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Chlorhexidine skin antisepsis is frequently recommended for most surgical procedures; however, it is unclear if these recommendations should apply to surgery involving traumatic contaminated wounds where povidone-iodine has previously been preferred. We aimed to compare the effect of aqueous 10% povidone-iodine versus aqueous 4% chlorhexidine gluconate on the risk of surgical site infection in patients who required surgery for an open fracture.We conducted a multiple-period, cluster-randomised, crossover trial (Aqueous-PREP) at 14 hospitals in Canada, Spain, and the USA. Eligible patients were adults aged 18 years or older with an open extremity fracture treated with a surgical fixation implant. For inclusion, the open fracture required formal surgical debridement within 72 h of the injury. Participating sites were randomly assigned (1:1) to use either aqueous 10% povidone-iodine or aqueous 4% chlorhexidine gluconate immediately before surgical incision; sites then alternated between the study interventions every 2 months. Participants, health-care providers, and study personnel were aware of the treatment assignment due to the colour of the solutions. The outcome adjudicators and data analysts were masked to treatment allocation. The primary outcome was surgical site infection, guided by the 2017 US Centers for Disease Control and Prevention National Healthcare Safety Network reporting criteria, which included superficial incisional infection within 30 days or deep incisional or organ space infection within 90 days of surgery. The primary analyses followed the intention-to-treat principle and included all participants in the groups to which they were randomly assigned. This study is registered with ClinicalTrials.gov, NCT03385304.Between April 8, 2018, and June 8, 2021, 3619 patients were assessed for eligibility and 1683 were enrolled and randomly assigned to povidone-iodine (n=847) or chlorhexidine gluconate (n=836). The trial's adjudication committee determined that 45 participants were ineligible, leaving 1638 participants in the primary analysis, with 828 in the povidone-iodine group and 810 in the chlorhexidine gluconate group (mean age 44·9 years [SD 18·0]; 629 [38%] were female and 1009 [62%] were male). Among 1571 participants in whom the primary outcome was known, a surgical site infection occurred in 59 (7%) of 787 participants in the povidone-iodine group and 58 (7%) of 784 in the chlorhexidine gluconate group (odds ratio 1·11, 95% CI 0·74 to 1·65; p=0·61; risk difference 0·6%, 95% CI -1·4 to 3·4).For patients who require surgical fixation of an open fracture, either aqueous 10% povidone-iodine or aqueous 4% chlorhexidine gluconate can be selected for skin antisepsis on the basis of solution availability, patient contraindications, or product cost. These findings might also have implications for antisepsis of other traumatic wounds.US Department of Defense, Canadian Institutes of Health Research, McMaster University Surgical Associates, PSI Foundation.

326 Background: HER2-low tumors, defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization (ISH), are not well characterized among gastric or gastroesophageal junction adenocarcinomas. More importantly, this patient population is currently treated as HER2-negative (HER2-low and HER2-zero [IHC score of 0]) without anti-HER-2 directed therapy. Herein, we describe a real world outcome analysis of this distinct genomically defined underrepresented population. Methods: De-identified, multimodal real-world data (RWD) of 429 advanced gastric, esophageal, and GEJ adenocarcinomas from the Tempus Lens database was analyzed. Inclusion criteria was a diagnosis of gastric, esophageal, or GEJ adenocarcinoma between January 2017 to May 2021 and treatment with first-line therapy. Median overall survival (mOS) was estimated using Kaplan-Meier methods. Results: HER2-low was identified in 24.9% (107/429) of the total cohort. Histologies within HER2 low group were 83.2% (89/107) adenocarcinoma (NOS), 7.5% (8/107) signet ring cell carcinoma, 5.6% (6/107) diffuse-type, and 3.7% (4/107) mucinous-type. PDL-1 TPS status was available in only 50.5% (54/107) of the HER2-low group. TPS distribution was: 74.1% (40/54) for TPS =1-= 10: 3.7% (2/54). ERBB2 amplification or focal gain was detected in 1.1% (1/88) of patients in the HER-2 low group that had undergone tumor genomic sequencing, and 0% (0/28) of patients that had circulating tumor DNA (ctDNA) sequenced. Median followup time was 20.7 (8.5, 35.6) months. Median OS (mOS, months) was 9.8 (9.0, 12.7) for HER2-low, 13.2 (8.9, 27.0) for HER2(-), and 14.1 (11.0, 19.2) for HER2(+). Survival differences were also compared with variations across ERBB2 RNA expression and copy number variation (CNV). HER2 groups were defined on RNA expression and copy number estimates based on thresholds determined from the proportion of samples in each of the HER2 groups from IHC/ISH data. For RNA expression analysis, the mOS was 10.8 (8.8, 13.5) months for HER2-low, 10.9 (7.2, 17.4) months for HER2(-), and 13.0 (11.4, 20.5) months for HER2(+). For CNV data, the mOS(months) was: HER2-low: 10.9 (8.5, 14.1), HER2(-): 10.2 (7.0, 15.7), HER2(+): 14.2 (11.5, 21.4). Conclusions: Our real world, biomarker outcome analysis suggests that advanced gastric and GEJ patients with HER2-low expression identified by IHC and RNA expression have a poor prognosis with shortest survival. Furthermore, our data suggest that there is a heterogeneity of PDL-1 enrichment within this group. Hence, targeting expression of low levels of HER2 similar to HER2+ group alone or in combination with immunotherapy should be evaluated in future clinical trials to improve efficacy outcomes.

Background Low‐molecular‐weight heparin has been the preferred treatment of cancer‐associated thrombosis (CAT); however, emerging data support the use of direct oral anticoagulants (DOACs). Objectives The Memorial Sloan Kettering Cancer Center Clinical Pathway has served as the institutional guideline for the use of rivaroxaban to treat CAT since 2014. Key elements are to recommend against use of a DOAC in patients with active gastrointestinal (GI) or genitourinary tract lesions, and a prespecified dose reduction in the elderly (75+ years old). We present our institutional experience for treatment of CAT. Methods From January 2014 through September 2016, 1072 patients began rivaroxaban treatment for CAT; 91.9% had a solid tumor, 8.1% had hematologic malignancies, and 75% of patients with solid tumors had metastatic disease. All patients with CAT treated with rivaroxaban were included in this analysis, regardless of adherence to the Clinical Pathway. Results The 6‐month cumulative incidence of recurrent venous thromboembolism and major bleeding were 4.2% (95% confidence interval [CI], 2.7%‐5.7%) and 2.2% (95% CI, 1.1%‐3.2%), respectively. The incidence of clinically relevant non–major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI, 3.7%‐7.1%), and 73.3% of major bleeds occurred in the GI tract. The 6‐month cumulative mortality rate was 22.2% (95% CI, 19.4%‐24.9%). The elderly had similar rates of recurrent thrombosis and bleeding as those aged under 75 years. Conclusion Our institutional experience suggests that in appropriately selected patients, rivaroxaban may be used for treatment of CAT with promising safety and efficacy.

Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT™ platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11,695 evaluable individuals, 72% had metastatic disease at time of IMPACT. Tumor-specific mutations in KRAS (HR=1.34 [1.09-1.64]; adjusted p=0.08), STK11 (HR=2.12 [1.55-2.89]; adjusted pKEAP1 (HR=1.84 [1.21-2.79]; adjusted p=0.07), CTNNB1 (HR=1.73 [1.15-2.60]; adjusted p=0.09), CDKN2B (HR= 1.45 [1.13-1.85], adjusted p=0.07) and MET (HR=1.83 [1.15-2.92]; adjusted p=0.09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR=0.35 [0.16-0.79], adjusted p=0.09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B and MET were associated with an increased risk of VTE in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.Key PointsTumor mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, MET and SETD2 modulate the risk of cancer-associated thrombosis.The presence of clonal hematopoiesis does not affect the risk of cancer-associated thrombosis.

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

This study assesses 18F–FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer. In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent 18F–FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.18F–FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI). A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, 18F–FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, 18F–FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9–20%). 18F–FDG-PET/CT revealed distant metastases in 14% (95% CI: 9–20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9–24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with 18F–FDG-PET/CT at the time of initial diagnosis.

The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein).

Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. Rivaroxaban was approved in 2012 for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but no prior studies have been reported specifically evaluating the efficacy and safety of rivaroxaban for cancer-associated thrombosis (CAT). Under a Quality Assessment Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT and now report a validation analysis of our first 200 patients. A 200 patient cohort with CAT (PE or symptomatic, proximal DVT), whose full course of anticoagulation was with rivaroxaban, were accrued. In competing risk analysis, primary endpoints at 6 months included new or recurrent PE or symptomatic proximal lower extremity DVT, major bleeding, clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. In competing risk analysis, the 6 months cumulative incidence of new or recurrent VTE was 4.4 % (95 % CI = 1.4–7.4 %), major bleeding was 2.2 % (95 % CI = 0−4.2 %) and all-cause mortality 17.6 % (95 % CI = 11.7–23.0 %). In this cohort of 200 patients with active cancer and CAT the rates of new or recurrent VTE and major bleeding were comparable to the cancer subgroup analysis from the EINSTEIN studies. The results of our Clinical Pathway provide guidance on Rivaroxaban use for treatment of CAT, and suggest that safety and efficacy is preserved, compared with past-published experience with LMWH. Electronic supplementary material The online version of this article (doi:10.1007/s11239-016-1429-1) contains supplementary material, which is available to authorized users.

Objective Thiamine deficiency (TD) is increasingly recognized in medically ill patients. The prevalence of TD among cancer patients is unknown. This study aims to characterize the prevalence of TD among inpatients with cancer. Methods Retrospective chart review of patients admitted to a large cancer center who were referred for psychiatric consultation and whose serum thiamine concentration was measured. Patients with alcohol use were excluded. Results Among 217 patients with various cancer types, TD was found in 55.3%. Risk factors included fluorouracil-based chemotherapy, significant weight loss, and undergoing active cancer treatment. Almost all patients were normal weight, overweight, or obese, and few had concomitant vitamin B12 or folate deficiency. A total of 17.5% were receiving multivitamin supplementation. Nearly half (49.8%) did not receive empiric treatment with thiamine and among those who did, treatment delay occurred in the majority of cases (59.6%). Measurement of serum thiamine concentration preceded psychiatric consultation in only 10.6% of cases. Conclusions Our findings suggest that TD is highly prevalent among inpatients with cancer, even among normal and overweight individuals, in the absence of other vitamin deficiencies, and while receiving multivitamin supplements. Several potential risk factors were identified, including active cancer treatment. Evaluation of TD was most commonly not initiated by oncologists. Failure to treat and treatment delay were common. Given these findings, oncologists must be vigilant about detecting TD among inpatients with cancer. Copyright © 2016 John Wiley & Sons, Ltd.

The Information Systems Department at Memorial Sloan Kettering Cancer Center developed the DARWIN Cohort Management System (DCMS). The DCMS identifies and tracks cohorts of patients based on genotypic and clinical data. It assists researchers and treating physicians in enrolling patients to genotype-matched IRB-approved clinical trials. The DCMS sends automated, actionable, and secure email notifications to users with information about eligible or enrolled patients before their upcoming appointments. The system also captures investigators input via annotations on patient eligibility and preferences on future status updates. As of August 2015, the DCMS is tracking 159,893 patients on both clinical operations and research cohorts. 134 research cohorts have been established and track 64,473 patients. 51,192 of these have had one or more genomic tests including MSK-IMPACT, comprising the pool eligible for genotype-matched studies. This paper describes the design and evolution of this Informatics solution.

Background: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has reclassified up to one third of differentiated thyroid cancer patients into one of the younger prognostic stage groups (

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: Research Funding.

Background Observational studies have identified same room occupancy with a hospital-onset Clostridium difficile infection (HO-CDI) case as a risk factor for subsequent CDI diagnosis. Despite this, the risk remains poorly characterized in endemic settings. Furthermore, genotyping techniques have not been applied to examine concordance between infecting strains in index patients and exposed roommates who eventually develop CDI. The study seeks to quantify transmission of C. difficile from an index case to their roommates and identify if concordance was present among strain types by the application of multi-locus sequence typing (MLST). Methods Laboratory-identified cases of hospital onset C. difficile infection (CDI) from October 1, 2017 through March 31, 2018, were included in the study. Patients with HO-CDI are placed in private room once diagnosis is established. Roommates who were in the same room as cases for at least 24 hours prior to diagnosis, regardless of duration of overlap, were identified through of the hospital patient tracking database to establish spatial link. Next, all exposed roommates who developed CDI within 3 months after exposure (defined as date of CDI diagnosis of index case) were identified. Strain types of linked cases was examined by MLST. Results During the 6-month period, 279 cases of CDI were diagnosed. Of these cases, 156 were hospitalized at the time of diagnosis including 83 (53%) in a room with shared occupancy. These 83 patients had 109 roommates that met exposure criteria. Four (3.7%) roommates developed CDI over a 90-day follow-up period. None of the examined pairs were genetically concordant. Conclusion Indirect patient to patient transmission of C. difficile from newly diagnosed CDI cases to roommates is not common despite the spatial proximity with shared occupancy. Disclosures All authors: No reported disclosures.

INTRODUCTION: Patients living with neuroendocrine tumors have high rates of depression, often necessitating antidepressants, including selective serotonin reuptake inhibitors (SSRI). Neuroendocrine tumors (NETs) secrete vasoactive substances, including serotonin, which contribute to the cluster of symptoms known as carcinoid syndrome (flushing and diarrhea). Controversy exists over whether or not antidepressants are safe in NET. We aimed to study the safety of antidepressant use in NET patients. METHODS: We conducted a retrospective chart review of patients with well differentiated NET who were also prescribed antidepressants from January 2008 through April 2015. The study took place at Memorial Sloan Kettering Cancer Center and was approved by the hospital’s institutional review board. RESULTS: Ninety-two patients were included. There were 16 (17.4%) patients with carcinoid syndrome (10 ileum, 1 duodenum, 1 jejunum and 4 unknown primary); and 76 (82.6%) patients without (41 lung, 9 pancreas, 8 ileal, 5 duodenum, 5 appendix, 2 unknown primary, 1 jejunum and 5 other). Median duration of antidepressant prescription was 11.6 months (range, 0–121) among those with carcinoid syndrome (N=16) and 14.3 months (range, 0–172) among those without carcinoid syndrome (n=76). Antidepressants were stopped in 31 cases (33.7%), though the reason was not specified in the majority of cases (n=18;58%). None of the patients developed carcinoid syndrome while being prescribed antidepressants. No patients developed carcinoid crisis. CONCLUSION: Our findings do not support previous authors’ recommendations that SSRIs must be avoided in NET patients. Several classes of antidepressants appeared safe in NET patients with and without carcinoid syndrome.

The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. α-Synuclein (α-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that α-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which α-syn inhibits ATF6 signaling expands our understanding of the role ER stress and the UPR play in neurodegenerative diseases such as PD.

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically-defined tumor types, coupled with an expanding portfolio of molecularly-targeted therapies, demands flexible and comprehensive approaches to profile clinically significant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative utilizing a comprehensive assay, MSK-IMPACT, through which we have compiled matched tumor and normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures that were shared among common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

BACKGROUND: The link between aging, cancer and atrial fibrillation is well known and the appropriate anticoagulation management of non-valvular atrial fibrillation (NVAF) in patients with active cancer is of growing clinical concern. Rivaroxaban has been broadly used for the primary prevention of stroke and systemic embolism in the general population of patients with NVAF. However, individuals with a serious concomitant illness associated with a life expectancy of less than 2 years were excluded from pivotal trials including the ROCKET-AF study, limiting the generalizability of results to patients with active cancer. There is little published evidence on the safety and efficacy of rivaroxaban for NVAF in this specific subgroup. OBJECTIVES: The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and NVAF. METHODS: The use of rivaroxaban in cancer patients at Memorial Sloan Kettering Cancer Center (MSKCC) was monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and NVAF treated with rivaroxaban from 1/1/2014 through 3/31/2016 are included in this analysis. Endpoints of interest were defined a priori and include stroke, systemic embolism, major bleeding and clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days (CRNMB). Clinical events were assessed through text searches of medical records. The analysis was performed respecting different times on previous anticoagulation, considering the first 90 days as the acute phase of treatment and contrasting it with the subsequent chronic phase. RESULTS: A total of 163 evaluable patients were included in the analysis, with a median age of 72.0 years (interquartile range=67.0-77.5 years) and 56% of these individuals being men. The majority had a solid tumor (85%), with stage IV disease reported in 50% of cases. The mean CHA2DS2-Vasc score was 3.2 (standard deviation=1.5) and 64% of patients were already in the chronic phase of anticoagulation. Results for the acute, chronic and combined phases of anticoagulation are presented in the Table and plotted in the Figure. The estimated cumulative incidence of ischemic stroke, major bleeding, and CRNMB at 1 year were 1.4% (95% CI=0-3.4%), 1.2% (95% CI=0-2.9%) and 14.0% (95% CI=4.2-22.7%) respectively, after adjusting for competing risks. Interestingly, the cumulative incidence of major bleeding in our cohort is lower than the value reported for the ORBIT-AF registry of cancer patients on dabigatran or a vitamin K antagonist for NVAF, in which the estimated rate of this complication was 5.1/100 patient-years. Lastly, the 1-year cumulative incidence of mortality was 22.6% (95% CI=12.2-31.7%). This high risk of death was present throughout the observation period and reflects the cancer population. One patient died after developing an acute ischemic cerebrovascular insult and a myocardial infarction. There were no deaths related to bleeding and no recorded systemic embolism episodes. CONCLUSIONS: The safety and efficacy profile of rivaroxaban treatment for NVAF in patients with active cancer seems comparable to what was observed for the general population in the ROCKET-AF study, but ideally a prospective study would be required to confirm these findings. Table Cumulative Incidence of Competing risks for Patients in the Acute, Chronic and Combined Phases of Anticoagulation* *Cumulative incidence estimates for the chronic phase are conditional to reaching day 90 of anticoagulation without sustaining an event. The chronic phase was defined as lasting 275 days and the combined period encompasses 365 days. CRNMB: Clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days. *Clinically-relevant non-major bleeding leading to discontinuation of rivaroxabanfor at least7 days. Table. Cumulative Incidence of Competing risks for Patients in the Acute, Chronic and Combined Phases of Anticoagulation*. / *Cumulative incidence estimates for the chronic phase are conditional to reaching day 90 of anticoagulation without sustaining an event. The chronic phase was defined as lasting 275 days and the combined period encompasses 365 days. / CRNMB: Clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days. / *Clinically-relevant non-major bleeding leading to discontinuation of rivaroxabanfor at least7 days. Figure Figure. Disclosures Yu: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Soff:Janssen Scientific Affairs, LLC: Consultancy, Research Funding. Mantha:Janssen Scientific Affairs, LLC: Research Funding.

The distribution, metabolism, excretion and hepatic effects of the human hepatotoxin fenclozic acid were investigated following single oral doses of 10 mg/kg to normal and bile duct-cannulated male C57BL/6J mice. Whole body autoradiography showed distribution into all tissues except the brain, with radioactivity still detectable in blood, kidney and liver at 72 h post-dose. Mice dosed with [14C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected. The majority of the [14C]-fenclozic acid-related material recovered was found in the urine/aqueous cage wash, (49%) whilst a smaller portion (13%) was eliminated via the faeces. Metabolic profiles for urine, bile and faecal extracts, obtained using liquid chromatography and a combination of mass spectrometric and radioactivity detection, revealed extensive metabolism of fenclozic acid in mice that involved biotransformations via both oxidation and conjugation. These profiling studies also revealed the presence of glutathione-derived metabolites providing evidence for the production of reactive species by mice administered fenclozic acid. Covalent binding to proteins from liver, kidney and plasma was also demonstrated, although this binding was relatively low (less than 50 pmol eq./mg protein). Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1894-5) contains supplementary material, which is available to authorized users.

1. The distribution, metabolism, excretion and hepatic effects of fenclozic acid were investigated following a single oral dose of 10 mg/kg to hepatic reductase null (HRN) mice. 2. The majority of the [(14)C]-fenclozic acid was eliminated via the urine/aqueous cage wash, (55%) with a smaller portion excreted in the faeces, (5%). The total recovery of radioactivity in the excreta over the 72 h period studied was ca. 60%. 3. Metabolism of fenclozic acid in the HRN mice was entirely to the carboxylic acid function and was dominated by amino acid conjugation to glycine and taurine, with lesser amounts of an acyl glucuronide. 4. Whole body autoradiography of mice showed general distribution into all tissues except the brain. Radioactivity was still detectable in the kidney and liver of the HRN mice at 72 h post-dose. Covalent binding studies showed evidence of binding to kidney, liver and plasma proteins however, the degree of binding was less than 50 pmol equiv/mg protein for all tissues. 5. The HRN mouse appears to be a useful in vivo model for the study of the Phase II conjugation metabolism of fenclozic acid in the absence of hepatic cytochrome P450-related oxidative metabolism.

Introduction: Cancer associated thrombosis (CAT) is a common complication of cancer, associated with significant morbidity and mortality. While incidence varies with cancer type, stage, chemotherapy, and other factors, estimates are that up to 20% of cancer patients will experience at least one venous thromboembolic (VTE) episode. VTE consist of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and there is a spectrum of vascular involvement. DVTs are classified as proximal (popliteal vein or above) and PE may be subsegmental, segmental, lobar, main, or saddle embolism. Our standard approach has been to treat all DVTs and all PEs in cancer patients, regardless of the size of the involved vessel. However, it is not clear if the risk of recurrent VTE in a patient with a "small" subsegmental PE, or a calf vein DVT, is comparable to that of an individual with a larger vascular involvement. In this study, we characterized the largest vessel involved in the initial VTE episode, and the relationship with recurrent VTE. Methods: All patients at MSKCC with CAT are monitored within an existing Quality Assessment initiative. From 1/1/2014 through 10/31/2016, 1072 patients with CAT were treated with rivaroxaban (Riva). (The overall outcomes of this cohort are the subject of a separate abstract.) In this study we compared the rate of recurrent VTE in patients with a distal (calf) DVT with proximal DVT, and PE. We designated the most proximal, or largest thrombosed vessel. As patients with a PE do not routinely undergo Doppler leg ultrasound, we are unable to differentiate PE with a DVT from those without. We also analyzed if the PE was unilateral or bilateral. We used competing risk endpoints for the purpose of this analysis, including recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of Riva, and death. Results: In the Table, we present the data on the relationship of the initial VTE and the risk of recurrence. The majority of CAT events (55%) were PE. There were no significant differences in the rates of recurrent VTE between patients with a PE, a distal DVT or proximal DVT. Within patients with a PE as the index VTE event, there was no significant association between the risk of recurrent VTE and the size of the PE. A subsegmental PE as an index event was associated with a comparable rate of recurrent VTE when compared with segmental and more proximal vessel involvement. The only meaningful trend towards a higher rate of recurrent VTE was in patients whose index event was a bilateral PE, compared with unilateral, although this association did not reach statistical significance. Conclusions: The goal of this Quality Assessment initiative was to evaluate the risk of recurrent VTE in cancer patients to determine if distal DVT's or subsegmental PEs had a significantly lower rate of recurrence than other VTE episodes. Our analysis indicated that the risk of recurrent VTE is not related to the size of the index thrombosed vessel. Within PE, from large, proximal index events through to subsegmental PE, the risk of recurrent VTE is comparable. Similarly, there was only a trend towards lower risk of recurrent VTE in patients with an index distal DVT, versus proximal DVT. But this association was not statistically significant, with overlapping 95% confidence intervals. The one parameter that appeared to have the strongest prediction of recurrent VTE was patients with bilateral PE, versus unilateral. However, this too was only a trend, not statistically significant, and was not one of the parameters within our initial hypotheses. We were unable to identify any subgroup of index VTE, based on vessels involved, that had a significantly lower rate of recurrent VTE while on anticoagulation. Within cancer patients, a subsegmental PE or a distal, calf vein DVT are associated with a risk of recurrent VTE comparable to thrombosis of larger vessels. Table Table. Disclosures Soff: Janssen: Research Funding; Amgen: Research Funding. Mantha:Janssen: Research Funding; GLG: Consultancy; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy.

Introduction: Venous thromboembolism (VTE) is a common complication of cancer, associated with significant morbidity and mortality. Low-molecular weight heparin (LMWH), the most widely used anticoagulant in this setting, is expensive and burdensome. Rivaroxaban (Riva) was approved for treatment of VTE in 2012, but there is limited experience in cancer-associated thrombosis (CAT). In 2014, we established a Clinical Pathway (CP) to guide use of rivaroxaban (Riva) for CAT at Memorial Sloan Kettering Cancer Center. We were concerned that a direct oral anticoagulant (DOAC) would be more likely than LMWH to cause upper gastrointestinal (GI) bleeding in the presence of abnormal mucosa. DOACs have partial renal clearance and are active in the urine, in contrast to LMWH, and we also anticipated increased genitourinary (GU) tract bleeding in the presence of GU lesions. Therefore, the key to our CP has been to recommend against use of Riva or other DOAC in the setting of active (GI) or (GU) tract lesions. As the elderly are known to be at higher risk of bleeding from anticoagulation, the CP recommended reduced dose Riva in patients≥75 year old (yo), (10 mg bid X 3 wks., followed by 15 mg daily). Otherwise, we adhere to the standard FDA approved guidelines. We published a 200-patient cohort in 2016 demonstrating rates of recurrent VTE and bleeding that were at least as low as historical controls with LMWH. This past year, two randomized clinical trials were published comparing a DOAC with dalteparin ("Hokusai VTE Cancer" of edoxaban, Raskob G.E. et al, NEJM, 2017, and "Select-D" of Riva, Young A.M. et al, JCO 2018). Both studies showed a trend towards better efficacy with the DOAC, but with increased GI/GU bleeding. However, those studies did not exclude patients with known GI/GU lesions. We now report our expanded experience with Riva treatment of CAT, confirming the safety and efficacy of Riva treatment of CAT when guided by our CP. Methods: From 1/1/2014 through 10/31/2016, 2000 patients at MSKCC received Riva. 1072 had CAT, defined as a lower extremity DVT and/or PE in a patient with active cancer or receiving cancer therapy. (The other 928 patients did not have active cancer, or received Riva for other indication). All patients treated with Riva for CAT are included in this analysis, even in the presence of active GI/GU lesions. Recurrent VTE, major bleeding (MB), clinically relevant non-major bleeding (CRNMB) leading to discontinuation of Riva, and death were competing risk endpoints for the purpose of the analysis. We also evaluated the outcomes of the subgroup of patients ≥75 yo. Results: At 6 months, the cumulative incidence for the various endpoints estimated within a competing risks framework were; recurrent VTE (4.2%), MB (2.2%), CRNMB (5.5%). Overall, the 6-month incidence of death was 22.2%. In the elderly patients, the risks of recurrent VTE and bleeding were similar to the Conclusions: In our expanded experience of Riva therapy for CAT, applying our CP, we continue to maintain low rates of recurrent VTE and bleeding. Allowing for differences in methodology between a cohort study and randomized clinical trials, the rate of recurrent VTE was as low as the DOAC arm in Hokusai VTE Cancer and Select-D studies. Further, by applying the exclusion criteria in our CP, and not treating patients with known GI/GU lesions, we achieved a low rate of bleeding compared with the DOAC treatment arms in the two recent randomized clinical trials. Those two trials demonstrated bleeding rates greater than LMWH, particularly GI/GU bleeds. We saw no increased rates of recurrent VTE or bleeding in the elderly, which is reassuring, but we cannot conclude if reduced dose is of benefit. These new expanded observations further support the validity of our CP. The key to anticoagulation choice for CAT is not which anticoagulant is "better," but rather which anticoagulant to choose for a specific patient. In the absence of GI/GU contraindications, Riva provides effective and safe anticoagulation, at substantially lower cost and burden to the patient than LMWH. In contrast, we propose that LMWH is preferable in patients with GI/GU lesions. (We are now obtaining specific data for that subgroup). Disclosures Soff: Amgen: Research Funding; Janssen: Research Funding. Mantha:Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; GLG: Consultancy; Janssen: Research Funding.

National Comprehensive Cancer Network guidelines recommend (18)F-FDG-PET/CT, in addition to standard staging procedures, for systemic staging of newly diagnosed stage III breast cancer patients. However, factors in addition to stage may influence PET/CT utility. As breast cancers that are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (triple-negative breast cancer, or TNBC) are more aggressive and metastasize earlier than other breast cancers, we hypothesized that receptor expression may be one such factor. This study assesses (18)F-FDG-PET/CT for systemic staging of newly diagnosed TNBC.In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with TNBC who underwent (18)F-FDG-PET/CT in 2007-2013 prior to systemic or radiation therapy. Initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery, if performed prior to (18)F-FDG-PET/CT. (18)F-FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases, as well as unsuspected synchronous malignancies. Kaplan Meier survival estimates were calculated for initial stage IIB patients stratified by whether or not stage 4 disease was detected by (18)F-FDG-PET/CT.A total of 232 patients with TNBC met inclusion criteria. (18)F-FDG-PET/CT revealed unsuspected distant metastases in 30 (13 %): 0/23 initial stage I, 4/82 (5 %) stage IIA, 13/87 (15 %) stage IIB, 4/23 (17 %) stage IIIA, 8/14 (57 %) stage IIIB, and 1/3 (33 %) stage IIIC. Twenty-six of 30 patients upstaged to IV by (18)F-FDG-PET/CT were confirmed by pathology, with the remaining four patients confirmed by follow-up imaging. In addition, seven unsuspected synchronous malignancies were identified in six patients. Initial stage 2B patients who were upstaged to 4 by (18)F-FDG-PET/CT had significantly shorter survival compared to initial stage 2B patients who were not (3-year Kaplan Meier estimate 0.33, 95 % CI 0.13-0.55 versus 0.97, CI 0.76-0.93, p .0001).F-FDG-PET/CT revealed distant metastases in 15 % of patients with stage IIB TNBC. Stage IIB patients upstaged to 4 by (18)F-FDG-PET/CT had significantly shorter survival than those who were not, consistent with (18)F-FDG-PET/CT detecting an increased burden of disease. This study provides further evidence that populations of patients with stage IIB breast cancer, such as TNBC, should be considered for systemic staging with (18)F-FDG-PET/CT at the time of initial diagnosis.

Thiamine deficiency (TD) is increasingly recognized in medically ill patients. The prevalence of TD among cancer patients is unknown. This study aims to characterize the prevalence of TD among inpatients with cancer.Retrospective chart review of patients admitted to a large cancer center who were referred for psychiatric consultation and whose serum thiamine concentration was measured. Patients with alcohol use were excluded.Among 217 patients with various cancer types, TD was found in 55.3%. Risk factors included fluorouracil-based chemotherapy, significant weight loss, and undergoing active cancer treatment. Almost all patients were normal weight, overweight, or obese, and few had concomitant vitamin B12 or folate deficiency. A total of 17.5% were receiving multivitamin supplementation. Nearly half (49.8%) did not receive empiric treatment with thiamine and among those who did, treatment delay occurred in the majority of cases (59.6%). Measurement of serum thiamine concentration preceded psychiatric consultation in only 10.6% of cases.Our findings suggest that TD is highly prevalent among inpatients with cancer, even among normal and overweight individuals, in the absence of other vitamin deficiencies, and while receiving multivitamin supplements. Several potential risk factors were identified, including active cancer treatment. Evaluation of TD was most commonly not initiated by oncologists. Failure to treat and treatment delay were common. Given these findings, oncologists must be vigilant about detecting TD among inpatients with cancer. Copyright © 2016 John WileySons, Ltd.

Sporadic Parkinson’s disease [PD] is a progressive neurodegenerative disease of unknown etiology [Pollanen et al, 1993], resulting in loss of motor function and degeneration of dopaminergic neurons [Pollanen et al, 1993; Jakes et al, 1994; Forno, 1996; Spillantini et al, 1998; Corti et al 2005]. Alpha-synuclein [α-Syn], a presynaptic protein, is causal in the genesis of PD [Forno, 1996; Spillantini et al, 1998], and gene duplication and triplication of α-Syn are found in sporadic and early onset forms of PD [Singleton et al, 2003], while mutations [A30P, A53T and E46K] in the gene are linked to autosomal dominant familial forms of the disease [Polymeropoulos et al, 1997; Kruger et al, 1998]. Although a soluble protein, under pathological conditions, α-Syn becomes insoluble, self-aggregates and accumulates into intra-neuronal inclusion bodies [Spillantini et al, 1998; Masliah et al, 2000; El-Agnaf et al, 1998; Gosavi et al, 2002]. Similar to α-Syn, Tau is also a highly soluble protein that becomes insoluble by pathological hyperphosphorylation, leading to tauopathies, including Alzheimer’s disease (AD), [Dickson et al, 2002; Esper et al, 2007; Gasparini et al, 2007; Wadia & Lang, 2007; Gong & Iqbal, 2008; Ling et al, 2010; Ludolph et al, 2009; Williams & Lees, 2009]. Whereas both primary synucleinopathies and tauopathies have distinct clinical features, significant overlap exists between these neurodegenerative diseases, particularly manifest in the variable co-morbidity of dementia and Parkinsonism [Murray et al, 2005]. Moreover, p-Tau is often found in Lewy bodies in PD, while α-Syn pathology is seen in Alzheimer’s disease [Crews et al, 2009]. There is increasing evidence that suggests a direct interaction between these proteins [Giasson et al, 2003]. Using the MPTP mouse neurotoxin model of PD, we recently demonstrated that increases in α-Syn can initiate and sustain Tau hyperphosphorylation in vivo and in vitro [Duka et al, 2006; Duka & Sidhu, 2006; Kozikowski et al, 2006; Duka et al, 2009]. The hyperphosphorylation of Tau was absolutely dependent on the presence of α-Syn, as indexed by lack of p-Tau formation in MPTP-treated α-Syn−/− mice or in cells lacking α-Syn. Our more recent studies indicates that α-Syn induces p-Tau formation through specific activation and recruitment of p-GSK-3β, a kinase known to hyperphosphorylate Tau at distinct sites in AD, which itself becomes activated through autophosphorylation at Tyr216 [Duka et al, 2009]. Importantly, we also found tauopathy in postmortem brains of PD and PDD patients, where we found high levels of p-Tau, α-Syn and p-GSK-3β in striatum, but not in the inferior frontal gyrus, suggesting a different anatomical distribution of Tau pathology in PD patients as compared to AD patients [Wills et al, 2010]. In the current study, we have investigated the state of tauopathy in a transgenic mouse model of PD that over-expresses the human α-Syn transgene under the control of the platelet derived growth factor [PDGF] promoter [Rockenstein et al, 2002]. Our results indicate a spontaneous age-dependent development of tauopathy in these mice, and provide further support for the concept that PD is a form of tauopathy.

This article will concentrate on factors that accelerate or delay the onset of severe hypoxaemia during apnoea (Fig. 1). In the anaesthetized patient, the oxygen consumption (VO2) remains fairly constant at 250 ml min. This is delivered to the tissues by haemoglobin whose oxygen is then replenished, on return to the pulmonary circulation, by the diminishing store of oxygen within the lungs. The alveolar partial pressure of oxygen (PAO2) decreases steadily, not only because the oxygen is being removed from the lungs but also because this oxygen removal generates a substantial negative intrathoracic pressure if the airway is obstructed. Although the arterial partial pressure of oxygen (PaO2) decreases in direct relation to the PAO2, the arterial haemoglobin oxygen saturation (SaO2) remains .90% as long as the haemoglobin can be re-oxygenated in the lungs. The SaO2 only starts to decrease when the store of oxygen in the lungs is depleted and the PaO2 is of the order of 6–7 kPa. Its subsequent decline is of a constant and rapid nature, about 30% every minute. At the start of this rapid decline, the SaO2 is still 90–95%. This inflection point we will define as ‘critical hypoxia’. It is for this reason that oximetry is not a good tool for predicting impending severe hypoxaemia. However, because oximetry detects the decrease in SaO2 before any clinical signs are apparent, it has proved invaluable in detecting critical situations and has helped improve clinical practice to avoid these situations. Various factors significantly influence the time period from the onset of apnoea to critical hypoxia.

An expedient synthesis of the polymer-supported aldehyde 3, as a Garner aldehyde equivalent, is described. Oxazolidine 3 may be obtained through preformation of aldehyde linker 4 in solution and loaded onto amine-terminating resin under peptide-coupling conditions, or alternatively via oxidation of polymer-bound alcohol 14. The integrity of the serine-derived stereocenter is maintained through all steps of the synthesis.

Background: Low-molecular weight heparin (LMWH) has been the standard of care for treatment of venous thromboembolism (VTE) in patients with cancer. LMWH injections are painful and costly. Rivaroxaban, an oral direct factor Xa inhibitor, was FDA approved in 2012 for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), but there has been a knowledge gap for its use in patients with cancer-associated thrombosis (CAT). Under a Quality Assurance Initiative (QAI), we established a Clinical Pathway to guide rivaroxaban use for CAT, and began to offer rivaroxaban as an alternative to enoxaparin, in January 2014, for patients who met appropriate clinical criteria. We are tracking all cancer patients with PE or symptomatic proximal DVT, whose full course of anticoagulation is with rivaroxaban (allowing up to 3 days of initial parenteral anticoagulation). We now report the characteristics of the first 200 patients, and an outcome analysis of our first 100 patients, who have been treated for at least 6 months or otherwise reached an endpoint. Materials and Methods: The Clinical Pathway guidelines will be available on request, pending publication. Patients were not treated with rivaroxaban if they had active gastrointestinal or genitourinary lesions, or had undergone gastric resection due to anticipated excess bleeding risk or reduced absorption. This excluded under 5% of patients. The Pathway provided dosing guidelines in the setting of thrombocytopenia, advanced age, transient renal, or hepatic dysfunction. Primary endpoints include new or recurrent PE, symptomatic proximal lower extremity DVT, major bleeding (ISTH definition), clinically-relevant non-major bleeding leading to discontinuation of rivaroxaban, or death. Considering those outcomes as competing risks, the cumulative incidence of each event type was calculated using R 3.2.0 for Windows and package "Survival". Results: The characteristics of our first 200 patients are in Table 1. 70% of the patients had PE. Of the solid tumor patients, 65.6% had metastatic disease. The first 100 patients have completed at least 6 months of rivaroxaban anticoagulation or otherwise reached a primary endpoint. At 6 months, the cumulative incidence of death was 14.4% (95% CI=6.8-21.4%), new or recurrent VTE was 4.3% (95% CI=0.1-8.4%), major bleeding was 1.1% (95% CI=0-3.1%), and clinically relevant non-major bleeding leading to rivaroxaban discontinuation was 7.9% (95% CI=2.1-13.3%). Conclusions: In the analysis of the first 100 patients entered into our QAI program, the rates of major bleeding, and new or recurrent VTE compare favorably to two published studies of LMWH for treatment of cancer associated thrombosis. In the CLOT study (Lee et al, NEJM, 2003) and the Daltecan study (Francis et al, JTH, 2015), the 6-month rates of new or recurrent VTE were approximately 9%, and the rates of major bleeding were 6% and 9.5% respectively. Our final analysis awaits the completion of 6 months follow-up on 200 patients, to be completed in December 2015. But the rates of major bleeding and recurrent VTE at this point suggest safety and efficacy to be at least non-inferior to LMWH, with the advantage of reduced patient burden, and support the ongoing use of our Clinical Pathway. Our low rate of major bleeding likely is influenced by the exclusion of patients with active GI or GU lesions, who would be expected to have a high bleeding risk with an oral direct anticoagulant. However, we estimate this excluded less than 5% of cancer patients with VTE. Further, we anticipated reduced drug clearance in the elderly, and used a reduced dose for patients greater than 75 years of age. This appeared to be associated with no loss in efficacy, and helped maintain a low rate of major bleeding. A randomized trial is the optimal approach to establish non-inferiority or superiority of rivaroxaban to LMWH for cancer associated thrombosis. However, our QAI Clinical Pathway provides guidance and reassurance for rivaroxaban use until a randomized trial is conducted. Table. Baseline Characteristics of Patients Characteristic Number of Individuals Gender Male 82 Female 118 Event Type PE, with or without DVT 140 Proximal, Symptomatic Lower extremity DVT 60 Cancer Type Solid Tumor 186 Hematologic Malignancy 14 Cancer Stage (Of Solid Tumors) No Evidence of Disease (Post-Cancer Surgery) 11 (5.9%) 1 1 (0.5%) 2 4 (2.2%) 3 16 (8.6%) 4 122 (65.6%) Unknown 32 (17.2%) Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Legend of the Guardians: The Owls of Ga'Hoole (LotG) features over sixty distinctive, art-directed, hyper-realistic feathered characters. We developed a procedural feathering pipeline, Quill, to efficiently realise more than fifteen unique bird species required by the story. This toolset allows a procedural representation of feathers to be developed by surfacing artists, augmented with automatic deintersection, animation, character effects and dynamics and rendered with extensive level-of-detail support.

Although clinically distinct diseases, tauopathies and synucleinopathies share a common genesis and mechanisms, leading to overlapping degenerative changes within neurons. In human postmortem striatum of Parkinson's disease (PD) and PD with dementia, we have recently described elevated levels of tauopathy, indexed as increased hyperphosphorylated Tau (p-Tau). Here we assessed tauopathy in striatum of a transgenic animal model of PD, overexpressing human α-synuclein under the platelet-derived growth factor promoter. At 11 months of age, large and progressive increases in p-Tau in transgenic mice, hyperphosphorylated at sites reminiscent of Alzheimer's disease, were noted, along with elevated levels of α-synuclein and glycogen synthase kinase 3β phosphorylated at Tyr216 (p-GSK-3β), a major kinase involved in the hyperphosphorylation of Tau. Differential Triton X-100 extraction of striata showed the presence of aggregated α-synuclein in the transgenic mice, along with p-Tau and p-GSK-3β, which was also confirmed through immunohistochemistry. After p-Tau formation, both Tau and microtubule-associated protein 1 (MAP1) dissociated from the cytoskeleton, consistent with the diminished ability of these cytoskeleton-binding proteins to bind microtubules. Increases in free tubulin and actin were also noted, indicative of cytoskeleton remodeling and destabilization. In vivo magnetic resonance imaging of the transgenic animals showed a reduction in brain volume of transgenic mice, indicating substantial atrophy. From immunohistochemical studies, α-synuclein, p-Tau and p-GSK-3β were found to be overexpressed and co-localized in large inclusion bodies, reminiscent of Lewy bodies. The elevated state of tauopathy seen in these platelet-derived growth factor-α-synuclein mice provides further confirmation that PD may be a tauopathic disease.

Tauopathic pathways lead to degenerative changes in Alzheimer's disease and there is evidence that they are also involved in the neurodegenerative pathology of Parkinson's disease [PD]. We have examined tauopathic changes in striatum of the α-synuclein (α-Syn) A53T mutant mouse. Elevated levels of α-Syn were observed in striatum of the adult A53T α-Syn mice. This was accompanied by increases in hyperphosphorylated Tau [p-Tau], phosphorylated at Ser202, Ser262 and Ser396/404, which are the same toxic sites also seen in Alzheimer's disease. There was an increase in active p-GSK-3β, hyperphosphorylated at Tyr216, a major and primary kinase known to phosphorylate Tau at multiple sites. The sites of hyperphosphorylation of Tau in the A53T mutant mice were similar to those seen in post-mortem striata from PD patients, attesting to their pathophysiological relevance. Increases in p-Tau were not due to alterations on protein phosphatases in either A53T mice or in human PD, suggesting lack of involvement of these proteins in tauopathy. Extraction of striata with Triton X-100 showed large increases in oligomeric forms of α-Syn suggesting that α-Syn had formed aggregates the mutant mice. In addition, increased levels of p-GSK-3β and pSer396/404 were also found associated with aggregated α-Syn. Differential solubilization to measure protein binding to cytoskeletal proteins demonstrated that p-Tau in the A53T mutant mouse were unbound to cytoskeletal proteins, consistent with dissociation of p-Tau from the microtubules upon hyperphosphorylation. Interestingly, α-Syn remained tightly bound to the cytoskeleton, while p-GSK-3β was seen in the cytoskeleton-free fractions. Immunohistochemical studies showed that α-Syn, pSer396/404 Tau and p-GSK-3β co-localized with one another and was aggregated and accumulated into large inclusion bodies, leading to cell death of Substantia nigral neurons. Together, these data demonstrate an elevated state of tauopathy in striata of the A53T α-Syn mutant mice, suggesting that tauopathy is a common feature of synucleinopathies.

Parkinson's disease (PD), a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein (alpha-Syn) in dopaminergic neurons. Here we examined tauopathic changes and the alpha-Syn/p-GSK-3beta/proteasome pathway in postmortem striata and inferior frontal gyri (IFG) from patients with PD and PD with dementia (PDD). In both PD and PDD, alpha-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble alpha-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3beta phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of alpha-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3beta in IFG. Unlike Alzheimer's disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.

e17716 Background: 30-day readmission has been shown to be an indicator of poor quality of care. However, it is largely unknown if readmission amongst cancer patients actively receiving treatment i...

Purpose: The diversion of ambulances away from their intended emergency departments (EDs) in the United States has become commonplace and may compromise patient care. Although ambulance diversion resulting from ED overcrowding has been well described in the literature, little is known about how to reduce the incidence of ambulance diversion on a regional level. We describe the development, implementation, and impact of a region-wide program to reduce ambulance diversion. Basic Procedures: This study was undertaken in the greater Sacramento, California region from January 2001 to December 2003. This comprehensive ambulance diversion reduction program was implemented May 15, 2002, with analysis of data for this 3-year time frame. The data for this study were obtained from 17 hospitals with ambulance diversion hours being the main outcome measure for this study. Findings: The greater Sacramento region had 23785 hours of ambulance diversion in 2001. In 2003, there were 7143 ambulance diversion hours. Comparing the 17-month period before implementation of this program with the 19-month period after implementation, the difference in the means of these two groups was 1428 hours per month (95% confidence interval, 1252 to 1597), a 74% decrease in ambulance diversion hours. Notably, this reduction occurred despite overall increases in ED census (6.5%), hospital admissions from the ED (8.8%), EMS arrivals to the ED (17.1%), inpatient hospital census (7.4%), and overall Sacramento population (5.7%). Conclusions: Our results demonstrate a sizeable reduction of ambulance diversion in a large urban region after the successful implementation of a comprehensive ambulance diversion reduction program. The description of this effort may serve as a model for other regions across the country that do not have an organized approach in place for ambulance diversion, although boarding of admitted patients will still be a major hurdle to effective reduction of ambulance diversion.

A chemical stability study on the oxazolidine linker system has been carried out using a dual-linker analytical construct within a parallel reaction scan. The study established the compatibility of the oxazolidine platform with a wide range of commonly employed synthetic reaction conditions including nucleophilic, oxidizing, and reducing conditions. The scan was further used to probe and optimize acidic conditions under which the oxazolidine could release the substrate from the solid-support and to identify reagents that could cleave while retaining other acid-labile groups. The solid-phase synthesis of a small molecular array established the utility of oxazolidine aldehyde 1 as a building block for asymmetric chemistry while exploiting the data generated by the reaction scan.

The linker connecting the solid support and the substrate is critical to the ultimate success of a solid-phase synthesis. The evolution of linker constructs continues, offering new approaches to the analysis, release and deconvolution of resin-bound material and allowing entry to new structural motifs.

ObjectiveMost neurodegenerative diseases contain hyperphosphorylated Tau [p-Tau]. We examined for the first time epitopes at which Tau is hyperphosphorylated in Parkinson’s disease, dementia with Lewy bodies and Alzheimer’s disease, and also select Tau kinases. MethodsPostmortem frontal cortex from Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease and striata from Parkinson’s disease, were analyzed by immunoblots using commercially available antibodies against 20 different phospho-epitopes of Tau. Major Tau kinases were also screened. Results in diseased tissues were compared to nondiseased controls. ResultsIn Alzheimer’s disease, Tau was hyperphosphorylated at all the 20 epitopes of p-Tau. In dementia with Lewy bodies, p-Tau formation occurred at 6 sites sharing 30% overlap with Alzheimer’s disease, while in Parkinson’s frontal cortex, an area which does not degenerate, Tau hyperphosphorylation was seen at just 3 epitopes, indicating 15% overlap with Alzheimer’s disease. In Parkinson’s disease striatum, an area which undergoes considerable neurodegeneration, Tau was hyperphosphorylated at 10 epitopes, sharing 50% overlap with Alzheimer’s disease. Between frontal cortex of Parkinson’s disease and dementia with Lewy bodies, there were only two p-Tau epitopes in common. In striata of Parkinson’s disease, there were 3 clusters of Tau hyperphosphorylated at 3 contiguous sites, while two such clusters were detected in dementia with Lewy bodies; such clusters disrupt axonal transport of mitochondria, cause microtubule remodeling and result in cell death. p-GSK-3β, a major Tau kinase, was activated in all brain regions examined, except in dementia with Lewy bodies. Activation of other Tau kinases was seen in all brain regions, with no clear pattern of activation. InterpretationOur studies suggest that the three neurodegenerative diseases each have a signature-specific profile of p-Tau formation which may be useful in understanding the genesis of the diseases and for the development of a panel of specific biomarkers.

SNCA and MAPT genes and environmental factors are important risk factors of Parkinson's disease [PD], the second-most common neurodegenerative disease. The agrichemicals maneb and paraquat selectively target dopaminergic neurons, leading to parkinsonism, through ill-defined mechanisms. In the current studies we have analyzed the ability of maneb and paraquat, separately and together, to induce synucleinopathy and tauopathy in wild type mice. Maneb was ineffective in increasing α-synuclein [α-Syn] or p-Tau levels. By contrast, paraquat treatment of mice resulted in robust accumulation of α-Syn and hyperphosphorylation of Tau in striata, through activation of p-GSK-3β, a major Tau kinase. Co-treatment with maneb did not enhance the effects of paraquat. Increased hyperacetylation of α-tubulin was observed in paraquat-treated mice, suggesting cytoskeleton remodeling. Paraquat, but not maneb, inhibited soluble proteasomal activity on a peptide substrate but this was not associated with a decreased expression of 26S proteasome subunits. Both paraquat and maneb treatments increased levels of the autophagy inhibitor, mammalian target of rapamycin, mTOR, suggesting impaired axonal autophagy, despite increases in certain autophagic proteins, such as beclin 1 and Agt12. Autophagic flux was also impaired, as ratios of LC3 II to LC3 I were reduced in treated animals. Increased mTOR was also observed in postmortem human PD striata, where there was a reduction in the LC3 II to LC3 I ratio. Heat shock proteins were either increased or unchanged upon paraquat-treatment suggesting that chaperone-mediated autophagy is not hampered by the agrichemicals. These studies provide novel insight into the mechanisms of action of these agrichemicals, which indicate that paraquat is much more toxic than maneb, via its inhibitory effects on proteasomes and autophagy, which lead to accumulation of α-Syn and p-Tau.

Background: The development of chemotherapy-induced thrombocytopenia (CIT) in the setting of therapeutic anticoagulation for venous thromboembolic (VTE) disease is a common problem in cancer patients. The current approach to low molecular weight heparin (LMWH) dosing in the setting of CIT (Lee, AYY. J. Clin. Onc. 2009) is empirical and based on limited published experience. This approach was never validated prospectively. Since 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented a similar guideline: administer full dose LMWH for a platelet count >50,000/mcL, half dose for a platelet count 25,000/mcL to 50,000/mcL and hold LMWH temporarily for a platelet count Materials and Methods: In a Quality Assessment project, we evaluated cancer patients at MSKCC who were on a therapeutic dose of enoxaparin for a VTE during the years 2011 through 2013, who experienced at least one period of thrombocytopenia (platelet count ≤50,000/mcL) for at least 7 days. We assessed for adherence to the LMWH dose modification guidelines reflected by dose reduction and/or temporary hold for existing or anticipated thrombocytopenia. In addition, major bleeding, clinically relevant non-major bleeding, recurrent VTE events, and death were recorded during the episodes of thrombocytopenia. Results: We identified 101 patients with 144 episodes of thrombocytopenia, with an average duration of 21.3 days per episode. The LMWH dose was modified in 137 of the 144 episodes (95%), reflecting adherence to our institutional guidelines. The LMWH doses were reduced in 20 episodes, held in 90 episodes, and managed with combination of reduction/hold in 27 episodes. In general, the more severe thrombocytopenic episodes were managed with holding LMWH as opposed to dose reduction. The unweighted mean platelet count during episodes managed with holding LMWH was 27,000/mcL with a standard deviation (STD) of 16,000, while the mean platelet count during episodes of dose reduction was 36,000/mcL with a STD of 15,000. There were no recurrent VTE events or major bleeding episodes when the LMWH was reduced or held. In our cohort, there was only one major bleeding episode, a trauma-associated retroperitoneal hemorrhage, which occurred on the third day of a thrombocytopenic episode, prior to enoxaparin dose modification. That patient's platelet count was 28,000/mcL at the time of the event. There were 14 clinically relevant non-major bleeding episodes, of which 7 cases consisted of ecchymosis, epistaxis or gingival bleeding. Lastly, 10 patients died during the episode of thrombocytopenia. Discussion: This Quality Assessment project supports the safety and efficacy of our guidelines for therapeutic LMWH dose modification in the setting of CIT. In contrast to past case series, these patients were managed under direction of an institutional dosing guideline. We observed a 95% level of compliance with the guidelines. These data support the conclusion that the current LMWH dose reduction approach provides safety and efficacy, balancing the risks of recurrent thrombosis and bleeding during periods of CIT in cancer patients. It remains to be determined if a similar strategy would be appropriate for the new generation of oral anticoagulants. Disclosures No relevant conflicts of interest to declare.