KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. EXPERIMENTAL DESIGN: We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. RESULTS: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. CONCLUSIONS: Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.

Single-session EUS-guided gastrogastrostomy to facilitate cystgastrostomy in Roux-en-Y gastric bypass.

Video 1Single-session EUS-guided gastrogastrostomy creation to facilitate cystgastrostomy in Roux-en-Y gastric bypass.

Intragastric Balloon Significantly Improves Metabolic Parameters at 6 Months: a Meta-Analysis.

INTRODUCTION: It is estimated that by 2030, 38% of the world population will be overweight, and another 20% will be people with obesity. Intragastric balloons (IGBs) are an option in conjunction with lifestyle modification for the treatment of obesity. We sought to investigate the effects of IGB therapy on hemoglobin A1c (A1c), systolic and diastolic blood pressure (SBP, DBP), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TGs). METHODS: PubMed, Embase, and Google Scholar were queried through November 2021 to identify studies that evaluated the effects of IGB therapy on selected variables at 6 months. A total of 17 studies and 1198 patients met inclusion criteria. Results were pooled using a random-effects model. RESULTS: At 6-month post-IGB insertion, patients had a significant reduction in A1c (mean difference (MD): - 0.62, 95% confidence interval (CI): - 0.884 to - 0.355, p < 0.001), SBP (MD: - 8.39, 95% CI: - 11.39 to - 5.386, p < 0.001), DBP (MD: - 5.807, 95% CI: - 8.852 to - 2.76, p < 0.001), TC (MD: - 9.189, 95% CI: - 15.763 to - 2.616, p = 0.006), LDL (MD: - 5.20, 95% CI: - 9.05 to - 1.35, p = 0.008), and TGs (MD: - 25.35, 95% CI: - 40.30 to - 10.10, p = 0.001). There was no significant difference in HDL (MD: 1.245, 95% CI: - 0.11 to 2.60, p = 0.071). CONCLUSIONS: Our meta-analysis suggests that IGB therapy is associated with improvements in insulin resistance, blood pressure, and dyslipidemia at 6 months. The results of this analysis suggest that IGB placement can be a viable treatment option to improve important metabolic parameters beyond weight loss alone.

Sporadic Neurofibroma of the Peritoneal Cavity.

Neurofibromas are peripheral nerve sheath tumors that are typically seen in syndromic conditions such as neurofibromatosis 1. We present the case of a 26-year-old woman suffering from chronic abdominal pain for over 5 years. Prior workup showed a large retroperitoneal mass extending into the abdomen and encasing multiple major vessels. She underwent endoscopic ultrasound (EUS)-guided biopsy, which was histologically consistent with a solitary neurofibroma. There is no prior report of solitary neurofibroma of the abdomen diagnosed with the use of EUS-guided biopsy. This case highlights the utility of EUS-guided biopsy in the evaluation of intra-abdominal pathology.

Transjejunal drainage of an infected postsurgical fluid collection using a 6-mm lumen-apposing metal stent.

Video 1The successful placement of a 6-mm lumen-apposing metal stent for transjejunal drainage of an infected collection after recent surgery, with resolution of collection after removal of stents.

Pneumatic Balloon Dilation of Gastric Sleeve Stenosis Is Not Associated with Weight Regain.

BACKGROUND: Gastric sleeve stenosis (GSS) occurs in up to 4% of patients after laparoscopic sleeve gastrectomy (LSG). Typical symptoms include reflux, abdominal pain, dysphagia, and regurgitation. Serial pneumatic balloon dilation (PBD) is a successful treatment in many cases obviating the need for revisional surgery, but the potential for weight regain is unknown. The aim of the current study was to assess weight trends following serial pneumatic dilation for GSS. METHODS: Retrospective analysis of a prospectively maintained database of patients undergoing serial PBD for GSS at one institution. Primary outcome was change in BMI before and after serial PBD. Secondary outcomes included complication rates and need for revisional surgery. Sub-group analyses were performed to determine the relationship of patient and procedural factors to BMI after PBD. RESULTS: Forty-four patients met inclusion criteria, 34 (84.1%) women. Mean age was 46.7 (SD 11.9). Mean pre-sleeve BMI was 47.8 (SD 9.2), and mean BMI prior to first dilation was 34.2 (SD 6.8). Median follow-up was 395 days (range 48-571). Mean BMI at time of last follow up was 33.7 (SD 6.7). There was no statistical difference in BMI pre- or post-PBD (p 0.980). The lowest 10th and highest 90th BMI percentile trended toward a higher and lower BMI after PBD, respectively, though not significant. DISCUSSION: As the prevalence of sleeve gastrectomy continues to rise, an increasing number of patients will require treatment for GSS. Stenosis is effectively treated with serial PBD in most patients without any impact on weight gain, making this an effective and appealing option for many patients.

Quantification of gastric sleeve stenosis using endoscopic parameters and image analysis.

BACKGROUND AND AIMS: Sleeve gastrectomy has quickly become the most commonly performed bariatric surgery. In light of its increasing popularity, the prevalence of gastric sleeve stenosis (GSS) continues to rise. Management with serial pneumatic dilation is highly successful but underused because of a lack of quantitative diagnostic criteria. We aimed to develop quantifiable endoscopic criteria to characterize GSS based on the (1) ratio of narrowest to widest gastric lumen diameter, (2) endoscope angulation/trajectory required for passage, and (3) presence of bilious fluid pooling in the proximal sleeve and compare it with endoluminal functional lumen imaging probe (EndoFLIP) diameter and distensibility indices (DIs) and endoscopic documentation of gastric lumen morphology. METHODS: We retrospectively reviewed a prospectively maintained database of patients undergoing endoscopy to assess for GSS. Endoscopic images were reviewed in a blinded fashion by 2 bariatric endoscopists. The narrowest and widest part of the gastric lumen diameters were noted on each image, in addition to a hypothetical trajectory required for endoscope passage. Using image processing software, we calculated the the ratio of diameters (ie, narrowest divided by widest) and angle of endoscope trajectory. The presence of bilious fluid pooling in the proximal gastric lumen was noted. These values were then compared with EndoFLIP parameters and endoscopic documentation of gastric lumen morphology. RESULTS: Thirty patients met inclusion criteria, and 26 (87%) were found to have a stenosis on endoscopy. Of those, 9 (35%) were characterized as mild, 11 (42%) as moderate, and 6 (23%) as severe. There was no difference in demographic information between patients with and without stenosis. In patients with stenosis, mean EndoFLIP diameters and DIs were 12.9 ± 3.9 mm and 11.0 ± 6.8 mm2/mm Hg, respectively. In patients without stenosis, mean EndoFLIP diameters and DIs were 19.9 ± 2.9 mm and 21.5 ± 1.0 mm2/mm Hg, respectively. Patients with stenosis had significantly lower diameter ratios compared with those without stenosis (.27 ± .14 vs .48 ± .77, P = .01). Diameter ratios were also inversely related to severity of sleeve stenosis (ß = -.08, P = .01). Patients with stenosis were also more likely to have fluid pooling (96.2% vs 25%, P < .001). There was no significant difference in the trajectory of endoscope passage between the 2 groups. CONCLUSIONS: Endoscopic criteria for diagnosis of GSS are lacking. Our data suggest the ratio between the narrowest and widest gastric lumen diameters and presence of pooled fluid is associated with diagnosis of stenosis by EndoFLIP and gastric lumen morphology. Future studies to validate these criteria are needed.

Upper gastrointestinal series after sleeve gastrectomy is unnecessary to evaluate for gastric sleeve stenosis.

BACKGROUND: There has been an increase in sleeve gastrectomy (SG) procedures being performed worldwide, and a paralleled rise in prevalence of gastric sleeve stenosis (GSS). Symptoms include dysphagia, reflux, and obstructive symptoms. Upper gastrointestinal series (UGIS) is commonly performed in the diagnostic algorithm prior to referral for endoscopic dilation; however, little is known about its utility in making a diagnosis. Our aim was to evaluate positive predictive value (PPV) and negative predictive value (NPV) of UGIS in detection of GSS. METHODS: We performed a retrospective analysis of a prospectively collected database at a tertiary center for patients referred with nausea/vomiting or obstructive symptoms following SG between 2017 and 2019. All patients underwent upper endoscopy (EGD) for evaluation of GSS. Serial balloon dilations were performed for GSS with increasing balloon size and/or filling pressure until symptom resolution or referral for surgical revision. Primary outcomes were PPV and NPV for UGIS in predicting GSS. Secondary outcomes included EGD findings and symptom response to dilation. RESULTS: Thirty consecutive patients were included in the analyses. The most common presenting symptoms were nausea (66.7%), vomiting (60.0%) reflux (66.7%), and abdominal pain (54.8%). Twenty-two (73.3%) patients underwent UGIS prior to EGD. On diagnostic EGD, 27 (87.1%) patients were diagnosed with GSS. The sensitivity and NPV of UGIS to detect GSS was 30.0%, and 12.5%, respectively. All 6 patients with GSS on UGIS also had GSS on endoscopic evaluation (specificity = 100%, PPV = 100%). Twenty-six (86.6%) patients had resolution of symptoms with a mean 1.97 ± 1.13 dilations. CONCLUSION: UGIS following SG has low NPV to evaluate for GSS. Independent of the UGIS findings, majority of patients found to have GSS on EGD had symptom improvement with dilations. The utility of UGIS is limited for diagnosing GSS and when suspicion for GSS is high, patients should be referred directly for EGD.

Endoscopic ultrasound-guided gallbladder drainage as a rescue therapy for unresectable malignant biliary obstruction: a multicenter experience.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is often unsuccessful in patients with duodenal stenosis or malignant ampullary infiltration. While endoscopic ultrasound-guided biliary drainage (EUS-BD) has been proposed as an alternative, EUS-guided gallbladder drainage (EUS-GBD) is an attractive option when both approaches fail. We aimed to assess the effectiveness and safety of EUS-GBD as rescue therapy for malignant distal bile duct obstruction. METHODS: A multicenter retrospective study was performed on patients with unresectable malignant distal bile duct obstruction who underwent EUS-GBD between 2014 and 2019 after unsuccessful ERCP and EUS-BD. Clinical success was defined as a decrease in serum bilirubin of > 50 % within 2 weeks. RESULTS: 28 patients were included, with a lumen-apposing metal stent used in 26 (93 %) and a self-expandable metal stent in two (7 %). The technical success rate was 100 %. The clinical success rate was 93 %, with an improvement in bilirubin (7.3 [SD 5.4] pre-procedure vs. 2.8 [SD 1.1] post-procedure; P = 0.001). Delayed adverse events included food impaction of the stent (n = 3), with a further two patients developing cholecystitis and bleeding. CONCLUSION: This study demonstrates the feasibility of gallbladder drainage to relieve malignant distal bile duct obstruction in patients with failed ERCP and EUS-BD.

Safety of perioperative subcutaneous heparin for partial nephrectomy.

INTRODUCTION: The development of deep venous thrombosis (DVT) or pulmonary embolism (PE) following urologic surgery is a life threatening, but largely preventable complication. Patients undergoing partial nephrectomy are at increased risk for the development of DVT or PE as they often possess multiple risk factors including malignancy, advanced age, and prolonged surgical time. This risk can be significantly reduced by administration of perioperative subcutaneous heparin (SQH), however many surgeons feel this is contraindicated due to potential blood loss and related complications. MATERIALS AND METHODS: The medical records of 293 consecutive patients undergoing planned open, laparoscopic, or robotic assisted partial nephrectomy by a single surgeon over a 7 year period were reviewed. Approximately halfway through the period, the standard DVT prevention practice was changed from sequential compression stockings and early ambulation to include 5000 units of SQH administered 30-60 minutes prior to incision and continuing every 8 hours until discharge. RESULTS: A total of 158 patients received perioperative SQH. There was no significant difference in surgical blood loss, transfusions, operative time, change in pre to postoperative hemoglobin or creatinine, conversion to radical nephrectomy, or duration of stay between the groups. There were no DVTs in either group. There was one PE in the group receiving SQH which was incidentally discovered. CONCLUSIONS: Patients undergoing renal surgery for cancer are at increased risk for the development of DVT and PE. Prophylaxis against this serious complication with perioperative SQH is safe in patients undergoing partial nephrectomy despite common surgeon concerns regarding blood loss and related complications.

beta(1)-integrin mediates pressure-stimulated phagocytosis.

BACKGROUND: Extracellular pressure alterations in infection, inflammation, or positive pressure ventilation may influence macrophage phagocytosis. We hypothesized that pressure modulates beta1-integrins to stimulate phagocytosis. METHODS: We assayed fibroblast phagocytosis of fluorescent latex beads at ambient or 20 mm Hg increased pressure, and macrophage integrin phosphorylation by Western blot. RESULTS: Pressure did not alter phagocytosis in beta(1)-integrin null GD25 fibroblasts, but stimulated phagocytosis in fibroblasts expressing wild-type beta(1)-integrin. In phorbol myristate acetate-differentiated THP-1 macrophages, pressure stimulated beta(1)-integrin T788/789 phosphorylation, but not S785 phosphorylation. Furthermore, pressure stimulated phagocytosis in cells expressing an inactivating S785A point mutation or a T788D substitution to mimic a constitutively phosphorylated threonine, but not in cells expressing an inactivating TT788/9AA mutation. CONCLUSIONS: The effects of pressure on phagocytosis are not limited to macrophages but generalize to other phagocytic cells. These results suggest that pressure stimulates phagocytosis via increasing beta(1)-integrin T789 phosphorylation. Interventions that target beta(1)-integrin threonine 789 phosphorylation may modulate phagocytic function.