A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

The Gulf War Era Cohort and Biorepository: A Longitudinal Research Resource of Veterans of the 1990-1991 Gulf War Era.

The US Department of Veterans Affairs (VA) Gulf War Era Cohort and Biorepository (GWECB) is a nationally representative longitudinal cohort of US veterans who served during the 1990-1991 Gulf War era. The GWECB combines survey data, such as demographic, health behavior, and environmental exposure data; medical records; and a linked biorepository of blood specimens that can support a broad range of future research regarding health concerns unique to veterans of this era. To build this resource, the VA Cooperative Studies Program initiated a pilot study (2014-2016) to establish the GWECB and evaluate the processes required to build and maintain the resource. Participants (n = 1,275) consented to future sharing of their data and biospecimens for research purposes. Here we describe the pilot study, including recruitment and enrollment procedures, data collection and management, quality control, and challenges experienced. The GWECB data available to investigators under approved sharing mechanisms and the procedures for accessing them are extensively detailed. The study's consenting documents and a website link for the research survey are provided. Our hope is that new research drawing on the GWECB data and biospecimens will result in effective treatments and improved approaches to address the health concerns of Gulf War-era veterans.

Population-based assessment of cancer survivors' financial burden and quality of life: a prospective cohort study.

PURPOSE: The impact of financial burden among patients with cancer has not yet been measured in a way that accounts for inter-relationships between quality of life, perceived quality of care, disease status, and sociodemographic characteristics. PATIENTS AND METHODS: In a national, prospective, observational, population- and health care systems-based cohort study, patients with colorectal or lung cancer were enrolled from 2003 to 2006 within 3 months of diagnosis. For this analysis, surviving patients who were either disease free or had advanced disease were resurveyed a median 7.3 years from diagnosis. Structural equation modeling was used to investigate relationships between financial burden, quality of life, perceived quality of care, and sociodemographic characteristics. RESULTS: Among 1,000 participants enrolled from five geographic regions, five integrated health care systems, or 15 Veterans Administration Hospitals, 89% (n = 889) were cancer free, and 11% (n = 111) had advanced cancer. Overall, 48% (n = 482) reported difficulties living on their household income, and 41% (n = 396) believed their health care to be "excellent." High financial burden was associated with lower household income (adjusted odds ratio [OR] = 0.61 per $20k per year, P < .001) and younger age (adjusted OR = 0.63 per 10 years; P < .001). High financial burden was also associated with poorer quality of life (adjusted beta = -0.06 per burden category; P < .001). Better quality of life was associated with fewer perceptions of poorer quality of care (adjusted OR = 0.85 per 0.10 EuroQol units; P < .001). CONCLUSION: Financial burden is prevalent among cancer survivors and is related to patients' health-related quality of life. Future studies should consider interventions to improve patient education and engagement with regard to financial burden.

An assessment of survey measures used across key epidemiologic studies of United States Gulf War I Era veterans.

Over the past two decades, 12 large epidemiologic studies and 2 registries have focused on U.S. veterans of the 1990-1991 Gulf War Era. We conducted a review of these studies' research tools to identify existing gaps and overlaps of efforts to date, and to advance development of the next generation of Gulf War Era survey tools. Overall, we found that many of the studies used similar instruments. Questions regarding exposures were more similar across studies than other domains, while neurocognitive and psychological tools were the most variable. Many studies focused on self-reported survey results, with a range of validation practices. However, physical exams, biomedical assessments, and specimen storage were not common. This review suggests that while research may be able to pool data from past surveys, future surveys need to consider how their design can yield data comparable with previous surveys. Additionally, data that incorporate recent technologies in specimen and genetic analyses would greatly enhance such survey data. When combined with existing data on deployment-related exposures and post-deployment health conditions, longitudinal follow-up of existing studies within this collaborative framework could represent an important step toward improving the health of veterans.

Method Issues in Epidemiological Studies of Medically Unexplained Symptom-based Conditions in Veterans.

Symptom-based conditions such as chronic fatigue syndrome (CFS) and medically unexplained multi-symptom illness (MSI) are fairly common in the general population and are also important veteran's health concerns due to their higher frequency among U.S. veterans who served during the 1990-1991 Gulf War. CFS, MSI, and other symptom-based conditions are often associated with considerable morbidity due to fatigue, chronic pain, neurologic symptoms, and other symptoms that can impair the quality of life. This article discusses several important issues of methodology that arise in population studies of CFS and MSI. These include the exclusion criteria that have been used in population studies to define CFS-like illness and unexplained MSI, the potential for false positive and false negative assessments of illness status, the potential for sex differences, and the poorly understood natural history of these symptom-based conditions across the life span. As an empirical example of these methodology issues, we examined existing data from a 2005 follow-up survey. We found that 64.9% (762 of 1,175) of female Gulf War veterans and 53.4% (2,530 of 4,739) of male Gulf War veterans had 1 or more exclusionary medical conditions. The prevalence among veterans with one or more exclusionary medical conditions increased markedly by age among females and those with a low income.

Cancer incidence among patients of the U.S. Veterans Affairs Health Care System.

OBJECTIVE: Approximately 40,000 incident cancer cases are reported in the Veterans Affairs Central Cancer Registry (VACCR) annually (approximately 3% of U.S. cancer cases). Our objective was to provide the first comprehensive description of cancer incidence as reported in VACCR. METHODS: Data were obtained from VACCR for incident cancers diagnosed in VA. Analyses focused on 2007 data. Cancer incidence among VA patients was compared to the general U.S. cancer population. RESULTS: In 2007, 97.5% of VA cancers were diagnosed among men. Approximately 78.5% of newly diagnosed patients were White, 19.0% Black, and 2.5% were another race. Median age at diagnosis was 66 years. The geographic distribution of cancer patients in VA aligns that of VA users. The most commonly diagnosed cancers were similar between VA and the U.S. male cancer population. The five most frequently diagnosed cancers among VA cancer patients were: prostate (31.8%), lung/bronchus (18.8%), colon/rectum (8.6%), urinary bladder (3.6%), and skin melanomas (3.4%). VA patients were diagnosed at an earlier stage of disease for the three most commonly diagnosed cancers--lung/bronchus, colon/rectum, and prostate--compared to the U.S. male cancer population. CONCLUSIONS: Registry data indicate that incident cancers in VA in 2007 approximately mirrored those observed among U.S. men.

Factors associated with survival of veterans with gastrointestinal neuroendocrine tumors.

Background. Gastrointestinal (GI) neuroendocrine tumor (NET) incidence has been increasing; however, GI NET within the national Veterans Affairs (VA) health system has not been described. Methods. We used the VA Central Cancer Registry to identify the cohort of patients diagnosed with GI NET in 1995-2009. Cox regression models were constructed to explore factors associated with survival. Results. We included 1793 patients with NET of the stomach (9%), duodenum (10%), small intestine (24%), colon (19%) or rectum (38%). Twenty percent were diagnosed in 1995-1999, 35% in 2000-2004, and 45% in 2005-2009. Unadjusted 5-year survival rates were: stomach 56%, duodenum 66%, small intestine 52%, colon 67%, and rectum 84%. Factors associated with shorter survival were increasing age, hazard ratio (HR) 1.05 (95% CI 1.04-1.06), NET location [compared to rectum: stomach HR 2.26 (95% CI 1.68-3.05), duodenum HR 1.70 (95% CI 1.26-2.28), small intestine HR 1.85 (95% CI 1.42-2.42), and colon 1.83 (95% CI 1.41-2.39)], stage [compared to in situ/local: regional HR 1.15 (95% CI 0.90-1.47), distant HR 2.38 (95% CI 1.87-3.05)], and earlier period of diagnosis [compared to 1995-1999: 2000-2004 HR 0.70 (95% CI 0.59-0.85), 2005-2009 HR 0.43 (95% CI 0.34-0.54)]. Conclusions. The incidence of GI NET has also increased over time in the VA system with similar survival rates to those observed in non-VA settings. Worsened survival was associated with older age, tumor site, advanced stage, and earlier year of diagnosis.

Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood.

The ongoing development of the hippocampus in adolescence may be vulnerable to stressors. The effects of social instability stress (SS) in adolescence (daily 1 h isolation and change of cage partner postnatal days 30-45) on cell proliferation in the dentate gyrus (DG) in adolescence (on days 33 and 46, experiment 1) and in adulthood (experiment 2) was examined in Long Evans male rats and compared to nonstressed controls (CTL). Additionally, in experiment 2, a separate group of SS and CTL rats was tested on either a spatial (hippocampal-dependent) or nonspatial (nonhippocampal dependent) version of an object memory test and also were used to investigate hippocampal expression of markers of synaptic plasticity. No memory impairment was evident until the SS rats were adults, and the impairment was only on the spatial test. SS rats initially (postnatal day 33) had increased cell proliferation based on counts of Ki67 immunoreactive (ir) cells and greater survival of immature neurons based on counts of doublecortin ir cells on day 46 and in adulthood, irrespective of behavioral testing. Counts of microglia in the DG did not differ by stress group, but behavioral testing was associated with reduced microglia counts compared to nontested rats. As adults, SS and CTL rats did not differ in hippocampal expression of synaptophysin, but compared to CTL rats, SS rats had higher expression of basal calcium/calmodulin-dependent kinase II (CamKII), and lower expression of the phosphorylated CamKII subunit threonine 286, signaling molecules related to synaptic plasticity. The results are contrasted with those from previous reports of chronic stress in adult rats, and we conclude that adolescent stress alters the ongoing development of the hippocampus leading to impaired spatial memory in adulthood, highlighting the heightened vulnerability to stressors in adolescence.

Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress.

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H(2)O(2)) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H(2)O(2)-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r=0.92, p<0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences.