Citations

Abstract This book comprises a collection of case studies of patients with acute and critical neurological disease, along with pertinent discussion of approaches to each particular condition. Case studies provide a way to examine how difficult it is to approach these patients situated in the neurosciences intensive care unit. Some patients need close observation and management of emerging problems, others need a neurosurgical intervention or a neurointerventional procedure, a few patients are in extremis. The examples provided in this book are quintessential to the practice of neurocritical care. Some are less common conditions that need to be recognized and appropriately treated. Another purpose of this book is to introduce the reader to the field of neurocritical care and to show what goes on. The book shows the complexity of care and urgent decision-making involved in treating patients who deteriorate. Practical suggestions are included for each topic it covers. Not only is treatment of serious neurological disorders discussed but also prognostication in practice and end-of-life care discussions. In some ways this book summarizes the entire spectrum of presenting acute illness and how best to intervene.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Abstract Background LIV-1, a multispan transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells (Sussman 2014). It has been associated with lymph node involvement and linked with malignant progression to metastasis (Manning 1994). SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods A phase 1, open-label, dose-escalation study is ongoing to evaluate the safety, tolerability, antitumor activity, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of SGN-LIV1A monotherapy (q3 wks IV) in women with LIV-1-positive, metastatic breast cancer (MBC) (NCT01969643). Patients (pts) with either hormone receptor-positive/HER2-negative (HR+/HER2–) or triple-negative (TN) disease were eligible if they had measurable disease and received ≥2 prior cytotoxic regimens in the metastatic setting. Pts with ≥ Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1, and pts with stable disease (SD) or better were eligible to continue treatment until disease progression or intolerable toxicity. Fresh tumor biopsies were obtained pre- and post-treatment to evaluate the LIV-1 expression-response relationship, mechanism of action, and tumor sensitivity to SGN-LIV1A. Results To date, 21 pts (17 HR+/HER2–, 4 TN) have received a median of 3 cycles (range, 1–7) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 58 yrs (range, 34–73), and pts had a median of 8 prior systemic metastatic therapies (range, 2–15). At baseline, 19 pts had visceral disease and 15 had bone involvement. No dose-limiting toxicities (DLTs) in Cycle 1 were observed in the 18 DLT-evaluable pts; MTD has not yet been identified. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were primarily Grade 1/2 in severity and were: nausea (57%), fatigue and peripheral neuropathy (43% each), alopecia (38%), and vomiting (33%). Two pts discontinued treatment due to AEs (1 nausea, 1 tachycardia). Preliminary PK data suggest a linear increase in antibody-drug conjugate (ADC) exposure with increasing dose. In the 19 efficacy-evaluable pts, the overall response rate (ORR) was 11% (2 partial responses [PRs]) with clinical benefit of SD or better achieved in 63% (2 PR, 10 SD) of pts. Of note, all 4 pts with TN MBC achieved clinical benefit: 2 PR and 2 SD. Currently, the median duration of clinical benefit is 12.7 wks (range, 6.1–26.3). Four pts remain on treatment. To date, of the 179 MBC tumor specimens evaluated for LIV-1, 156 (87%) were LIV-1-positive; moderate-to-high LIV-1 expression (H-score ≥100) was present in 91% (94 of 103) of HR+/HER2– and 81% (47 of 58) of TN samples. Conclusions LIV-1 is expressed in the majority of metastatic breast cancer tissue samples, with moderate-to-high expression in both HR+/HER2- and TN disease. To date, SGN-LIV1A monotherapy has been generally well tolerated and resulted in a clinical benefit of SD or better in 63% of these heavily pre-treated pts, including 2 PRs in the 4 TN MBC pts. Response duration data continue to evolve. Clinical subtype-specific expansion cohorts are planned. Citation Format: Forero A, Burris III H, Mita M, Specht J, Weise A, Liu MC, Modi S, Pusztai L, Kostic A, Yang J, Li M, Hengel S, Miller K. Interim analysis of a phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-05.

Abstract Background: Young women with breast cancer need highly effective contraception given the potential implications of unplanned pregnancy for optimal treatment, and the teratogenic risks. We sought to determine the contraceptive methods used by young women after diagnosis (dx) of breast cancer and factors associated with use of less effective methods or no contraceptive method, which confers a 6-90% annual risk of pregnancy in sexually active women in contrast to highly effective methods (risk <1%). Methods: As part of a randomized trial conducted in 54 sites to test an education and support intervention for young women with breast cancer and their oncologists, we surveyed women about their pre-dx, current, and planned contraceptive use, and about communication with their providers regarding contraception. Women enrolled within 3 months of dx; contraception items were included on 3- and 12-month post-enrollment surveys. Intrauterine device (IUD) use, tubal sterilization, hysterectomy or bilateral salpingo-oophorectomy (hyst/BSO) after dx, or male partner vasectomy were classified as highly effective methods; all other methods and non-use were categorized as less effective. We excluded women not at risk of pregnancy: hyst/BSO prior to dx, or no indication for contraception. We used logistic regression to explore factors associated with use of less effective methods. Results: Of 424 women who completed the 3-month post-enrollment survey, median age at dx was 39 (range 22-45). 312 women at risk of pregnancy were included in this analysis, including 291 reporting sexual activity with a male partner within the last 6 months, and 21 reporting no recent sexual activity but reporting use of birth control. 123 women (39%) used highly effective contraceptive methods prior to dx; after dx, 161 (52%) reported current use of or a plan to use a highly effective method. 19 women (6%) reported use of a hormonal birth control method since dx; 7 (2%) reported withdrawal as their only contraceptive method; 25 (8%) reported no contraception. 30% of women did not recall a discussion of avoiding pregnancy or need for contraception during treatment with their providers. In multivariable analyses (N=310), desire for additional biologic children (OR 7.54, 95% CI 3.88-14.66) and provider discussion of contraception and pregnancy (OR 2.13 95% CI 1.20-3.78) were associated with use of less effective contraception. Age, race/ethnicity, disease stage, and partner status were not significantly associated with use of less effective methods. Conclusion: About half of women who are at risk of pregnancy reported use or planned use of less effective contraceptive methods or no method of contraception following dx of breast cancer. Women with breast cancer and their providers may benefit from targeted education on contraceptive options and method effectiveness. Citation Format: Rosenberg SM, Dutton CR, Ligibel J, Barry W, Ruddy KJ, Sprunck-Harrild K, Emmons KM, Partridge AH. Contraception use in young women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-18.

Abstract Purpose: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental Design: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, IHC, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results: In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacologic inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in downregulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer-associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions: Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Clin Cancer Res; 22(16); 4259–70. ©2016 AACR.

Objective The objective of this study was to provide recommendations for provision of training for sponsor and investigators at Academic Health Centers. Background A subgroup of the Investigational New Drug/Investigational Device Exemption (IND/IDE) Task Force of the Clinical and Translational Science Award (CTSA) program Regulatory Knowledge Key Function Committee was assembled to specifically address how clinical investigators who hold an IND/IDE and thus assume the role of sponsor-investigators are adequately trained to meet the additional regulatory requirements of this role. Methods The participants who developed the recommendations were representatives of institutions with IND/IDE support programs. Through an informal survey, the task force determined that a variety and mix of models are used to provide support for IND/IDE holders within CTSA institutions. In addition, a CTSA consortium-wide resources survey was used. The participants worked from the models and survey results to develop consensus recommendations to address institutional support, training content, and implementation. Recommendations The CTSA IND/IDE Task Force recommendations are as follows: (1) Institutions should assess the scope of Food and Drug Administration–regulated research, perform a needs analysis, and provide resources to implement a suitable training program; (2) The model of training program should be tailored to each institution; (3) The training should specifically address the unique role of sponsor-investigators, and the effectiveness of training should be evaluated regularly by methods that fit the model adopted by the institution; and (4) Institutional leadership should mandate sponsor-investigator training and effectively communicate the necessity and availability of training.

Abstract Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

BACKGROUNDAutologous stem cell transplantation (SCT) is a common management strategy for select patients with immunoglobulin light‐chain amyloidosis, but no trials have documented improved overall survival.METHODSEighty‐nine patients with biopsy‐proven immunoglobulin light‐chain amyloidosis were allowed to select treatment with melphalan plus dexamethasone (n = 34) or SCT (n = 55); all patients were transplant eligible. Treatment preference resulted in imbalanced study arms. Patients who selected SCT were younger, more frequently had an Eastern Cooperative Oncology Group performance status score less than 2, had lower‐stage amyloidosis, and had a lower incidence of cardiac amyloidosis.RESULTSPatients receiving melphalan plus dexamethasone had a 3‐year progression‐free survival rate of 29.1% and an overall survival rate of 58.8%. Patients undergoing SCT had a 3‐year progression‐free survival rate of 51.7% and an overall survival rate of 83.6%. An attempt to match patients between the 2 arms in terms of risk produced 24 matched triplet sets (2 SCT patients for each melphalan‐dexamethasone patient); there was no difference in hematologic response, but there was better survival after autologous SCT. A propensity score–matched analysis of the cohorts (melphalan plus dexamethasone vs SCT) showed an overall mortality hazard ratio of 2.56 (P < .01).CONCLUSIONSAlthough the study had limitations, similar hematologic responses and improved survival were observed after SCT versus melphalan plus dexamethasone. Cancer 2016;122:2197–205. © 2016 American Cancer Society.

Objective: The objective was to assess the clinical utility of the Adult ADHD Self-Report Scale (ASRS-v1.1) in identifying ADHD in alcoholics using the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) as the diagnostic “gold standard.” Method: We performed a secondary analysis of data from 379 treatment-seeking alcoholics who completed the ASRS-v1.1 and the ADHD module of the PRISM. Data analysis included descriptive statistics. Results: The prevalence of ADHD was 7.7% (95% CI = [5.4, 10.8]). The positive predictive value (PPV) of the ASRS-v1.1 was 18.1% (95% CI = [12.4, 25.7]) and the negative predictive value (NPV) was 97.6% (95% CI = [94.9, 98.9]). The ASRS-v1.1 demonstrated a sensitivity of 79.3% (95% CI = [61.6, 90.2]) and a specificity of 70.3% (95% CI = [65.3, 74.8]). Conclusion: The ASRS-v1.1 demonstrated acceptable sensitivity and specificity in a sample of treatment-seeking alcoholics when compared with the PRISM as the reference standard for ADHD diagnosis.