The emerging role of FAM46C as a biomarker and therapeutic target in gastric adenocarcinoma.

On a global scale, gastric adenocarcinoma (GCa) accounts for a large burden of death from cancer. Despite advances in systemic therapy and surgical technique, the fatality rate for GCa remains unacceptably high in Europe and North America, where diagnosis is typically made at an advanced stage. Biomarkers that can accurately predict response to new therapies and provide novel therapeutic strategies are urgently sought. FAM46C, a putative noncanonical nucleotidyltransferase, has garnered interest for its tumor suppressor function in multiple myeloma. A frequent and profound depletion of FAM46C has been described in GCa patients from China, Japan and now Canada. Furthermore, the degree of FAM46C depletion meaningfully portends cancer recurrence following resection, and death from GCa. In this review, we provide an updated summary of the literature regarding FAM46C as a biomarker in GCa and explore the potential mechanism(s) through which FAM46C depletion promotes GCa progression, including dis-inhibition of oncogenic Plk4 kinase activity. We highlight the potential for restoration of FAM46C levels as a therapeutic strategy. Norcantharidin, a synthetic analogue of the traditional Chinese medicine cantharidin derived from the blister beetle, is the only bio-available compound presently known to upregulate FAM46C expression and is under investigation in phase one trials in cancer patients.

Prognostic Significance of Tumour Budding and Desmoplastic Reaction in Intestinal-Type Gastric Adenocarcinoma.

Objective. Tumour budding and desmoplastic reactions in peritumoural stroma are features of the tumour microenvironment that are associated with colorectal cancer prognosis but have not been as thoroughly examined in gastric cancer. We aimed to further characterize the prognostic role of tumour budding and desmoplastic reaction in gastric adenocarcinoma with intestinal differentiation. Methods. 76 curative gastrectomy specimens were identified, excluding post-neoadjuvant cases or cases with >50% diffuse-type histology. Tumour budding was defined and graded according to the International Tumor Budding Consensus Conference recommendations and desmoplastic reaction was classified as described by Ueno et al 2017. Tumour budding and desmoplastic reaction were analyzed for associations with pathologic features and clinical outcomes. Results. Tumour budding was associated with pT (P < .001), pN (P < .004), overall stage (P < .001), LVI (P < .001) and PNI (P = .002). Desmoplastic reaction was associated with pT (P < .001), pN (P = .005), overall stage (P = .031) and PNI (P < .001), but not LVI. Survival analysis showed decreased overall survival (OS) and recurrence-free survival (RFS) for intermediate and high grade tumour budding (P = .031, .014 respectively). Immature stroma was significantly associated with RFS but not OS. Neither tumour budding nor desmoplastic reaction were independent predictors of OS or RFS on multivariate analysis in this cohort. Conclusion. Tumour budding and desmoplastic reaction were associated with known pathologic risk factors. Prognostically, tumour budding was associated with OS and RFS while desmoplastic reaction was associated with RFS only. Our data suggest that tumour budding and desmoplastic reaction have prognostic value in intestinal-type gastric adenocarcinoma.

Waking up the next morning: surgeons' emotional reactions to adverse events.

CONTEXT: The adverse patient event is an inherent component of surgical practice, but many surgeons are unprepared for the profound emotional responses these events can evoke. This study explored surgeons' reactions to adverse events and their impact on subsequent judgement and decision making. METHODS: Using a constructivist grounded theory approach, we conducted 20 semi-structured, 60-minute interviews with surgeons across subspecialties, experience levels, and sexes to explore surgeons' recollections of reactions to adverse events. Further interviews were conducted with six general surgeons to explore more immediate reactions after 28 adverse events. Data coding was both inductive, developing a new framework based on emergent themes, and deductive, using an existing framework for care providers' reactions to adverse events. RESULTS: Surgeons expressed feeling unique and alone in the depths of their reactions to adverse events and consistently described four phases of response, each containing cognitive and emotive components, following such events. The initial phase (the kick) involved feelings of failure ('Am I good enough?') experienced with a significant physiological response. This was shortly followed by a second phase (the fall), during which the surgeon experienced a sense of chaos and assessed the extent of his or her contribution to the event ('Was it my fault?'). During the third phase (the recovery), the surgeon reflected on the adverse event ('What can I learn?') and experienced a sense of 'moving on'. In the fourth phase (the long-term impact), the surgeon experienced the prolonged and cumulative effects of these reactions on his or her own personal and professional identities. Surgeons also described an effect on their clinical judgement, both for the case in question (minimisation) and future cases (overcompensation). CONCLUSIONS: Surgeons progress through a series of four phases following adverse events that are potentially caused by or directly linked to surgeon error. The framework provided by this study has implications for teaching, surgeon wellness and surgeon error.

Investigating the mechanisms of peritoneal metastasis in gastric adenocarcinoma using a novel ex vivo peritoneal explant model.

Gastric adenocarcinoma, commonly known as stomach cancer, has a predilection for metastasis to the peritoneum, which portends limited survival. The peritoneal metastatic cascade remains poorly understood, and existing models fail to recapitulate key elements of the interaction between cancer cells and the peritoneal layer. To explore the underlying cellular and molecular mechanisms of peritoneal metastasis, we developed an ex vivo human peritoneal explant model. Fresh peritoneal tissue samples were suspended, mesothelial layer down but without direct contact, above a monolayer of red-fluorescent dye stained AGS human gastric adenocarcinoma cells for 24 h, then washed thoroughly. Implantation of AGS cells within the explanted peritoneum and invasion beyond the mesothelial layer were examined serially using real-time confocal fluorescence microscopy. Histoarchitecture of the explanted peritoneum was preserved over 5 days ex vivo. Both implantation and invasion were suppressed by restoration of functional E-cadherin through stable transfection of AGS cells, demonstrating sensitivity of the model to molecular manipulation. Thus, our ex vivo human peritoneal explant model permits meaningful investigation of the pathways and mechanism that contribute to peritoneal metastasis. The model will facilitate screening of new therapies that target peritoneal dissemination of gastric, ovarian and colorectal cancer.

What surgeons can learn from athletes: mental practice in sports and surgery.

BACKGROUND: Mental practice has been successfully applied in professional sports for skills acquisition and performance enhancement. The goals of this review are to describe the literature on mental practice within sport psychology and surgery and to explore how the specific principles of mental practice can be applied to the improvement of surgical performance-both in novice and expert surgeons. METHOD: The authors reviewed the sports psychology, education, and surgery literatures through Medline, PubMed, PsycINFO, and Embase. RESULTS: In sports, mental practice is a valuable tool for optimizing existing motor skill sets once core competencies have been mastered. These techniques have been shown to be more advantageous when used by elite athletes. Within surgery, mental practice studies have focused on skill acquisition among novices with little study of how expert surgeons use it to optimize surgical preparation. CONCLUSIONS: We propose that performance optimization and skills acquisition should be viewed as 2 separate domains of mental practice. Further understanding of this phenomenon has implications for changing how we teach and train not only novice surgeons but also how experienced surgeons continue to maintain their skills, acquire new ones, and excel in surgery.

Predictors of treatment failure for pneumatic retinopexy.

OBJECTIVE: The purpose of this study was to define the overall anatomic success rate in pneumatic retinopexy and to identify morphologic features that may be predictive of treatment failure in pneumatic retinopexy. DESIGN AND PARTICIPANTS: Prospective consecutive interventional case series of patients with new-onset primary rhegmatogenous retinal detachments treated with pneumatic retinopexy. METHODS: In this interventional case series, consecutive patients with new-onset primary rhegmatogenous retinal detachments were treated with pneumatic retinopexy and followed prospectively. Morphologic data were collected on 3-colour fundus drawings. The primary outcome measure was treatment failure, defined as requirement for scleral buckle or vitrectomy within the follow-up period. Rates of failure for each morphologic feature were compared and a logistic regression model was fit. RESULTS: A total of 113 eyes were included in the study. Anatomic success was achieved in 69.6% of patients. Morphologic criteria including the position and number of breaks, position and extent of lattice degeneration, size of the detached area, and macular status were all found not to be significantly related to failure. In multivariate analysis, only 3 predictors, pseudophakic status (p < 0.05, odds ratio [OR] 2.9, 95% CI, 1.06-7.88), presence of retinal break greater than 1 clock-hour (p < 0.05, OR 3.41, 1.06-11.02), and presence of grade C or D proliferative vitreoretinopathy (PVR) (p < 0.01, OR 31.83, 95% CI, 3.59-282.24), gained statistical significance. CONCLUSIONS: Only pseudophakia, a large retinal break, and/or PVR was associated with an increased likelihood of failure.

When bad things happen to good surgeons: reactions to adverse events.

Adverse events are, unfortunately, common components of surgical practice. Much has been done to develop safer systems to prevent these adverse events; however, there has been less focus on the surgeon experiencing these events. This article presents a framework to understand surgeons' reactions to adverse events that was derived from a more recent study as well as a review of relevant psychology literatures. This framework is then situated within the broader picture of mindful practice to explore how the psychological and social dimensions of the surgeon can affect judgment and cognition.

"First, do no harm": balancing competing priorities in surgical practice.

PURPOSE: To explore surgeons' perceptions of the factors that influence their intraoperative decision making, and implications for professional self-regulation and patient safety. METHOD: Semistructured interviews were conducted with 39 academic surgeons from various specialties at four hospitals associated with the University of Toronto Faculty of Medicine. Purposive and theoretical sampling was performed until saturation was achieved. Thematic analysis of the transcripts was conducted using a constructivist grounded-theory approach and was iteratively elaborated and refined as data collection progressed. A preexisting theoretical professionalism framework was particularly useful in describing the emergent themes; thus, the analysis was both inductive and deductive. RESULTS: Several factors that surgeons described as influencing their decision making are widely accepted ("avowed," or in patients' best interests). Some are considered reasonable for managing multiple priorities external to the patient but are not discussed openly ("unavowed," e.g., teaching pressures). Others are actively denied and consider the surgeon's best interests rather than the patient's ("disavowed," e.g., reputation). Surgeons acknowledged tension in balancing avowed factors with unavowed and disavowed factors; when directly asked, they found it difficult to acknowledge that unavowed and disavowed factors could lead to patient harm. CONCLUSIONS: Some factors that are not directly related to the patient enter into surgeons' intraoperative decision making. Although these are probably reasonable to consider within "real-world" practice, they are not sanctioned in current patient care constructs or taught to trainees. Acknowledging unavowed and disavowed factors as sources of pressure in practice may foster critical self-reflection and transparency when discussing surgical errors.