MedicalResearch.com: Medical Research Exclusive Interviews April 28 2015

MedicalResearch.com
Exclusive Interviews with Medical Research and
Health Care Researchers from Major and Specialty Medical
Research Journals and Meetings
Editor: Marie Benz, MD
info@medicalresearch.com
April 28 2015
For Informational Purposes Only: Not for Specific Medical Advice.

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Selective Estrogen Receptor Degrader May Help Patients With Resistant ER+ Breast Cancer
MedicalResearch.com Interview with:
Presented by Dr. Maura N. Dickler MD
Associate member of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and
Weill Medical College of Cornell University in New York
• Medical Research: What is the background for this study?
• This year, breast cancer will claim the lives of nearly 40,000 women in the United States, and
up to half of these women will have a disease that is driven by the estrogen receptor.
• Although medicines have been approved for the treatment of hormone receptor-positive
breast cancer for decades, more treatment options are needed.
• Resistance to endocrine therapies causes morbidity and mortality for women with metastatic
estrogen receptor-positive (ER+) breast cancer as many patients relapse or develop
resistance to available hormonal agents via estrogen-dependent and estrogen-independent
mechanisms.
• Dual-acting investigational Selective Estrogen Receptor Degrader (SERDs) could potentially
lead to a new treatment option for people with hormone receptor-positive breast cancer and
may help overcome resistance to current anti-hormonal medicines.
• GDC-0810 is a dual-acting investigational next-generation oral SERD that works in a number
of ways to prevent estrogen fueling tumor growth. It is not only designed to target the
estrogen receptor (ER) as an antagonist, but also to cause degradation of the ER protein. In
preclinical studies, GDC-0810 was shown to induce tumor regressions in both tamoxifen
sensitive and tamoxifen resistant tumor models in vivo.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

• Medical Research: What are the main findings?
• Clinical data from the dose-escalation portion of a Phase I/IIa study evaluating GDC-0810
appears to have an acceptable safety profile with encouraging anti-tumor activity in
postmenopausal women with advanced breast cancer positive for the estrogen receptor (ER),
all of whom were previously treated with standard endocrine therapy.
• Promising anti-tumor activity was observed in 38% of patients on study for six months or
longer. At all doses tested, there was robust engagement of the estrogen receptor by GDC-
0810 as demonstrated by fluoroestradiol (FES) PET scans. Overall, the most common adverse
events of any grade related to GDC-0810 were diarrhea, nausea and fatigue.

• Medical Research: What should clinicians and patients take away from your report?
• SERDs could potentially lead to a new treatment option for women with hormone receptor-positive
breast cancer and may help overcome resistance to current anti-hormonal medicines, such as
tamoxifen, aromatase inhibitors, and fulvestrant.
• We believe these investigational next-generation oral SERDs could one day redefine the standard of
care for hormone receptor-positive breast cancer.
• New therapies, like GDC-0810, that potentially have activity against treatment-resistant tumors are
needed.
• When some women become resistant to anti-hormonal medicines and see their disease return or
worsen, preclinical and clinical data suggest that the cancer continues to be driven by the actual
estrogen receptor (not by natural hormones).
• We believe that when the SERDs bind to the estrogen receptor, they induce degradation and
turnover of the estrogen receptor so that it is eliminated from the cell. So you could hypothesize
that if the SERDs have the ability to eliminate the estrogen receptor from the cell altogether, this
may circumvent the problem of resistance.
• These small molecules have been rationally designed to enter the cell, change the shape of the
estrogen receptor, and mark it for elimination.
• Note: Philip Rosenberg from the NCI will present data at AACR reporting that the total number of
breast cancer cases in the US is forecast to be 50% greater in 2030 than it was in 2011, when
invasive and in-situ or screening-detected cancers are counted together, and this increase is driven
mostly by a marked increase in cases of estrogen receptor (ER)–positive tumors and in women older
than 70.

• Medical Research: What recommendations do you have for future research as a result of this
study?
• In the Phase II portion of the study, we are evaluating GDC-0810 in patients previously treated with
aromatase inhibitors and fulvestrant, including those with estrogen receptor mutations. We expect
to enroll approximately 140 patients.
• Randomized studies are being planned to compare GDC-0810 against other standard of care
therapies.
• Citation:
• Presented at the 2015 American Association of Cancer Research meeting
April 19 2015
• Abstract Number: 8953 Title: A first-in-human Phase I study to evaluate the oral selective estrogen
receptor (ER) degrader GDC-0810
• (ARN-810) in postmenopausal women with ER+ HER2-, advanced/metastatic breast cancer (BC)
• Author Block: Maura Dickler1, Aditya Bardia2, Ingrid Mayer3, Eric Winer4, Peter Rix5, Jeff Hager5,
Meng Chen6, Iris Chan6, Edna Chow-Maneval5, Carlos Arteaga3, Jose Baselga1. 1Memorial Sloan
Kettering Cancer Center, New York, NY; 2Massachusetts General Hospital Cancer Center, Boston,
MA; 3Vanderbilt-Ingram Cancer Center, Nashville, TN; 4Dana-Farber Cancer Institute, New York, NY;
5Seragon Pharmaceuticals, San Diego, CA; 6Genentech, Inc, South San Francisco, CA

Osteoporosis May Increase Risk of Hearing Loss
Dr. Kai-Jen Tien MD
Division of Endocrinology and Metabolism, Department of Internal Medicine
Chi Mei Medical Center, Tainan, Taiwan
• Medical Research: What is the background for this study? What are the main findings?
Response: Previous studies investigating the relationship between osteoporosis and sudden
sensorineural hearing loss were rare. Most of the studies were of small sample size, or cross-
sectional designs and their results were inconclusive. Our population-based study found an
approximately 1.76-fold increase in the incidence of sensorineural hearing loss for patients
with osteoporosis compared with the comparison group.Patients with more severe
osteoporosis may have a higher risk of SSNHL than patients with osteoporosis of milder
severity.
• Response: The prevalence of osteoporosis is increasing around the world, and it increases the
risk of bone fracture, systemic disease, medical expenses, and mortality. Our study also
shows the relationship between osteoporosis and the risk of sensorineural hearing loss.
Osteoporotic patient should be aware to have an early intervention if they suffer from
suspected hearing impairment.

Osteoporosis May Increase Risk of Hearing Loss
Dr. Kai-Jen Tien MD
Division of Endocrinology and Metabolism, Department of Internal Medicine
Chi Mei Medical Center, Tainan, Taiwan
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Response: Our study can not answer if early detection and treat osteoporotic patients with
antiosteoporotic therapy can reduce the risk of sudden sensorineural hearing loss. Further
prospective and intervention study containing detail information should be done to resolve
the question.
• Citation:
• Increased Risk of Sudden Sensorineural Hearing Loss in Patients With Osteoporosis: A
Population-based, Propensity Score-matched, Longitudinal Follow-up Study.
Yeh MC1, Weng SF, Shen YC, Chou CW, Yang CY, Wang JJ, Tien KJ.
J Clin Endocrinol Metab. 2015 Apr 16:jc20144316. [Epub ahead of print]

Decreased Medicare Payment Did Not Mean Increased Volume For Most Glaucoma Procedures
MedicalResearch.com Interview with: Dan Gong BA
Icahn School of Medicine at Mount Sinai James C. Tsai, M.D., M.B.A.
President – New York Eye and Ear Infirmary of Mount Sinai Delafield-Rodgers Professor and Chair Department of Ophthalmology
Icahn School of Medicine at Mount Sinai

• Congress first introduced the Medicare Physician Fee Schedule built on the resource-based
relative value scale (RBRVS) in the Omnibus Budget Reconciliation Act of 1989. Until recently,
Medicare payments to physicians were adjusted annually based on the sustainable growth
rate (SGR) formula.
• When adjusting physician payments, one controversial belief by policymakers was the
assumption that in response to fee reductions, physicians would recuperate one-half of lost
revenue by increasing the volume and complexity of services.
• This study questioned this assumption that this inverse relationship between Medicare
payment and procedural volume is uniform across all procedures. In particular, glaucoma
procedures have not been studied in the past.
• Using a fixed effects regression model, we found that for six commonly performed glaucoma
procedures, four did not have any significant Medicare payment and procedural volume
relationship (laser trabeculoplasty, trabeculectomy with and without previous surgery,
aqueous shunt to reservoir). Two procedures, laser iridotomy and scleral reinforcement with
graft, did have significant and inverse associations between Medicare payment and
procedural volume.

• Our research suggests that for many glaucoma procedures, decreased payment does not lead
ophthalmologists to compensate by performing more procedures.
• More broadly speaking, it is incorrect to assume that one number can adequately and
accurately describe how physicians respond to Medicare payment changes
this study?
• The relationship between Medicare payment and procedural volume is complex, requiring a
more nuanced perspective that takes into account individual procedural and specialty
variation.
• To more accurately project future Medicare spending, more research is necessary to study
how physicians respond to changes in both Medicare payment rates and payment models.
• Citation:
• A Quantitative Analysis of the Relationship between Medicare Payment and Service Volume
for Glaucoma Procedures from 2005 through 2009
• Gong D1, Jun L1, Tsai JC2.
• Ophthalmology. 2015 Jan 23. pii: S0161-6420(14)01146-4. doi:
10.1016/j.ophtha.2014.12.006. [Epub ahead of print]

Norovirus and Rotovirus May Be Resistant to Alcohol Based Hand Disinfectants
Erwin Duizer, PhD
Head of section Enteric Viruses Centre for Infectious Diseases Control
National Institute for Public Health and the Environment The Netherlands
Medical Research: What is the background for this study?
Dr. Duizer: Hand hygiene is important for interrupting the transmission chain of viruses through
hands. Alcohol-based hand disinfectants are widely used in hospitals and healthcare facilities, due
to convenience, rapidity, and broad acceptance by healthcare personnel. The effectiveness of
alcohol-based hand disinfectant has been shown for bacteria and enveloped viruses but their
effectiveness in reducing transmission of non-enveloped viruses, such as norovirus, is less certain.
Therefore we tested, in a joint project of the RIVM and Wageningen University, the virucidal
activity of a propanol based product and an ethanol based product in quantitative carrier tests.
Additionally, the virus reducing effect of hand washing (according to health care guidelines) and
the use the propanol based product was tested in a quantitative finger pad test.

Erwin Duizer, PhD
• Dr. Duizer: With the quantitative carrier test we found that the virucidal effect of the ethanol
and propanol based products against the non-enveloped noroviruses, enteroviruses,
parechoviruses and adenoviruses was limited; after 3 min still 1% or more was left infectious.
The propanol based product performed slightly better than the ethanol based product, with
good activity, within 30 s, against rotavirus and influenzavirus.
• The average virus reduction from finger pads was close to 3log10 (ie from 100% to 0.1%) for
the propanol based products, but a transferable quantity of virus could still be detected on 5
out of 12 fingers. After hand washing with water and soap, no virus was detected on any of
the finger pads.

Erwin Duizer, PhD
• Dr. Duizer: Often, the use of alcohol based hand hygiene products will contribute to reduced
spread of many pathogens, including bacteria, enveloped viruses and rotavirus. However,
many non-enveloped viruses such as noroviruses and enteroviruses, are quite resistant to
alcohols and may require strict hand washing to prevent transmission.
• Citation:
• Reducing viral contamination from finger pads: handwashing is more effective than alcohol-
based hand disinfectants, by Tuladhar et al.
Journal of Hospital Infection Published Online: April 09, 2015
• DOI: http://dx.doi.org/10.1016/j.jhin.2015.02.019

CPAP For Sleep Apnea May Decrease Atrial Fibrillation Recurrence
Dr. Larry Chinitz MD
Professor of Medicine and Director, Cardiac Electrophysiology
NYU Langone Medical Center
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Chinitz: The treatment algorithms proposed currently for maintenance of sinus rhythm in
patients with atrial fibrillation focus on use of anti-arrhythmic drugs and catheter ablation.
Data available to evaluate the effect of modification of known adverse clinical factors on
atrial fibrillation recurrence is scant.
• Obstructive sleep apnea in a known factor associated with both new onset atrial fibrillation
as well as its recurrence after catheter ablation. Through a meta-analysis of available data we
found that use of continuous positive airway pressure in patients with sleep apnea was
associated with a 42% relative risk reduction in recurrence of atrial fibrillation. This effect was
similar across patient groups irrespective of whether they were medically managed or with
catheter ablation.

• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Chinitz: Treatment of Obstructive sleep apnea with continuous positive airway pressure is
a significant means to reduce atrial fibrillation recurrence. Thus, sleep apnea should be
suspected in patients with atrial fibrillation and in patients with its confirmed diagnosis, use
of continuous positive airway pressure should be strongly advocated with the intention to
reduce recurrence of atrial fibrillation.

• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Dr. Chinitz: Randomized clinical trials are necessary to shed more light on the interaction
between use of continuous positive airway pressure use and atrial fibrillation recurrence in
patients with sleep apnea.
• Citation:
• Journal of the American College of Cardiology: Clinical Electrophysiology, news release, April
20, 2015

Targeted Melanoma Panel Identifies Genetic Subsets of Melanoma
Melissa Wilson, MD, PhD
Assisstant Professor Perlmutter Cancer Center
NYU Langone Medical Center New York, NY
Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin
cancer. Traditionally, it has been characterized by clinicopathologic characteristics. More recently,
melanoma tumors have also been stratified by common somatic mutations for which targeted
therapies have been developed or are under investigation, including BRAF, NRAS and KIT. In
addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption
contribute to melanoma pathogenesis. Indeed, recent next generation sequencing studies have
identified a number of new genes involved in melanomagenesis. A comprehensive evaluation and
understanding of concurrent and mutually exclusive mutations in tumors has been
lacking. Therefore, we developed a comprehensive custom targeted capture of 108 genes
previously implicated in melanoma pathogenesis. We used the targeted panel to perform
massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-
derived xenografts (PDX), and 5 cell lines made from PDX, all untreated.
• Samples were clustered based on deleterious mutations. Eighty-three percent of samples had
deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1. Ten percent
of samples had PI3K pathway mutations which were predominantly associated with BRAF
mutations. TP53 was found to be mutated in 24% of the samples and were also associated with
mutations in the MAPK pathway. Mutations in chromatin remodeling genes were mutually
exclusive with each other, but were associated with BRAF and NRAS mutations. Of particular
interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or
MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of
samples.

• Dr. Wilson: This study provides a comprehensive examination of melanoma genetics and
provides novel insights in addition to the known, prevalent somatic mutations which identify
melanoma tumors currently. Of course, functional studies are needed to confirm the biology
of these genetic observations.

study?
• Dr. Wilson: It will be important to evaluate these novel genetic subsets in tumor samples from
melanoma patients. In addition, correlation of these novel genetic subsets with clinicopathologic
characteristics and response to treatment is imperative. Identification of a genetic profile for
melanoma tumors has potential implications for treatment decisions.
• Citation:
• Abstract presented at the 2015 AACR
• 4668: Targeted, massively parallel sequencing identifies novel genetic subsets of cutaneous
melanoma
Tuesday, Apr 21, 2015
Bradley Garman1, Clemens Krepler2, Katrin Sproesser2, Patrica Brafford2, Melissa Wilson3, Bradley
Wubbenhorst1, Ravi Amaravadi4, Joseph Bennett5, Marilda Beqiri2, Michael Davies6, David Elder4,
Keith Flaherty7, Dennie Frederick7, Tara C. Gangadhar4, Michael Guarino5, David Hoon8, Giorgos
Karakousis4, Nandita Mitra1, Nicholas J. Petrelli5, Lynn Schuchter4, Batool Shannan2, Jennifer
Wargo6, Min Xiao2, Wei Xu4, Xaiowei Xu4, Meenhard Herlyn2, Katherine Nathanson1. 1Perelman
School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2The Wistar Institute,
Melanoma Research Center, Philadelphia, PA; 3Perlmutter Cancer Center, NYU School of Medicine,
NYU Langone Medical Center, New York, NY; 4University of Pennsylvania Abramson Cancer Center,
Philadelphia, PA; 5Helen F. Graham Cancer Center, Newark, DE; 6MD Anderson Cancer Center,
Houston, TX; 7Massachusetts General Hospital, Boston, MA; 8John Wayne Cancer Institute, Santa
Monica, CA

Epigenetic Changes May Account For How Some Lymphoma Tumors Change Over Time
Olivier Elemento, PhD Associate Professor
Head, Laboratory of Cancer Systems Biology Department of Physiology and Biophysics
Institute for Computational Biomedicine Weill Cornell Medical College New York, NY, 10021
Dr. Elemento: In many cancer patients, initial treatment with chemotherapy or targeted
therapy shrinks the tumor or makes it disappear; however the tumor eventually comes back
in a form that is frequently resistant to treatment. This process is called relapse. In diffuse
large B-cell lymphomas (an aggressive type of blood cancer), approximately 40% of patients
eventually relapse. How relapse occurs and how these tumors adapt and become resistant to
treatment is not well understood. Why 60% of patients do not relapse and are essentially
cured of their disease while 40% relapse is not known. Many think the relapse process
involves tumor cells acquiring DNA alterations that make them resistant to therapy. We have
indeed previously identified such DNA mutations in diffuse large B-cell lymphomas
(http://genomebiology.com/2014/15/8/432/abstract).
• However it became apparent to us and others that DNA mutations do not explain fully why
these tumors become treatment-resistant and come back, sometimes years after initial
diagnosis and therapy. We therefore turned to the epigenome to look for possible reasons.
Specifically, we studied chemical modifications of DNA called DNA methylation. DNA
methylation is transmitted faithfully from one cancer cell division to the next but can also be
modified by specific enzymes. DNA methylation is thought to impact the way genes are
expressed in tumors by modulating accessibility of DNA to proteins that regulate gene
expression. DNA methylation is known to be altered in tumors. Could DNA methylation
alterations also be at least partially responsible for relapse and resistance to treatment ?

To address this question, we used a high-throughput DNA methylation profiling method to
capture the DNA methylation landscape genome-wide. That is, we queried DNA methylation
status at millions of locations in the tumor genome. We profiled B cell lymphoma biopsies from
patients treated at Cornell and Torino. Since we were interested in how tumors change upon
treatment, we profiled the initial tumor biopsy obtained at time of diagnosis (pre-treatment)
then profiled the biopsy obtained at time of relapse in the same patients. The profiling produces
enormous amounts of epigenomic data and we therefore had to use customized Big Data
analytical algorithms together with supercomputers to interpret the methylation patterns.

• Our main findings are as follows:
• 1) We found extensive changes in DNA methylation between diagnosis and relapse – many
more epigenomic changes than DNA changes. The changes are partially random – every
patient’s tumor changed in different ways. However, we observed many convergent changes.
That is, near some genes, all or many patients undergo the same changes. Some of the genes
are known to impact tumor biology, for example genes in the TGFbeta pathway. We also
found significant epigenomic changes at genetic switches – the regions in the genome that
control which genes are expressed. We think that DNA methylation changes occurring at
relapse interfere with the function of these switches, and perturb expression of genes
controlled by these switches.
• 2) Perhaps most interestingly, we found that the cell-to-cell methylation heterogeneity within
tumors at time of diagnosis is highly predictive of relapse. Tumors with elevated cell-to-cell
methylation heterogeneity, that is, tumors where every cell has a different methylation
landscape, are more likely to relapse. The higher cell-to-cell methylation heterogeneity is, the
faster tumors relapse.
• These are exciting findings that for the first time indicate a major role of the epigenome in
supporting the evolution and adaptation of tumors in response to treatment.

• Dr. Elemento:
• 1) It is important to understand how tumors change in time, especially after treatment. This
applies to all tumors, not only B cell lymphomas. A tumor found at relapse is not the same as
the tumor found at initial diagnosis. Relapse tumors have evolved at the genomic level and
even more so at the epigenomic level as our study shows. We cannot treat a relapse tumor
as if it was the same tumor as the diagnosis one. The tumor changed – we need to
understand what changed in order to tailor the treatment to the new tumor. This is
important because for many patients, no biopsy is performed at time of relapse. This has to
change.
• 2) The epigenome has potential clinical relevance. In our study we found that intra-tumor
methylation heterogeneity early at diagnosis can predict which patients will eventually
relapse and how fast they will relapse. The precise predictive power of the epigenome needs
to be studied further but one may envision that eventually patients with elevated intra-tumor
methylation heterogeneity will be monitored more aggressively for signs of relapse and/or
given more aggressive treatment regimens since they may be at higher risk of relapse.

this study?
• Dr. Elemento: We need to better understand the role that the epigenome plays in tumor
progression. What genes are affected and how? How does the tumor genome cooperate with
the tumor epigenome ? Once we understand how the epigenome contributes to tumor
progression, we may be able to find new ways to block or slow down such progression,
maybe by modifying the epigenome. There are already FDA-approved drugs that can
interfere with DNA methylation and other epigenetic mechanisms. Maybe such drugs will be
used one day to limit the ability of tumors to evolve and adapt.
• At a time where precision medicine programs are put in place in hospitals across the country,
we think it will be important to not only sequence the genome of patients but also
characterize their epigenome. The epigenome may help understand the blueprint and
alterations that led to disease (not only cancer) and provide a rich source of clinically
actionable information.
• Citation:
• Olivier Elemento et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nature
Communications, April 2015 DOI: 10.1038/ncomms7921

PARP Inhibitor Combo For Cancer Patients With and Without BRCA Mutation
Timothy Yap, MD, PhD, NIHR BRC
The Institute of Cancer Research and
The Royal Marsden NHS Foundation Trust London, United Kingdom.
Dr. Yap: This is a novel phase I trial assessing for the first time if the PARP inhibitor olaparib
can be combined with the AKT inhibitor AZD5363. The study was undertaken at the Royal
Marsden and The Institute of Cancer Research in London, England. This targeted combination
was based on strong preclinical rationale demonstrating synergy between both drugs in BRCA
positive tumors and also antitumor activity in non-BRCA positive tumors. Although olaparib
was recently approved by the FDA for treating advanced ovarian cancer associated with
defective BRCA genes, antitumor efficacy in different non-BRCA tumors is yet to be
established.
• The key finding for this study was that it was indeed possible to combine both drugs safely,
with multiple patients with different cancers responding, including patients with and without
BRCA1/2 mutations. We also assessed a new intrapatient dose escalation phase I trial design
in this study, and demonstrated that the novel design could be successfully implemented,
with completion of the dose escalation phase in 2 schedules of the combination with just 20
patients in 7.5 months.

• Dr. Yap: The combination of olaparib and AZD5363 was well tolerated, with side effects
including gastrointestinal symptoms, such as nausea, vomiting, diarrhea, as well as rash and
fatigue. Out of 20 patients with advanced solid tumors, seven patients had either RECIST
partial responses or prolonged disease stabilization. There were four confirmed RECIST
partial responses, including in a patient with BRCA wild-type ovarian cancer, two patients
with BRCA mutant breast cancer, and a patient with BRCA1-mutant ovarian cancer; two
patients had ongoing prolonged RECIST disease stabilization, including a patient with BRCA
unknown breast cancer at six months and a patient with peritoneal mesothelioma at one
year, who had previously responded before progressing on treatment with a PI3K/mTOR
inhibitor. One patient with BRCA-mutant advanced prostate cancer also continues to have a
sustained radiological response on MRI and by PSA tumor marker response criteria at 11
months.

this study?
• Dr. Yap: We have now established safe doses for this novel targeted combination and
observed anticancer responses in patients with both BRCA positive and BRCA negative
cancers. We are currently assessing this promising targeted combination of olaparib and
AZD5363 in a larger cohort of patients with both BRCA and non-BRCA mutations. We believe
that such PARP inhibitor based treatments have the potential to extend the use of PARP
inhibitors to include patients with different types of non-BRCA positive cancers, such as
breast, ovarian, prostate, small cell and pancreatic cancers. We also believe that other phase I
trials of targeted combinations should incorporate the novel intrapatient dose escalation
design assessed in this study to validate it independently.
• Citation:
• April 2015 AACR abstract:
• New PARP Inhibitor Combo Shows Early Promise for Cancer Patients With and Without BRCA
Mutation
• MedicalResearch.com Interview with: Timothy Yap, MD, PhD, NIHR BRC (2015). PARP
Inhibitor Combo For Cancer Patients With and Without BRCA Mutation

Opioid Tampering By Health Care Providers Can Lead To Hepatitis C Transmission
Chong-Gee Teo, MD, PhD
Chief, Laboratory Branch
Division of Viral Hepatitis
CDC
• Medical Research: What is the background for this study?
Dr. Teo: Hepatitis C outbreaks in the course of providing healthcare continue to occur. Some
happen when hepatitis C virus (HCV) is transmitted to patients following breakdowns in safe
injection and infection control practices, and mishaps during surgery. Another route of
provider – to patient HCV transmission is diversion, self-injection and substitution of opioids
intended for anesthetic use (collectively referred to as “tampering”). A patient acquires
infection when an HCV-infected provider, who is an injecting drug user, self-injects from a
syringe prefilled with opioid anesthetic, fills the syringe with a volume substitute (e.g., saline
or water), and then administers the adulterated preparation to the patient.
• The study consisted of two parts:
1) to quantify the extent that anesthetic opioid tampering contributes to hepatitis C
outbreaks by analyzing healthcare-associated outbreaks occurring between 1990 and 2012 in
developed countries.
• 2) to estimate the probabilities of provider-to-patient transmission reflecting the “real-world”
setting in which a patient presents for health care, unaware of risks posed by procedures
conducted by a provider who may or may not be an injecting drug user or HCV infected.

CDC
• Dr. Teo: Disproportionately many cases of HCV infection from healthcare-associated hepatitis
C outbreaks were attributable to provider tampering of anesthetic opioids. Thus, tampering
was associated with 17% (8/46) of these outbreaks, but 53% (438/833) of cases.
• Of the eight tampering outbreaks studied, four (50%) were transmitted by anesthesiologists
or nurse anesthetists, and the other four by allied health professionals. Six of the outbreaks
(75%) involved fentanyl tampering. Spain hosted the largest outbreak (between 1988
and1997), involving 275 cases, and Australia the next largest (between 2006 and 2009), with
49 cases. Five outbreaks were reported from the United States, which generated 81 infected
patients; the largest outbreak occurred in New Hampshire (between 2010 and 2012),
involving 32 cases.
• Modeling studies showed that the likelihood of HCV transmission to a patient from exposure
to an opioid preparation tampered by a provider unknown to be an injecting drug user or
HCV infected (0·004%) is about >100 higher than from exposure to surgery conducted by a
surgeon unknown to be HCV-infected (0·0004%). This risk escalates >15,000 times when
exposure is to an opioid preparation tampered by a provider who is an injector. To pose a
50% risk of transmission, a surgeon, even when HCV-infected, can take as long 30 years, but a
provider who is an injector takes only weeks or months, depending on how successful the
provider is with opioid tampering at the workplace.

CDC
• Dr. Teo: Testing for and treatment of HCV infection in providers, regardless of whether or not
they are injectors, have access to controlled substances, or conduct exposure prone
procedures, are beneficial and can extend from care and management recommendations and
guidelines already developed for providers infected by blood-borne viruses. In the era of
highly efficacious anti-HCV therapy, providers should feel less helpless after being found HCV
infected and be more willing to avail themselves to testing and curative treatment.

CDC
this study?
• Dr. Teo: To reduce the risk of harm to patients from providers who tamper with anesthetic
opioids, the following measures are suggested:
• periodic opioid screening of providers
• raising greater awareness among healthcare staff about provider substance abuse and
provider diversion of controlled drugs
• educating healthcare staff on how colleagues abusing narcotics might be identified
• adopting computerized dispensing and charting systems to monitor controlled drug access
• and enabling staff recruitment agencies and bodies that credential and license healthcare
professionals to verify past criminal history and reports of adverse actions taken by
regulatory authorities and employers.
• Citation:
• Nosocomial hepatitis C virus transmission from tampering with injectable anesthetic opioids.
• Hepatology. 2015 Mar 22. doi: 10.1002/hep.27800. [Epub ahead of print]
• Hatia RI1, Dimitrova Z, Skums P, Teo EY, Teo CG.

Parent-Training Improves Behavioral Problems In Children With Autism
Lawrence Scahill, MSN, PhD and Karen Bearss, PhD
Department of Pediatrics, Marcus Autism Center
Children’s Healthcare of Atlanta and Emory University Atlanta, Georgia
Response: Autism spectrum disorder (ASD) affects an estimated 0.6 to 1% of children worldwide.
• In young children with ASD (e.g. 3 to 7 years of age) up to 50% also have disruptive
behaviors such as tantrums, aggression, self-injury and noncompliance. When present,
these disruptive behaviors interfere with the child’s readiness to make use of educational and other
supportive services. The presence of disruptive behaviors also hinders the acquisition of routine
daily living skills.
• Parent Training has been shown to be effective for young children with disruptive behaviors who do
not have Autism spectrum disorder – but it has not be well-studied in children with ASD.
• The current multisite study shows that parent training is effective in reducing serious behavioral
problems in young children with ASD. This is the largest randomized trial of a behavioral
intervention in children with ASD. 180 children were randomly assigned to parent training or
parent education. Both treatments were delivered individually to parents over 24 weeks.
• Serious behavioral problems were reduced by almost 50% in the parent-training group compared to
about 30% for parent education. A clinician who was blind to treatment assignment rated positive
response in 69% of children in the parent training group compared to 40% for parent education. In
addition, 79% of children who showed a positive response to parent training at the end of the 24-
week trial maintained benefit at 6 months post treatment.
• Parent training provided parents with specific strategies on how to manage tantrums, aggression,
self-injury and noncompliance in children with autism spectrum disorder. Parent education
provided up-to-date and useful information about ASD, but no instruction on how to address
behavioral problems. Parents were engaged in the study treatments as evidenced by the low drop-
out rate of 10% .

• Response: Both treatments resulted in improvement – but parent training was clearly better.
• The parent training program consists of 11 core sessions, 2 optional sessions, 2 telephone
boosters, and 2 home visits. Our parent training program is relatively brief and can be
implemented in a wide range of settings. With training, it can delivered by a wide range of
practitioners.
• Persistent disruptive behavior often promotes uncertainty for parents about how to deal with
these behaviors.
• By providing practical tools, parent training fosters parental confidence and promotes success
in everyday life for the child and family.

this study?
• Response: Over the past decade our multisite group has developed and now tested a
structured parent training program designed to teach parents how to address behavioral
problems in young children with ASD. The intervention is acceptable to parents and it can be
reliably delivered by therapists trained in the manual.
• This multi-site randomized trial showed that parent training is effective in reducing behavioral
problems in young children with Autism spectrum disorder. Parent training is ready for wider
implementation.
• The study was conducted by the Research Units on Behavioral Intervention (RUBI) Autism
Network (Emory University, Indiana University, Ohio State University, University of Pittsburgh,
University of Rochester and Yale University).
• The study was funded by the National Institute of Mental Health with addition support from
Marcus Foundation and the JB Whitehead Foundation.
• Citation:
• Bearss K, Johnson C, Smith T, et al. Effect of Parent Training vs Parent Education on Behavioral
Problems in Children With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA.
2015;313(15):1524-1533. doi:10.1001/jama.2015.3150.

increased Air Pollution Linked To More Strokes, Smaller Brain Volumes
Elissa Hope Wilker, Sc.D.
Beth Israel Deaconess Medical Center
Cardiovascular Epidemiology Research
Harvard Medical School
Medical Research: What is the background for this study? What are the main findings?
Dr. Wilke: Long-term exposure to ambient air pollution is associated with cerebrovascular disease
and cognitive impairment, but the impact on structural changes in the brain is not well
understood. We studied older adults living in the greater Boston area and throughout New
England and New York and we looked at the air pollution levels and how far they lived from major
roads. We then linked this information to findings from MRI studies of structural brain images.
Although air pollution levels in this area are fairly low compared to levels observed in other parts
of the world, we found that people who lived in areas with higher levels of air pollution had
smaller brain volumes, and higher risk of silent strokes. The magnitude of association that we
observed for a 2 µg/m3 increase in fine particulate matter (PM2.5) (a range commonly observed
across urban areas) was approximately equivalent to one year of brain aging. The association with
silent strokes is of concern, because these are associated with increased risk of overt strokes,
walking problems, and depression.

• Dr. Wilke: Our findings suggest that air pollution is associated with insidious effects on
structural brain aging, even in dementia- and stroke-free individuals. This work aids in our
understanding of what might be going on in terms of associations observed between
particulate air pollution exposures and clinically observed outcomes like stroke and impaired
cognitive function.

study?
• Dr. Wilke: These are findings that will need to be confirmed or refuted in future work. We believe it
will be interesting to investigate the impact of air pollution over a longer period, its effect on more
sensitive MRI measures, on brain shrinkage over time, and other risks including of stroke and
dementia.
• Citation:
• Long-Term Exposure to Fine Particulate Matter and Residential Proximity to Major Roads and
Measures of Brain Structure
• Elissa Wilker*, Beth Israel Deaconess Medical Center, United States, ewilker@bidmc.harvard.edu;
Sarah Preis, Boston University School of Medicine, United States, srpreis@bu.edu; Alexa Beiser,
Boston University School of Medicine, United States, alexab@bu.edu; Philip Wolf, Boston University
School of Medicine, United States, pawolf@bu.edu; Joel Schwartz, Harvard School of Public Health,
United States, jschwrtz@hsph.harvard.edu; Petros Koutrakis, Harvard School of Public Health,
United States, petros@hsph.harvard.edu; Rhoda Au, Boston University School of Medicine, United
States, rhodaau@bu.edu; Sudha Seshadri, Boston University School of Medicine, United States,
suseshad@bu.edu; Murray Mittleman, Beth Israel Deaconess Medical Center, United States,
mmittlem@bidmc.harvard.edu;
• Environmental Health Perspectives
Abstract Number : 1641 | ID : O-024

AFib Increases Hospital Costs For Young and Older Stroke Patients
Guijing Wang, PhD Senior health economist
Division for Heart Disease and Stroke Prevention
Centers for Disease Control and Prevention
Dr. Wang: Our study is one of the first to analyze the impact of hospital costs related to atrial
fibrillation (or AFib) in a younger stroke population. To determine these findings, we
examined more than 40,000 hospital admissions information involving adults between the
ages of 18 and 64 with a primary diagnosis of ischemic stroke between 2010 and 2012.
• Although AFib is more common among those ages 65 and older, with strokes among younger
adults on the rise in the U.S., we wanted to take a comprehensive look at AFib’s impact on
hospital costs for these patients. AFib is associated with a 4- to 5-fold increased risk of
ischemic stroke, which is the most common type of stroke.
• Overall, our research found that AFib substantially increased hospital costs for patients with
ischemic stroke – and that was consistent across different age groups and genders of those
aged 18-64. Of the 33,500 first-time stroke admissions, more than seven percent had AFib,
and these admissions cost nearly $5,000 more than those without the condition. In addition,
we found that both the costs of hospitalization, as well as the costs associated with AFib,
were higher among younger adults (18-54) than those aged 55 to 64.

• Dr. Wang: Stroke is the fifth leading cause of death in the United States, killing nearly
130,000 Americans each year and costing an estimated $34 billion annually in health care and
lost productivity. This study helps to identify future research areas, such as the need to
separately examine the health and economic burden of initial and recurrent strokes, or
evaluate the cost-effectiveness of interventions for AFib and stroke prevention and control.
And these findings will help clinicians, patients and public health representatives focus efforts
as needed.
• For example, although research and public health efforts have focused on stroke
management and prevention among those over 65-years-old, stroke interventions among
younger adults may have great potential from an economic perspective. In addition, the
higher costs associated with AFib could suggest that strokes related to the disorder might be
more severe than those not linked to it – or it may reflect the added costs of diagnosis and
treatment of AFib. Prevention of ischemic stroke in patients with AFib is potentially effective
in reducing the disability and economic burden associated with stroke.

this study?
• Dr. Wang: AFib-associated costs among the elder population are still unknown, so further
research is necessary to better understand the total economic burden nationwide. In
addition, more examination of the impact of AFib on hospital costs for repeat stroke
admissions is recommended, as well as research into variations in hospital costs across
geographic regions of the U.S.
• Citation:
• Hospital Costs Associated With Atrial Fibrillation for Patients With Ischemic Stroke Aged 18–
64 Years in the United States
• Wang G1, Joo H2, Tong X2, George MG2.
• Stroke. 2015 Apr 7. pii: STROKEAHA.114.008563. [Epub ahead of print]
• http://www.ncbi.nlm.nih.gov/pubmed/25851767

HPV Vaccine Provides Protection at Multiple Sites
Daniel C. Beachler, PhD Postdoctoral fellow
Infections and Immunoepidemiology Branch of the
National Cancer Institute (NCI)
• Dr. Beachler: HPV is a common sexually transmitted infection. Individuals can acquire HPV
infections in the epithelium of their cervical, anal and oral sites, and occasionally these
infections lead to cancer. There are three prophylactic HPV vaccines on the market that can
protect against HPV at these sites among those not been previously exposed to HPV.
This study examined the effect of HPV vaccination of 18-25 year old women at all three
anatomic sites. The combined multi-site HPV vaccine efficacy has not been reported
previously. It was unknown whether the vaccine may protect non-infected sites against HPV
infection or re-infection in women exposed to HPV prior to vaccination.
We observed that the HPV vaccine provides the strongest protection at all three sites among
women unexposed to HPV before vaccination. Additionally, we observed some protection at
the non-infected sites in women who were previously infected with HPV

• Dr. Beachler: This research supports current US guidelines for HPV vaccination from the CDC.
They recommend routine vaccination in 11-12 year olds, who are the least likely to be
previously exposed to HPV. In addition, vaccination is recommended through the age of 26 in
females who were not vaccinated previously. This is important given that only half of US
females under 18 have been HPV vaccinated.

this study?
• Dr. Beachler: Further research into better understanding HPV infection occurring outside the
cervix is necessary, particularly determining how often oral and anal HPV infections are
acquired at older ages.
• Citation:
• Presented at the AACR Annual Meeting 2015 April 2014
• HPV Vaccine Provides Protection at Multiple Sites Even Among Some Previously Exposed

Seizure Medication Reduced Optic Neuritis In Multiple Sclerosis
Dr. Raj Kapoor
National Hospital for Neurology and Neurosurgery
University College London Hospitals NHS Foundation Trust
Medical Research: What is the background for this study?
Dr. Kapoor: Current treatments for Multiple Sclerosis do not prevent disability which accumulates
from relapses, or which progresses between relapses. Experimental work suggests that the
neurodegeneration which underlies disability could be prevented using agents which block
voltage gated sodium channels. We have tested this possibility using treatment with the sodium
channel blocker phenytoin in patients with acute optic neuritis. We tested whether phenytoin
could prevent the degeneration seen in the retinal nerve fiber layer and macula after an attack of
optic neuritis.

Dr. Raj Kapoor
Medical Research: What are the main findings?
Dr. Kapoor: The main findings are that the group of patients treated with phenytoin had less
degeneration in the retinal nerve fiber layer (rnfl) and in the macula (mv) in the eye affected by
optic neuritis than the group treated with placebo. Phenytoin treatment reduced the
degeneration by 30 % (rnfl) – 34% (mv).

Dr. Raj Kapoor
• Dr. Kapoor: This is a study designed to test the concept of neuroprotection, and it appears
that the treatment was successful. Phenytoin did not lead to better vision after optic neuritis,
but our trial was too small to determine whether phenytoin could achieve this. By providing
proof of concept for the treatment target, however, and by demonstrating neuroprotection
so robustly, we hope to open a door to even better treatments to prevent disability in
Multiple Sclerosis.

Dr. Raj Kapoor
this study?
• Dr. Kapoor: The trial suggests that proof of neuroprotection using different treatment targets
could be sought in similar trials in optic neuritis. Better treatment effects could be achieved
by refining the trial design, for example by looking for drugs with more potent effects on the
relevant sodium channels, by treating even earlier from the onset of optic neuritis, and by
combining such neuroprotection with other treatments to promote remyelination and to
suppress inflammation in Multiple Sclerosis.
• Citation:
• 2015 AAN abstract :
• Phenytoin is Neuroprotective in Acute Optic Neuritis: Results of a Phase 2 Randomized
Controlled Trial

Gene Expression Profile Improves Melanoma Risk Assessment
Pedram Gerami, M.D.
Associate Professor of Dermatology Director, Melanoma Research
Northwestern Skin Cancer Institute Northwestern University
• MedicalResearch: What is the basis and background for performing this study?
• Dr. Gerami: Most of the existing literature shows that Sentinel Lymph Node Biopsy (SLNB)
will identify 25 to 35 percent of patients who will ultimately die of metastatic melanoma.
Hence while SLNB is reported to be the strongest predictor of outcome for melanoma, the
vast majority of patients who ultimately die of metastatic melanoma have a negative Sentinel
Lymph Node Biopsy result. Hence in this study we aimed to determine whether a GEP assay
developed by Castle bioscience could be used independently or in conjunction with SLNB to
better detect those patients who are at high risk for developing metastatic disease and dying
from melanoma.

Pedram Gerami, M.D.
• MedicalResearch: What are the findings of the study?
• Dr. Gerami: Our study, which examined the use of a Gene Expression Profile (GEP) assay developed by Castle Biosciences
and Sentinel Lymph Node Biopsy alone and in combination in a multi-center cohort of 217 patients, demonstrated that the
use of the GEP identified more than 80 percent of patients who develop melanoma
• Combining the two methods showed that patients predicted to be high risk based on the GEP test alone had similar rates of
disease progression whether they were SLNB positive or negative. Patients who were SLNB negative and predicted to be low
risk using the GEP test had lower rates of disease progression than the SLNB negative group as a whole.
• Primary tumor tissue from 217 Stage I, II, III, or IV cutaneous melanoma patients with documented sentinel lymph node
biopsy (SLNB) results was analyzed using the DecisionDx-Melanoma GEP test, developed by Castle Biosciences, Inc., under a
multicenter, prospectively-planned, archival tissue study protocol. DecisionDx-Melanoma is a noninvasive test developed to
identify high risk disease independent of other staging methods, such as AJCC stage and SLNB status. Using tissue from the
primary melanoma, the DecisionDx-Melanoma test measures the expression of 31 genes and stratifies patients as either low
risk Class 1 or high risk Class 2
• The predictive accuracy of the DecisionDx-Melanoma and SLNB prognostic tools were evaluated individually and in
combination to assess primary endpoints of disease-free survival (DFS), distant metastasis free survival (DMFS), and overall
survival (OS). Independently, the Gene Expression Profile and SLNB tests were shown to stratify patients according to their
risk (univariate analysis using Cox proportional hazards p<0.0001 for GEP for all endpoints, SLNB for DFS and DMFS; SLNB for
OS p=0.0099).
• Multivariate analysis found GEP Class to be independent of SLNB status for all endpoints (p<0.0001) and SLNB status to be
independent of GEP Class for DFS (p=0.008) and DMFS (p=0.001) but not OS (p=0.11).
• Combining the GEP and SLNB tests showed improvements in stratifying patients who were SLNB negative. The SLNB negative
group as a whole had a DFS of 55 percent. Using the GEP test to further stratify those patients resulted in identification of a
higher risk (Class 2) sub-group of SLNB negative patients who had a DFS of 35 percent. Likewise, SLNB negative patients who
were predicted to be low risk (Class 1) using the GEP had a DFS of 83 percent.

Pedram Gerami, M.D.
• MedicalResearch: What are the conclusions of the study?
• Dr. Gerami: Use of the GEP test, both independently and in combination with SLNB will help
clinicians identify high-risk SLNB-negative patients with aggressive disease and patients
identified as high-risk by conventional parameters who are unlikely to have progression of
their disease. Based on data from our study and a prior validation study (published earlier
this year in Clinical Cancer Resrearch), this non-invasive GEP prognostic tool could be used to
help clinicians more accurately stratify patients as higher versus lower risk. We believe that
the use of GEP prognostic testing may identify the majority of patients who are at risk for
metastasis.
• Citation:
• J Am Acad Dermatol. 2015 May;72(5):780-785.e3. doi: 10.1016/j.jaad.2015.01.009. Epub
2015 Mar 3.
• Gene expression profiling for molecular staging of cutaneous melanoma in patients
undergoing sentinel lymph node biopsy.
• Gerami P1, Cook RW2, Russell MC3, Wilkinson J4, Amaria RN5, Gonzalez R6, Lyle S7, Jackson
GL8, Greisinger AJ9, Johnson CE2, Oelschlager KM2, Stone JF4, Maetzold DJ2, Ferris LK10, Wayne
JD11, Cooper C12, Obregon R12, Delman KA3, Lawson D3.

Leveraging Big Data to Accelerate Drug Discovery
Neel S. Madhukar Graduate student in the lab of
Olivier Elemento, PhD, Associate Professor
Head, Laboratory of Cancer Systems BiologyDepartment of Physiology and Biophysics Institute for Computational Biomedicine
Weill Cornell Medical College
• findings?
• Response: It takes on average 2.6 billion dollars and 10-15 years to develop a single new
drug. Despite massive investment in drug discovery by pharmaceutical companies, the
number of drugs obtaining FDA approval each year has remained constant over the past
decade. One of biggest bottlenecks in the process of developing a new drug is to understand
precisely how a drug works, that is, what it binds to in cells, how it binds, and what it does
when it is bound. This process is collectively called target identification and characterization
of mechanisms of action. At present, target identification is a slow and failure-prone process,
driven by laborious experimentation. Every time we seek to develop a new drug, such
laborious experimentation needs to be redone from scratch. We are not learning from data
acquired from our past successes and failures.
• In Dr Olivier Elemento’s research laboratory at Weill Cornell Medical College, we have
embarked on a journey to reboot the drug discovery process by adopting a Big Data strategy
leveraging the plethora of drug data available.
• In work presented at AACR’15 in Phildadelphia
(http://meyercancer.weill.cornell.edu/news/2015-04-21/new-tool-predicts-drug-targets-and-
ids-new-anticancer-compounds)
(http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3682&sKey=260955b6-
99db-46c5-afd1-d0f832af42b5&cKey=d9d0b004-de88-4d49-962d-
214863b271ba&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424),

we described a new Big Data technique for accelerating drug discovery called BANDIT –a
Bayesian Approach to determine Novel Drug Interaction Targets. BANDIT takes in information
from a variety of datasets – in vitro drug efficacy across hundreds of cell lines, change in gene
expression of thousands of genes upon drug treatment, millions of bioassays, complex
description of drug structure, and reported side effects – and combines them through a
probabilistic approach to predict the targets of a given small molecule. Each of these datasets is
independently quite large and, thus combining them produced an enormous database that we
had to use Big Data analytical algorithms together with supercomputers to analyze.

• Here are the main findings of this study :
• Through the creation of BANDIT we have put together the largest and most comprehensive
database of small molecule target and effect information. This database will be invaluable to future
research on improving drug discovery.
• We created a Big Data driven method that predicts the targets of drugs in a rapid and
comprehensive manner. Using drugs with known targets and a statistical procedure called cross-
validation, we clearly demonstrated that when it comes to drug discovery, the more data the better.
The more data describing small molecule activity we integrated into BANDIT the more accurately
we recovered their targets across a test set of known drugs.
• We applied BANDIT to over 50,000 small molecules with no known target or mechanistic
information to predict targets and identify a potential therapeutic role. We made predictions for
over 40% of these small molecules. In some cases, these predictions point to a new role for known
drugs. One example is that we predicted Vismodegib a drug used to treat forms of skin cancer, to
also act as a tyrosine kinase inhibitor, indicating its potential to be utilized in other treatment
avenues.
• We found a set of novel molecules that BANDIT predicted to disrupt microtubules. We focused on
microtubules because they are important targets for cancer chemotherapy. Together with our
colleagues Evi Giannakakou and Prashant Khade at Weill Cornell Medical College, we performed
experiments that clearly validate BANDIT’s prediction that these small molecules inhibit
microtubules.
• We also demonstrated that BANDIT not only predicts the target of small molecules with high
accuracy, but it also predicts precise mechanisms of action of small molecules, for example whether
a molecule that acts on microtubules works by perturbing microtubule polymerization or
depolymerization or works through a completely novel mechanism.

• Using BANDIT, we predict that the time and cost of drug development will be significantly
alleviated, and will allow treatments to reach patients much quicker than current practices would
allow. BANDIT will help not only by predicting individual targets, but also by helping researchers
determine the most cost-effective way to proceed with their drug development efforts. That is,
BANDIT can indicate which data-generating experiment is most informative about a small
molecule’s mechanism of action.
• Some of the new molecules that we showed computationally and experimentally to target
microtubules might end up being valuable novel chemotherapeutic agents. Microtubules play a key
role in cell proliferation and inhibiting them has tremendous efficacy in killing cancer cells and
targeting other proliferative diseases. A commonly used antimicrotubule drug such as Docetaxel
represents more than a 3 billion dollars market. However many patients do not respond to
approved antimicrotubule agents or develop resistance. Adding new antimicrotubule drugs to the
oncologist’s arsenal would enable to better treat many patients and perhaps target certain cancers
that are hard to treat with standard microtubule chemotherapy and/or provide additional options
for patients who have become resistant to existing antimicrotubule drugs.
• More broadly, one of the major problems in cancer patient care is developed drug resistance. There
are many drugs that work well for a short period of time but eventually patients develop resistance
and their condition relapses. By finding new molecules that act upon clinically relevant targets,
there is a potential to discover new drugs that could overcome resistance mechanisms. BANDIT has
the potential to dramatically accelerate the discovery of such molecules.
• Additionally, many diseases – such as brain cancers – are difficult to treat because of the inability of
drugs to permeate the brain barrier. But, by determining a set of molecules with varying structures
that all have the same target there is the potential to find a new drug able to overcome this
challenge.

this study?
• Response: We think that Big Data analytics will play an increasingly important role in drug
discovery. As discussed before, we are not developing drugs fast enough. On the other hand,
we have accumulated tremendous amounts of data on small molecule’s clinical safety,
efficacy, and toxicity. Technologies such as automation, next-generation sequencing, genome
engineering (CRISPR) can now be used to generate ever more such data. Now is the time to
integrate everything we know about small molecules to predict their activity. We can build
predictive models of drug toxicity and Big Data-driven models that predict how to combine
drugs to maximize efficacy, decrease the likelihood of acquired resistance and minimize
toxicity.
• To complement the work presented at AACR15, in our laboratory at Weill Cornell, we are
essentially adopting a “Moneyball” approach to drug discovery. Using machine learning, we
are actively seeking features of small molecules that predict a drug’s lack of toxicity, efficacy
and eventual FDA approval. For these analyses we are combing through large databases of
successful and failed clinical trials in humans, seeking to combine these data with small
molecule activity and target information. Our initial results look promising and indicate for
example that one can predict with reasonably high accuracy which clinical trials will fail early
due to toxicity reasons. Such Big Data models may speed up the drug discovery process by
identifying early the drugs and targets that are most likely to fail to reach FDA approval.
• Presented at the April 2015 AACR Conference in Philadelphia

Antibacterial Gloves May Reduce Cross Contamination In ICU Setting
Ojan Assadian, M.D., DTMH
Professor for Skin Integrity and Infection Prevention Institute for Skin Integrity and Infection Prevention
School of Human & Health Sciences University of Huddersfield Queensgate, Huddersfield UK
• Prof. Assadian: Although medical gloves serve as an important mechanical barrier to prevent
healthcare workers’ hands from getting contaminated with potentially pathogenic
microorganisms, their inappropriate and incorrect use may support microbial transmission,
eventually resulting in indirect horizontal cross-contamination of other patients.
• We conducted a clinical study designed to determine the efficacy of a newly developed
synthetic antibacterial nitrile medical glove coated with an antiseptic, polyhexamethylen-
biguanid hydrochloride (PHMB), on its external surface, and compared this antibacterial glove
to an identical non-antibacterial glove in reducing surface contamination after common
patient care measures in an intensive care unit.
• We found significantly lower numbers of bacteria on surfaces after performing typical clinical
activities such as intravenous fluid handling, oral toilet, or physiotherapy, if touched with
antibacterial gloves.

• Prof. Assadian: Hand hygiene is one of the most important measures to prevent infection in
the health care setting. The concept of hand hygiene, however, does not start and end with
using alcohol-based hand rubs before and after patient care, but includes also the correct use
of medical gloves.
• In 1996, the US Hospital Infection Control Practices Advisory Committee (HICPAC) published
its “Guideline for isolation precautions in hospitals”. This guideline adjusted the previous
concept of isolation precautions and introduced the concept of “Standard Precautions”,
which mandates that all health-care workers who come in contact with body fluids should
wear gloves. However, in practice it is largely ignored that this recommendation does not
advocate the use of gloves for all clinical procedures; instead, healthcare workers are advised
to assess the risk for possible contamination of hands in each clinical situation. However,
frequent and often incorrect usage of glove is increasing observed without adequate risk
assessment.

this study?
• Prof. Assadian: Although our study demonstrated that the use of antibacterial medical gloves
does support reduction of cross-contamination in the ICU setting, such technical solutions
alone do not help in solving issues with compliance to hand hygiene. Certainly it would be
wrong to advocate universal use of antibacterial gloves as a measure to reduce cross-
contamination instead of following the principles of hand hygiene. We still have to
understand reasons for non-compliance to hand hygiene better.
• Citation:
• Evaluation of the efficacy of an antibacterial medical glove in the ICU setting
• Kahar-Bador, V. Rai, M.Y. Yusof, W.K. Kwong, O. Assadian
• Journal of Hospital Infection
DOI: http://dx.doi.org/10.1016/j.jhin.2015.03.009
• Publication stage: In Press Accepted Manuscript Published online: April 22, 2015

Carotid Artery Stenting: Comparison Of Embolic-Prevention Devices
MedicalResearch.com Interview with
Jay Giri, MD MPH
Director, Peripheral Intervention
Assistant Professor of Clinical Medicine University of Pennsylvania
• Dr. Giri: Carotid artery stents are placed by vascular surgeons or interventional cardiologists to
decrease the risk of long-term stroke in patients with severe atherosclerotic disease of the carotid
artery. When these procedures are performed, there is a risk of releasing small amounts of debris
into the brain’s circulation, causing a stroke around the time of the procedure (peri-procedural
stroke). In order to mitigate this issue, embolic protection devices (EPD) have been developed to
decrease the chances of small debris reaching the brain.
• Two types of EPD exist. The first is a small filter meant to catch the debris released by placement of
the carotid stent (distal filter EPD).
• The second is a more complex device type that leads to transient halting of blood flow to the brain
in the carotid artery being stented (proximal EPD). Debris-containing blood is removed from the
body prior to allowing normal blood flow to proceed back to the brain after stent placement.
• Our prior research has shown that nearly all (>95%) of domestic carotid stenting procedures are
performed with utilization of one of these devices. We sought to compare important clinical
outcomes of stroke and death between these 2 device types within a large national sample of
patients undergoing carotid stenting.
• Some small prior studies have investigated whether the total amount of debris reaching the brain is
less with proximal embolic protection devices. These studies have shown mixed results. However,
no prior study has investigated important clinical outcomes of stroke and death in relation to these
devices.
• We found that overall uptake of proximal embolic protection devices utilization in America has not
been robust. Less than 7% of all domestic CAS procedures are performed with this
technology. Our analysis showed that in-hospital and 30-day stroke/death rates with proximal EPD
and distal filter EPD were similar (1.6% vs. 2.0%, p = 0.56 and 2.7% vs. 4.0%, p = 0.22, respectively).

Jay Giri, MD MPH
• Dr. Giri: Use of proximal EPD during CAS was associated with low rates of in-hospital
stroke/death similar to those with distal filter embolic protection devices. We cannot rule out
a small benefit of proximal embolic protection devices and it certainly did not appear
harmful. As such, we believe operator discretion should be used to select between the
devices in given circumstances.

Jay Giri, MD MPH
this study?
• Dr. Giri: Given our results, we have concluded that it is unlikely that a large controlled trial
randomizing patients to these 2 devices will be feasible. This is because population-wide
differences between the devices are small, so the scope of such a trial would be have to be
very large (greater than 6,000 patients all followed for at least 30 days after the procedure).
• Citation:
• Giri J, Parikh SA, Kennedy KF, et al. Proximal Versus Distal Embolic Protection for Carotid
Artery Stenting: A National Cardiovascular Data Registry Analysis. J Am Coll Cardiol Intv.
2015;8(4):609-615. doi:10.1016/j.jcin.2015.02.001.

Malaria Vaccine Has Potential To Contribute To Disease Control
Dr. Mary Hamel MedicalResearch.com Interview with:
Mary J Hamel, M.D. Chief, Strategic and Applied Sciences Unit,
And Deputy Branch Chief for Science, CDC Malaria Branch US Centers for Disease Control and Prevention
Atlanta GA 30333
• Dr. Hamel: Major progress has been made in malaria control during the past decade with the scale up of
proven interventions including insecticide treated nets (ITNs), indoor residual spraying, effective diagnosis
and treatment for malaria, and intermittent preventive treatment of malaria in pregnancy. Nonetheless,
malaria remains a major cause of morbidity and mortality, and a leading cause of pediatric death
worldwide. An estimated 198 million cases of malaria and 580,000 deaths occurred in 2013 – most of
these in African children.
• Now we face additional challenges in malaria control – the emergence of insecticide and drug resistance
threatens some of our most effective interventions. New tools are needed to reach the goal of malaria
elimination and eventual eradication. Vaccines are some of our most cost-effective interventions, and an
effective malaria vaccine would be an important addition to our current malaria control tools.
• This week, the RTS,S Clinical Trials Partnership published the final vaccine efficacy and safety results from
the RTS,S/AS01 malaria vaccine phase 3 trial in the Lancet (Efficacy and safety of RTS,S/AS01 malaria
vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3,
individually randomised, controlled trial, http://www.thelancet.com/journals/lancet/article/PIIS0140-
6736(15)60721-8/abstract). This large randomized controlled double-blind phase 3 clinical trial was
conducted in 11 sites in 7 African countries across a range of malaria transmission levels. In all, 15,460
children and young infants were enrolled in two age-categories, those first vaccinated at 5-17 months of
age (referred to as children), and those first vaccinated at 6-12 weeks of age (referred to as young infants)
who received the RTS,S/AS01 vaccine along with their routine childhood immunizations. Participants were
randomized into 3 groups – the first group received three doses of the RTS,S/AS01 vaccine followed 18
months later by a booster dose; the second group received three doses of the RTS,S/AS01 vaccine without
a booster; and the third group received a comparator vaccine. All participants received an ITN. Children
were followed for an average of 48 months and infants for an average of 38 months.

Atlanta GA 30333
• We found that vaccine efficacy was modest. Vaccine efficacy against clinical malaria in
children was 36% with a booster and 28% without, and vaccine efficacy against severe
malaria was 32% with a booster and non-significant without. Efficacy results in young infants
were lower than those in children– vaccine efficacy against clinical malaria was 36% with a
booster and 28% without, and vaccine efficacy against severe malaria was non-significant.
• However, impact, defined as the number of cases averted per 1000 participants vaccinated,
was substantial in both age-categories, and highest where malaria burden was greatest. In
children who received the booster, during 4 years follow-up, 1700 cases of clinical malaria
were averted per 1000 children vaccinated. In young infants, during 3 years follow-up, nearly
1000 cases were averted per 1000 young infants vaccinated.
• The safety findings were comparable overall in the different study arms, but two safety
findings are notable. Meningitis occurred more frequently among children (but not young
infants) who received RTS,S/AS01 than among those who received the comparator vaccines.
There was no relationship between when the vaccine was administered and when meningitis
occurred, most cases occurred in only two study sites, and the finding may be due to chance.
If RTS,S/AS01 is licensed, post-licensing studies will be done to establish the significance of
this finding. Both children and young infants experienced more episodes of fever and
associated febrile convulsions during the 7 days following vaccination; convulsions occurred
in 2.2 – 2.5/1000 vaccine doses.

Atlanta GA 30333
• Dr. Hamel: Malaria continues to be a major cause of morbidity and mortality, and a major
cause of pediatric deaths in Africa. To date, there is no licensed vaccine against malaria. The
RTS,S/AS01 malaria vaccine is the first malaria vaccine to show efficacy in a phase 3 clinical
trial. Vaccine efficacy is modest, but impact is considerable. The vaccine has the potential to
make a substantial contribution to malaria control when used with other effective malaria
control interventions, especially in areas of high transmission.

Atlanta GA 30333
this study?
• Dr. Hamel: Should the RTS,S/AS01 be recommended for use, it will be the first vaccine against
malaria, but it will not be the last. Early trials to improve the efficacy of RTS,S/AS01 have
already begun, as have malaria vaccine trials using different platforms.
• Citation:
• RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or
without a booster dose in infants and children in Africa: final results of a phase 3,
individually randomised, controlled trial. The Lancet, 2015 DOI: 10.1016/S0140-
6736(15)60721-8

MedicalResearch.com: Medical Research Exclusive Interviews April 28 2015

MedicalResearch.com: Medical Research Exclusive Interviews April 28 2015

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