The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression.

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.

Presentation and Management of Arterial Thromboembolisms during Active Inflammatory Bowel Disease: Case Series and Literature Review.

BACKGROUND: Active inflammatory bowel disease (IBD) is associated with considerable risk for thromboembolism; however, arterial thromboembolism is rare and associated with considerable morbidity and mortality. Their management requires careful coordination between multiple providers, and as a consequence, much of the published literature is limited to case reports published across specialties. METHODS: We examined our recent institutional experience with aortoiliac, mesenteric, and peripheral arterial thromboembolisms in patients with either Crohn's disease or ulcerative colitis. To supplement our experience, a comprehensive literature review was performed using MEDLINE and EMBASE databases from 1966 to 2019. Patient demographics, flare/thromboembolism management, and outcomes were abstracted from the selected articles and our case series. RESULTS: Fifty-two patients with IBD, who developed an arterial thromboembolism, were identified (49 from published literature and 3 from our institution). More than 82% of patients presented during an active IBD flare. Surgical intervention was attempted in 77% of patients, which included open thromboembolectomy, catheter-directed thrombolysis, or bowel resection. Thromboembolism resolution was achieved in 76% of patients with comparable outcomes with either catheter-directed thrombolysis or open thrombectomy (83.3% vs. 68.2%). Nearly one-third of patients underwent small bowel resection or colectomy. In 2 patients, thromboembolism resolution was achieved only after total abdominal colectomy for severe pancolitis. Multiple thromboembolectomies were associated with higher risk for amputation. Overall mortality was 11.5% but was greatest for occlusive aortoiliac and mesenteric thromboembolism (14.3% and 57%, respectively). All survivors of occlusive superior mesenteric artery thromboembolism suffered short gut syndrome requiring small bowel transplant. CONCLUSIONS: Patients with IBD, who develop an arterial thromboembolism, can expect overall poor outcomes. Catheter-directed thrombolysis achieved comparable outcomes with open thromboembolectomy without undue bleeding risk. Total abdominal colectomy for moderate-to-severe pancolitis is an emerging strategy in the management of refractory arterial thromboembolism. Successful surgical management may include open thromboembolectomy, catheter-directed thrombolysis, and bowel resection when indicated.

Endovascular stenting of the ascending aorta for visceral malperfusion in a patient with type A aortic dissection.

A type A aortic dissection is a challenging condition for both cardiothoracic and vascular surgeons. Although open surgery remains the gold standard, there is considerable interest in the use of endovascular techniques for patients who present with malperfusion. We present the case of an unstable 55-year-old man with visceral malperfusion from a type A dissection who was stabilized using an endovascular technique as a bridge to open surgery. A bare metal thoracic endograft was used in the ascending aorta to rapidly restore perfusion. This hybrid approach to the problem of malperfusion in type A dissection could be useful for these patients with complicated cases.

Relationship between iliofemoral venous stenting and femoropopliteal deep venous reflux.

OBJECTIVE: Severe presentations of chronic venous insufficiency can result from reflux or obstruction at the deep venous, perforator, or superficial venous levels. Iliofemoral venous stenting can be used to address central venous obstruction; however, its effects on deep venous reflux (DVR) have remained unclear. The purpose of the present study was to evaluate the effects of iliac vein stenting on femoropopliteal DVR with the hypothesis that ultrasound evidence of DVR would remain absent or would have improved after iliac vein stenting. METHODS: The present study was a retrospective review of patients who had undergone iliofemoral venous stenting from 2013 to 2018. The patients were divided into two cohorts according to the preprocedural presence (group A) or absence (group B) of femoropopliteal DVR. Baseline patient variables were collected, including age, gender, CEAP (clinical, etiologic, anatomic, pathophysiologic) class, presence of concomitant superficial or perforator reflux, deep vein thrombosis history, and additional venous interventions. The primary outcome evaluated was the persistent absence or resolution of DVR on the latest venous duplex ultrasound at follow-up. Other outcomes included the follow-up CEAP classification and the need for secondary deep venous interventions. RESULTS: A total of 275 consecutive patients had undergone iliofemoral venous stenting. Of the 275 patients, 58 had presented with DVR (group A). A comparison of groups A and B revealed that group A had had a greater likelihood of prior deep vein thrombosis (P = .0001) and a higher frequency of superficial venous ablation. The remaining demographic variables did not differ significantly between the two groups. Of the 58 patients in group A, DVR had resolved at follow-up in 17 (P = .0001). When stratified by level, 7 of these 17 patients had had isolated popliteal reflux. In group B, DVR had developed at follow-up in 6 of the 217 patients. The CEAP class had improved from before intervention (C0, 1.1%; C1, 0.4%; C2, 1.8%; C3, 41.4%; C4, 24.9%; C5, 5.9%; C6, 24.5%) to the latest follow up (C0, 4.9%; C1, 1.9%; C2, 5.7%; C3, 34.2%; C4, 22.8%; C5, 17.1%; C6, 13.3%). Significant improvement had occurred in C6 disease within both groups (group A, 16 of 58 [27.6%; P = .0078]; group B, 19 of 217 [8.8%; P = .0203]). CONCLUSIONS: For patients who undergo iliofemoral venous stenting, DVR could improve if present initially and is unlikely to develop if not present before stenting. A cohort of patients had experienced persistent DVR and warranted further evaluation. Prospective studies are required to corroborate the safety, efficacy, and durability of iliofemoral venous stenting for patients with DVR.

An algorithm combining VVSYmQ® and VCSS scores may help to predict disease severity in C2 patients.

OBJECTIVES: The purpose was to assess whether combining patient reported scores (VVSymQ®) and physician reported scores (VCSS) stratifies disease severity in C2 patients. METHODS: Consecutive patients were pooled from the VANISH-1 and VANISH-2 cohorts. VCSS and VVSymQ® were calculated for each patient. The relationship between scoring systems was evaluated using Pearson's correlation and frequency distribution analysis. RESULTS: Two-hundred and ten C2 limbs were included. Scoring systems demonstrated: VVSymQ®: mean = 8.72; VCSS: mean = 6.32; correlation (r = 0.22, p = 0.05). Frequency distribution analysis demonstrated 61.4% of patients had low VVSymQ® and low VCSS; 31.3% had elevated VVSymQ® and increased VCSS; 7.3% were inconsistent with C2 disease. Strict concordance analysis revealed 40.5% had VVSymQ® (< 9)/VCSS (0-6), 18.6% had VVSymQ® (≥ 9)/VCSS (7-9), and 2.9% had VVSymQ® (≥9)/VCSS (≥10). CONCLUSIONS: For combined elevated VVSymQ® and VCSS, moderate/severe disease is corroborated, and intervention may be indicated. For combined lower scores, the disease severity is mild and conservative therapy is more appropriate.

The Effect of Laparoscopic Sleeve Gastrectomy on Gastroesophageal Reflux Disease.

BACKGROUND: The laparoscopic sleeve gastrectomy (LSG) has become one of the most popular surgical weight loss options. Since its inception as a procedure intended to promote durable weight loss, the association between LSG and gastroesophageal reflux disease (GERD) has been a point of debate. First and foremost, it is known that GERD occurs more frequently in the obese population. With the sleeve gastrectomy growing to be the predominant primary bariatric operation in the United States, it is imperative that we understand the impact of LSG on GERD. OBJECTIVE: To examine the effects of LSG on GERD symptoms. METHODS: One hundred and ninety-one bariatric surgery candidates completed a Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) questionnaire before and after undergoing elective LSG (mean follow-up time of 20.4 ± 2.7 months). Values were stratified by the presence or absence of preoperative GERD, GERD medications, age, gender, crural repair, patient satisfaction with present condition, and percent total weight loss (%TWL). RESULTS: For the entire group, mean weight loss, %TWL, and reduction in BMI were 79 pounds, 28.1%, and 12.7 kg/m2 respectively. Within the overall cohort, there was no significant change in GERD symptoms from before to after surgery (mean GERD-HRQL scores were 6.1 before and after surgery, p = 0.981). However, in a subgroup analysis, patients without GERD preoperatively demonstrated a worsening in mean GERD-HRQL scores after surgery (from 2.4 to 4.5, p = 0.0020). The percentage of change in the usage of medications to treat GERD was not statistically significant (from 37 to 32%, p = 0.233). The percent of patients satisfied with their condition postoperatively was significantly increased in those with preoperative GERD, older age, crural repair intraoperatively, and in those with the highest %TWL. CONCLUSION: These results suggest that while overall LSG does not significantly affect GERD symptoms, patients without GERD preoperatively may be at risk for developing new or worsening GERD symptoms after surgery. It is important to remark that this is a review of the patient's clinical symptoms of GERD, not related to any endoscopic, pathological, or manometry studies. Such studies are necessary to fully establish the effect of LSG on esophageal health.

Gastric band conversion to Roux-en-Y gastric bypass shows greater weight loss than conversion to sleeve gastrectomy: 5-year outcomes.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are often used as revisional surgeries for a failed laparoscopic adjustable gastric band (LAGB). There is debate over which procedure provides better long-term weight loss. OBJECTIVE: To compare the weight loss results of these 2 surgeries. SETTING: University hospital, United States. METHODS: A retrospective review was conducted of all LAGB to RYGB and LAGB to LSG surgeries performed at a single institution. Primary outcomes were change in body mass index (BMI), percent excess BMI lost, and percent weight loss. Secondary outcomes included 30-day complications and reoperations. RESULTS: The cohort included 192 conversions from LAGB to RYGB and 283 LAGB to LSG. The baseline age and BMI were similar in the 2 groups. Statistical comparisons made between the 2 groups at 24 months postconversion were significant for BMI (RYGB = 32.93, LSG = 38.34, P = .0004), percent excess BMI lost (RYGB = 57.8%, LSG = 29.3%, P < .0001), and percent weight loss (RYGB = 23.4%, LSG = 12.6%, P < .0001). However, the conversion to RYGB group had a higher rate of reoperation (7.3% versus 1.4%, P = .0022), longer operating room time (RYGB = 120.1 min versus LSG = 115.5 min, P < .0001), and longer length of stay (RYGB = 3.33 d versus LSG = 2.11 d, P < .0001) than the LAGB to LSG group. Although not significant, the conversion to RYGB group had a higher rate of readmission (7.3% versus 3.5%, P = .087). CONCLUSION: Weight loss is significantly greater for patients undergoing LAGB conversion to RYGB than LAGB to LSG. However, those undergoing LAGB conversion to RYGB had higher rates of reoperation and readmission. Patients looking for the most effective weight loss surgery after failed LAGB should be advised to have RYGB performed, while also understanding the increased risks of the procedure.

Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.

Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.