In GA patients who recur after resection, patterns of recurrence vary significantly based on Lauren histologic type.

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with COVID-19. Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. The electronic health record (EHR) of a New Orleans–based health system was searched for all patients with polymerase chain reaction–confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between 1 March 2020 and 1 May 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.: Between 1 March 2020 and 1 May 2020, 6153 patients with COVID-19 were identified; 2748 of these patients were admitted, while 3405 received care exclusively through the emergency department. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2075 admitted who were discharged alive (0.14%). Among 6153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19.

Lauren diffuse-type gastric adenocarcinomas (DGAs) are generally genomically stable. We identified lysine (K)-specific methyltransferase 2C () as a frequently mutated gene and examined its role in DGA progression. We performed whole exome sequencing on tumor samples of 27 patients with DGA who underwent gastrectomy. Lysine (K)-specific methyltransferase 2C () was analyzed in DGA cell lines and in patient tumors. was the most frequently mutated gene (11 of 27 tumors [41%]). KMT2C expression by immunohistochemistry in tumors from 135 patients with DGA undergoing gastrectomy inversely correlated with more advanced tumor stage ( = 0.023) and worse overall survival ( = 0.017). KMT2C shRNA knockdown in non-transformed HFE-145 gastric epithelial cells promoted epithelial-to-mesenchymal transition (EMT) as demonstrated by increased expression of EMT-related proteins N-cadherin and Slug. Migration and invasion in gastric epithelial cells following KMT2C knockdown increased by 47- to 88-fold. In the DGA cell lines MKN-45 and SNU-668, which have lost KMT2C expression, KMT2C re-expression decreased expression of EMT-related proteins, reduced cell migration by 52% to 60%, and reduced cell invasion by 50% to 74%. Flank xenografts derived from KMT2C-expressing DGA organoids, compared with wild-type organoids, grew more slowly and lost their infiltrative leading edge. EMT can lead to the acquisition of cancer stem cell (CSC) phenotypes. KMT2C re-expression in DGA cell lines reduced spheroid formation by 77% to 78% and reversed CSC resistance to chemotherapy via promotion of DNA damage and apoptosis. is frequently mutated in certain populations with DGA. KMT2C loss in DGA promotes EMT and is associated with worse overall survival.

Rac1, a Rho GTPase family member, is dysregulated in a variety of tumor types including gastric adenocarcinoma (GA), but little is known about its role in cancer stem-like cells (CSCs). Therefore, Rac1 activity and inhibition were examined in GA cells and mouse xenograft models for epithelial-to-mesenchymal transition (EMT) and CSC phenotypes. Rac1 activity was significantly higher in spheroid-forming or CD44(+) GA CSCs compared to unselected cells. Rac1 inhibition using Rac1 shRNA or a Rac1 inhibitor (NSC23766) decreased expression of the self-renewal transcription factor, Sox-2, decreased spheroid formation by 78–81%, and prevented tumor initiation in immunodeficient mice. GA CSCs had increased expression of the EMT transcription factor Slug, 4.4–8.3 fold greater migration, and 4.2–12.6 fold greater invasion than unselected cells, and these increases could be blocked completely with Rac1 inhibition. GA spheroid cells were resistant to 5-fluorouracil and cisplatin chemotherapy, and this chemotherapy resistance could be reversed with Rac1 shRNA or NSC23766. The PI3K/Akt pathway may be upstream of Rac1, and JNK may be downstream of Rac1. In the MKN-45 xenograft model, cisplatin inhibited tumor growth by 50%, Rac1 inhibition by 35%, and the combination by 77%. Higher Rac1 activity, in clinical specimens from GA patients who underwent potentially curative surgery, correlated with significantly worse survival (p=0.017). In conclusion, Rac1 promotes the EMT program in GA and the acquisition of a CSC state. Rac1 inhibition in GA cells blocks EMT and CSC phenotypes, and thus may prevent metastasis and augment chemotherapy.

Noninvasive and longitudinal monitoring of tumor oxygenation status using quantitative diffuse reflectance spectroscopy is used to test whether a final treatment outcome could be estimated from early optical signatures in a murine model of head and neck cancer when treated with radiation. Implanted tumors in the flank of 23 nude mice are exposed to 39 Gy of radiation, while 11 animals exposed to sham irradiation serve as controls. Diffuse optical reflectance is measured from the tumors at baseline (prior to irradiation) and then serially until 17 days posttreatment. The fastest and greatest increase in baseline-corrected blood oxygen saturation levels are observed from the animals that show complete tumor regression with no recurrence 90 days postirradiation, relative to both untreated and treated animals with local recurrences. These increases in saturation are observed starting 5 days posttreatment and last up to 17 days posttreatment. This preclinical study demonstrates that diffuse reflectance spectroscopy could provide a practical method far more effective than the growth delay assay to prognosticate treatment outcome in solid tumors and may hold significant translational promise.

Purpose The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. Experimental design In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models. Candidate genes were characterized in 19 human PDAC cell lines, heterotopic xenograft tumor models, and a genetically engineered mouse (GEM) model of PDAC. Gene expression, immunohistochemistry, and immunoprecipitation experiments were performed to analyze the pathways by which candidate genes contribute to PDAC. Results In vivo shRNA screens identified BRD2 and BRD3, members of the BET family of chromatin adaptors, as key regulators of PDAC tumor growth. Pharmacological inhibition of BET bromodomains enhanced survival in a PDAC GEM model and inhibited growth of human-derived xenograft tumors. BET proteins contribute to PDAC cell growth through direct interaction with members of the GLI family of transcription factors and modulating their activity. Within cancer cells, BET bromodomain inhibition results in down-regulation of SHH, a key mediator of the tumor microenvironment and canonical activator of GLI. Consistent with this, inhibition of BET bromodomains decreases cancer associated fibroblast content of tumors in both GEM and xenograft tumor models. Conclusions Therapeutic inhibition of BET proteins offers a novel mechanism to target both the neoplastic and stromal components of PDAC. Translational Relevance Pancreatic ductal adenocarcinoma is extraordinarily chemoresistant and the abundant stromal content of these tumors contributes to the ineffective treatment of this disease. Current approaches in the treatment of PDAC are largely ineffective and utilize drugs that target either the neoplastic cells or the stroma of this disease. This study reveals the broad dependence of pancreatic cancer cell lines and tumor models on the activity of the BET family of chromatin adaptors. BET proteins contribute to PDAC biology by regulating multiple key nodal pathways of this disease, including the direct and indirect regulation of GLI, a family of transcription factors that plays key roles in both epithelial and stromal cells of PDAC tumors. Therapeutic inhibition of BET proteins provides a unique opportunity to simultaneously target both the stromal and neoplastic cells of PDAC.

Steady-state diffuse reflection spectroscopy is a well-studied optical technique that can provide a noninvasive and quantitative method for characterizing the absorption and scattering properties of biological tissues. Here, we compare three fiber-based diffuse reflection spectroscopy systems that were assembled to create a light-weight, portable, and robust optical spectrometer that could be easily translated for repeated and reliable use in mobile settings. The three systems were built using a broadband light source and a compact, commercially available spectrograph. We tested two different light sources and two spectrographs (manufactured by two different vendors). The assembled systems were characterized by their signal-to-noise ratios, the source-intensity drifts, and detector linearity. We quantified the performance of these instruments in extracting optical properties from diffuse reflectance spectra in tissue-mimicking liquid phantoms with wellcontrolled optical absorption and scattering coefficients. We show that all assembled systems were able to extract the optical absorption and scattering properties with errors less than 10%, while providing greater than ten-fold decrease in footprint and cost (relative to a previously wellcharacterized and widely used commercial system). Finally, we demonstrate the use of these small systems to measure optical biomarkers in vivo in a small-animal model cancer therapy study. We show that optical measurements from the simple portable system provide estimates of tumor oxygen saturation similar to those detected using the commercial system in murine tumor models of head and neck cancer.

Purpose-We previously reported on the feasibility of a Web-based system to capture patientreported outcomes (PROs) in the immediate postoperative period. The purpose of this study was to update the experience of these patients and assess patient and provider satisfaction and feedback regarding the system.Methods-This is a prospective cohort study of patients scheduled to undergo laparotomy for presumed gynecologic malignancy. Patients completed a Web-based Symptom Tracking and Reporting (STAR) questionnaire preoperatively and weekly during a 6-week postoperative period. Email alerts were sent to study nurses when concerning patient responses were entered. The patient and the nurse assessments of STAR's usefulness were measured via an exit survey.Corresponding Author: Dennis S. Chi, MD, Attending, Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Professor of Surgery, Weill Cornell Medical College, 1275 York Ave, New York, NY 10065, USA, Phone: +1 212-639-5016, Fax: +1 212-717-3095, chid@mskcc.org. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptResults-The study enrolled 96 eligible patients. Of these, 71 patients (74%) completed at least four of seven total sessions. Of the patients who completed the exit satisfaction survey, 98% found STAR easy to use; 84% found it useful; and 82% would recommend it to other patients. Despite positive feedback from patients, clinical personnel found that the STAR system increased their current workload without enhancing patient care.Conclusions-Application of an electronic program for PROs in those recovering from major gynecologic cancer surgery is feasible, and acceptable to most patients. While most clinicians did not find STAR clinically helpful, the majority of patients reported a positive experience with the system and would recommend its use. The program helped many patients feel more empowered in their postoperative recovery.