Update on Venous Thromboembolism in Orthopaedic Trauma Surgery.

Venous thromboembolism (VTE) is a notable contributor to the morbidity and mortality of patients with orthopaedic trauma. Several associations have published guidelines on VTE prophylaxis, with a strong predilection toward low-molecular-weight heparin for chemoprophylaxis. However, previous recommendations may be revisited because recent high-level evidence demonstrated aspirin to be noninferior to low-molecular-weight heparin in preventing serious complications of VTE.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors.

Venous thromboembolism (VTE) associated with cancer (CAT) is a well-described complication of cancer and a leading cause of death in patients with cancer. 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 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform to identify somatic alterations associated with VTE.

Rivaroxaban treatment of cancer-associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience.

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).

Using the American Thyroid Association Risk-Stratification System to Refine and Individualize the American Joint Committee on Cancer Eighth Edition Disease-Specific Survival Estimates in Differentiated Thyroid Cancer.

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 (<55 years of age at diagnosis, stage I or stage II). This reclassification widens the spectrum of disease in these lower stages without significantly impacting overall disease-specific survival (DSS) for the entire stage group. However, the optimistic DSS estimates in the <55-year-old stage groups may not accurately reflect the prognosis of individual patients with American Thyroid Association (ATA) high-risk features.

Antidepressants appear safe in patients with carcinoid tumor: Results of a retrospective review.

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.

The Tri-Institutional Pain Registry-Analysis of Outpatient Pain Management at a Specialized Cancer Center.

Objectives: The Outpatient Pain Clinics at Memorial Sloan Kettering Cancer Center participated in developing a pain registry to gain insight on the referral and management of cancer pain as related to demographic information, cancer history, prescription records, and interventional pain procedures stored in the institutional database.

Methods: Five cohorts (subsets of one another) were defined and compared to describe demographics and differences in management and outcomes by age, race, sex, and cancer type. Clinic patients were compared with the entire institution to determine factors associated with better pain relief and reduced side effects.

Rivaroxaban for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation and Active Cancer.

Rivaroxaban is broadly used for the primary prevention of stroke and systemic embolism in the general population with nonvalvular atrial fibrillation (AF). However, there is little published evidence on the safety and efficacy of rivaroxaban for AF in patients with active cancer. The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and AF.

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

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.

F-FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer.

Objectives: This study assesses F-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.

Methods: 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 F-FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.

Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study.

The development of thrombocytopenia in the setting of therapeutic anticoagulation for venous thromboembolic disease (VTE) is common in cancer patients, but guidelines for management are based on limited past data and have not been validated. In 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented the following guidelines in this setting: administer full dose enoxaparin for a platelet count > 50,000/mcL, half-dose enoxaparin for a platelet count of 25,000-50,000/mcL, and hold anticoagulation for a platelet count < 25,000/mcL. We now report validation of safety and efficacy of these guidelines.

Acute liver effects, disposition and metabolic fate of [C]-fenclozic acid following oral administration to normal and bile-cannulated male C57BL/6J mice.

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 [C]-fenclozic acid showed acute centrilobular hepatocellular necrosis, but no other regions of the liver were affected.

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study.

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.

High rate of thiamine deficiency among inpatients with cancer referred for psychiatric consultation: results of a single site prevalence study.

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.

(18)F-FDG-PET/CT for systemic staging of newly diagnosed triple-negative breast cancer.

Purpose: 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.

Automated eligibility screening and monitoring for genotype-driven precision oncology trials.

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.

α-Synuclein-mediated inhibition of ATF6 processing into COPII vesicles disrupts UPR signaling in Parkinson's disease.

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.

The metabolic fate of [14C]-fenclozic acid in the hepatic reductase null (HRN) mouse.

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.

Identification of the sites of tau hyperphosphorylation and activation of tau kinases in synucleinopathies and Alzheimer's diseases.

Objective: Most 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.

Methods: Postmortem 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.

Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways.

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.

Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson's disease.

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.

Tauopathic changes in the striatum of A53T α-synuclein mutant mouse model of Parkinson's 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.

Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia.

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.