Cardiac Recurrence in a Patient with Long-Term Survival from Metastatic Colon Cancer

Metastatic colorectal cancer represents a major health problem in the US and worldwide. Forty percent of patients undergoing resection of the primary tumor will experience relapse. In this brief review, we describe a case of a woman with metastatic disease and long-term survival culminating with an unusual myocardial recurrence. Over three decades, a multimodality approach has evolved to allow for long-term survival in selected patients with metastatic colorectal cancer. In this case report, the role of multiple aggressive surgical resections is emphasized

Web-Based Educational Seminars Compare Favorably with In-House Seminars for Bariatric Surgery Patients

Background Comprehensive preparative patient education is a key element in bariatric patient success. The primary objective of this study was to compare attrition rates, demographics, and surgery outcomes between patients who participated in the online vs in-house preparative seminars. Methods A retrospective chart review was performed involving patients who chose to participate in online vs in-house educational seminar between July of 2014 and December of 2016. The patients were divided into two groups based on their choice of educational seminar and tracked to see how many made it to an initial visit and to surgery. In those who had bariatric surgery, data was collected on age, type of insurance, length of stay (LOS), longest follow-up, and change in body mass index. Results Total of 1230 patients were included in this study. There was no difference in attrition rate to initial consultation visit (29.1% vs 29.9%), but there was a statistically higher attrition to surgery in the in-house seminar attendees (72.9%) compared to online participants (66.6%, p < 0.05). Between January 2015 and December 2016, 291 patients underwent primary bariatric surgery. The online group was on average 3 years younger which was statistically significant. There were no differences in LOS, longest follow-up, and weight loss at 12 months between the groups. Conclusion When comparing attrition rates and bariatric surgery outcomes, no overall difference was noted between patients who received web- or hospital-based preparative education. Bariatric programs should provide access to online seminars to attract younger population and save resources and cost

A behavioral rating system predicts weight loss and quality of life after bariatric surgery

Background Bariatric surgery represents the most effective intervention for severe obesity available today; however, significant variability in postoperative outcomes exists. Effective tools that predict postoperative outcomes are needed for decision-making and patient counseling. Objectives We hypothesized that a validated behavioral assessment tool, the Cleveland Clinic Behavioral Rating Scale (CCBRS), would predict excess weight loss, health-related quality of life, depression, anxiety, and alcohol use after bariatric surgery. Setting Hospital in the United States. Methods A prospective observational study with 2-year planned follow-up was conducted with patients who completed a psychological clinical interview, the Short Form 36 (SF-36) v.2 Health Survey and brief self-report questionnaires measuring depression (PHQ-9), anxiety (GAD-7), and alcohol use (AUDIT) preoperatively. At the conclusion of the preoperative psychological evaluation, the psychologist completed the CCBRS. All questionnaires were readministered at 6, 12, 18, and 24 months after surgery. Generalized estimating equations were used to assess whether any CCBRS ratings predicted surgery outcomes. Results One hundred seventy-nine patients (113 Roux-en-Y gastric bypass and 66 sleeve gastrectomy) were included in the analyses. SF-36 scores, PHQ-9 scores, and the AUDIT total scores improved significantly after surgery, while GAD-7 scores did not change appreciably. Higher preoperative CCBRS ratings predicted higher SF-36 scores, and lower PHQ-9, GAD-7 and AUDIT scores. The CCBRS social support rating predicted higher postoperative percent excess weight loss. Conclusion A behavioral rating scale (CCBRS) completed before bariatric surgery predicted postoperative weight loss, quality of life, depression, and anxiety. Therefore, this tool may prove useful in patient counseling and expectation management before surgery

Development of ASMBS Research Agenda for Bariatric Surgery Using the Delphi Methodology

Background While the number of research publications related to bariatric surgery have increased remarkably in the past decade, research efforts remain uncoordinated and have limited focus, and numerous important questions remain unanswered. Objective To generate a research agenda in bariatric surgery. Setting National survey. Methods The membership of the American Society of Metabolic and Bariatric Surgery (ASMBS) was asked to submit research questions needed to advance the field of bariatric surgery. An expert panel grouped and collated submitted questions and redistributed them back to the membership to rate their importance on a 5-point Likert scale using a 3-round modified Delphi methodology. The top research questions were determined based on provided rankings. Results Two hundred ninety-two research questions were initially submitted that were collapsed to 59 unique questions. The ratings for the top 40 questions ranged from 2.67–4.33 (overall mean, 3.46). The highest-ranked questions centered on the mechanisms of effectiveness of bariatric surgery for weight loss and diabetes resolution, the underlying etiology of weight recidivism, and predictors of success. Conclusions A research agenda for bariatric surgery was developed using the Delphi methodology. This research agenda may enhance the ability of investigators and funding organizations, including the ASMBS, to focus attention to areas most likely to advance the field, and by editors and reviewers to assess the merit and relevance of scientific contributions

What delays your case start? Exploring operating room inefficiencies

Introduction Improving operating room (OR) inefficiencies benefits the OR team, hospital, and patients alike but the available literature is limited. Our goal was, using a novel surgical application, to identify any OR incidents that cause delays from the time the patient enters the OR till procedure start (preparatory phase). Materials and methods We conducted an IRB approved, prospective, observational study between July 2018 and January 2019. Using a novel surgical application (ExplORer Surgical) three observers recorded disrupting incidents and their duration during the preparatory phase of a variety of general surgery cases. Specifically, the number and duration of anesthesia delays, unnecessary/distracting conversations, missing items, and other delays were recorded from the moment they started until they stopped affecting the normal workflow. Results Ninety-six OR cases were assessed. 20 incidents occurred in 18 (19%) of those cases. The average preparatory duration for all the cases was 20.7 ± 8.6 min. Cases without incidents lasted 19.5 ± 7.4 min while cases with incidents lasted 25.9 ± 11.2 min, p = 0.03. The average incident lasted 3.7 min, approximately 18% of the preparatory phase duration. Conclusion The use of the ExplORer Surgical app allowed us to accurately record the incidents happening during the preparatory phase of various general surgery operations. Such incidents significantly prolonged the preparatory duration. The identification of those inefficiencies is the first step to targeted interventions that may eventually optimize the efficiency of preoperative preparation

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / +, KINSSHIP/KINSSHIP, LoF/ +, LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.</p

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / +, KINSSHIP/KINSSHIP, LoF/ +, LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements