Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

Pets, Health, China, Natural experiment,

We thank the surgeons and research assistants who contributed patients and data from the following institutions constituting the Ampullary Carcinoma Study Group and Pancreas Fistula Study Group:

Some controversy surrounds the postoperative feeding regimen utilized in patients who undergo esophagectomy. Variation in practices during the perioperative period exists including the type of nutrition started, the delivery route, and its timing. Adequate nutrition is essential for this patient population as these patients often present with weight loss and have altered eating patterns after surgery, which can affect their ability to regain or maintain weight. Methods of feeding after an esophagectomy include total parenteral nutrition, nasoduodenal/nasojejunal tube feeding, jejunostomy tube feeding, and oral feeding. Recent evidence suggests that early oral feeding is associated with shorter LOS, faster return of bowel function, and improved quality of life. Enhanced recovery pathways after surgery pathways after esophagectomy with a component of early oral feeding also seem to be safe, feasible, and cost-effective, albeit with limited data. However, data on anastomotic leaks is mixed, and some studies suggest that the incidence of leaks may be higher with early oral feeding. This risk of anastomotic leak with early feeding may be heavily modulated by surgical approach. No definitive data is currently available to definitively answer this question, and further studies should look at how these early feeding regimens vary by surgical technique. This review aims to discuss the existing literature on the optimal route and timing of feeding after esophagectomy.

This case highlights the management of a rare entity and advocates for enucleation of noncommunicating, extraluminal esophageal bronchogenic cysts and closure of the esophageal muscular layers over intact mucosa as a viable surgical approach to this unusual pathology. Other cases of laparascopic enucleation of bronchogenic cysts have shown similarly uneventful postoperative courses and rapid recovery with no apparent return of symptoms.

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Purpose To identify factors associated with best-corrected visual acuity (BCVA) presentation and two-year outcome in 479 intermediate, posterior, and panuveitic eyes. Design Cohort study using randomized controlled trial data Methods Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and 2 years’ follow-up used gold standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and two-year change in BCVA. Results Baseline factors significantly associated with reduced BCVA included: age ≥50 vs. <50 years; posterior vs. intermediate uveitis; uveitis duration >10 vs. <6 years; anterior chamber (AC) flare > grade 0; cataract; macular thickening; and exudative retinal detachment. Over two years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter (p=0.52) and 10 letters (p<0.001) respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6–10 or >10 vs. <6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening. Conclusions Intermediate, posterior and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.