What's the best VTE treatment for patients with cancer?

Q: What's the best VTE treatment for patients with cancer? Evidence-based answer: No. Head-to-head studies directly compare all the main treatments for venous thromboembolism (VTE) in cancer patients. Long-term treatment (3-12 months) with low-molecular-weight heparin (LMWH) reduces recurrence of VTE by 40% compared with vitamin K antagonists (VKA), but doesn't change rates of mortality, major or minor bleeding, or intracranial hemorrhage in patients with solid or hematologic cancer at any stage or in any age group. Initial treatment with LMWH reduces mortality by 30% compared with unfractionated heparin (UFH) for 5 to 10 days followed by warfarin, but doesn't alter recurrent VTE or bleeding. Non-vitamin K oral anticoagulants (NOACs) have risks of recurrent VTE or VTE-related death (composite outcome) and clinically significant bleeding comparable to VKA or LMWH/VKA (strength of recommendation [SOR]: B, meta-analyses of randomized controlled trials [RCTs], mostly of low quality).Thuy Pham, DO; Hannah Sundquist, PharmD; Gary Kelsberg, MD, Valley Family Medicine Residency, University of Washington at Valley Medical Center, Renton ; Sarah Safranek, MLIS, University of Washington Health Sciences Library, Seattle

Non-pharmacological Interventions for Alcohol, Marijuana, and Opioid Use During Pregnancy: A Systematic Review

The purpose of this review is to analyze evidence on prevalence of opioid, alcohol and marijuana use during pregnancy and answer the PICOT question: In pregnant women addicted to or using marijuana, opioids, and alcohol, how do non-pharmacological interventions, compared to standard care of pharmacological interventions alone, affect health outcomes in mothers and neonates between birth to hospital discharge? Diagnosis of substance use disorder is increasing and with it comes increased risk of complications to mother and neonate including neonatal abstinence syndrome (NAS), fetal alcohol syndrome (FAS) and other negative neonatal and maternal outcomes. Evidence was identified on the online databases, PubMed and CINAHL. Twenty studies from 2013-2018 were reviewed. Interventions included specialized comprehensive care, individual care, motivational interviewing (MI), and brief intervention. There was limited research about the topic, indicating a need for more research to find the most effective non-pharmacological interventions for these populations

Multicentre cohort study to define and validate pathological assessment of response to neoadjuvant therapy in oesophagogastric adenocarcinoma

BACKGROUND: This multicentre cohort study sought to define a robust pathological indicator of clinically meaningful response to neoadjuvant chemotherapy in oesophageal adenocarcinoma. METHODS: A questionnaire was distributed to 11 UK upper gastrointestinal cancer centres to determine the use of assessment of response to neoadjuvant chemotherapy. Records of consecutive patients undergoing oesophagogastric resection at seven centres between January 2000 and December 2013 were reviewed. Pathological response to neoadjuvant chemotherapy was assessed using the Mandard Tumour Regression Grade (TRG) and lymph node downstaging. RESULTS: TRG (8 of 11 centres) was the most widely used system to assess response to neoadjuvant chemotherapy, but there was discordance on how it was used in practice. Of 1392 patients, 1293 had TRG assessment; data were available for clinical and pathological nodal status (cN and pN) in 981 patients, and TRG, cN and pN in 885. There was a significant difference in survival between responders (TRG 1–2; median overall survival (OS) not reached) and non-responders (TRG 3–5; median OS 2·22 (95 per cent c.i. 1·94 to 2·51) years; P < 0·001); the hazard ratio was 2·46 (95 per cent c.i. 1·22 to 4·95; P = 0·012). Among local non-responders, the presence of lymph node downstaging was associated with significantly improved OS compared with that of patients without lymph node downstaging (median OS not reached versus 1·92 (1·68 to 2·16) years; P < 0·001). CONCLUSION: A clinically meaningful local response to neoadjuvant chemotherapy was restricted to the small minority of patients (14·8 per cent) with TRG 1–2. Among local non-responders, a subset of patients (21·3 per cent) derived benefit from neoadjuvant chemotherapy by lymph node downstaging and their survival mirrored that of local responders

The transcriptional landscape of endogenous retroelements delineates esophageal adenocarcinoma subtypes

Most cancer types exhibit aberrant transcriptional activity, including derepression of retrotransposable elements (RTEs). However, the degree, specificity and potential consequences of RTE transcriptional activation may differ substantially among cancer types and subtypes. Representing one extreme of the spectrum, we characterize the transcriptional activity of RTEs in cohorts of esophageal adenocarcinoma (EAC) and its precursor Barrett's esophagus (BE) from the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) consortium, and from TCGA (The Cancer Genome Atlas). We found exceptionally high RTE inclusion in the EAC transcriptome, driven primarily by transcription of genes incorporating intronic or adjacent RTEs, rather than by autonomous RTE transcription. Nevertheless, numerous chimeric transcripts straddling RTEs and genes, and transcripts from stand-alone RTEs, particularly KLF5- and SOX9-controlled HERVH proviruses, were overexpressed specifically in EAC. Notably, incomplete mRNA splicing and EAC-characteristic intronic RTE inclusion was mirrored by relative loss of the respective fully-spliced, functional mRNA isoforms, consistent with compromised cellular fitness. Defective RNA splicing was linked with strong transcriptional activation of a HERVH provirus on Chr Xp22.32 and defined EAC subtypes with distinct molecular features and prognosis. Our study defines distinguishable RTE transcriptional profiles of EAC, reflecting distinct underlying processes and prognosis, thus providing a framework for targeted studies.</p

Disentangling oncogenic amplicons in esophageal adenocarcinoma

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma