Long-term outcomes following endoscopic stenting in the management of leaks after foregut and bariatric surgery.

INTRODUCTION: Endoscopic stenting has been shown to be effective in treating leaks after bariatric surgery. However, concerns remain regarding its long-term efficacy. The purpose of this study was to assess the evolution of endoscopic stenting and its efficacy over time, as well as the impact of stent fixation on migration rates and long-term outcomes. In addition, the effect of stenting on long-term weight loss and chronic reflux was also evaluated. METHODS: A retrospective review was conducted including 37 patients from 2005 to 2017 who had undergone placement of stents after various bariatric procedures. Stents were placed endoscopically and, after 2012, secured with a figure-of-eight overstitch. Demographics, weight loss data, stent migration rates, incidence of revision surgery, chronic PPI use, and chronic symptoms of reflux data were obtained and analyzed. RESULTS: Thirty-seven patients from 2005 to 2017 required endoscopic stenting for leaks. 43.24% patients underwent sleeve gastrectomy, 40.54% gastric bypass, 5.40% patients underwent duodenal switch, and 10.81% underwent miscellaneous foregut procedures. The overall success rate was 94.59% (35 of 37 patients). The incidence of stent migration before 2012 was 41.18% versus 15% after 2012 (p = 0.136271). There were 2 treatment failures, one treated successfully with re-stenting and another other requiring revision surgery. Overall, the percent of excess body weight lost was 57.21% over an average of 21 months. 58.82% of patients used PPI chronically; however 41.17% noted actual symptoms of reflux. 16.22% (6 of 37) patients ultimately underwent revision surgery. CONCLUSION: Endoscopic stenting is a safe and effective treatment for leaks after bariatric surgery. While complications can include stent migration, newer stent technology and endoscopic overstitching techniques show promise in reducing the incidence of stent migration. Despite undergoing treatment with stenting, these patients had successful weight loss with relatively low rates of chronic PPI use and reflux symptoms.

Expanding the Molecular and Clinical Phenotype of SSR4-CDG.

Congenital disorders of glycosylation (CDG) are a group of mostly autosomal recessive disorders primarily characterized by neurological abnormalities. Recently, we described a single CDG patient with a de novo mutation in the X-linked gene, Signal Sequence Receptor 4 (SSR4). We performed whole-exome sequencing to identify causal variants in several affected individuals who had either an undifferentiated neurological disorder or unsolved CDG of unknown etiology based on abnormal transferrin glycosylation. We now report eight affected males with either de novo (4) or inherited (4) loss of function mutations in SSR4. Western blot analysis revealed that the mutations caused a complete loss of SSR4 protein. In nearly all cases, the abnormal glycosylation of serum transferrin was only slightly above the accepted normal cutoff range.

Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma.

BACKGROUND: Glypican-3 (GPC-3) is an oncofetal protein that is highly expressed in various solid tumors, but rarely expressed in healthy adult tissues and represents a rational target of particular relevance in hepatocellular carcinoma (HCC). Autologous chimeric antigen receptor (CAR) αß T cell therapies have established significant clinical benefit in hematologic malignancies, although efficacy in solid tumors has been limited due to several challenges including T cell homing, target antigen heterogeneity, and immunosuppressive tumor microenvironments. Gamma delta (γδ) T cells are highly cytolytic effectors that can recognize and kill tumor cells through major histocompatibility complex (MHC)-independent antigens upregulated under stress. The Vδ1 subset is preferentially localized in peripheral tissue and engineering with CARs to further enhance intrinsic antitumor activity represents an attractive approach to overcome challenges for conventional T cell therapies in solid tumors. Allogeneic Vδ1 CAR T cell therapy may also overcome other hurdles faced by allogeneic αß T cell therapy, including graft-versus-host disease (GvHD). METHODS: We developed the first example of allogeneic CAR Vδ1 T cells that have been expanded from peripheral blood mononuclear cells (PBMCs) and genetically modified to express a 4-1BB/CD3z CAR against GPC-3. The CAR construct (GPC-3.CAR/secreted interleukin-15 (sIL)-15) additionally encodes a constitutively-secreted form of IL-15, which we hypothesized could sustain proliferation and antitumor activity of intratumoral Vδ1 T cells expressing GPC-3.CAR. RESULTS: GPC-3.CAR/sIL-15 Vδ1 T cells expanded from PBMCs on average 20,000-fold and routinely reached >80% purity. Expanded Vδ1 T cells showed a primarily naïve-like memory phenotype with limited exhaustion marker expression and displayed robust in vitro proliferation, cytokine production, and cytotoxic activity against HCC cell lines expressing low (PLC/PRF/5) and high (HepG2) GPC-3 levels. In a subcutaneous HepG2 mouse model in immunodeficient NSG mice, GPC-3.CAR/sIL-15 Vδ1 T cells primarily accumulated and proliferated in the tumor, and a single dose efficiently controlled tumor growth without evidence of xenogeneic GvHD. Importantly, compared with GPC-3.CAR Vδ1 T cells lacking sIL-15, GPC-3.CAR/sIL-15 Vδ1 T cells displayed greater proliferation and resulted in enhanced therapeutic activity. CONCLUSIONS: Expanded Vδ1 T cells engineered with a GPC-3 CAR and sIL-15 represent a promising platform warranting further clinical evaluation as an off-the-shelf treatment of HCC and potentially other GPC-3-expressing solid tumors.

Preclinical studies of VS-505: a non-absorbable highly effective phosphate binder.

BACKGROUND AND PURPOSE: Phosphate imbalance is often present in chronic kidney disease (CKD), and it contributes to a higher cardiovascular mortality rate. A phosphate binder is typically part of a treatment strategy for controlling phosphate imbalance. However, safety concerns and low compliance are two well-recognized disadvantages of on-market phosphate binders. This report describes the preclinical studies of VS-505, a non-absorbable, calcium- and aluminum-free, plant-derived polymer currently being evaluated in haemodialysis patients in Australia. EXPERIMENTAL APPROACH: Normal Sprague Dawley (SD) rats or uraemic SD rats induced by 5/6 nephrectomy fed a high-phosphate diet were treated with VS-505 or sevelamer (0.05-10% in food) for 5 and 28 days respectively. KEY RESULTS: Urinary and serum phosphate levels were significantly elevated in untreated rats, and were decreased by VS-505 and sevelamer. VS-505 increased faecal phosphate levels in a dose-dependent manner. High-phosphate diet also caused an increase in serum FGF-23 and parathyroid hormone in nephrectomized (NX) rats, effects prevented by VS-505 or sevelamer. Significant aortic calcification was observed in NX rats treated with 5% sevelamer, whereas VS-505 at all doses tested did not show effects. VS-505 had no effects on small intestine histomorphology and intestinal sodium-dependent phosphate cotransporter gene expression. In vitro characterizations showed that VS-505 has a relatively high density and low expansion volume when exposed to simulated gastric fluid. CONCLUSIONS AND IMPLICATIONS: VS-505 is a safe and effective phosphate binder and may offer the advantage of having a reduced pill burden and minimal GI side effects for CKD patients.

VS-501: A NOVEL, NON-ABSORBED, CALCIUM- AND ALUMINUM-FREE, HIGHLY EFFECTIVE PHOSPHATE BINDER DERIVED FROM NATURAL PLANT POLYMER.

Inadequate control of serum phosphate in chronic kidney disease can lead to pathologies of clinical importance. Effectiveness of on-market phosphate binders is limited by safety concerns and low compliance due to high pill size/burden and gastrointestinal discomfort. VS-501 is a non-absorbed, calcium- and aluminum-free, chemically-modified, plant-derived polymer. In vitro studies show that VS-501 has a high density and a low swell volume when exposed to simulated gastric fluid (vs. sevelamer). When male Sprague Dawley (SD) rats on normal diet were treated with VS-501 or sevelamer, serum phosphate was not significantly altered, but urinary phosphate levels decreased by >90%. VS-501 had no effect on serum calcium (Ca) or urinary Ca, while 3% sevelamer significantly increased serum and urine Ca. In 5/6 nephrectomized (NX) uremic SD rats on high-phosphate diet, increasing dietary phosphate led to an increase in serum and urine phosphate, which was prevented in rats treated with VS-501 or sevelamer (0.2-5% in food). High phosphate diet also increased serum FGF-23 and parathyroid hormone in 5/6 NX rats, which was prevented by VS-501 or sevelamer. VS-501 or sevelamer increased fecal phosphate in a dose-dependent manner. More aortic calcification was observed in 5/6 NX rats treated with 5% sevelamer, while VS-501 and sevelamer did not show significant effects on cardiac parameters, fibrosis, intestine histology and intestinal sodium-dependent phosphate cotransporter gene expression. These results suggest that VS-501 is effective in binding phosphate with no effects on calcium homeostasis, and may have improved pill burden and gastrointestinal side effects.