Contrasting seasonality of the incidence of incisional surgical site infection after general and gastroenterological surgery: An analysis of 8,436 patients in a single institute.

BACKGROUND: While seasonality of hospital-acquired infections, including incisional SSI after orthopaedic surgery, is recognized, the seasonality of incisional SSI after general and gastroenterological surgeries remains unclear. STUDY DESIGN: This retrospective single-institute observational study analysed the seasonality and risk factors of incisional SSI after general and gastroenterological surgeries using univariate and multivariable analyses. The evaluated variables included age, sex, surgical approach, surgical urgency, operation time, wound classification, and the American Society of Anesthesiologists physical status (ASA-PS). RESULTS: 8,436 patients were enrolled. General surgeries (n=2,241) showed a pronounced SSI incidence in summer (3.9%; odds ratio [OR] 1.87; 95% confidence interval [CI] 1.05-3.27; p=0.025) compared to other seasons (2.1%). Conversely, gastroenterological surgeries (n=6,195) showed a higher incidence in winter (8.3%; OR 1.38; 95% CI 1.10-1.73; p=0.005) than in other seasons (6.1%). Summer for general surgery (OR 1.90; 95% CI 1.12-3.24; p=0.018) and winter for gastroenterological surgery (OR 1.46; 95% CI 1.17-1.82; p=0.001) emerged as independent risk factors for incisional SSI. Open surgery (OR, 2.72; 95% CI 1.73-4.29, p<0.001) and an ASA-PS score ≥3 (OR, 1.64; 95% CI 1.08-2.50, p=0.021) were independent risk factors for incisional SSI in patients undergoing gastroenterological surgery during winter. CONCLUSION: Seasonality exists in the incisional SSI incidence following general and gastroenterological surgeries. Recognizing these trends may help enhance preventive strategies, highlighting the elevated risk in summer for general surgery and in winter for gastroenterological surgery.

Thick mesopancreas is a novel predictor of surgical outcomes of patients who undergo pancreaticoduodenectomy.

PURPOSE: Mesopancreas resection is a crucial but difficult procedure when performing pancreaticoduodenectomy. This study evaluated the influence of mesopancreas thickness on surgical outcomes in patients undergoing pancreaticoduodenectomy. METHODS: We measured the thickness of the fat tissue on the right side of the superior mesenteric artery from the dorsal margin of the confluence of the superior mesenteric vein and portal vein to the ventral margin of the left renal vein on preoperative contrast-enhanced computed tomography and defined it as the mesopancreas thickness. We evaluated the correlation between mesopancreas thickness and intraoperative and postoperative variables in 357 patients who underwent pancreaticoduodenectomy. RESULTS: Multivariate analysis revealed that a thick mesopancreas was significantly associated with a long operative time (ß = 10.361; 95% confidence interval, 0.370-20.353, p = 0.042), high estimated blood loss (ß = 36.038; 95% confidence interval, -27.192-99.268, p = 0.013), and a low number of resected lymph nodes (ß = -1.551; 95% confidence interval, -2.662--0.439, p = 0.006). This analysis further revealed that thick mesopancreas was a significant risk factor for overall morbidity (odds ratio 2.170; 95% confidence interval 1.340-3.520, p = 0.002), major morbidity (odds ratio 2.430; 95% confidence interval 1.360-4.340, p = 0.003), and a longer hospital stay (ß = 2.386; 95% confidence interval 0.299-4.474, p = 0.025). CONCLUSION: A thick mesopancreas could predict a longer operation time, higher estimated blood loss, fewer resected lymph nodes, more frequent overall and major morbidities, and a longer hospital stay in patients who underwent pancreaticoduodenectomy more precisely than the body mass index.

Superiority trial for the development of an ideal method for the closure of midline abdominal wall incisions to reduce the incidence of wound complications after elective gastroenterological surgery: study protocol for a randomized controlled trial.

BACKGROUND: The recent guidelines from the European and American Hernia Societies recommend a continuous small-bite suturing technique with slowly absorbable sutures for fascial closure of midline abdominal wall incisions to reduce the incidence of wound complications, especially for incisional hernia. However, this is based on low-certainty evidence. We could not find any recommendations for skin closure. The wound closure technique is an important determinant of the risk of wound complications, and a comprehensive approach to prevent wound complications should be developed. METHODS: We propose a single-institute, prospective, randomized, blinded-endpoint trial to assess the superiority of the combination of continuous suturing of the fascia without peritoneal closure and continuous suturing of the subcuticular tissue (study group) over that of interrupted suturing of the fascia together with the peritoneum and interrupted suturing of the subcuticular tissue (control group) for reducing the incidence of midline abdominal wall incision wound complications after elective gastroenterological surgery with a clean-contaminated wound. Permuted-block randomization with an allocation ratio of 1:1 and blocking will be used. We hypothesize that the study group will show a 50% reduction in the incidence of wound complications. The target number of cases is set at 284. The primary outcome is the incidence of wound complications, including incisional surgical site infection, hemorrhage, seroma, wound dehiscence within 30 days after surgery, and incisional hernia at approximately 1 year after surgery. DISCUSSION: This trial will provide initial evidence on the ideal combination of fascial and skin closure for midline abdominal wall incision to reduce the incidence of overall postoperative wound complications after gastroenterological surgery with a clean-contaminated wound. This trial is expected to generate high-quality evidence that supports the current guidelines for the closure of abdominal wall incisions from the European and American Hernia Societies and to contribute to their next updates. TRIAL REGISTRATION: UMIN-CTR UMIN000048442. Registered on 1 August 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055205.

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

CA19-9 With Two-stage Resection Is Useful for Conversion Surgery in PDAC With Synchronous Oligometastases.

BACKGROUND/AIM: Pancreatic adenocarcinoma (PDAC) with synchronous oligometastases may indicate a surgical benefit after chemotherapy. We investigated whether primary and metastatic resection of PDAC with oligometastases can improve the survival and then explored prognostic factors to identify indications for conversion surgery. PATIENTS AND METHODS: We reviewed 425 patients with PDAC who underwent pancreatic resection from 2005 to 2019. Clinical characteristics and outcomes were analyzed. Two-stage resection was defined as preceding metastasectomy and subsequent primary resection after chemotherapy. RESULTS: Fifteen patients (3.5%) had synchronous oligometastases. We evaluated the overall survival of the patients with oligometastases and those without metastases. The survival curves almost completely overlapped (median survival time: 35.9 vs. 32.1 months). The univariate Cox regression analysis revealed a normal level of preoperative CA19-9 (p=0.075), two-stage resection (p=0.072), and R0 resection (p=0.064) were likely promising prognostic factors. The combination of a normal level of preoperative CA19-9 with two-stage resection was a significant prognostic factor (p=0.038). In addition, patients with a normal preoperative CA19-9 level and two-stage resection had better survival (46.1 vs. 28.1 months, p=0.026). CONCLUSION: The combination of normal preoperative CA19-9 with two-stage resection can be a useful way to identify patients with PDAC and oligometastases for surgical indication.

A postoperative body weight increase is a novel risk factor for incisional hernia of midline abdominal incision after elective gastroenterological surgery.

PURPOSE: Midline abdominal incisions (MAIs) are widely used in both open and minimally invasive surgery. Incisional hernia (IH) accounts for most long-term postoperative wound complications. This study explored the risk factors for IH due to MAI in patients with clean-contaminated wounds after elective gastroenterological surgery. METHODS: The present study targeted patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional SSI prevention after gastroenterological surgery for clean-contaminated wounds. The patients were reassessed, and pre- and intraoperative variables and postoperative outcomes were collected. IH was defined as any abdominal wall gap, regardless of bulge, in the area of a postoperative scar that was perceptible or palpable on clinical examination or computed tomography according to the European Hernia Society guidelines. The risk factors for IH were identified using univariate and multivariate analyses. RESULTS: The study population included 1,281 patients, of whom 273 (21.3%) developed IH. Seventy-four (5.8%) patients developed incisional SSI. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR], 1.39; 95% confidence interval [CI] 1.03-1.86, p = 0.031), high preoperative body mass index (OR, 1.81; 95% CI 1.19-2.77, p = 0.006), incisional SSI (OR, 2.29; 95% CI 1.34-3.93, p = 0.003), and postoperative body weight increase (OR, 1.49; 95% CI 1.09-2.04, p = 0.012) were independent risk factors for IH due to MAI in patients who underwent elective gastroenterological surgery. CONCLUSION: We identified postoperative body weight increase at one year as a novel risk factor for IH in patients with MAI after elective gastroenterological surgery.

Collagen XVII regulates tumor growth in pancreatic cancer through interaction with the tumor microenvironment.

Expression of the gene for collagen XVII (COL17A1) in tumor tissue is positively or negatively associated with patient survival depending on cancer type. High COL17A1 expression is thus a favorable prognostic marker for breast cancer but unfavorable for pancreatic cancer. This study explored the effects of COL17A1 expression on pancreatic tumor growth and their underlying mechanisms. Analysis of published single-cell RNA-sequencing data for human pancreatic cancer tissue revealed that COL17A1 was expressed predominantly in cancer cells rather than surrounding stromal cells. Forced expression of COL17A1 did not substantially affect the proliferation rate of the mouse pancreatic cancer cell lines KPC and AK4.4 in vitro. However, in mouse homograft tumor models in which KPC or AK4.4 cells were injected into syngeneic C57BL/6 or FVB mice, respectively, COL17A1 expression promoted or suppressed tumor growth, respectively, suggesting that the effect of COL17A1 on tumor growth was influenced by the tumor microenvironment. RNA-sequencing analysis of tumor tissue revealed effects of COL17A1 on gene expression profiles (including the expression of genes related to cell proliferation, the immune response, Wnt signaling, and Hippo signaling) that differed between C57BL/6-KPC and FVB-AK4.4 tumors. Our data thus suggest that COL17A1 promotes or suppresses cancer progression in a manner dependent on the interaction of tumor cells with the tumor microenvironment.

Chronic Glucocorticoid Use is a Potential Risk Factor for Delayed Pancreatic Fistula after Laparoscopic Distal Pancreatectomy: A Retrospective Analysis.

Pancreatic fistula is a potentially morbid complication after distal pancreatectomy. Chronic glucocorticoid use is one of the risk factors for pancreatic fistula in pancreaticoduodenectomy, though it has not been reported in distal pancreatectomy. We explored whether chronic glucocorticoid use can be a risk factor for pancreatic fistula in distal pancreatectomy. We reviewed 408 consecutive patients who underwent elective distal pancreatectomy from 2011 to 2021. We evaluated two kinds of pancreatic fistula (postoperative pancreatic fistula and delayed pancreatic fistula). We defined delayed pancreatic fistula as a patient who was re-admitted for pancreatic fistula after the first discharge from the hospital. Preoperative characteristics and postoperative outcomes were analyzed. Two hundred sixty-seven patients underwent open distal pancreatectomy, while 141 patients had laparoscopic distal pancreatectomy. A comparison of patient with and without chronic glucocorticoid use showed that only patients with chronic glucocorticoid use developed delayed pancreatic fistula (0% vs. 16.7%; p < 0.001). In addition, delayed pancreatic fistula occurred in only laparoscopic distal pancreatectomy patients with chronic glucocorticoid use (0% vs. 25.0%; p < 0.001). Although sample size is small, it is reasonable to presume that chronic glucocorticoid use is a potential risk factor for delayed pancreatic fistula in laparoscopic distal pancreatectomy.

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, and in vivo T-cell depletion and CD8+ T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-γ+ T-cells. Depletion of CD8+ but not CD4+ T-cells compromised efficacy. Conversely, CD8+ T-cell transfer from Cxcr3-/- versus Cxcr3+/+ mice into Rag1-/- immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 "priming") with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.

[A Case of an Elderly Patient Who Underwent Conversion Resection for Pancreatic Cancer with Positive Peritoneal Cytology].

We report a case of an elderly patient, 82 years-old, with initially-unresectable pancreatic head cancer, who successfully underwent complete resection of the primary lesion after systemic chemotherapy for 6 months. The patient had a history of pancreatic body-tail resection for intraductal papillary mucinous carcinoma in 2005. In 2020, a routine examination revealed an increased CA19-9 value of 1,958 U/mL and showed a pancreatic head tumor of 35 mm on CT images. Finally, the tumor was pathologically diagnosed as pancreatic cancer by a biopsied sample. Although CT images showed no distant metastasis, peritoneal lavage cytology was indicated as positivity(H0P0CY1)in the staging laparoscopy. We implanted a peritoneal port and introduced systemic chemotherapy of gemcitabine and nab-paclitaxel combination therapy. This treatment for 6 months induced tumor shrinkage to 30 mm on the CT image, normalized CA19-9 value to 22.6 U/mL, and negative cytology in the collected lavage fluid from the peritoneal port. The patient's general condition was maintained even after the chemotherapy and the lavage cytology was pathologically diagnosed as negative(H0P0CY0)in the repeated staging laparoscopy, therefore we decided to perform pancreaticoduodenectomy as a conversion surgery. The patient was discharged on the 21st postoperative day with an uneventful course and underwent adjuvant chemotherapy of S-1 for 6 months. No recurrence was found in 8 months after the surgery. In such a case of the selected elderly patient with a maintained general condition, it is feasible to undergo multimodal treatments including conversion surgery for an initially-unresectable pancreatic cancer with positive peritoneal cytology.

Negative prognostic impact of sarcopenia before and after neoadjuvant chemotherapy for pancreatic cancer.

OBJECTIVES: To elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). METHODS: We retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models. RESULTS: The MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14-3.78, p = 0.016) than that before NAC (2.14, 1.23-3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26-4.05, p = 0.007); borderline resectability (1.96, 1.04-3.69, p = 0.038); operative blood loss (2.60, 1.38-4.88, p = 0.003); and distant metastasis (3.31, 1.40-7.82, p = 0.006). CONCLUSIONS: Sarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.

Pancreaticoduodenectomy for pancreatic head cancer with cavernous transformation of the portal vein: a case report.

BACKGROUND: Cavernous transformation of the portal vein (CTPV) due to extrahepatic portal vein obstruction is a rare vascular anomaly. Since its symptoms usually appear in childhood, most of the adult cases are detected unexpectedly with other diseases. Only a few reports have described surgical difficulties in patients with CTPV. We report a case of pancreatic head cancer with CTPV in a patient who underwent pancreaticoduodenectomy. CASE PRESENTATION: A 77-year-old man with epigastric and back pain was referred to our hospital. Computed tomography revealed a tumor in the pancreatic head and a CTPV near the hepatic hilum. CTPV consisted of two main collateral vessels connected by multiple surrounding small vessels. Also, portal vein obstruction was observed near the hepatic hilum, which was far from the pancreatic head tumor. After confirming that there was no distant metastasis by a thorough whole-body search, we performed a pancreaticoduodenectomy following neoadjuvant chemotherapy. During the operation, we carefully manipulated the area of the CTPV and omitted lymph node dissection in the hepatoduodenal ligament to prevent massive venous bleeding and intestinal congestion. Pancreaticoduodenectomy was performed without any intraoperative complications and the postoperative course was uneventful. Complete tumor resection was histologically confirmed. CONCLUSION: Although pancreaticoduodenectomy for patients with CTPV involves many surgical difficulties, we successfully performed it by determining specific treatment strategies tailored to the patient and following careful and delicate surgical procedures.

Increased CD8+ T-cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma.

Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8-9 mice per group, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti-PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. DESIGN: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. RESULTS: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. BASIC PROCEDURES: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. MAIN FINDINGS: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. PRINCIPAL CONCLUSIONS: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.

Risk factors for difficulty of laparoscopic cholecystectomy in grade II acute cholecystitis according to the Tokyo guidelines 2013.

BACKGROUND: The Tokyo Guidelines 2013 classifies acute cholecystitis (AC) into three grades and recommends appropriate therapy for each grade. For grade II AC, either early laparoscopic cholecystectomy (LC) or percutaneous transhepatic gallbladder drainage (PTGBD) should be performed. This study aimed to identify the risk factors for difficulty of LC for treating grade II AC. METHODS: Totally, 122 patients who underwent LC for grade II AC were enrolled and divided into difficult LC (DLC) and nondifficult LC (NDLC) groups. The DLC group included patients who experienced one of the following conditions: conversion from LC to open cholecystectomy, operating time ≥ 180 min, or blood loss ≥300 ml. Preoperative characteristics and postoperative outcomes were analyzed. RESULTS: In univariate analysis, risk factors included male sex, interval between symptom onset and admission, interval between symptom onset and LC, and anticoagulant therapy. The incidence of postoperative complications was higher in the DLC group than in the NDLC group (23.5% vs. 4.6%, p = 0.0016). According to receiver operating characteristic curves, the optimal cutoff value was calculated, and multivariate analysis showed that male sex [odds ratio (OR), 5.76; 95% confidence interval (CI), 1.979-19.51; p = 0.0009) and interval between symptom onset and LC of over 96 h (OR, 6.32; 95% CI, 2.126-20.15; p = 0.0009) were independent risk factors for difficulty of LC. CONCLUSIONS: In patients with grade II AC, LC was technically difficult when performed over 96 h after symptom onset. Moreover, male sex was a risk factor. Therefore, PTGBD should be considered in these patients.

Extreme dilatation of the interposed jejunal pouch after proximal gastrectomy associated with portal venous gas: A case report.

INTRODUCTION: The jejunal pouch interposition (JPI) after proximal gastrectomy (PG) was proposed as a reconstructive procedure to provide a gastric reservoir substitute and prevent postgastrectomy syndrome. However, food residue remaining in some of the pouches resulted in the adverse effect of abdominal bloating, thereby body weight loss. Here, we report a rare case with an extreme dilation of the interposed jejunal pouch (JP) 8 years after PG, requiring pouch resection. PRESENTATION OF CASE: A 65-year-old-man who had undergone PG with an inverted U-shaped JPI for early gastric cancer 8 years previously, suffered from shock after right hip joint implantation. Abdominal enhanced CT scan revealed an extremely dilated JP accompanied by portal venous gas. After 5 months of conservative therapy, he underwent resection of the JP and gastric remnant with Roux-en-Y esophagojejunostomy reconstruction. After the operation, the patient has remained in good health for over 3 years. DISCUSSION AND CONCLUSION: Long-term operative outcome following pouch operation for gastric cancer still remains controversial. Surgical intervention should be considered when we encounter patients who have refractory pouch dilatation after surgery for gastric cancer.

Optimal timing of cholecystectomy after percutaneous gallbladder drainage for severe cholecystitis.

BACKGROUND: The Tokyo guideline for acute cholecystitis recommended percutaneous transhepatic gallbladder drainage followed by cholecystectomy for severe acute cholecystitis, but the optimal timing for the subsequent cholecystectomy remains controversial. METHODS: Sixty-seven patients who underwent either laparoscopic or open cholecystectomy after percutaneous transhepatic gallbladder drainage for severe acute cholecystitis were enrolled and divided into difficult cholecystectomy (group A) and non-difficult cholecystectomy (group B). Patients who had one of these conditions were placed in group A: 1) conversion from laparoscopic to open cholecystectomy; 2) subtotal cholecystectomy and/or mucoclasis; 3) necrotizing cholecystitis or pericholecystic abscess formation; 4) tight adhesions around the gallbladder neck; and 5) unsuccessfully treated using PTGBD. Preoperative characteristics and postoperative outcomes were analyzed. RESULTS: The interval between percutaneous transhepatic gallbladder drainage and cholecystectomy in Group B was longer than that in Group A (631 h vs. 325 h; p = 0.031). Postoperative complications occurred more frequently when the interval was less than 216 h compared to when it was more than 216 h (35.7 vs. 7.6%; p = 0.006). CONCLUSIONS: Cholecystectomy for severe acute cholecystitis was technically difficult when performed within 216 h after percutaneous transhepatic gallbladder drainage.

All-trans retinoic acid enhances gemcitabine cytotoxicity in human pancreatic cancer cell line AsPC-1 by up-regulating protein expression of deoxycytidine kinase.

We previously showed that gemcitabine resistance in pancreatic cancer chemotherapy correlates with suppressed expression of deoxycytidine kinase (dCK), which catalyzes the rate-limiting step of gemcitabine activation. The purpose of the present study was to find a drug that might be useful to enhance the cytotoxicity of gemcitabine by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cell line AsPC-1. Screening of 40 prescription drugs identified 35 with no intrinsic cytotoxicity towards AsPC-1 cells. When AsPC-1 cells were pre-incubated with these drugs and then incubated with gemcitabine, we found that all-trans retinoic acid (ATRA) significantly decreased the viability by 28% compared with that of non-treated cells. Luciferase assay showed that ATRA transactivated the DCK promoter in AsPC-1 cells by about 2-fold compared with the untreated control, and an increase of dCK protein expression was confirmed by immunoblotting. ATRA decreased the half-maximal inhibitory concentration (IC50) of gemcitabine by 2.8-fold (ATRA-non-treated cells, 28.8nM; ATRA-treated cells, 10.0nM). The ATRA concentration of 0.03µM was sufficient to enhance gemcitabine cytotoxicity, and the effect was well maintained in the concentration range from 0.03 to 50µM. These results indicate that ATRA enhances gemcitabine cytotoxicity by increasing dCK expression in gemcitabine-resistant human pancreatic cancer cells.

MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells.

OBJECTIVES: Platelet-derived growth factor receptor beta (PDGFRß) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRß, on the interaction between PCCs and PSCs. METHODS: In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRß and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. RESULTS: In PSCs, PDGFRß and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. CONCLUSIONS: The PDGFRß and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.