University Hospitals Case Medical Center Remains Among the Elite in U.S. News & World Report Annual Survey

University Hospitals Case Medical Center (UHCMC) has again ranked among the elite in the latest U.S. News & World Report hospital rankings.  In this year’s survey, UHCMC ranked seven clinical specialties in the top 50 for hospitals and health systems nationwide.

Top among clinical departments at UHCMC, the Department of Medicine again contributed four of the specialties – Gastroenterology (28), Geriatrics (28), Cancer (34), and Pulmonology (42). This contribution by the Department of Medicine figured significantly into UHCMC joining only 152 other hospitals, or the top 3% of the nation’s 5,000 eligible healthcare organizations.

“This consistent level of excellence in compassionate, cost-effective patient care is a testament to the quality and dedication of the full time faculty in the Department of Medicine and to the leadership of our organizations.”

Richard A. Walsh, MD, Chairman, Department of Medicine

Angiotensin-Receptor Blockades (ARBs) Found to Raise Risk of Cancer

Dr. Daniel Simon M.D., Division Chief of Cardiovascular Medicine and Director of HM-Heart and Vascular Institute at UHCMC; Dr. James Fang M.D., Section Chief of Heart Failure and Medical Director of Heart Transplantation at UHCMC; IIke Sipahi M.D., Associate Director of Heart Failure & Transplantation at UHCMC at the Harrington-McLaughlin Heart & Vascular Institute of UHCMC researched the effects of Angiotensin-Receptor Blockers (ARBs) on the risk of cancer.

ARBs are a widely utilized drug class used for treatment of hypertension, heart failure, diabetic nephropathy, and recently, for cardiovascular risk reduction.

Randomized controlled trials of ARBs with a follow-up of at least 1 year, and enrolling at least 100 patients were included in this meta-analysis. Information on new cancer development (first diagnosis) was available for 61,590 patients from five trials. Cancer data on common types of solid organ cancers such as lung and prostate cancer were available for 68,402 patients from five trials, and data on cancer deaths were available for 93,515 patients from eight trials.

The meta-analysis showed that patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2%vs 6.0%). Specifically, the risk of lung cancer was increased by 25%, which was also statistically significant.

“We have found the risk of new cancers was increased with these medications by 8-11 percent.  Most importantly, risk of lung cancer was increased by 25 percent,” said Dr. Sipahi. Although there was no statistically significant excess in cancer deaths (1.8% with ARBs vs 1.6% with control) the investigators pointed out that the average duration of follow-up of 4 years may be too short to capture cancer deaths.

“In medicine, physicians must balance the benefits and risks of all drug and device therapies.  We recommend that patients discuss the findings of this study with their physicians since ARBs are effective agents in the treatment of high blood pressure and heart failure,” said Dr. Simon.

They conclude that because of the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each individual ARB on the market, but they stated that their findings need further investigation.

In response to this publication from Case Western Reserve University, the European Medicines Agency (EMA) of the European Union announced that they started an investigation about the possible cancer risk of ARBs.

“This is the first time an association between ARBs and cancer development is suggested,” Dr. Sipahi continued. “While our findings are robust, they need to be replicated in other studies before they can be considered as definitive.”

The US Food and Drug Administration has not made any statement regarding this issue yet.

Prostate Cancer at CWRUmedicine

Worldwide, prostate cancer is one of the most common types of cancer found in men. Learning more about prostate cancer and treatment options can help you and your loved ones take an active part in making choices about care.

* Click here to read about new research conducted by the Division of Hematology Oncology at Case Western Reserve University.

The prostate is a chestnut-sized gland below the bladder, which contributes most of the fluid that combines with a man’s sperm to make semen.

Prostate cancer is the most common cancer other than skin cancer in American men and is the second leading cause of cancer death in men.

The American Cancer Society estimates that more than 234,000 men will be diagnosed with prostate cancer in 2006. Incidence rates for the disease are higher for African-American men than for white men.

Other Prostate Cancer Survivors ::

Harry Belafonte
Musician, actor and social activist Harry Belafonte

Robert De Niro
Actor Robert De Niro

Rudy Giuliani
Former New York City Mayor Rudy Giuliani

John Kerry
U.S. Senator & 2004 Presidential candidate John Kerry

Nelson Mandela
Former President of South Africa Nelson Mandela

2010 Health Care Hero, Dr Joseph Baar, presented by Crain’s Cleveland Businesss

Congratulations on Joseph Baar on selection as a 2010 Health Care Hero presented by Crain’s Cleveland Business. We are pleased to recognize him as a Winner in the category of Advancements in Health Care.

The nomination submitted on Dr Baar’s behalf is a testament to the impact he has had on patients, colleagues and Northeast Ohio’s medical community.

Again, congratulations to Joseph Baar on his selection for this very special honor. As one of Northeast Ohio’s Health Care Heroes, he plays a vital role in the quality of our everyday lives and the economic future of the region.

New Research on Older Patients with Acute Myeloid Leukemia in their first complete remission

“Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome”

McClune BL, Weisdorf DJ, Pedersen TL, da Silva GT, Tallman MS, Sierra J, Dipersio J, Keating A, Gale RP, George B, Gupta V, Hahn T, Isola L, Jagasia M, Lazarus H, Marks D, Maziarz R, Waller EK, Bredeson C, Giralt S.
J Clin Oncol. 2010 Mar 8

PURPOSE:
Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

PATIENTS AND METHODS:
We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS).

RESULTS:
Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and >/= 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION: With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.

Read about “Gab2 Promotes Hematopoietic Stem Cell Maintenance & Self-Renewal with STAT5″

BACKGROUND ::
Grb2-associated binding (Gab) adapter proteins play major roles in coordinating signaling downstream of hematopoietic cytokine receptors. In hematopoietic cells, Gab2 can modulate phosphatidylinositol-3 kinase and mitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoietic stem cells (HSCs). Gab2 may also act in a linear pathway upstream or downstream of signal transducer and activator of transcription-5 (STAT5), a major positive regulator of HSC function. Therefore, we aimed to determine whether Gab2 and STAT5 function in hematopoiesis in a redundant or non-redundant manner.

METHODOLOGY & PRINCIPAL FINDINGS ::
To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth response to early-acting cytokines from sorted double mutant c-Kit(+)Lin(-)Sca-1(+) (KLS) cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background. Fetal liver cells isolated from homozygous STAT5 mutant mice lacking Gab2 showed significant reduction in HSC number (KLS CD150(+)CD48(-)), reduced HSC survival, and dramatic loss of self-renewal potential as measured by serial transplantation.

CONCLUSIONS & SIGNIFICANCE ::
These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non-redundant with STAT5. Furthermore, important synergy between STAT5 and Gab2 was observed in HSC self-renewal, which might be exploited to optimize stem cell-based therapeutics.

Read the full article on CWRUmedicine.org

Read about “A Segregation Analysis of Barrett’s Esophagus and Associated Adenocarcinomas”

Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barrett’s esophagus (BE) has been termed familial BE (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. I

n this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881 singly ascertained pedigrees to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaike’s A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather, there is segregation of a major type transmitted from one generation to the next (P < 10(-10)). An incompletely dominant inheritance model together with a polygenic component fits the data best.

For this dominant model, the estimated penetrance of the dominant allele is 0.1005 [95% confidence interval (95% CI), 0.0587-0.1667] and the sporadic rate is 0.0012 (95% CI, 0.0004-0.0042), corresponding to a relative risk of 82.53 (95% CI, 28.70-237.35) or odds ratio of 91.63 (95% CI, 32.01-262.29). This segregation analysis provides epidemiologic evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families and, hence, motivates linkage analyses.

Read the full article on CWRUmedicine.org

Read about “Direct detection and quantification of abasic sites for in vivo studies of DNA damage & repair”

Use of chemotherapeutic agents to induce cytotoxic DNA damage and programmed cell death is a key strategy in cancer treatments. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway resulted in formation of abasic or apurinic/apyrimidinic (AP) sites, and blockage of AP sites led to a significant enhancement of drug sensitivity due to reduction of DNA base excision repair. Since a number of chemotherapeutic agents also induce formation of AP sites, monitoring of these sites as a clinical correlate of drug effect will provide a useful tool in the development of DNA-targeted chemotherapies aimed at blocking abasic sites from repair. Here we report an imaging technique based on positron emission tomography (PET) that allows for direct quantification of AP sites in vivo. For this purpose, positron-emitting carbon-11 has been incorporated into methoxyamine ([(11)C]MX) that binds covalently to AP sites with high specificity. The binding specificity of [(11)C]MX for AP sites was demonstrated by in vivo blocking experiments. Using [(11)C]MX as a radiotracer, animal PET studies have been conducted in melanoma and glioma xenografts for quantification of AP sites. Following induction of AP sites by temozolomide, both tumor models showed significant increase of [(11)C]MX uptake in tumor regions in terms of radioactivity concentration as a function of time, which correlates well with conventional aldehyde reactive probe (ARP)-based bioassays for AP sites.

Read the full article on CWRUmedicine.org

Read about “Non-Hodgkin’s lymphoma in the elderly”

The expansion of older population segments and the continuous increase in the incidence of non-Hodgkin’s lymphoma (NHL) makes this group of neoplasms an important and growing problem. Older NHL patients have increased risk of therapy-related toxicity as a result of age-related physiological changes and frequent co-morbidities. A functional assessment of the elderly patient is necessary to determine the likelihood of tolerating and responding to therapy. The comprehensive geriatric assessment (CGA) is one multidisciplinary tool that has been applied successfully to older cancer patients and aids in identification of subjects who will or will not benefit from anti-neoplastic treatment. Although indolent lymphomas present more frequently at advanced stage, randomized trials do not show better outcomes with early therapy, supporting close observation until specific therapeutic indications arise. Use of the monoclonal antibody rituximab as a single agent or in combination with chemotherapy improves survival and has become the standard of care in first-line treatment. Radioimmunoconjugates, bendamustine, and other monoclonal antibodies as well as novel targeted agents also are active against indolent lymphomas. Diffuse large B-cell lymphoma is an aggressive but potentially curable disease. Several trials performed exclusively in elderly patients have demonstrated improved response rates and survival with the addition of rituximab to CHOP (cyclophosphamide, doxorubicin [adriamycin], vincristine, prednisone) chemotherapy in the front-line setting. Salvage chemotherapy followed by autologous haematopoietic cell transplant (autoHCT) has been shown to have better failure-free and overall survival in randomized trials involving younger patients. Highly selected individuals up to age 70 years may attain long-term survival benefit from autoHCT, although transplant-related mortality is higher than in younger patients.

Read the full article on CWRUmedicine.org

Dr. Afshin Dowlati discusses a new way to predict effectiveness of chemotherapy

Doctors often have trouble knowing who might respond to certain cancer treatments. “We kind of give chemotherapy and wish for a good result,” says Dr. Afshin Dowlati. That could change.

Dowlati led a study that revealed lung cancer patients with low levels of a molecule that controls cellular interaction have twice the chance of responding to chemotherapy than those with high levels. Those levels can also predict how likely a patient is to live a year after diagnosis. The difference could help patients decide whether to try chemotherapy, drugs or pursue alternative therapies, Dowlati says.

Learn more at CWRUmedicine.org