cancer consult - my.clevelandclinic.org · hyperthermia aids recurrent cancer therapy highlights...

Ta u s s i g C a n c e r I n s t i t u t e | W i n t e r 2 0 1 4

Cancer ConsultCancer Genomics:

From Prostate Tumors to Myeloid Leukemias, Our Discoveries Are Revolutionizing Patients’ Risk Assessment and Treatment

Ranked as one of the top 10 hospitals in America for cancer care by U.S. News & World Report.

Also Inside:

HDL Cholesterol as a Cancer Fighter

Hyperthermia Aids Recurrent Cancer Therapy

Highlights from the American Society of Hematology Annual Meeting

Table of Contents

First Mutation Identified That

Increases DHT Synthesis to

Promote Hormone Therapy

Resistance...3

Next-Generation Cancer Genomic

Testing in a Real-World Setting...4

Genetic Advances Fuel New

Hope in Fight Against Myeloid

Leukemias...6

Highlights from the ASH Annual

Meeting...8

From Bench to Bedside: Genomics

for Active Surveillance Now in

Clinical Practice...10

Clinical Trials...12

Promising Research Shows HDL,

the Carrier of ‘Good’ Cholesterol,

Has Cancer-Fighting Punch...13

Hyperthermia Improves Response

Rates in Recurrent Cancers...14

Scoring the Risks: Khorana Score

Predicts Risk of Cancer-associated

Thrombosis and Mortality...16

New Staff...18

Selected Publications...19

On the cover: Investigators in the

lab of Cleveland Clinic researcher

Nima Sharifi, MD, have identified

the first genetic mutation that helps

prostate cancer tumors acquire

resistance to hormone therapy.

Dear Colleagues,

Welcome to the latest edition of Cleveland Clinic’s Cancer Consult.

I hope you find this issue informative and inspiring.

The history of progress in cancer medicine has been focused in two

basic areas: early detection and improved therapeutics. Recently,

we have been witnessing an explosion of progress as our knowledge

of cancer genomics increases. Genomics is revolutionizing risk

assessment, tumor classification and treatment.

Our physicians and researchers are involved in several high-profile

genomic initiatives. We have initiated a clinical trial to assess the

feasibility and clinical utility of next-generation genomic sequencing

in 15 solid tumors with historically poor prognosis. Our colleagues at

the Glickman Urological & Kidney Institute were instrumental in the

research and development of a genetic test — Oncotype DX® Prostate —

for prostate cancer, which helps identify men who are good candidates

for active surveillance.

In an era of personalized cancer care, there is increased focus on

defining and treating cancer by its genetic abnormalities. Tumor-

promoting enzyme mutations in several cancers have been identified

by Cleveland Clinic researchers, including the androgen-synthesizing

enzyme 3βHSD1 in castration-resistant prostate cancer, and the

SETBP1 gene, which frequently mutates in a subset of leukemias.

My goal is that you find the information in these pages useful in your

practice. Please do not hesitate to contact me with any questions,

concerns or suggestions at 216.444.6922 or [email protected].

Sincerely,

Brian J. Bolwell, MD

Chairman, Taussig Cancer Institute

CANCER CONSULT WINTER 2014

2 | 3 | clevelandclinic.org/cancer

The development of castration-resistant prostate

cancer (CRPC) occurs in large part by tumors

acquiring the capability of synthesizing their

own supply of 5α-dihydrotestosterone (DHT)

from nongonadal sources, particularly from

adrenal precursors. The role and requirement for

intratumoral DHT synthesis in the development

of CRPC is demonstrated by the efficacy of next-

generation hormone therapies that have entered

into clinical practice. This includes abiraterone

acetate, which blocks androgen synthesis, and

enzalutamide, which is a potent androgen

receptor antagonist.

Despite the long-recognized phenomenon of

elevated androgens in CRPC, no mutation has yet

been described that is responsible for increasing

DHT synthesis. At Cleveland Clinic, researchers

have identified the first such example of a genetic

alteration that increases the conversion of

precursor steroids to DHT, permitting tumors

to grow in the absence of gonadal testosterone.

The enzyme 3β-hydroxysteroid dehydrogenase-

isoenzyme-1 (3βHSD1) is required for the first and

rate-limiting step in the conversion of adrenal

dehydroepiandrosterone (DHEA) en route to

DHT. A mutation occurs in 3βHSD1 in a subset

of human CRPC tumors that blocks degradation

of this enzyme, increasing the amount of enzyme

available in the cell and resulting in an increase in

the flow of precursor steroids to DHT. The essential

consequence is that this mutation opens the

floodgates to DHT synthesis, permitting tumors to

grow in the absence of gonadal testosterone.

Cleveland Clinic investigators found not only

that this mutant 3βHSD1 occurs in human CRPC

tumors, but also that it occurs in a mouse model

of resistance to abiraterone acetate. Current

studies are aimed at determining whether clinical

resistance to abiraterone acetate and enzalutamide

is attributable in part to 3βHSD1 mutations.

In addition to the 3βHSD1 mutation that occurs

in tumors with the development of CRPC, the

same genetic alteration exists as an inherited

germline variant. In this form, it is possible

that this germline variant plays a part in upfront

resistance to hormonal therapy. Other ongoing

studies will identify how germline variant

inheritance regulates androgen metabolism in

localized prostate cancer. It is conceivable that

upfront genetic information on hormone therapy

response/resistance may help determine the best

treatment modality for a specific patient.

First Mutation Identified That Increases DHT Synthesis to Promote Hormone Therapy Resistance

For more information, contact Dr. Sharifi at 216.445.9750 or [email protected].

For references, please email the editor.

Nima Sharifi, MD, holds the Kendrick Family Endowed Chair for Prostate Cancer Research in Lerner Research Institute’s Department of Cancer Biology, and is an associate staff member of the Department of Solid Tumor Oncology.

By Nima Sharifi, MD

Nima Sharifi, MD, (left) with

Kai-Hsiung Chang, PhD


Since August, oncologists at Cleveland Clinic’s

Taussig Cancer Institute have been enrolling

patients in an expanded genomic testing clinical

study. Over the next year, 250 patients with a

variety of 15 different tumor types will have their

tumor sample analyzed for 236 cancer-related

genes as part of the investigation. The genes tested

have been implicated in cancer, with ramifications

for cancer therapeutics. They are all included in

the FoundationOne™ genomics assessment test.

For this clinical investigation, Cleveland Clinic

has partnered with FoundationOne’s developer,

Foundation Medicine, a molecular information

company specializing in comprehensive genomic

analysis of tumors.

In the study, each patient’s tumor sample is tested

with the FoundationOne genomics profile, which

detects several types of DNA alterations — base

substitutions, small insertions/deletions, copy

number alterations and gene rearrangements.

The test includes those genes that show a high

frequency of common alterations but also those

on a tail on the curve, such as those mutations

occurring at low frequency but across many

different tumor types. This type of approach

provides a strong rationale for looking broadly

rather than just looking with disease-specific

genes.

For more information, contact Dr. Sohal at 216.444.8258 or [email protected].

Next-Generation Cancer Genomic Testing in a Real-World Setting

Nearly every major hospital or cancer treatment practice performs specific genomic testing

on every cancer patient’s tumor sample. Examples include KRAS oncogene analysis for

those with colorectal cancer or HER2 analysis in breast cancer. These standard-of-care

tests detect a single genetic mutation associated with a patient’s tumor type.

Davendra Sohal, MD, MPH, staff physician

in the Department of Solid Tumor Oncology

CLEVELAND CLINIC | TAUSSIG CANCER INSTITUTE | CANCER CONSULT

“There is an opportunity to make a difference for people

if we can apply the existing knowledge about cancer

mutations to making useful treatment decisions.”

Brian J. Bolwell MD, Chairman, Taussig Cancer Institute


The ultimate goal is to probe the clinical useful-

ness of expanded genomic testing. Every test

result includes molecular details about a patient’s

tumor along with supporting data suggesting a

particular targeted therapy. This information is

provided to a panel of oncologists within Taussig

Cancer Institute. This Genomics Tumor Board

meets weekly to review each result independently

and make recommendations for treatment —

whether with approved drugs or as part of clinical

trials in and around Cleveland. These recommen-

dations are transmitted to the primary oncologist,

who makes final personalized recommendations

to the patient. “If many patients can get to useful

treatments — whether FDA-approved or off-label,

or under a clinical trial of a targeted therapy —

then it can make a real difference,” says Dr. Sohal.

Because the science behind genomic testing is

evolving rapidly, new genetic mutations are rapidly

emerging. Cleveland Clinic has chosen to partner

with Foundation Medicine as the company con-

tinually updates its testing panel to keep current

with the latest research in cancer-related genetics.

“We have chosen a variety of cancers that includes

the most common cancers,” says Davendra Sohal,

MD, MPH, staff physician in the Department of

Solid Tumor Oncology and principal investiga-

tor of the study. “The goal is to see if this type of

expanded genomic testing can impact clinical

outcomes in a meaningful way.”

“We understand the importance of genomic

testing in a broad fashion and are investing heavily

in this,” adds Brian J. Bolwell, MD, FACP, chairman

of Cleveland Clinic’s Taussig Cancer Institute.

The target population for the study includes

patients lacking good treatment options, such as

those with metastatic disease or whose cancer has

progressed despite one or two rounds of standard

chemotherapy. “There is an opportunity to make

a difference for these people if we can apply the

existing knowledge about cancer mutations to

making useful treatment decisions.”

Feasibility and Utility

One of the trial’s goals is to study the feasibility

of doing genomic analyses in a real-world setting.

“We want to see how well tests like FoundationOne

can be performed in a real-world setting in a

variety of tumors,” comments Dr. Sohal. Questions

to be answered include: How long does it take for

a patient to be consented to receive this testing?

How long does it take to process the test and for

doctors at Cleveland Clinic to get the result? How

long does it take for the patient to learn the result

and get recommendations for treatment?


Genetic Advances Fuel New Hope in Fight Against Myeloid Leukemias

For more information, contact Dr. Maciejewski at 216.445.5962 or [email protected].

“We are on the forefront with the new, incredibly

efficient genomic technologies that exponen-

tially increase our ability to characterize genomic

defects leading to leukemia. Our team has discov-

ered multiple new mutations, including those in

the SETBP1 gene, which frequently mutate in a

subset of leukemias,” says Jaroslaw Maciejewski,

MD, PhD, Chairman of the Department of

Translational Hematology and Oncology Research.

“Now we are moving into the clinical application

of these technologies to generate comprehensive

testing panels for the most commonly occurring

mutations.”

Dr. Maciejewski says SETBP1 mutations hold great

promise as a novel therapeutic target. SETBP1

mutations ramp up evolution of myeloid leukemia.

Conceptually, development of a drug to turn off or

silence an overactive gene mutation is easier, he

explains, compared with devising a strategy to turn

on an essential gene switched off or damaged by a

cancer.

“We’ve discovered a very important mutation,

a somatic mutation, in a subset of leukemia

patients that can be targeted with drugs,” says Dr.

Maciejewski, who is also Professor of Medicine at

Cleveland Clinic Lerner College of Medicine.

The implications go beyond identification of spe-

cific mutations to aid the approximately 10 percent

of leukemia or myelodysplastic syndrome patients

who carry SETBP1 mutations. These innovations

coming out of Cleveland Clinic will usher in a

new era of individualized medicine for patients

fighting these cancers. “That’s the big picture,” Dr.

Maciejewski says.

The genetic profile of individual lesions can help

clinicians identify which patients are likely or

unlikely to respond to individualized therapy.

“Many of the drugs we have now work very well but

they are not very targeted, so we don’t know who

will respond,” Dr. Maciejewski says. “By target-

ing therapy to a specific genomic lesion, we avoid

Driven by leading-edge genetic discoveries that reveal how myeloid leukemias and

myelodysplastic syndrome acquire specific genetic mutations that can help predict the clinical

behavior of these diseases, researchers at Cleveland Clinic’s Taussig Cancer Institute continue to

lead as the focus shifts to translating this research. They now are moving from a discovery phase

into clinical application and innovative diagnostic, individualized therapies.

WT 1871T D868N

Two leukemia-specific mutations in the SETBP1 gene (middle and right

panel) were introduced into normal stem cells (left panel). The mutant

genes prevented cells from maturing and rendered them immortal.


“By targeting therapy to a specific

genomic lesion, we avoid potentially

toxic and futile therapies for

patients who do not have the lesion

and we maximize response among

those who do.”

Jaroslaw Maciejewski, MD, PhD,

Chairman, Department of Translational

Hematology and Oncology Research

potentially toxic and futile therapies for patients

who do not have the lesion and we maximize

response among those who do.”

Without such knowledge, administration of an

agent that effectively shuts down the SETBP1

mutation and its promotion of cancer progression

would work in only about 10 percent of leukemia

patients. Dr. Maciejewski says, “But if you only

treat the 10 percent of patients who have the

mutations, your response rate in this subgroup of

patients will be very, very high. Thus we can pro-

vide effective therapy to a subset of patients while

working on drugs for the next variant of leukemia.”

Discovery of the surprising role of SETBP1 somatic

mutations in fostering leukemias and myelodys-

plastic disease is the latest in a series of important

advances to emerge from Cleveland Clinic.

The findings were simultaneously published in two

studies in the August 2013 Nature Genetics by Dr.

Maciejewski and colleagues. The studies outline

the promise of SETBP1 findings for a subset of

adults fighting these cancers (2013;45(8):942-946)

as well as for children combating chronic juvenile

myelomonocytic leukemia (2013;45(8):937-941).

The SETBP1 research was one of only five studies

highlighted during the plenary session at the 2012

American Society of Hematology Annual Meeting

in Atlanta.

All these advances in understanding the genetic

framework behind myeloid leukemias and

myelodysplastic syndrome are a reality due to

rapid developments in next-generation genetic

sequencing and high-throughput genetic arrays.

These technologies have led to a realization and

appreciation of the great diversity of these cancers.

“These mutations, or combinations of these

mutations, are individual to each patient,” Dr.

Maciejewski says.

Previously, SETBP1 mutations primarily were

associated with Schinzel-Giedion syndrome.

Notably, children with this rare congenital condi-

tion and its characteristic physical malformations

inherit the genetic abnormality. In contrast, the

new discoveries at Cleveland Clinic show that the

SETBP1 mutations are acquired during the cancer

development process.

“These research findings exemplify our Cancer

Institute’s strengths. We are on the forefront of

driving discoveries with this set of diseases, and

we hope to translate these discoveries into the

development of individualized therapies,” Dr.

Maciejewski says.


Inhibition of JAK-STAT Pathway as a Therapeutic Option for Myelofibrosis Associated Pulmonary Hypertension

Ali Tabarroki, MD, Daniel Lindner, MD, PhD, Valeria Visconte, PhD, Li Zhang, PhD, Edy Hasrouni, Yvonne Parker, Heesun J. Rogers, MD, PhD, Tracy Cinalli, RN, Kristin Dodd, RN, Gina Rupp, RN, Hien Kim Duong, MD, Alan E. Lichtin, MD, Matt Kalaycio, MD, Mikkael A. Sekeres, MD, MS, Anjali S. Advani, MD, Betty K. Hamilton, MD, Sudipto Mukherjee, MD, PhD, MPH, Yogen Saunthararajah, MD, Stavros E. Mountantonakis, MD, Gustavo A. Heresi, MD, and Ramon V. Tiu, MD

Background: Pulmonary hypertension (PH) is an under-recognized complication of myelofibrosis (MF), occurring in 30 percent of MF patients and associated with poor survival. The pathophysiology of PH in MF has not been elucidated, although in idiopathic PH, the proliferation of pulmonary artery endothelial cells has been linked to activation of the STAT3 pathway.

Dysregulation of the JAK-STAT pathway has been implicated in the pathogenesis of MF. Ruxolitinib, a JAK1/2 inhibitor, was approved for management of splenomegaly and cytokine-mediated symptoms in MF. No specific therapy in the management of MF-associated PH has been established. Given the association between MF and PH and the possible pathophysiologic link mediated by JAK signaling, we prospectively followed 19 patients with MF-associated PH and compared their echo-cardiographic findings and PH-relevant serum biomarker levels pre- and post-ruxolitinib therapy.

Results: Nitric oxide (NO), a primary regulator of vascular endothelial function, is reduced in MF patients with PH compared to normal individuals. Treatment with ruxolitinib resulted in marked increase in NO levels compared to baseline, while no changes in NO levels were observed after treatment with hydroxyurea and lenalidomide. Treatment with ruxolitinib also resulted in reduction of key cytokines that inhibit NO production and induction of cytokines that lead to increase in NO synthesis, supporting the role of cytokines in PH pathogenesis in MF.

Conclusion: Aberrant JAK-STAT signaling in MF mediates PH by dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors. This suggests that inhibition of the JAK-STAT signaling pathway is a novel, viable target for the management of patients with MF-associated PH.

Differences in Perceptions of Disease and Treatment Effectiveness and Adherence Between Physicians and Patients with Myelodysplastic Syndromes (MDS)

David P. Steensma, MD, Richard M. Stone, MD, John Huber, MS, Betsy Dennison, MS, RN and Mikkael A. Sekeres, MD, MS

Background and Methods: MDS are complex conditions, described with sometimes confusing terminology. Contemporary drug therapies (tx) for MDS require repeated treatment administration cycles to achieve clinical effect. Lack of disease understanding or premature discontinuation of tx may result in poorer outcomes for patients (pts). To better understand physician (MD) and pt perceptions about MDS and tx decisions, we conducted two online surveys: one for MDS pts and one for healthcare providers (HCP). Pt and HCP surveys assessed understanding of MDS, perceptions of specific tx, barriers to tx adherence, and overall tx experience.

Results: Of 4,039 pts invited to participate, 477 (12%) complete responses were received. Of 4,594 HCPs invited to participate, 120 (3%) complete responses were received. Because of low participation among other HCP groups, only MD responses were examined. Only 10% of pts reported MDS (p < .001) was described to them as “cancer” compared to how it was described by 59% of MDs. Only 29% of pts reported that MDS was “curable,” compared to 52% of MDs(p < .001). Forty-two percent of pts had received at least one disease-modifying tx. MD and pt perceptions of active tx were significantly different, with MDs overestimating quality of life (QOL) benefits for drugs and underestimating the negative impact of tx on pt activities for hypomethylating agents. MDs interpreted the benefit of active tx significantly higher than pts; however, pts perceived the actual tx experience more positively than MDs.

Most pts (81%) reported the MD had the most influence on their decision to stop tx, correlating to 69% of MDs who reported recommending stopping tx prior to the completion of tx regimen. Reported reasons diverged significantly between MD and pt, and included the burden of tx exceeding benefit to the pt, as well as perceptions that the impact on the pt and family was too great.

Conclusion: Physicians and MDS pts have distinct views of the value of tx for MDS, with MDs underestimating the impact of tx on QOL, but overestimating it as a justification for stopping tx. Improved communication may improve understanding of MDS and the impact of active treatment to achieve better tx adherence and ultimately response.

Prospective Study of an Emergency Department Febrile Neutropenia Pathway in Patients with Hematologic Malignancies

Michael K. Keng, MD, Elaine Thallner, MD, MS, Paul Elson, ScD, Christine Zayac, MA, Jennifer Sekeres, PharmD, BCPS, Candice M. Wenzell, PharmD, BCOP, Erika M. Gallagher, PharmD, BCOP, Catherine M. Weber, PharmD, BCOP, Marc A. Earl, PharmD, BCOP, Sudipto Mukherjee, MD, PhD, MPH, David J. Seastone, DO, PhD, Brad Pohlman, MD, Eric Cober, MD, Beth Rodgers, RN, MSN, CEN, Virginia B. Foster, PhD, MPH, Joy Yuhas, RN, MSN, Matt E. Kalaycio, MD, Brian J. Bolwell, MD, and Mikkael A. Sekeres, MD, MS

Background: Febrile neutropenia (FN) is an oncologic emergency associated with high morbidity and mortality, particularly in patients (pts) with hematologic malignancies. Delays in antibiotic administration, which can occur in busy emergency departments (EDs), lead to worse outcomes. We instituted an FN pathway (FNP) in Cleveland Clinic’s (CC) ED to reduce antibiotic delays.

Methods: We compared patients from 06/2012 to 06/2013 to historical pts from 02/2010 to 05/2012. Fever was defined as temperature≥ 38°C, while neutropenia as absolute neutrophil count < 0.5 x 109/L. All CC cancer pts received a special “Neutropenic Risk Hospital Medical Alert Card,” which they presented upon CC ED registration with fever. The pathway formally recognized “fever with a history of cancer” as a distinct chief complaint and categorized FN as Emergency Severity Index level 2 (equivalent to stroke or myocardial infarction) for immediate triage and care. ED-specific electronic FN order sets were created to facilitate antibiotic, laboratory, and blood culture ordering, with antibiotics administered prior to return of neutrophil count. The primary goal of the FNP is administration of empiric broad-spectrum antibiotics within 120 minutes of ED presentation, per Infectious Diseases Society of America

HIGHLIGHTSfrom the

A S HANNUAL MEETING

Physicians and investigators from Cleveland Clinic’s Taussig Cancer Institute made major contributions to the American Society of Hematology (ASH) 2013 Annual Meeting in New Orleans, describing their research in more than 30 oral presentations and more than 60 poster presentations. Here we feature condensed abstracts from five of the presented research papers (Cleveland Clinic authors are listed in bold).

For complete abstracts, see https://ash.confex.com/ash/2013/webprogram/start.html


guidelines. The primary outcomes measured were time intervals related to it, e.g. time to blood draw, physician assessment, and antibiotic order/administration. All reported times were from ED registration.

Results: FNP study pts had significantly shorter time to having blood drawn (median 38.5 vs. 70 minutes, p < 0.0001), seeing a doctor (median 44 vs. 71 minutes, p = 0.0002) and to receiving antibiotics (median 79 vs. 228 minutes, p < 0.0001). Time to admission was also shorter for FNP study pts, though study pts (4.2 vs. 6.0 hours,p < 0.0001) were less likely to be admitted than historical controls (83% vs. 97%, p = 0.005), p < 0.0001). For FNP pts admitted to the hospital, there was a non-significant decrease in length of stay, ICU admission and length of ICU stay compared to historical controls. Comparing the two FNP groups treated or not treated per the order set, those treated using the order set had shorter times to antibiotics being ordered (median 28.0 vs. 60.5 minutes, p < 0.0001) and administered (100% vs. 90%, p = 0.02). ED order set pts also had a higher rate of antibiotic use. Correct antibiotic use, antibiotic overuse, hospital and ICU admission rates, time to hospital admission, and length of hospital stay were all similar between the two groups (all p ≥ 0.28).

Conclusion: The FNP significantly decreased time from ED registration to all set time-points, including time to antibiotics by almost threefold, compared to historical controls in pts with hematologic malignancies. Rate of hospitalization was significantly lower, and ICU and length of stay numerically lower. The FNP is an effective clinical tool to provide prompt antibiotic administration to FN pts and likely represents a significant mechanism for improved outcomes and cost savings to patients with hematologic malignancies presenting with FN.

Distinct Pattern of Genomic Changes Associated with Smoking in Patients with Myelodysplastic Syndromes (MDS)

David J. Seastone, DO, PhD, Sudipto Mukherjee, MD, PhD, MPH, Zaher K. Otrock, MD, Paul Elson, ScD, Michael K. Keng, MD, Bartlomiej Przychodzen, PhD, Hideki Makishima, MD, PhD, Brittney Dienes, Sean Hobson, Kristin Dodd, RN, Tracy Cinalli, RN, Ramon V. Tiu, MD, Yogen Saunthararajah, MD, Jaroslaw P. Maciejewski, MD, PhD, FACP and Mikkael A. Sekeres, MD, MS

Background: Smoking is a risk factor for development of MDS and for overall survival. The pathogenesis of MDS is a multistep process with environmental and genetic influences. The link between smoking and MDS is thought to be mediated by organic solvents in tobacco. We identified specific molecular abnormalities associated with smoking exposure in MDS patients (pts).

Methods: 151 MDS pts seen from 2000 to 2012 with complete smoking and molecular data were included. We assessed associations between the number of mutations present and demographic and clinical factors. Analysis was performed using next-generation targeted deep gene sequencing with 22 common gene mutations, selected based on the frequency observed in a cohort of MDS patients analyzed by whole exome sequencing. Mutations were considered individually and in functional groups: methylation (TET2, IDH1, IDH2), histone modification (ASXL1, EZH2), and gene splicing (SRSF2, U2AF1, SF3B1).

Results: Overall 68% of pts had at least one mutation of the 22 screened mutations: 32% had a single mutation, 22% had 2, and 13% had 3 to 6 mutations. The most common mutations were in TET2, SF3B1, ASXL1, DNMT3A and U2AF1; 32% of pts had one or more mutation in genes involved in methylation, 19% in histone modification, and 32% with splicing. In univariable analyses, current/ex-smokers were more likely to have at least one of the common mutations than never smokers. The number of mutations increased with smoking exposure, particularly with genes involved with histone modification. Certain mutations increased in prevalence with age, e.g.: pts < 60 had fewer mutations overall than pts ≥ 60, and in particular fewer mutations in methylation-associated genes. Older age and greater smoking history/exposure were

both associated with more mutations. Current and ex-smokers and heavier smoking exposure (> 20 pack years) were also associated with worse survival, though current or ex-smokers with < 20 pack years had similar survival to never smokers. Multivariable analyses confirmed smoking as a risk factor for survival.

Conclusion: Smoking is associated with a greater number of molecular abnormalities in MDS pts, and may generate a distinct mutational signature pattern, particularly along histone acetylation pathways. This study identifies specific environmentally mediated pathways in the multistep pathogenesis of MDS.

Somatic Mutational Screen for Improved Prediction of the Outcomes of Epigenetic Therapy in Myelodysplastic Syndromes (MDS)

Swapna Thota, MD, Paul Lakin, Holleh Husseinzadeh, MD, Hideki Makishima, MD, PhD, Bartlomiej P. Przychodzen, PhD, Brittney Dienes, Kathryn M. Guinta, Naoko Hosono, MD, PhD, Tomas Radivoyevitch, PhD, Mikkael A. Sekeres, MD, MS, Yogen Saunthararajah, MD and Jaroslaw P. Maciejewski, MD, PhD

Background: Hypomethylating agents decitabine and azacitidine are standard treatments for MDS. However, individual treatment responses vary from complete remissions (CR) to complete refractoriness. In general, at least months of therapy are needed prior to assessing response. Thus, patients may be subjected to prolonged exposure to ineffective therapy, suffering toxicities without clinical benefit, while potentially more effective alternative treatments are delayed. Currently, there are no reliable phenotypic or mutational markers for predicting response to hypomethylating agents. With the availability of whole exome sequencing (WES) for more routine analysis, we theorized that somatic mutational patterns may help identify patients who would most benefit from these drugs, thereby maximizing response rate by rational patient selection.

Methods: We screened 168 patients with MDS who received either azacitidine or decitabine for the presence of somatic mutations. Only those who received sufficient therapy, i.e., completed at least 4 cycles, were selected for outcome analysis. WES and targeted deep next-generation sequencing for a subset of 60 genes most frequently affected by somatic mutations in MDS was applied to 94 evaluable patients.

Overall, the most frequently mutated genes include: TET2, IDH1/IDH2, SRSF2, ASXL1, SF3B1, RUNX1, EZH2/EED/SUZ12, SETBP1, CBL and PPFIA2. For some analyses we also divided mutations into functional gene families; e.g., DNMT family (DNMT1, DNMT3A, DNMT3B), PRC2 family (EZH2, EED, SUZ12, JARID2, RBBP4, PHF1), IDH family (IDH1, IDH2), CBL family (CBL, CBLB), and RAS family (NRAS, KRAS, HRAS, NF1, NF2, RIT1, PTPN11), among others.

Results: The most common molecular abnormalities in responders included the presence of complex karyotype, del7q/-7, del5q and mutations in DNMT3, ASXL1 and others. Similarly, the most common defects found in refractory included the U2AF1/2 family of genes. When compared and selected by the lowest p value, the top mutations in terms of predicting response were SRSF2 (OR 2.4), cohesin (5.1), ATM (OR 5.6) and PHF6 (OR 4.22). Mutations predicting non-response include RAS (OR 0.3), U2AF1/2 (OR 0.4) and LUC7L defects (OR 0.53). To generate better predictors, we combined mutations in “either/or” fashion. For instance, the presence of either SRSF2 and cohesin, or cohesin and PHF6 mutations, will be considered predictors of response, and the presence of either RAS/U2AF1 and/or cohesin/ATM and SRSF2 are predictors of refractoriness.

Conclusions: Mutational patterns may be helpful in identifying patients who may benefit from hypomethylating therapies. Identification of the most predictive genes could guide development of molecular marker-based selection of patients for hypomethylating agent therapy, but will require ongoing analysis and additional prospective testing for validation.

Clinical Risk Groups

Very Low

Low

Intermediate

High GPS

Unfavorable Biology

Intermediate Risk

Individual RiskLow GPS

Favorable Biology

Very Low Risk

Figure 1 A patient’s Genomic Prostate Score (GPS) helps

distinguish individual risk of unfavorable pathology across a

spectrum of clinical disease categories.

A presentation at the American Urological

Association in San Diego on May 8, 2013, marked

a watershed moment for patients with early-stage

prostate cancer considering active surveillance.

That morning, the results of a validation study

performed at the University of California at San

Francisco (UCSF) that was based on developmen-

tal work undertaken at Cleveland Clinic showed

that a 17-gene signature (Figure 2) performed on

prostate biopsies could accurately predict the

presence or absence of adverse pathology on radi-

cal prostatectomy specimens.

The signature, called the Genomic Prostate Score

(GPS) and marketed by Genomic Health Inc. as the

Oncotype DX Prostate, helps identify men who are

good candidates for active surveillance. The com-

mercialization of GPS represented the culmination

of seven years of developmental work and clinical

validation studies.

From Bench to Bedside:

Genomics for Active Surveillance Now in Clinical Practice

By Eric A. Klein, MD

Cancer Consult provides information from Cleveland Clinic Taussig Cancer Institute specialists about innovative research and diagnostic and management techniques.

Please direct correspondence to

Taussig Cancer Institute/R35 Cleveland Clinic 9500 Euclid Ave. Cleveland, OH 44195

Cleveland Clinic Taussig Cancer Institute annually serves more than 28,000 cancer patients. More than 250 cancer specialists are committed to researching and applying the latest, most effective techniques for diagnosis and treatment to achieve long-term survival and improved quality of life for all cancer patients. Taussig Cancer Institute is part of Cleveland Clinic, an independent, nonprofit, multispecialty academic medical center.

Cancer Consult Medical EditorBrian Rini, MDSolid Tumor Oncology

Cancer Consult Editorial BoardBrian J. Bolwell, MD, Chairman, Taussig Cancer Institute

Robert Dreicer, MD, Chairman, Solid Tumor Oncology

Timothy Spiro, MD, Chairman, Regional Oncology

John Suh, MD, Chairman, Radiation Oncology

Gene Barnett, MD, Director,Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center

Eric Klein, MD, Chairman,Glickman Urological & Kidney Institute

Managing Editor John Mangels [email protected]

DesignerAmy Buskey-Wood

PhotographyRussell Lee

Cancer Consult is written for physicians and should be relied on for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient.

© 2013 The Cleveland Clinic Foundation

Dr. Klein is chairman of Cleveland Clinic’s Glickman Urological & Kidney Institute. For more information, contact him at 216.444.5591 or [email protected].

For references, please email the editor.




Figure 2 The 17 genes comprising

the Genomic Prostate Score

Androgen Signaling

AZGP1

FAM13C

KLK2

SRD5A2

Stromal Response

BGN

COL1A1

SFRP4

Proliferation

TPX2

Cellular Organization

FLNC

GSN

GSTM2

TPM2

Reference

ARF1

ATP5E

CLTC

GPS1

PGK1

One major barrier to more widespread adoption

of active surveillance is uncertainty on the part

of both patients and physicians as to whether a

biopsy showing low-volume Gleason 6 cancer is

reflective of the biology of the entire prostate.

Current clinical practice is typically to perform

a repeat biopsy soon after initial diagnosis, and

at some centers to perform a prostate MRI, but

neither of these methods has been sufficiently

clinically validated to completely assuage concerns

about undergrading or understaging.

GPS was specifically designed to address this issue.

In the initial development study, the primary and

highest Gleason pattern tumors contained in radi-

cal prostatectomy specimens were microdissected,

and gene expression signatures were measured

independently in each tumor. The results showed

that a subset of genes could predict clinical out-

comes regardless of whether they were measured

in the primary or highest grade. This suggests that

if expression of the same genes was measured in

a prostate biopsy, the result would be informative

about the biology of the entire prostate.

Two subsequent studies, one at Cleveland Clinic

and the one at UCSF previously mentioned, dem-

onstrated that gene expression on biopsy could

predict for the presence of a dominant pattern 4

cancer or extracapsular disease, both of which are

features that are desirably avoided in men man-

aged by surveillance. The clinically available GPS

is derived from biopsy material from an individual

patient and is reported on a scale of 0 to 100. Lower

scores are indicative of a higher likelihood of hav-

ing favorable pathology (i.e., absence of dominant

pattern 4 disease and absence of extracapsular

disease), which helps discriminate individual risk

in men categorized with National Comprehensive

Cancer Network very low-, low- or intermediate-

risk disease (Figure 1).

The overdiagnosis of nonlethal prostate cancer by

PSA screening has resulted in a paradigm shift in

From Bench to Bedside:

Genomics for Active Surveillance Now in Clinical Practice

the management of newly diagnosed disease. The

main question men should ask is no longer “What

is the best treatment for my cancer?”, but rather,

“Does my cancer need to be treated at all?”

The development of the GPS helps usher in an era

of precision medicine, where the correct answer

to the question on need for treatment is less a

clinical judgment than a decision informed by an

individual’s tumor biology.


GLIOBLASTOMA

CCF IRB 12-1084Phase II study of TKI258 (dovitinib) in

patients with recurrent or progressive

glioblastoma who have progressed with

or without anti-angiogenic therapy

(including anti-VEGF therapy)

CCF IRB 12-344Phase II Evaluation of TRC105 in

combination with bevacizumab for the

treatment of recurrent or progressive

glioblastoma that has progressed on

bevacizumab

CCF IRB 13-445Prospective Phase II trial of NovoTTF-

100A with bevacizumab (Avastin®) in

patients with recurrent glioblastoma

LYMPHOMA

CCF IRB 13- 1081Phase II study of radioimmunotherapy

with Zevalin® (ibritumomab tiuxetan)

therapy for patients with refractory

or relapsed primary central nervous

system lymphoma (PCNSL)

MESOTHELIOMA

VERA 1513 / 13-885 Phase II randomized double-blind,

placebo-controlled, multicenter study

of VS-6063 in subjects with malignant

pleural mesothelioma (Verastem Inc)

New: SARCOMA

THRS 1711Randomized Phase III, multicenter,

open-label study comparing TH-302

in combination with doxorubicin vs.

doxorubicin alone in subjects with

locally advanced unresectable or

metastatic soft tissue sarcoma.

MYELOMA

CASE1A09 / CC-902 Azacitidine with lenalidomide and

dexamethasone for relapsed/refractory

myeloma

CASE2A10 / CC-00079 Placebo-controlled trial to assess

efficacy of glutamine in prevention of

bortezomib-induced neuropathy

CASE1A13 / 13-870“Mini” allogeneic stem cell transplant

with bortezomib as graft-vs.-host

disease prophylaxis and delayed

low-dose lenalidomide maintenance

with the goal to maximize graft versus

myeloma effects

SWOG1211 / 13-063 The antiCS-1 antibody elotuzumab

together with bortezomib, lenalidomide

and dexamethasone for high-risk

multiple myeloma

RENAL

GENE 1813 Phase II randomized study of

MPDL3280A administered as mono-

therapy or in combination with

bevacizumab vs. sunitinib in patients

with untreated advanced renal cell

carcinoma

At any given time, Taussig Cancer Institute has more than 100 cancer clinical trials underway on the main campus and at some Cleveland Clinic community facilities. Here is a representative sample of trials that are currently accepting patients:

Stay up to date on Cleveland Clinic’s more than 100 active clinical trials for cancer patients. Our free Cancer Clinical Trials app — available for iPhone®, iPad®, AndroidTM phone and Android tablet — makes it easy.

With this app, you can:

Search the database of open clinical trials by disease, phase, physician or location.

Browse real-time information on each trial’s objective, eligibility criteria, stage(s) and more.

Connect to our Cancer Answer Line for more information about a trial or to enroll patients.

“Making clinical trials accessible offers patients important treat-ment options,” says Brian Rini, MD, a staff member in Solid Tumor Oncology. “This app is one more way for doctors to know what trials are available, in real time.”

Get the Latest on Cancer Trials with Our New Mobile App

Clinical Trials

To download, go toclevelandclinic.org/cancertrialapp.

For information about clinical trials, call the Cancer Answer Line at 866.223.8100.

To search the database, visit clevelandclinic.org/cancerclinicaltrials.

apoA1In a series of innovative experiments, Stanley

Hazen, MD, PhD, and his team determined that

apolipoprotein A1 (apoA1), or the major cardio-

protective protein component of high-density

lipoprotein (HDL), combats metastatic malignant

melanoma and lung cancer through multiple path-

ways. ApoA1 injections not only inhibited tumor

growth and progression in experiments with

mice, but actually spurred tumor and metastases

regression.

Researchers at Cleveland Clinic, including Dr.

Hazen; Joseph DiDonato, PhD; Maryam Zamanian-

Daryoush, PhD; and Daniel Lindner, MD, PhD, are

now poised to translate these advances to thera-

peutic strategies for the clinical setting.

The apoA1 findings are a prime example of new

advances coming from the evolving field of cardio-

oncology. “Cardiovascular disease and cancer are

not so disparate in the sense that there are major

contributing pathways that operate in concert in

both diseases,” says Dr. Hazen, Chair of Cellular

and Molecular Medicine, the Jan Bleeksma Chair

in Vascular Cell Biology and Atherosclerosis, and

the Leonard Krieger Chair in Preventive Cardiology

at Cleveland Clinic. “In apoA1, we may have identi-

fied an important central player nexus and a pos-

sible intervention that works positively to combat

both diseases.”

Interestingly, after in vitro studies ruled out a

direct effect of apoA1 on tumor cells, the Cleveland

Clinic team determined apoA1 instead modulates

innate and adaptive immune systems in the host

in multiple ways to create a micro-environment

that works against cancer development. For

example, they demonstrated apoA1 can actually

switch tumor-associated macrophages from an M2

phenotype to a more beneficial M1; can decrease

tumor angiogenesis independent of vascular endo-

thelial growth factor pathways; and can increase

levels of tumor-killing CD8 T cells circulating in

and around a tumor.

Although complexity usually works in cancer’s

favor, here it may be a distinct disadvantage. “The

simple elegance of a multipronged approach is

that the tumor cell should have a very difficult

time in coming up with a solution to negate apoA1

effects,” says Dr. DiDonato, Supervisor of the

Cellular and Molecular Medicine Laboratory at

Cleveland Clinic. “If apoA1 had a direct effect on

the tumor, the tumor could mutate to circumvent

apoA1’s direct effect, much like tumors do in

response to chemotherapeutic agents that target

a single pathway or protein in the tumor cell.” Dr.

Hazen says, “In contrast to most chemotherapies,

which weaken the immune system and have

infection risk as a side effect, apoA1 therapy for

these tumors augments the immune system’s

functions, harnessing the body’s natural

tumor-fighting potential to promote tumor and

metastases regression — it’s exciting.”

The investigators observed zero to very limited

metastatic melanoma tumor growth in transgenic

animals overexpressing apoA1 at approximately

twice the normal circulating levels. In further

experiments, Dr. Hazen, Dr. DiDonato and their

colleagues found palpable tumors regressed 50

percent from their peak volume within one week

among animals injected with apoA1, a beneficial

result maintained over time.

It remains unknown if apoA1’s anti-inflammatory

action is the shared underlying etiology between

the benefits of HDL seen in cardiology and poten-

tially now also observed in oncology. “That is the

$64,000 question,” Dr. DiDonato says. “What we

do know is that inflammation plays a major role,

not only in the initiation or establishment of the

tumor, but also in the propagation and migration

or metastasis of the tumor cells.”

It may be time to add ‘potential cancer fighter’ to the list of promising benefits of HDL, the carrier of “good

cholesterol,” according to cutting-edge research emerging from Cleveland Clinic’s Lerner Research Institute.

Promising Research Shows HDL, the Carrier of ‘Good’ Cholesterol, Has Cancer-Fighting Punch


For more information, contact Dr. Hazen at 216.445.9763 or [email protected].

Dr. DiDonato can be reached at 216.445.2174 or [email protected].


Hyperthermia is a noninvasive method of

increasing tumor temperature that makes it more

sensitive to the effects of radiation. “Our group

has shown that the addition of hypothermia

to radiation can sensitize cancer stem cells —

which are fairly resistant to radiation and to

chemotherapy alone — to subsequent radiation

treatment,” says Jennifer Yu, MD, PhD, radiation

oncologist at Taussig Cancer Institute, and

a cancer researcher in Stem Cell Biology and

Regenerative Medicine at Lerner Research

Institute. “Hyperthermia makes radiation much

more efficacious,” she says.” The combination

of hyperthermia and radiation in particular is a

great treatment for patients who have failed prior

chemotherapy and failed prior radiation therapy.”

Taussig Cancer Institute houses a hyperthermia

unit that is primarily used for treating superficial

cancers. Within the past 18 months, more than

20 patients have received this treatment. Most

patients seen have recurrent breast cancers and

some patients have unresectable melanoma and

recurrent vulvar cancers that previously had been

irradiated. “We have the capacity to treat deeper

tumors as well, such as advanced cervical cancer,”

Dr. Yu adds.

Hyperthermia helps address the limitations of

repeat radiation for many patients by effectively

increasing the radiation dose without substan-

tially increasing side effects. “With the addition

of hyperthermia we are able to use lower radia-

tion doses and yet have comparable results seen

with higher doses,” says Dr. Yu. She explains that

hyperthermia effectively increases the amount of

radiation a patient receives by about 50 percent.

Hyperthermia Improves Response Rates in Recurrent Cancers

A large number of clinical studies show that treatment with hyperthermia

in combination with radiation leads to a better response than radiation

alone in a variety of cancers, particularly for superficial cancers. Well-

controlled studies show that the combination treatment can increase

complete response rates in patients with recurrent breast cancer compared

with radiation alone, particularly for those patients who have had prior

radiation. Yet despite these benefits, the treatment is not widely available.

Cleveland Clinic’s Taussig Cancer Institute is the only cancer program in

Ohio and one of the few in the United States to offer hyperthermia.

For more information, contact Dr. Yu at 216.445.9799 or [email protected]



Proven Protocols

Hyperthermia is done prior to each radiation

treatment. For recurrent breast cancer, treatment

requires about 60 minutes of hyperthermia

followed by radiation. During the treatment, a

heated water bolus is placed on the area to be

treated, which is the tumor plus a small area

around it. A microwave unit is added on top that

heats the treatment area to 109 to 110 degrees

Fahrenheit. Physicians use thermistors to measure

temperature in real time to make sure the tumor

is receiving adequate heating, not over- or

underheating. “The hyperthermia we use involves

mild but effective temperatures,” adds Dr. Yu. “It

is not so high that the tumor is destroyed, such as

with thermal ablation.”

“The combination of hyperthermia

and radiation in particular is a great

treatment for patients who have failed

prior chemotherapy and failed prior

radiation therapy.”

Jennifer Yu, MD PhD, Radiation Oncologist

After the procedure, some patients may feel

mild to moderate pain; others just feel warm.

Most patients do not require pain medications.

Many patients are sufficiently relaxed that they

fall asleep during the hyperthermia treatment.

Patients typically receive hyperthermia/radiation

treatment twice a week, but it may vary due to the

radiation protocol prescribed. Each hyperthermia

session must be accompanied by radiation or, in

some cases, chemotherapy. Hyperthermia is gener-

ally well-tolerated. A minority of patients develop

skin blistering or ulceration that typically heals

with conservative measures.

Most patients referred to Taussig Cancer

Institute’s hyperthermia unit are sent by medical

oncologists who have tried multiple types of che-

motherapy, or radiation oncologists who are aware

of the benefits of hyperthermia and radiation.


For the past eight years, Alok Khorana, MD,

Director of the Gastrointestinal Malignancies

Program at Cleveland Clinic’s Taussig Cancer

Institute since April 2013, has been studying this

link. In 2008, he published what has become

a seminal paper in the field of thrombosis and

cancer, detailing a risk score protocol that

helps predict a cancer patient’s risk of venous

thromboembolism (VTE).

The Khorana score, as it known, predicts

thrombosis risk based on a collection of simple

variables — type of cancer, body mass index (BMI)

and complete blood count (platelet, leukocyte,

hemoglobin). “Not only is the score effective for

assessing risk, but it is also easy to use because

expensive tests are not required,” says Dr.

Khorana. “It is data everyone already has for their

patients.” Each variable in the score is assigned a

value. Elevated pre-chemotherapy platelet counts

over 350,000/mcL, BMI of at least 35 kg/m2, and

cancer types such as stomach and pancreas cancer

each raise the risk, for example. Cancer patients

with a Khorana score of 3 or greater are at high

risk for developing blood clots. “Our initial study

of 4,000 patients also showed that patients who

are at high risk of developing clots experience

shorter progression-free survival and early

mortality,” he adds.

Today, nearly 10,000 patients in the United States

and Europe have been part of clinical studies

assessing the effectiveness of the Khorana

score in predicting the risk of cancer-associated

thrombosis. “Since our first study, multiple

institutions have validated the score in predicting

blood clot risk,” he adds. “All of the studies show it

works exceedingly well.”

In June 2013, the American Society of Clinical

Oncology (ASCO) issued guidelines affirming

the use of a slightly modified Khorana score as a

well-established risk calculator for thromboem-

bolism. Specifically, new ASCO guidelines recom-

mend that patients with cancer be assessed for

VTE risk at the time of chemotherapy initiation

and periodically thereafter. The guidelines also

suggest that physicians consider using the score

when deciding if VTE prophylaxis is an appropri-

ate intervention for a particular patient. This is an

important recommendation because several ran-

domized clinical trials, including the Prophylaxis

of Thromboembolism During Chemotherapy Trial

(PROTECHT) study and the SAVE-ONCO investiga-

tion, the largest thromboprophylaxis study ever

conducted in cancer patients, have recently dem-

onstrated that outpatient anti-coagulation prophy-

laxis is feasible, safe and effective. But it remains

unclear which cancer patients should be selected

for VTE prophylaxis. The ASCO guidelines suggest

that only those ambulatory cancer patients at high

risk for VTE receive anti-coagulation therapy on a

prophylactic basis.

Thrombosis and cancer are integrally linked. Patients with cancer carry a fourfold

increase in thrombosis risk, with chemotherapy elevating the risk even higher.

Scoring the Risks:

Khorana Score Predicts Risk of Cancer-associated Thrombosis and Mortality

For more information, contact Dr. Khorana at 216.636.2690 or [email protected]



Predicts Mortality in Cancer

The main use of the score is to assess risk of blood

clots and to inform a recommendation for anti-

coagulation prophylaxis. “The new use of the score

is that it is predictive of mortality,” explains Dr.

Khorana. A European analysis of more than 1,500

patients with a variety of cancers determined

that higher Khorana scores correlate with higher

mortality rates independent of the presence of

blood clots. After two years of follow-up, patients

with a Khorana score of 0 had a 27 percent

mortality rate; those with a Khorana score of 3 or

more had a 63 percent mortality rate, a fourfold-

higher mortality rate after adjustment compared

with patients with a score of 0.

While this study based in Vienna, Austria, was

performed in patients with several types of

cancers, Dr. Khorana and others are conducting

other investigations in specific cancer types to

validate the score’s efficacy and usefulness in

those patient populations. His research group has

already performed two studies using the score

in patients with gastrointestinal cancers. While

the results are pending publication, Dr. Khorana

explains that “when we look purely at colorectal

cancer patients, which are the patients I treat

personally, it appears highly effective in predicting

mortality in that population.”


Jame Abraham, MD, has been named director of the Breast Oncology Program at Cleveland Clinic Taussig Cancer Institute. Previously he was the first Bonnie Wells Wilson Distinguished Professor and Eminent Scholar in breast cancer research at West Virginia University’s Mary Babb Randolph Cancer Center, where he also served as Medical Director of the Cancer Service Line and Chief of Hematology/Oncology.

Dr. Abraham is the founding editor of the Bethesda Handbook of Clinical Oncology, as well as the chief editor of Emerging Cancer Therapeutics. He is a member of the NSABP Breast Cancer Working Group, and for four years was a member of the American Cancer Society’s Board of Directors. Among Dr. Abraham’s honors are the Dean’s Award for Excellence in Clinical Medicine from the West Virginia University School of Medicine, and a 2010 award from the president of India for contributions to medicine. “In this day and age, breast cancer treatment should be deliv-ered by a team of experts,” Dr. Abraham says. “Fortunately at Cleveland Clinic, we have an excellent breast cancer team. My goal is to work with our outstanding team members to operate one of the best patient-centered breast cancer programs in the country. That means continuing to provide excellent patient care; offering innovative, pathway-driven, novel treatment approaches through clinical trials; and, above all, making sure that every patient receives the highest quality of care, delivered in a coordinated way.”

Dr. Abraham earned his medical degree from India’s Calicut Medical College. He com-pleted his internal medicine residency at the University of Connecticut, and a hematology fellowship at the National Heart, Lung, and Blood Institute. He was a Senior Fellow at the National Cancer Institute, and took part in the Leadership for Development of Physicians in Academic Health Centers program at Harvard University’s School of Public Health.

Office: 216.445.0150

Navneet Majhail, MD, MS, has joined Cleveland Clinic Taussig Cancer Institute as director of the Blood and Marrow Transplant Program. He also serves as a staff physician in the Department of Hematologic Oncology and Blood Disorders.

Previously, Dr. Majhail was an adjunct associate professor in the University of Minnesota’s Blood and Marrow Transplant Program, and Medical Director of Health Services Research at the National Marrow Donor Program in Minneapolis.

Dr. Majhail’s research involves prevention and management of complications of blood and marrow transplantation. He also focuses on health policy issues such as healthcare disparities, quality of care, survivorship and economic issues related to transplant. He holds leadership positions with the Center for International Blood and Marrow Transplant Research, where he is the scientific direc-tor for the Late Effects and Health Policy Working Committees and their Health Services Research Program.

“Cleveland Clinic’s Blood and Marrow Transplant Program is a national leader in providing patient-centered, high-quality and cutting-edge care to transplant patients,” says Dr. Majhail. “I am committed to continuing and building on this legacy. It takes a village to take care of a transplant patient, and the excellent team of providers that we have in our program was an important factor in my decision to come here. I look forward to increasing collaboration with our interna-tionally recognized hematologic malignancy programs, and to further building our portfolio of clinical trials so that we can continue to provide highly innovative, leading-edge treat-ments to our patients.”

Dr. Majhail earned his medical degree from India’s Government Medical College in Chandigarh, India. He completed his internal medicine residency at Cleveland Clinic and a hematology/oncology fellowship at the University of Minnesota.

Office: 216.444.2199

Qing Yi, MD, PHD Department Chair, Cancer BiologySpecialty: Cancer Biology Office: 216.636.7532

Mohamed Abazeed, MD, PhDSpecialty: Translational Hematology Oncology ResearchOffice: 216 445-0061

Lanea Keller, MDSpecialty: Radiation OncologyOffice: 216.447.9747

Alberto Montero, MDSpecialty: Breast OncologyOffice: 216.445.1400

Nima Sharifi, MD Specialty: Prostate CancerOffice: 216.445.9750

NewStaff





Selected PUBLICATIONS

Sohal DPS, Metz JM, Sun W, Giantonio BJ, Plastaras JP, Ginsberg G, Kochman ML, Teitelbaum UR, Harlacker K, Heitjan DF, Feldman MD, Drebin JA, O’Dwyer PJ. Toxicity study of gemcitabine, oxaliplatin, and bevacizumab, followed by 5-fluoroura-cil, oxaliplatin, bevacizumab, and radio-therapy, in patients with locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2013 Jun;71(6):1485-1491.

Lane BR, Campbell SC, Gill IS. 10-year oncologic outcomes after laparoscopic and open partial nephrectomy. J Urol. 2013 Jul;190(1):44-49.

Przybycin CG, Magi-Galluzzi C, McKenney JK. Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens. Adv Anat Pathol. 2013 Jul;20(4):245-263.

Sloan AE, Ahluwalia MS, Valerio-Pascua J, Manjila S, Torchia MG, Jones SE, Sunshine JL, Phillips M, Griswold MA, Clampitt M, Brewer C, Jochum J, McGraw MV, Diorio D, Ditz G, Barnett GH. Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma. J Neurosurg. 2013 Jun;118(6):1202-1219.

Smith MR, Joshi I, Pei J, Slifker M, Jin F, Testa JR, Al-Saleem T. Murine mantle cell lymphoma model cell line. Leukemia. 2013 Jul;27(7):1592-1594.

Dreicer R, Garcia J, Rini B, Vogelzang N, Srinivas S, Somer B, Shi P, Kania M, Raghavan D. A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer. Invest New Drugs. 2013 Aug;31(4):1044-1050.

Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol. 2013 Aug;36(4):319-324.

Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, Gomez-Segui I, Takahashi M, Shiraishi Y, Nagata Y, Guinta K, Mori H, Sekeres MA, Chiba K, Tanaka H, Muramatsu H, Sakaguchi H, Paquette RL, McDevitt MA, Kojima S, Saunthararajah Y, Miyano S, Shih LY, Du Y, Ogawa S, Maciejewski JP.

Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013 Aug;45(8):942-946.

Rajala HLM, Eldfors S, Kuusanmaki H, van Adrichem AJ, Olson T, Lagstrom S, Andersson EI, Jerez A, Clemente MJ, Yan Y, Zhang D, Awwad A, Ellonen P, Kallioniemi O, Wennerberg K, Porkka K, Maciejewski JP, Loughran TP, Jr., Heckman C, Mustjoki S. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 2013 May 30;121(22):4541-4550.

Finke JH, Rayman PA, Ko JS, Bradley JM, Gendler SJ, Cohen PA. Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J. 2013 Jul;19(4):353-364.

Herts BR, Baker ME, Obuchowski N, Primak A, Schneider E, Rhana H, Dong F. Dose reduction for abdominal and pelvic MDCT after change to graduated weight-based protocol for selecting quality reference tube current, peak kilovoltage, and slice collimation. AJR Am J Roentgenol. 2013 Jun;200(6):1298-1303.

Jagadeesh D, Smith MR. Novel targeted therapies in peripheral T cell lymphoma. Discov Med. 2013 Jun;15(85):367-378.

ABSTRACTSKoyfman SA, Agre P, Carlisle R, Classen L,

Cheatham C, Finley JP, Kuhrik N, Kuhrik M, Mangskau TK, O’Neill J, Reddy CP, Kodish E, McCabe MS. Consent form heterogeneity in cancer trials: The cooperative group and institutional review board gap. J Natl Cancer Inst. 2013 Jul 3;105(13):947-953

Cooperative group (CG) provided consent forms (CGP-CFs) undergo re-review and revision by local institutional review boards (IRB) before institutional approval. We compared the relative readability and length of IRB-approved consent forms (IRB-CFs) used at seven academic institutions with their corresponding CGP-CFs. We also assessed the variability of these metrics across our institutions. This study included 197 consent forms (CFs) from 56 CG trials that were open in at least two of the participating institutions. The Flesch Reading Ease Score (FRES), the Flesch-Kincaid Grade Level (FKGL), and document length were collected on all CFs. Unpaired t test was used to compare length and readability of CGP-CF with the IRB-CF. Analysis of variance and Bonferroni-Dunn tests

were used to assess interinstitutional variability in readability for all IRB-CFs. All statistical tests were two-sided. IRB-CFs were statisti-cally significantly longer than CGP-CFs (mean number of pages = 17 vs 13; p < .001). Mean FKGLs were higher (10.3 vs 9.4; p < .0001) and the mean FRESs were lower (53.1 vs 57.1; p < .0001) for IRB-CFs compared with CGP-CFs. Readability varied statistically significantly between institutions for all sections of the IRB-CF (p < .0001). Finalized IRB-CFs for identical clinical trials at different institutions demonstrated substantial heterogeneity of readability and length. As CFs progress from National Cancer Institute (NCI)-sponsored CGs to local IRBs, they seem to become longer and less readable. Interinsti-tutional heterogeneity in CF readability is substantial and widespread. More consistent adherence to CGP-CFs based on the newly revised NCI CF template with minimal modification by local IRBs should help simplify and standardize CFs used in cancer clinical trials

Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, Vessella R, Nelson PS, Kapur P, Guo X, Mirzaei H, Auchus RJ, Sharifi N. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell. 2013 Aug 29;154(5):1074-1084.

Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandros-terone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumula-tion. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.

Resources for Physicians

Physician Directory

View all Cleveland Clinic staff online at clevelandclinic.org/staff.

Same-Day Appointments

Cleveland Clinic offers same-day appointments to help your patients get the care they need, right away. Have your patients call our same-day appointment line, 216.444.CARE (2273) or 800.223.CARE (2273).

Track Your Patients’ Care Online

Establish a secure online DrConnect account for real-time information about your patients’ treatment at Cleveland Clinic at clevelandclinic.org/drconnect.

Critical Care Transport Worldwide

To arrange for a critical care transfer, call 216.448.7000 or 866.547.1467. Visit clevelandclinic.org/criticalcaretransport to learn more.

CME Opportunities: Live and Online

Visit ccfcme.org to learn about the Cleveland Clinic Center for Continuing Education’s convenient, complimentary learning opportunities.

Outcomes Data

View Outcomes books atclevelandclinic.org/outcomes.

Clinical Trials

We offer thousands of clinical trials for qualifying patients.Visit clevelandclinic.org/clinicaltrials.

Executive Education

Learn about our Executive Visitors’ Program and two-week Samson Global Leadership Academy immersion program at clevelandclinic.org/executiveeducation.

Download Our New Physician Referral App! Contacting us is now easier than ever.

With our free Physician Referral App, you can view all our specialists and get in touch immediately with one click of your iPhone®, iPad®, or Android™ phone or tablet. Download today at the App Store or Google Play.

Cleveland Clinic is an integrated healthcare delivery system with local, national and international reach. At Cleveland Clinic, more than 3,000 physicians and scientists represent 120 medical specialties and subspecialties. We are a main campus, 18 family health centers, eight community hospitals, Cleveland Clinic Florida, the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, Sheikh Khalifa Medical City, and Cleveland Clinic Abu Dhabi.

In 2013, Cleveland Clinic was ranked one of America’s top four hospitals in U.S. News & World Report’s annual “America’s Best Hospitals” survey. The survey ranks Cleveland Clinic among the nation’s top 10 hospitals in 14 specialty areas, and the top hospital in three of those areas.

The Cleveland Clinic FoundationTaussig Cancer Institute9500 Euclid Ave. / AC311 Cleveland, OH 44195

13-CNR-909

24/7 Referrals

Referring Physician Hotline 855.REFER.123 (855.733.3712)

Hospital Transfers 800.553.5056

On the Web at: clevelandclinic.org/Refer123

Stay connected with us on …

The Cleveland Clinic WayBy Toby Cosgrove, MD,

CEO and President of Cleveland Clinic

Great things happen when a medical center puts patients first. Visit clevelandclinic.org/ClevelandClinicWayfor details or to order a copy.

cancer consult - my.clevelandclinic.org · hyperthermia aids recurrent cancer therapy highlights...

Documents