Faculty Bibliography

The myeloproliferative neoplasm, myelofibrosis, is a morbid and frequently fatal illness encompassing primary myelofibrosis, and end-stage essential thrombocythemia and polycythemia. Bevacizumab (15 mg/kg intravenous (i.v.) every 21 days) was tested in a phase II international trial conducted by the Myeloproliferative Disorders Research Consortium. Thirteen patients were enrolled in the first stage of this 2-stage trial. Among the 11 patients who received therapy, only 3 received more than 4 cycles of therapy; none of the patients achieved an objective response. Furthermore, significant toxicity, not directly related to the vascular or gastrointestinal events typically associated with the anti-VEGF monoclonal antibody preparation in other disease states, was observed. Lack of objective responses coupled with toxicity led to the decision to terminate the study early. If future studies incorporate bevacizumab in combination therapy for myelofibrosis, more modest doses should be considered. (clinicaltrials.gov Identifier 00667277).

Objective: Irinotecan and bevacizumab have single-agent activity in both platinum- sensitive and -resistant recurrent ovarian cancer. We sought to evaluate the efficacy and safety of irinotecan in combination with bevacizumab in these patients. The primary end point of the study was to estimate the progression-free survival (PFS) rate at 6 months. Secondary objectives included overall survival, observed response rate, duration of response, and toxicity. Methods: Patients with recurrent ovarian cancerwho had received any number of prior regimens were eligible. Irinotecan 250 mg/m2 (amended to 175 mg/m2 after treatment-related toxicities in the first 6 patients) and bevacizumab 15 mg/kg every 3 weeks were administered until disease progression or toxicity. Response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 2 cycles and by CA-125 criteria for those patients without measurable disease. Results: Thus far, 25 of the planned 35 patients have been enrolled in the study. Themedian age was 61 years (range, 45-78 years). Seven patients were platinum-sensitive and 18 patients were platinum-resistant. The median number of prior regimens was 5 (range, 1-12), with 10 patients having received prior bevacizumab-containing therapies and 9 patients prior topotecan-containing therapies. The median number of study treatments received was 6 cycles (range, 1-25 cycles); 4 patients withdrew after only 1 cycle (3 due to toxicity and 1 due to physician discretion). Of the 19 patients assessable for response at this time, 5 patients experienced partial response (PR), 11 patientsmaintained stable disease (SD), and 3 patients had progressive disease. Eleven of the patients with PR/SD were platinum-resistant. The observed clinical benefit rate (PR+SD) was 68% (95% CI: 50%, 86%) for the 25 enrolled patients (intention to treat). Durable responses were observed, with 9 patients having longer than 24 weeks of sustained response. Themedian PFS was 8.1 months, and the median overall survival was!

Primary myelofibrosis (PMF) is characterized by fibrosis, ineffective hematopoiesis in marrow, and hematopoiesis in extramedullary sites and is associated with abnormal megakaryocyte (MK) development and increased transforming growth factor (TGF)-beta1 release. To clarify the role of TGF-beta1 in the pathogenesis of this disease, the TGF-beta1 signaling pathway of marrow and spleen of the Gata1(low) mouse model of myelofibrosis (MF) was profiled and the consequences of inhibition of TGF-beta1 signaling on disease manifestations determined. The expression of 20 genes in marrow and 36 genes in spleen of Gata1(low) mice was altered. David-pathway analyses identified alterations of TGF-beta1, Hedgehog, and p53 signaling in marrow and spleen and of mammalian target of rapamycin (mTOR) in spleen only and predicted that these alterations would induce consequences consistent with the Gata1(low) phenotype (increased apoptosis and G1 arrest both in marrow and spleen and increased osteoblast differentiation and reduced ubiquitin-mediated proteolysis in marrow only). Inhibition of TGF-beta1 signaling normalized the expression of p53-related genes, restoring hematopoiesis and MK development and reducing fibrosis, neovascularization, and osteogenesis in marrow. It also normalized p53/mTOR/Hedgehog-related genes in spleen, reducing extramedullary hematopoiesis. These data identify altered expression signatures of TGF-beta1 signaling that may be responsible for MF in Gata1(low) mice and may represent additional targets for therapeutic intervention in PMF.

PURPOSE:: To increase usage of the herpes zoster (HZ) vaccine at an academic medical center by studying physicians' knowledge, attitudes, practices, and perceived barriers and analyze the findings by practice setting. METHODS:: A cross-sectional Internet-based survey administered to all 266 general internal medicine physicians in 4 clinical settings at an academic medical center between October 6 and December 12, 2011. Outcomes measures included knowledge questions regarding the disease and vaccine recommendations, Likert-type items about physician attitudes and practices, and questions about barriers and proposed interventions to improve utilization. RESULTS:: Response rate was 33.5% (89 of 266). Responders did not answer all questions. Only 66% (42 of 64) responded that HZ vaccination was an important clinical priority, and 48% (38 of 79) reported that less than 10% of their patients received the HZ vaccine. 95% responded that the influenza (61 of 64) and 92% that the pneumococcal (59 of 64) vaccines were important. Approximately 53% (42 of 79) and 51% (40 of 78) reported that more than 75% of their patients received these vaccines, respectively. Top barrier to vaccination was cost to patients (51 of 66; 77%). Lack of awareness of national recommendations (46 of 65, 71%) varied by setting. Physicians' preferred interventions included nurse-initiated prompting about vaccination (36 of 75, 48%) and chart reminders (34 of 74, 46%). CONCLUSIONS:: Not only increased knowledge but also a change in attitudes and practice are needed to enhance implementation of national recommendations. To improve use of this vaccine, physicians including ophthalmologists need to recommend it more strongly.

PURPOSE: Promoter hypermethylation has been recently proposed as mean for HNSCC detection in salivary rinses. In a prospective study of high-risk population, we showed that EDNRB promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was performed and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by Quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB and DCC methylation were associated (p=0.012; p<0.0001; p=0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (p=0.0003) or DCC (p=0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (p=0.008; p=0.026; p=0.046) and multivariate analysis (p=0.012; p=0.037; p=0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with similar AUC (0.61, 95%CI=0.60-0.81) when compared to EDNRB and DCC combined AUC (0.60, 95%CI=0.51-0.69), sensitivity of 46% and specificity of 72%. Combination of EDNRB, DCC and CRC was optimal AUC (0.67, 95%CI=0.58-0.76). CONCLUSION: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available.

PURPOSE: To increase the vaccination rate and identify barriers to administration of the vaccine against herpes zoster by having ophthalmologists screen and provide the vaccine. DESIGN: Prospective interventional cohort study. METHODS: setting: Academic City Hospital, Bellevue Hospital. participants: A total of 100 eligible patients based on recommended Centers for Disease Control (CDC) criteria and ability to speak English and Spanish who received the herpes zoster vaccine were compared with 66 patients who declined the vaccine. interventions: The vaccine was administered after written informed consent was obtained to complete a screening questionnaire evaluating the participants' eligibility and interest in receiving the vaccine. main outcome measures: Barriers to administration of the vaccine were evaluated. RESULTS: A total of 170 consenting patients, including 100 patients who were vaccinated, 66 patients who declined vaccination, and 4 patients who were ineligible, were analyzed. The proportion of subjects who would consider receiving the vaccine if recommended by a doctor among those who received the shingles vaccine, 98.0% (95% CI: 95%-100%), was significantly greater than the proportion in the group that declined, 74.2% (95% CI: 64%-85%) (P