Michael Silver

Polysomy for Chromosomes 1 and 19 Predicts Earlier Recurrence in Anaplastic Oligodendrogliomas with Concurrent 1p/19q Loss

Purpose: Loss of chromosome arms 1p and 19q is a molecular feature of oligodendroglial tumors characterized by responsiveness to chemotherapy and a favorable prognosis. The purpose of this study was to evaluate the prognostic significance of polysomy of chromosomes 1 and 19 in the setting of 1p/19q codeletion. Experimental Design: We analyzed 64 anaplastic oligodendrogliomas with 1p/19q loss or maintenance diagnosed at Massachusetts General Hospital and Brigham and Womens Hospital from 1996 to 2005; fluorescence in situ hybridization for 1p/19q and Ki-67 immunohistochemistry was done. Polysomy was defined as more than two 1q and 19p signals in >30% of the cells with concurrent 1p/19q deletion. Tumors were divided into groups based on their 1p/19q status and compared for progression-free survival, overall survival, and 5-year survival probabilities. Results: Forty-six tumors (72%) in our cohort had 1p/19q loss and 18 (28%) had 1p/19q maintenance. Of those with loss, 19 (41%) had concurrent polysomy and 27 (59%) lacked polysomy. In agreement with previous studies, the group of anaplastic oligodendrogliomas with 1p/19q loss had significantly better progression-free survival and overall survival than anaplastic oligodendrogliomas with 1p/19q maintenance (P = 0.0009 and P < 0.0003, respectively). Among anaplastic oligodendrogliomas with 1p/19q loss, those with polysomy showed shorter progression-free survival than those with 1p/19q loss without polysomy (P = 0.0048). Overall survival was similar in tumors with and without polysomy. The Ki-67 labeling index was not associated with polysomy and did not have prognostic significance. Conclusion: The presence of polysomy in anaplastic oligodendrogliomas with deletion of 1p/19q is a marker of earlier recurrence. (Clin Cancer Res 2009;15(20):6430–7)

Eszopiclone improves insomnia and depressive and anxious symptoms in perimenopausal and postmenopausal women with hot flashes: a randomized, double-blinded, placebo-controlled crossover trial

OBJECTIVE Menopause-associated insomnia is commonly associated with other symptoms (hot flashes, depression, anxiety). Given frequent symptom cooccurrence, therapies targeting sleep may provide an important approach to treatment during midlife. STUDY DESIGN Peri/postmenopausal women (40-65 years old) with sleep-onset and/or sleep-maintenance insomnia cooccurring with hot flashes and depressive and/or anxiety symptoms were randomized to eszopiclone 3 mg orally or placebo in a double-blinded, crossover 11 week trial. Changes in the Insomnia Severity Index (ISI) scale and secondary outcomes (diary-based sleep parameters, depression/anxiety, hot flashes, quality of life) were analyzed using repeated-measure linear models. RESULTS Of 59 women, 46 (78%) completed the study. Eszopiclone reduced ISI scores by 8.7 + or - 1.4 more points than placebo (P < .0001). Eszopiclone improved (P < .05) all sleep parameters, depressive symptoms, anxiety symptoms, quality of life, and nighttime but not daytime hot flashes. CONCLUSION Eszopiclone treats insomnia and cooccurring menopause-related symptoms. Our results provide evidence that hypnotic therapies may improve multiple domains of well-being during midlife.

Primary CNS Lymphoma in Children and Adolescents: A Descriptive Analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Purpose: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). Experimental Design: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. Results: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. Conclusion: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival. Clin Cancer Res; 17(2); 346–52. ©2011 AACR.

Ertapenem-Resistant Enterobacteriaceae: Risk Factors for Acquisition and Outcomes

BACKGROUND AND OBJECTIVE Carbapenem resistance among Enterobacteriaceae is of concern because of increasing prevalence and limited therapeutic options. Limited research has been focused on understanding ertapenem resistance as a more sensitive marker for resistance to other carbapenems. We sought to determine risk factors for acquisition of ertapenem-resistant, meropenem-susceptible, or intermediate Enterobacteriaceae and to assess associated patient outcomes. DESIGN Retrospective case-control study among adult hospitalized inpatients. SETTING A 902-bed quaternary care urban hospital. RESULTS Sixty-two cases of ertapenem-resistant Enterobacteriaceae were identified from March 14, 2006, through October 31, 2007, and 62 unmatched control patients were randomly selected from other inpatients with cultures positive for ertapenem-susceptible Enterobacteriaceae. Thirty-seven (60%) of case patient isolates were Enterobacter cloacae, 20 (32%) were Klebsiella pneumoniae, and 5 (8%) were other species of Enterobacteriaceae. Risk factors for ertapenem-resistant Enterobacteriaceae infection included intensive care unit stay (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0-10.3]), vancomycin-resistant Enterococcus colonization (OR, 7.1 [95% CI, 2.4-21.4]), prior central venous catheter use (OR, 10.0 [95% CI, 3.0-33.1]), prior receipt of mechanical ventilation (OR, 5.8 [95% CI, 2.1-16.2]), exposure to any antibiotic during the 30 days prior to a positive culture result (OR, 18.5 [95% CI, 4.9-69.9]), use of a β-lactam during the 30 days prior to a positive culture result (OR, 6.9 [95% CI, 3.0-16.0], and use of a carbapenem during the 30 days prior to a positive culture result (OR, 18.2 [95% CI, 2.6-130.0]). For the 62 case patients, 30-day outcomes from the time of positive culture result were 24 discharges (39%), 10 deaths (16%), and 28 continued hospitalizations (44%). The final end point of the hospitalization was discharge for 44 patients (71%) and death for 18 patients (29%). CONCLUSIONS Ertapenem-resistant Enterobacteriaceae are important nosocomial pathogens. Multiple mechanisms of resistance may be in operation. Additional study of ertapenem resistance is needed.

Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial

Objectives:We sought to obtain preliminary data regarding the efficacy of omega-3 fatty acids for major depressive disorder associated with the menopausal transition. Secondary outcomes were assessed for vasomotor symptoms (or hot flashes). Methods:After a single-blind placebo lead-in, participants received 8 weeks of treatment with open-label omega-3 fatty acid capsules (eicosapentaenoic acid and docosahexaenoic acid, 2 g/d). The Montgomery-Asberg Depression Rating Scale (MADRS) was the primary outcome measure. Hot flashes were monitored prospectively using daily diaries and the Hot Flash Related Daily Interference Scale. Blood samples for plasma pretreatment and posttreatment essential fatty acid assays were obtained. Because of the small sample size, data were analyzed using nonparametric techniques. Results:Of 20 participants treated with omega-3 fatty acids, 19 (95%) completed the study. None discontinued because of adverse effects. The pretreatment and final mean MADRS scores were 24.2 and 10.7, respectively, reflecting a significant decrease in MADRS scores (P < 0.0001). The response rate was 70% (MADRS score decrease of ≥50%), and the remission rate was 45% (final MADRS score of ≤7). Responders had significantly lower pretreatment docosahexaenoic acid levels than nonresponders did (P = 0.03). Hot flashes were present in 15 (75%) participants. Among those with hot flashes at baseline, the number of hot flashes per day improved significantly from baseline (P = 0.02) and Hot Flash Related Daily Interference Scale scores decreased significantly (P = 0.006). Conclusions:These data support further study of omega-3 fatty acids for major depressive disorder and hot flashes in women during the menopausal transition.

Genetic determinants of hearing loss associated with vestibular schwannomas.

Hypothesis: The severity of hearing loss (HL) associated with vestibular schwannomas (VSs) is influenced by genes expressed by the VSs. Background: Hearing loss is the most common presenting symptoms in patients with VSs, yet its pathophysiology remains elusive. Previous studies have suggested that VSs cause HL not only by inducing degeneration of the auditory nerve by compression but also by promoting degeneration of the inner ear. This study aimed to determine whether there is a molecular basis for differences in HL associated with VSs. Methods: Surgical specimens of VSs were collected from 13 patients and were divided into a group associated with good (word recognition >70% and pure-tone average ≤30 dB) or poor hearing. Whole-genome expression profiling of VSs was performed with the Affymetrix GeneChip Human X3P Array. The expression of select genes was validated using real-time quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. Because of a small sample size, exact nonparametric tests were used to assess the association between good versus poor hearing and specific histological features of the tumors and patient demographics. Results: Using gene set enrichment analysis, the chromosomal region 3q27 was found to be significantly different between the 2 groups of tumors. This region includes peroxisomal biogenesis factor 5-like gene, which was underexpressed in VSs with poor hearing. The expression of 3 other genes from different chromosomes was significantly different between the 2 groups: RAD54B, prostate-specific membrane antigen-like, and carcinoembryonic antigen. Conclusion: This study identified several molecular alterations in VSs stratified by hearing. These alterations may determine the severity of HL associated with VSs and may represent potential therapeutic targets to prevent or reduce HL in theses patients.

Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

OBJECTIVE GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 microg/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 microg/m(2) given with dose escalation. RESULTS Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women Under the Age of 50 Years

Background: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood‐based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. Patients and Methods: Provista‐001 and Provista‐002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor‐associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista‐001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista‐002 cohort one (validation set). Results: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow‐up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow‐up, a 67% reduction in FPs (P < .00001). Conclusions: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC. Micro‐Abstract: To improve breast cancer diagnosis, 2 prospective clinical trials were conducted to test (n = 351) and validate (n = 210) Videssa Breast. If used in conjunction with imaging, Videssa Breast could have reduced unnecessary biopsies by up to 67%. These results support the joint use of breast imaging and Videssa Breast to better inform clinical decisions for women under age 50.

Integration of Serum Protein Biomarker and Tumor Associated Autoantibody Expression Data Increases the Ability of a Blood-Based Proteomic Assay to Identify Breast Cancer

Despite significant advances in breast imaging, the ability to accurately detect Breast Cancer (BC) remains a challenge. With the discovery of key biomarkers and protein signatures for BC, proteomic technologies are currently poised to serve as an ideal diagnostic adjunct to imaging. Research studies have shown that breast tumors are associated with systemic changes in levels of both serum protein biomarkers (SPB) and tumor associated autoantibodies (TAAb). However, the independent contribution of SPB and TAAb expression data for identifying BC relative to a combinatorial SPB and TAAb approach has not been fully investigated. This study evaluates these contributions using a retrospective cohort of pre-biopsy serum samples with known clinical outcomes collected from a single site, thus minimizing potential site-to-site variation and enabling direct assessment of SPB and TAAb contributions to identify BC. All serum samples (n = 210) were collected prior to biopsy. These specimens were obtained from 18 participants with no evidence of breast disease (ND), 92 participants diagnosed with Benign Breast Disease (BBD) and 100 participants diagnosed with BC, including DCIS. All BBD and BC diagnoses were based on pathology results from biopsy. Statistical models were developed to differentiate BC from non-BC (i.e., BBD and ND) using expression data from SPB alone, TAAb alone, and a combination of SPB and TAAb. When SPB data was independently used for modeling, clinical sensitivity and specificity for detection of BC were 74.7% and 77.0%, respectively. When TAAb data was independently used, clinical sensitivity and specificity for detection of BC were 72.2% and 70.8%, respectively. When modeling integrated data from both SPB and TAAb, the clinical sensitivity and specificity for detection of BC improved to 81.0% and 78.8%, respectively. These data demonstrate the benefit of the integration of SPB and TAAb data and strongly support the further development of combinatorial proteomic approaches for detecting BC.

Breast density does not impact the ability of Videssa® Breast to detect breast cancer in women under age 50

Breast density is associated with reduced imaging resolution in the detection of breast cancer. A biochemical approach that is not affected by density would provide an important tool to healthcare professionals who are managing women with dense breasts and suspicious imaging findings. Videssa® Breast is a combinatorial proteomic biomarker assay (CPBA), comprised of Serum Protein Biomarkers (SPB) and Tumor Associated Autoantibodies (TAAb) integrated with patient-specific clinical data to produce a diagnostic score that reliably detects breast cancer (BC) as an adjunctive tool to imaging. The performance of Videssa® Breast was evaluated in the dense (a and b) and non-dense (c and d) groups in a population of n = 545 women under age 50. The sensitivity and specificity in the dense breast group were calculated to be 88.9% and 81.2%, respectively, and 92.3% and 86.6%, respectively, for the non-dense group. No significant differences were observed in the sensitivity (p = 1.0) or specificity (p = 0.18) between these groups. The NPV was 99.3% and 99.1% in non-dense and dense groups, respectively. Unlike imaging, Videssa® Breast does not appear to be impacted by breast density; it can effectively detect breast cancer in women with dense and non-dense breasts alike. Thus, Videssa® Breast provides a powerful tool for healthcare providers when women with dense breasts present with challenging imaging findings. In addition, Videssa® Breast provides assurance to women with dense breasts that they do not have breast cancer, reducing further anxiety in this higher risk patient population.