Citations

AbstractThe acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS‐like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high‐resolution, isoform‐specific context, we conducted genome‐wide chromatin‐immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial–mesenchymal transition (EMT)‐related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3‐induced migration and invasion. Assessing TBX3 by immunohistochemistry in early‐stage (stage 0 and stage I) breast cancers revealed high expression in low‐grade lesions. Within a second independent early‐stage non‐high‐grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early‐stage pre‐invasive breast cancer to invasive carcinoma through the low‐grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

End of life is difficult for all patients but sexual and gender minorities (SGM) are prone to isolation and loneliness, especially if their SGM status is unknown or unaccepted. In oncology clinics, where goals of care discussions about end of life are integral and frequent, querying patients about their SGM status and sexual health is of particular importance. The American Society of Clinical Oncology recently released a position statement that called for greater focus on SGM populations with the goal of reducing and eventually eliminating disparities in cancer care within this group. An important first step in addressing such disparities is learning how best to train cancer health-care providers to ask patients about their SGM status and about sexual health in general. This article summarizes the mandate for understanding cancer issues in SGM populations and the dearth of cancer-related data within this group. This article also describes an ongoing 3-part study intended to build a mini curriculum with the goal of helping cancer health-care providers to ask patients with cancer about SGM status and to ask all patients with cancer about sexual health issues. The results of this ongoing study could potentially improve end-of-life care for subgroups of patients.

Purpose of review The use of extracorporeal membrane oxygenation (ECMO) is increasing rapidly. Patients on ECMO have a high risk of developing acute kidney injury (AKI) and needing renal replacement therapy (RRT). The aim of this review is to describe different strategies of combining RRT and ECMO and to outline their advantages and drawbacks. Recent findings Fluid overload is the most common indication for RRT during ECMO, and continuous renal replacement therapy (CRRT) is the most commonly used modality. The optimal timing for initiation of CRRT should be individualized based on degree of fluid overload and severity of AKI-related metabolic derangements. In ECMO patients, CRRT can be provided via an integrated approach (i.e. in-line haemofilter or a fully integrated CRRT device) or a parallel system with separate ECMO and RRT circuits. In-depth knowledge of the resulting intra-circuit pressure changes, risks of air entrapment and haemolysis, and implications for ultrafiltration and solute clearance are essential. There is no evidence that the different methods of combining ECMO and CRRT impact mortality. Summary In patients on ECMO, CRRT can be provided via an integrated approach or independently via parallel systems. An in-depth understanding of the advantages and drawbacks of the different techniques is required.

Aims To perform a systematic review of studies reporting the outcomes of AMS‐800 artificial urinary sphincter (AUS) implantation in female patients with stress urinary incontinence (SUI) resulting from intrinsic sphincter deficiency (ISD). Methods A systematic literature search of the Medline and Embase databases was performed in June 2018 in accordance with the PRISMA statement. No time limit was used. The protocol was registered in PROSPERO (CRD42018099612). Study selection and data extraction were performed by two independent reviewers. Results Of 886 records screened, 17 were included. All were retrospective or prospective non‐comparative case series. One study reported on vaginal AUS implantation, 11 on open AUS implantation, two on laparoscopic AUS implantation, two on robot‐assisted AUS implantation and one compared open and robot‐assisted implantations. The vast majority of patients had undergone at least one anti‐incontinence surgical procedure prior to AUS implantation (69.1‐100%). The intraoperative bladder neck injury rates ranged from 0% to 43.8% and the intraoperative vaginal injury rates ranged from 0 to 25%. After mean follow‐up periods ranging from 5 to 204 months, the complete continence rates ranged from 61.1% to 100%. The rates of explantation, erosion and mechanical failure varied from 0% to 45.3%, 0% to 22.2% and 0% to 44.1%, respectively. Conclusions AMS‐800 AUS can provide excellent functional outcomes in female patients with SUI resulting from ISD but at the cost of a relatively high morbidity. High level of evidence studies are needed to help better define the role of AUS in the female SUI armamentarium.

Objective Bone marrow aspiration and concentration (BMAC) is becoming a more common regenerative therapy for musculoskeletal pathology. In our current pilot study, we studied patients with mild-to-moderate bilateral knee osteoarthritis, compared pain at 12-month follow-up between BMAC-injected and saline-injected knees, and examined cartilage appearance measured by magnetic resonance imaging (MRI) T2 quantitative mapping. Design Twenty-five patients with mild-to-moderate bilateral osteoarthritic knee pain were randomized to receive BMAC into one knee and saline placebo into the other. Bone marrow was aspirated from the iliac crests, concentrated in an automated centrifuge, combined with platelet-poor plasma for knee injection, and compared with saline injection into the contralateral knee. Primary outcome measures were T2 MRI cartilage mapping at 6-month and Visual Analog Scale and Osteoarthritis Research Society International Intermittent and Constant Osteoarthritis Pain scores and radiographs at 12-month follow-up. Results Constant, intermittent, and overall knee pain remained significantly decreased from baseline at 12-month follow-up (all P ⩽ 0.01), with no apparent difference between BMAC- and saline-treated knees (all P ⩾ 0.54). A similar significant increase from baseline to 12-month follow-up regarding quality of life was observed for both BMAC- and saline-treated knees (all P ⩽ 0.04). T2 quantitative MRI mapping showed no significant changes as a result of treatment. Conclusions BMAC is safe to perform and relieves pain from knee arthritis but showed no superiority to saline injection at 12-month follow-up. MRI cartilage sequences failed to show regenerative benefit with single BMAC injection. The mechanisms of action that led to pain relief remain unclear and warrant further studies.

Background There is currently a lack of consensus on how health-related quality of life and other patient-reported outcome measures in cancer randomized clinical trials are analyzed and interpreted. This makes it difficult to compare results across randomized controlled trials (RCTs) synthesize scientific research, and use that evidence to inform product labeling, clinical guidelines, and health policy. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data for Cancer Clinical Trials (SISAQOL) Consortium aims to develop guidelines and recommendations to standardize analyses of patient-reported outcome data in cancer RCTs. Methods and Results Members from the SISAQOL Consortium met in January 2017 to discuss relevant issues. Data from systematic reviews of the current state of published research in patient-reported outcomes in cancer RCTs indicated a lack of clear reporting of research hypothesis and analytic strategies, and inconsistency in definitions of terms, including “missing data,”“health-related quality of life,” and “patient-reported outcome.” Based on the meeting proceedings, the Consortium will focus on three key priorities in the coming year: developing a taxonomy of research objectives, identifying appropriate statistical methods to analyze patient-reported outcome data, and determining best practices to evaluate and deal with missing data. Conclusion The quality of the Consortium guidelines and recommendations are informed and enhanced by the broad Consortium membership which includes regulators, patients, clinicians, and academics.

Objectives: In the United States, physician training in Critical Care Medicine has developed as a subspecialty of different primary boards, despite significant commonality in knowledge and skills. The Society of Critical Care Medicine appointed a multidisciplinary Task Force to examine alternative approaches for future training. Design: The Task Force reviewed the literature and conducted informal discussions with key stakeholders. Specific topics reviewed included the history of critical care training, commonalities among subspecialties, developments since a similar review in 2004, international experience, quality patient care, and financial and workforce issues. Main Results: The Task Force believes that options for future training include establishment of a 1) primary specialty of critical care; 2) unified fellowship and certification process; or 3) unified certification process with separate fellowship programs within the current specialties versus 4) maintaining multiple specialty-based fellowship programs and certification processes. Conclusions: 1) Changing the current Critical Care Medicine training paradigms may benefit trainees and patient care. 2) Multiple pathways into critical care training for all interested trainees are desirable for meeting future intensivist workforce demands. 3) The current subspecialties within separate boards are not “distinct and well-defined field[s] of medical practice” per the American Board of Medical Specialties. Recommendations for first steps are as follows: 1) as the society representing multidisciplinary critical care, the Society of Critical Care Medicine has an opportunity to organize a meeting of all stakeholders to discuss the issues regarding Critical Care Medicine training and consider cooperative approaches for the future. 2) A common Critical Care Medicine examination, possibly with a small percentage of base-specialty–specific questions, should be considered. 3) Institutions with multiple Critical Care Medicine fellowship programs should consider developing joint, multidisciplinary training curricula. 4) The boards that offer Critical Care Medicine examinations, along with national critical care societies, should consider ways to shorten training time.