br />
proportion of cardiomyocytes (30%<br />
to 50%) was sufficient to rescue the<br />
mutant phenotype. Using CRISPR/Cas9<br />
in beagle puppies, Amoasii et al, <strong>2018</strong><br />
have fixed a genetic mutation that<br />
causes Duchenne Muscular Dystrophy.<br />
Researchers injected two 1-month-old<br />
beagle puppies having a mutation with<br />
different doses of a virus carrying the<br />
gene-editing machinery. They measured<br />
dystrophin levels in different muscles<br />
after eight weeks. Levels of the protein<br />
increased in every muscle group that the<br />
team studied, but the effect was variable.<br />
Dystrophin levels in the heart of the<br />
dog receiving the higher dose were 92<br />
percent of what was present in healthy<br />
pups without the mutation, but levels in<br />
the dog’s tongue were only 5 percent<br />
in comparison to normal. Therefore,<br />
these studies suggested that genome<br />
editing represents a potentially effective<br />
means of eliminating the genetic cause<br />
and correcting the muscle and cardiac<br />
abnormalities associated with DMD. One<br />
key concern for the CRISPR/Cas9 system<br />
is specificity because off-target effects<br />
may cause unexpected mutations in<br />
the genome that may lead to cancer.<br />
Several approaches have been reported<br />
to minimize potential off-target effects<br />
and/or to improve the specificity of the<br />
CRISPR/Cas9 system, including titration<br />
of dosage of Cas9 and guide RNA, and<br />
high-fidelity Cas9. Therefore, CRISPR/<br />
Cas9 has proved to be a powerful<br />
tool for genome editing research.<br />
Further optimization and improvement<br />
of this method are needed to meet<br />
the requirements of gene therapy<br />
application.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 93
calendar<br />
Upcoming conferences<br />
<strong>NOVEMBER</strong><br />
1-3 SKULL BASE SURGERY<br />
Annual Conference of Skull<br />
Base Surgery Society of India<br />
(SKULLBASECON)<br />
Ludhiana<br />
UROLOGY<br />
Annual Conference of Urological<br />
Society of India East Zone<br />
Chapter (ACUSIEZC)<br />
Ahmedabadt<br />
TELEMEDICINE<br />
Telemedicon <strong>2018</strong> - 14th<br />
International Conference of<br />
Telemedicine Society of India<br />
Amravati, Andhra Pradesh<br />
10-11 SLEEP APNEA<br />
AOCMF Seminar - Advances in<br />
Sleep Apnea and Orthognathic<br />
Chennai, Tamil Nadu<br />
14-16 RESPIRATORYDRUG<br />
DELIVERY<br />
Respiratory Drug Delivery (RDD)<br />
Asia Conference <strong>2018</strong><br />
Kochi, Kerala<br />
15-18<br />
PAEDIATRIC NEUROLOGY<br />
15th International Child<br />
Neurology Congress<br />
Mumbai, Maharashtra<br />
15-18 IPS<br />
46th IPS National Conference<br />
Mangalore <strong>2018</strong><br />
Mangalore, Karnataka<br />
19-22 PATHOLOGY<br />
International Conference on<br />
Microbiome Research (ICMR)<br />
Pune<br />
22-25<br />
NUCLEAR CARDIOLOGY<br />
American Society of Nuclear<br />
Cardiology (ASNC) Society of<br />
Nuclear Medicine<br />
Chandigarh, Chandigarh<br />
NUCLEAR CARDIOLOGY<br />
Annual Conference of<br />
Cardiological Society of India<br />
Mumbai<br />
25-29 ANAESTHESIOLOGY<br />
Conference of Indian Society of<br />
Anaesthesiologists<br />
Agra<br />
28-29<br />
28-<br />
Dec 1<br />
INFECTIOUS DISEASES<br />
World Congress on Infectious<br />
Diseases and Antibiotics<br />
Bengaluru<br />
GASTROENTEROLOGY<br />
Annual Conference of Indian<br />
Society of Gastroenterology<br />
(CISG)<br />
Ernakulam<br />
29-30 GENOMICS<br />
Next Generation Sequencing in<br />
Clinical Genomics<br />
Bengaluru<br />
29-<br />
Dec 2<br />
30-<br />
Dec 4<br />
OPHTHALMOLOGY<br />
Conference of Vitreo Retinal<br />
Society<br />
Jaipur<br />
BURN INJURIES<br />
19th Congress of the<br />
International Society for Burn<br />
Injuries (ISBI)<br />
Gurugram, Delhi<br />
DECEMBER<br />
4-7 BIOETHICS<br />
World Congress of Bioethics<br />
(WCB)<br />
New Delhi<br />
5-7 BIOETHICS<br />
World Congress Of Bioethics<br />
(WCB)<br />
Bengaluru<br />
7-8 CLINICAL RESEARCH<br />
SCDM India Conferenc<br />
Hyderabad<br />
6-9 RHEUMATOLOGY<br />
IRACON<br />
Guwahati<br />
13-16 NEUROLOGY<br />
Conference of Neurological<br />
Society of India (NSICON)<br />
Jaipur<br />
NEONATOLOGY<br />
Annual Convention of National<br />
Neonatology Forum (NEOCON)<br />
Varanasi<br />
14-16 GYENAECOLOGY<br />
Annual Congress of Indian<br />
Fertility Society (Fertivision)<br />
Kochi<br />
RADIOLOGY<br />
Annual State Conference of the<br />
TN & PY Chapter of IRIA<br />
Chennai<br />
PEDIATRIC UROLOGY<br />
Asia-Pacific Association Of<br />
Pediatric Urologists Congress<br />
(APAPU)<br />
New Delhi<br />
20-23 NEPHROLOGY<br />
Indian Society of Nephrology<br />
Conference (ISNCON)<br />
Bhubaneswar<br />
26-30 SURGERY<br />
Conference of Association of<br />
Surgeons of India<br />
Chennai<br />
JANUARY<br />
4-6 CLINICAL RESEARCH<br />
Joint International Conference<br />
Ahmedabad<br />
NEUROLOGY<br />
Neuro Updates Conference<br />
Chennai<br />
9-11 MENTAL HEALTH<br />
DYUTI International Symposium<br />
on Evidences in Global Mental<br />
Health<br />
Kakkanad<br />
17-19<br />
VENOUS DISEASES<br />
Vaicon<br />
Hyderabad<br />
17-20 DERMATOLOGY<br />
National Conference of Indian<br />
Association of Dermatologists,<br />
Venereologists & Leprologists<br />
Bengaluru<br />
RADIOLOGY<br />
Annual Conference of the<br />
Indian Radiological and Imaging<br />
Association (IRIA)<br />
Chandigarh<br />
23-26 UROLOGY<br />
Annual National Conference of<br />
The Urological Society of India<br />
Bhubaneswar<br />
24-26 GASTRO-ENTEROLOGY<br />
National Conference on Obesity<br />
and Metabolic Surgery Society<br />
of India<br />
Kolkata<br />
24-27 SURGERY<br />
Annual Conference of The<br />
Asociation of Spine Surgeons of<br />
India (ASSICON)<br />
Ahmedabad<br />
25-27 NEUROSURGERY<br />
International Conference on<br />
Complications in Neurosurgery<br />
(ICCN)<br />
Mumbai<br />
30-31<br />
31-<br />
Feb2<br />
ONCOLOGY<br />
International Conference on<br />
Cancer Rehabilitation (CAN-<br />
REHAB)<br />
Mumbai<br />
CRITICAL CARE<br />
Annual National Conference of<br />
Indian Society of Critical Care<br />
Medicine (CRITICARE)<br />
Mumbai<br />
PSYCHIATRY<br />
Annual National Conference of<br />
Indian Psychiatric Society<br />
Lucknow<br />
The announced dates of the conferences may change<br />
94 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
ook review<br />
A REBUTTAL TO<br />
VACCINE NAYSAYERS<br />
BETWEEN<br />
HOPE AND FEAR:<br />
A HISTORY OF<br />
VACCINE AND HUMAN<br />
IMMUNITY<br />
By Michael Kinch<br />
Pp 360 Pegasus Books<br />
Gardasil, a vaccine against cervical<br />
cancer, has been under attack for<br />
some time. The concern is not against<br />
its safety. But people think that the vaccine<br />
encourages promiscuous behaviour among<br />
adolescents: “Now that teenagers know they<br />
are not going to get cervical cancer, they’re<br />
going to be more sexually active.” Gardasil is<br />
simply the latest target of vaccine fears.<br />
The hostility to vaccines is as old as<br />
the history of the vaccine itself. Every<br />
introduction of a new vaccine met with some<br />
sort of skepticism throughout the history.<br />
But the most significant question today<br />
is whether the anti-vaccine movement is<br />
gaining ground. One look at social media<br />
will strengthen this suspicion. Anti-vaccine<br />
messages are certainly outperforming those<br />
from pro-vaccinators with a hefty margin. In<br />
a recent report, the CDC found that<br />
the percentage of 2-year-olds who had<br />
received no vaccinations grew to 1.3%<br />
among those born in 2015, up from 0.9% for<br />
those born in 2011. Supporters of vaccination<br />
are starting to lose, despite overwhelming<br />
evidence on the safety and efficacy of the<br />
technique.<br />
The biggest thing is to get access to the<br />
facts. The real facts, not what you see on<br />
Facebook or Twitter, according to Michael<br />
Kinch, the author of the book - Between<br />
Hope and Fear: A History of Vaccine and<br />
Human Immunity.<br />
Tracing the history of vaccines alongside<br />
the history of deadly pathogens and the role<br />
vaccines have played in human history, the<br />
book shines light on the history of vaccine<br />
hostility too.<br />
In his book, Kinch notes that terrifying<br />
ailments that have threatened humanity<br />
since time immemorial are staging a<br />
comeback, often infecting an unwitting<br />
population that assumes they have already<br />
been protected.<br />
Unfortunately, most of the criticism<br />
against the vaccine are centred around the<br />
unfounded notions about the link between<br />
vaccination and autism. Although all these<br />
arguments have been scoffed at with the<br />
backing of sound science and the safety of<br />
vaccines have been repeatedly underscored,<br />
negative sentiments have been winning the<br />
day. Now, these present very real dangers to<br />
ANTI-VACCINE PROPAGANDA<br />
ORIGINATES OFTEN FROM A<br />
RELATIVELY SMALL NUMBER<br />
OF HIGHLY EDUCATED AND<br />
POWERFUL ELITES, AND NOT<br />
FROM THE INNER CITY OR<br />
RURAL COUNTRYSIDE.<br />
our societies and our families.<br />
Most shockingly, anti-vaccine propaganda<br />
originates often from a relatively small<br />
number of highly educated and powerful<br />
elites, and not from the inner city or rural<br />
countryside. The waves of discoveries of<br />
life-saving vaccines are contrasted with an<br />
irrational rejection by fringe elements in the<br />
public.<br />
But Kinch is optimistic that it may not<br />
be a daunting task to dispel the ignorance<br />
of the vaccine naysayers with the objective<br />
evidence showing that other than clean<br />
water, nothing has saved more human lives<br />
than vaccines.<br />
<strong>NOVEMBER</strong> <strong>2018</strong> / FUTURE MEDICINE / 95
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96 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
DON’T RESTRICT YOURSELF<br />
TO ‘DOTCOM’ ERA<br />
PROF. BHASKAR D GOOLAB<br />
Professor, Dept. of Obstetrics & Gynaecology, University of Witwatersrand, Johannesburg<br />
One of the serious concerns about the new<br />
generation in our profession is obviously the<br />
increasing tendency to blindly follow modern<br />
clinical procedures. And, when it occurs at the<br />
cost of patient safety and comfort, it is all the more<br />
worrying.<br />
Completely ignoring time-tested conventional<br />
methods, which are often much safer and better in<br />
given circumstances, is not a good practice even in<br />
the ‘dotcom’ era: A small peep into the past is always<br />
rewarding.<br />
It is a general trend of late that many clinical<br />
procedures get over-mechanised in the name of<br />
sophistication and technological “advancements”.<br />
As we all know, many such trends do not often<br />
contribute to a better clinical outcome, but merely<br />
satisfy the of the promotion of the so-called<br />
sophistication.<br />
For instance, in gynaecological surgeries, the<br />
latest trend is to do every procedure endoscopically;<br />
rather, the young doctors learn it that way.<br />
Endoscopy is certainly a big boon to clinicians as it<br />
has made many surgical procedures easy and less<br />
invasive. In certain cases, it is necessary too. But the<br />
flip side is often an unnecessary cost escalation, and<br />
sometimes, the risks associated with electric powered<br />
scissors and other accessories.<br />
Many conventional procedures, like vaginal<br />
surgeries and bikini line incision etc., are proven to<br />
be much safer and less expensive. These procedures<br />
have been in practice for a very long time and often<br />
proved more comfortable for patients too.<br />
So, it is always good to put the patient at the<br />
centre by giving them the choice. Be wise enough<br />
to admit the good and bad of both the old and the<br />
new, and try to adopt a complementary approach,<br />
looking at what is ultimately good for the patient.<br />
And, don’t just be a ‘dotcom’ doctor.<br />
— As told to CH Unnikrishnan<br />
98 / FUTURE MEDICINE / <strong>NOVEMBER</strong> <strong>2018</strong>
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