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Background: Cancer diagnoses are associated with an increased risk for suicide. The aim of this study was to evaluate this association among Veterans receiving Veterans Health Administration (VHA) care, a population that has an especially high suicide risk. Methods: Among 4,926,373 Veterans with VHA use in 2011 and in 2012 or 2013, and without VHA cancer diagnoses in 2011, we assessed suicide risk following incident cancer diagnoses. Risk time was from initial VHA use in 2012–2013 to 12/31/2018 or death, whichever came first. Cox proportional hazards regression models evaluated associations between new cancer diagnoses and suicide risk, adjusting for age, sex, VHA regional network, and mental health comorbidities. Suicide rates were calculated among Veterans with new cancer diagnoses through 84 months following diagnosis. Results: A new cancer diagnosis corresponded to a 47% higher suicide risk (Adjusted Hazard Ratio [aHR] = 1.47, 95% CI: 1.33–1.63). The cancer subtype associated with the highest suicide risk was esophageal cancer (aHR = 6.01, 95% CI: 3.73–9.68), and other significant subtypes included head and neck (aHR = 3.55, 95% CI: 2.74–4.62) and lung cancer (aHR = 2.35, 95% CI: 1.85–3.00). Cancer stages 3 (aHR = 2.36, 95% CI: 1.80–3.11) and 4 (aHR = 3.53, 95% CI: 2.81–4.43) at diagnosis were positively associated with suicide risk. Suicide rates were highest within 3 months following diagnosis and remained elevated in the 3–6‐ and 6–12‐month periods following diagnosis. Conclusion: Among Veteran VHA users, suicide risk was elevated following new cancer diagnoses. Risk was particularly high in the first 3 months. Additional screening and suicide prevention efforts may be warranted for VHA Veterans newly diagnosed with cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND Adjuvant chemotherapy after surgical resection improves outcomes for patients with early-stage non-small cell lung cancer (NSCLC). To the authors' knowledge, there are no published prospective trials to date of adjuvant chemotherapy after surgical resection administered exclusively in older patients. In the current study, the authors sought to evaluate the efficacy of adjuvant chemotherapy in older patients in a Veterans Health Administration cohort. METHODS Patients who underwent surgical resection for American Joint Committee on Cancer stages IB to III NSCLC between 2001 and 2011 were analyzed. Data regarding patient demographics and comorbidities, tumor characteristics, and primary treatment were collected. Patients were divided into 2 groups based on age at diagnosis: those aged <70 years and those aged ≥70 years. The primary exposure was use of adjuvant chemotherapy. A Cox proportional hazards model was used to estimate the significance of patient characteristics. Survival curves were estimated using the Kaplan-Meier method and group comparisons were performed using the log-rank test. RESULTS The analysis included 7593 patients who underwent surgical resection for stage IB to stage III NSCLC. Among these, 2897 patients (38%) were aged ≥70 years. The percentage of older patients who received adjuvant chemotherapy was approximately one-half that of younger patients who did so (15.3% vs 31.6%; P<.0001). Carboplatin-based doublets were used most often in all patients (64.6%). Both younger patients (hazard ratio, 0.79; 95% confidence interval, 0.72-0.86) and older patients (hazard ratio, 0.81; 95% confidence interval, 0.71-0.92) were found to have a lower risk of death with receipt of adjuvant chemotherapy. CONCLUSIONS Older patients derive a similar magnitude of benefit from adjuvant chemotherapy as younger patients and therefore adjuvant chemotherapy should not be withheld based on age alone. Cancer 2015;121:2578-2585. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401. METHODS Patients with metastatic, castration-resistant prostate cancer were randomized to receive docetaxel and prednisone with or without bevacizumab once every 21 days. Cycle-to-event Cox regression models were used to investigate the association of bevacizumab with the incidence of grade 3 or greater (≥3) ATE and VTE. Age, prior ATE/VTE, baseline antiplatelet/anticoagulant use, and VTE risk score (based on leukocyte count, hemoglobin, platelet count, body mass index, and tumor location) were evaluated in univariate and multivariable analyses. RESULTS Of 1008 randomized patients, the odds of experiencing grade ≥3 ATE were significantly greater in those who received bevacizumab compared with those who received placebo (odds ratio, 2.79; P = .02), whereas an opposite trend was noted for grade ≥3 VTE (odds ratio, 0.60; P = .08). In the multivariable analysis, bevacizumab treatment (hazard ratio [HR], 3.00; P = .01) and age (HR, 1.06; P = .02) were significantly associated with the risk of ATE; whereas age (HR, 1.05; P = .01) and VTE risk score (HR, 1.83; P = .03) were significantly associated with the risk of VTE. CONCLUSIONS Bevacizumab was significantly associated with a greater risk of ATE in patients with metastatic, castration-resistant prostate cancer, but it was not significantly associated with the risk of VTE. Understanding clinical factors that increase the risk for experiencing ATE/VTE is essential to mitigate the risks and reduce the burden of these prevalent complications in cancer care. Cancer 2015;121:1025-1031. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Despite clinical trials demonstrating improved survival with adjuvant chemotherapy (AC) for patients with American Joint Committee on Cancer stages I to III non-small cell lung cancer (NSCLC), it is unclear whether this survival benefit extends to broader populations. The current study evaluated patterns of AC use and examined the impact of AC on survival. METHODS A retrospective analysis was conducted of patients in the Veterans Affairs Central Cancer Registry diagnosed with stages IB to IIIA NSCLC between 2001 and 2008. Descriptive statistics were used to examine patterns of AC use over an 8-year time period. Cox proportional hazards regression analyses were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CIs) to compare mortality risk among patients treated with and without AC. RESULTS Among 14,306 patients with stages IB to IIIA NSCLC, 4929 underwent surgery and 22% of these received AC. The percentages of patients diagnosed in 2001 through 2003, 2004 through 2005, and 2006 through 2008 receiving AC were 7.0%, 29.8%, and 29.5%, respectively. There was no survival benefit with AC noted for patients diagnosed between 2001 and 2003, but AC was associated with improved survival for the period between 2004 and 2005 (HR, 0.78; 95% CI, 0.67-0.91) and 2006 through 2008 (HR, 0.79; 95% CI, 0.69-0.91). Of those patients receiving AC, 89% received platinum-doublet chemotherapy. Carboplatin remained the most common agent, although cisplatin use reached 43% in the period between 2006 and 2008. The HR for cisplatin relative to carboplatin was 0.96 (95% CI, 0.80-1.15). CONCLUSIONS There was a significant increase in the use of AC between 2001 and 2008 and AC was associated with an improvement in overall survival. Cancer 2014;120:1939-1947. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A ( CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase ( MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis ( p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis ( p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Chordoma, a rare bone tumor originating from notochordal remnants, has a genetic predisposition in some families. Previously, we performed linkage analysis using microsatellite (STR) markers on 3 unrelated chordoma kindreds (16 patients with chordoma) and reported significant evidence for linkage to chromosome 7q33 ( Z [ABSTRACT FROM AUTHOR]

Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype–phenotype relationship. [ABSTRACT FROM AUTHOR]

To assess whether an experimental nutritional formula, given as a supplement, would reduce days of symptoms of upper respiratory tract infection (URTI) and affect antibody and lymphocyte proliferative responses to influenza vaccine. A prospective, randomized, double-blind, controlled trial was conducted between October 1999 and April 2000. Assisted- and independent-living facilities in North Central Florida. Sixty-six individuals, aged 65 and older. Subjects received 8 oz/d of an experimental formula containing antioxidants, zinc, selenium, fermentable oligosaccharides, and structured triacylglycerol or an isoenergetic, isonitrogenous control formula for 183 days. Subjects recorded daily symptoms of URTI. Antibody titers and lymphocyte proliferation to three influenza vaccine components were measured on Days 57 and 183. Eighteen subjects in the control group and 16 subjects in the experimental group consumed an average of 7 ounces of formula daily and completed the 183-day study. Median days of symptoms of URTI were 3 (range 0–69, total days=156) and 0 (range 0–49, total days=78) for the control and experimental groups, respectively ( P= .049). On Day 57, seven of 17 (41%) subjects in the control group and 13 of 15 (87%) subjects in the experimental group achieved a fourfold or greater increase in serum antibody titer to A/Beijing ( P=.012). Lymphocyte proliferation to influenza vaccine components was greater in the experimental (median=1,365 cpm, range=0–14,955 cpm) than the control group (median=136 cpm, range=0–4,270 cpm) ( P=.013). Subjects consuming an experimental nutritional formula experienced enhanced immune function and fewer days of URTI symptoms. [ABSTRACT FROM AUTHOR]

This document provides information on the use of Bruton tyrosine kinase inhibitors (BTKi) for patients with chronic lymphocytic leukemia (CLL) and severe renal dysfunction. The study, conducted on US veterans, found that BTKi can be a viable treatment option for CLL patients with significant renal impairment, including those on hemodialysis. The study also suggests that reducing the dose of BTKi may improve tolerability without compromising effectiveness. However, it is important to exercise caution when applying these findings to newer BTK inhibitors and subsequent treatment options. Further research is needed to fully understand the effects of BTKi in patients with severe renal dysfunction. [Extracted from the article]

Mutation of the non-muscle myosin heavy chain type II-A results in MYH9-related hereditary macrothrombocytopenia (HMTC), including four autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian (SBS), Fechtner (FS) and Epstein (EPS) syndrome. Denaturing high-performance liquid chromatography (DHPLC) was optimised for rapid screening of the seven exons harbouring all but one of the previously reported mutations of MYH9. Individuals from 13 families with phenotypes suggestive of MYH9-related HMTC were screened for mutations by DHPLC followed by direct sequencing of samples with aberrant column retention time. Mutations were identified in all 13 families. Six distinct missense heterozygous mutations were found in 10 families, including six families with MHA or SBS (E1841K, D1424N), three families with FS (R702H, R1165C, and D1424Y), and one family with EPS (S96L). A truncating mutation (R1933X) was found in three MHA families. A review of all published mutations suggests that mutation in the C-terminal coiled coil region or truncation of the tailpiece is associated with haematological-only phenotype, while mutation of the head ATPase domain frequently is associated with nephropathy and/or hearing loss. Mutations of other regions have intermediate expression of non-haematological characteristics. Further study is required to confirm these associations and understand the molecular basis for this genotype-phenotype relationship.

Medulloblastoma is the most common malignant central nervous system tumor of childhood and can occur sporadically or in association with inherited cancer susceptibility syndromes such as the nevoid basal cell carcinoma syndrome (NBCCS). To determine whether an association existed between the risk of developing medulloblastoma and undiagnosed syndromes, we retrospectively reviewed clinical data on 33 patients with medulloblastoma from a single institution and compared them with their unaffected relatives (n = 46). Six patients had tumors showing desmoplastic histology. Two of the six met diagnostic criteria for NBCCS. One NBCCS patient had a missense mutation of patched-1 (PTCH1); the other had no identifiable PTCH1 mutation. Two patients with isolated desmoplastic medulloblastoma had an insertion and splice site mutation, respectively, in suppressor of fused (SUFU). All patients with nondesmoplastic medulloblastoma histology received molecular testing for SUFU. None of these patients had an identifiable mutation in PTCH1 or SUFU. We performed a clinical evaluation for Greig cephalopolysyndactyly syndrome (GCPS) in four medulloblastoma families, who exhibited macrocephaly as the only finding consistent with the diagnosis of GCPS. Molecular analysis of GLI3 in these four families was negative. There was a paucity of clinical findings among the majority of medulloblastoma patients in this study group to suggest a definable cancer genetic syndrome. We conclude that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations are present at a low but significant frequency., (2005 Wiley-Liss, Inc.)