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BACKGROUND: The treatment of pancreatic cancer (PDAC) remains clinically challenging, and neoadjuvant therapy (NAT) offers down staging and improved surgical resectability. Abundant fibrous stroma is involved in malignant characteristic of PDAC. We aimed to investigate tissue remodelling, particularly the alteration of the collagen architecture of the PDAC microenvironment by NAT. METHODS: We analysed the alteration of collagen and gene expression profiles in PDAC tissues after NAT. Additionally, we examined the biological role of Ephrin-A5 using primary cultured cancer-associated fibroblasts (CAFs). RESULTS: The expression of type I, III, IV, and V collagen was reduced in PDAC tissues after effective NAT. The bioinformatics approach provided comprehensive insights into NAT-induced matrix remodelling, which showed Ephrin-A signalling as a likely pathway and Ephrin-A5 (encoded by EFNA5) as a crucial ligand. Effective NAT reduced the number of Ephrin-A5(+) cells, which were mainly CAFs; this inversely correlated with the clinical tumour shrinkage rate. Experimental exposure to radiation and chemotherapeutic agents suppressed proliferation, EFNA5 expression, and collagen synthesis in CAFs. Forced EFNA5 expression altered CAF collagen gene profiles similar to those found in PDAC tissues after NAT. CONCLUSION: These results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.

Background: In hepatocellular carcinoma (HCC), several standard regimens with angiogenesis inhibitors and immune checkpoint inhibitors have been established; however, novel therapeutic strategies to target key molecules associated with HCC are further required to improve treatment options. ErbB3 (HER3), a member of the HER receptor tyrosine kinase family, has recently emerged as a promising therapeutic target in various cancers. In this study, HER3 expression status after current targeted therapies in HCC was evaluated in order to explore an opportunity for developing anti-HER3 therapy for HCC. Methods: We collected clinical data and tumor tissue from HCC patients (pts) who received systemic therapy between January 2010 and June 2020 and the tissue samples at post systemic therapy were also obtained. Immunohistochemical staining for HER3 was conducted using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: Seventeen pts were eligible. Eight pts (47%) were HER3 2+/3+, (2+: 7, 3+: 1,), while nine pts (53%) were 0/1+ (0: 4, 1+: 5). For HER3 2+/3+ and HER3 0/1+ groups, median age (range) was 63(43-71)/69(47-78), median alpha-fetoprotein levels were 6071(4-23620)/19.1(1.2-1138) [ng/ml], and median des-gamma-carboxy prothrombin levels were 1351(135-92650)/302(10-10916) [mAU/ml], respectively. The proportions of patients with HER3 2+/3+ were 67% in HCV+ pts, 25% in HBV+ pts, and 43% in other etiologies. Median overall survival of HER3 2+/3+ and 0/1+ pts after start of first line systemic therapy was 32.3 (95% CI: 8.7-51.4) and 12.9 (95% CI: 6.1-20.7) months, respectively (HR: 0.28, 95% CI: 0.09-0.92, p=0.036).Paired pre- and post-treatment samples were available for eight pts. The median number of regimens administered between the pre- and post-treatment samples was 2(1-5). Treatment regimens were sorafenib: 7; lenvatinib: 2; ramucirumab: 1; others: 10, including duplicates. At post-treatment, HER3 was upregulated in 4 pts (1 pt: 0 to 1+, 3 pts: 1+ to 2+) and downregulated in 3 pts (all pts: 1+ to 0). Pts with HER3 upregulation had developed resistance after at least one prior tyrosine kinase inhibitor (TKI) with stable disease or partial response as best response. Conclusion: In this study, 47% of pts were HER3 2+/3+ at post-treatment. In paired analysis, half of pts upregulated HER3 expression after systemic therapy including TKIs, suggesting HER3 might be one of the factors associated with resistance to systemic therapy. Citation Format: Mao Okada, Chigusa Morizane, Tomoyuki Satake, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa, Maki Kobayashi, Kumiko Koyama, Minoru Esaki, Takuji Okusaka. HER3 expression after systemic therapy and clinical characteristics in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4484.

The expression of classical human leukocyte antigen class I antigens (HLA‐I) on the surfaces of cancer cells allows cytotoxic T cells to recognize and eliminate these cells. Reduction or loss of HLA‐I is a mechanism of escape from antitumor immunity. The present study aimed to investigate the clinicopathological impacts of HLA‐I and non–classical HLA‐I antigens expressed on pancreatic ductal adenocarcinoma (PDAC) cells. We performed immunohistochemistry to detect expression of HLA‐I antigens in PDAC using 243 PDAC cases and examined their clinicopathological influences. We also investigated the expression of immune‐related genes to characterize PDAC tumor microenvironments. Lower expression of HLA‐I, found in 33% of PDAC cases, was significantly associated with longer overall survival. Higher expression of both HLA‐E and HLA‐G was significantly associated with shorter survival. Multivariate analyses revealed that higher expression of these three HLA‐I antigens was significantly correlated with shorter survival. Higher HLA‐I expression on PDAC cells was significantly correlated with higher expression of IFNG, which also correlated with PD1, PD‐L1 and PD‐L2 expression. In vitro assay revealed that interferon gamma (IFNγ) stimulation increased surface expression of HLA‐I in three PDAC cell lines. It also upregulated surface expression of HLA‐E, HLA‐G and immune checkpoint molecules, including PD‐L1 and PD‐L2. These results suggest that the higher expression of HLA‐I, HLA‐E and HLA‐G on PDAC cells is an unfavorable prognosticator. It is possible that IFNγ promotes a tolerant microenvironment by inducing immune checkpoint molecules in PDAC tissues with higher HLA‐I expression on PDAC cells., human leukocyte antigen class I antigens (HLA‐I) are needed for T cells to recognize target cells. Here, we showed that higher HLA‐I expression on pancreatic cancer cells is associated with poor prognosis, where formation of the tolerant microenvironment may be involved in IFNγ.

BACKGROUND A right-sided round ligament (RSRL) is a rare, congenital anomaly of the intrahepatic portal vein, with a reported frequency of 0.2%-1.2%. For patients with perihilar cholangiocarcinoma associated with an RSRL, an accurate understanding of the vascular and biliary anatomy is indispensable. CASE SUMMARY We report a 70-year-old male with perihilar cholangiocarcinoma associated with an RSRL. After percutaneous transhepatic embolization of the left and anterior portal branches, we conducted a left trisectionectomy of the liver with extrahepatic bile duct resection and hepaticojejunostomy. The postoperative course was uneventful, and R0 resection was achieved. When the liver volume of each section was compared between 7 patients with an RSRL and 20 patients with normal portal vein anatomy, the posterior section in RSRL patients was significantly larger than that in patients with normal portal vein anatomy (median: 457 mL vs 306 mL, P = 0.031). In patients with perihilar cholangiocarcinoma associated with an RSRL, left trisectionectomy has several surgical advantages: (1) The posterior branch of the portal vein often ramifies independently, and the division of the portal vein is easily conducted; (2) A relatively large amount of remnant liver can be retained; and (3) The anatomy of the posterior branch of the Glissonian pedicle is similar to that in patients with normal anatomy. CONCLUSION In patients with an RSRL and perihilar cholangiocarcinoma that does not involve the posterior section, left trisectionectomy may be a favorable choice.

We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy.The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed.Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively.Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required.

Tissue amino acid profiles depend on the cell types and extracellular components that constitute the tissue, and their functions and activities. We aimed to characterize the tissue amino acid profiles in several types of pancreatic tumors and lesions. We examined tissue amino acid profiles in 311 patients with pancreatic tumors or lesions. We used newly developed LC-MS/MS methods to obtain the profiles, which were compared with clinicopathological data. Each tumor or lesion presented a characteristic tissue amino acid profile. Certain amino acids were markedly altered during the multistep pancreatic carcinogenesis and pancreatic ductal adenocarcinoma (PDAC) progression. A tissue amino acid index (TAAI) was developed based on the amino acids that were notably changed during both carcinogenesis and cancer progression. Univariate and multivariate survival analyses revealed that PDAC patients with a high TAAI exhibited a significantly shorter survival rate, and these findings were validated using a second cohort. We suggest that tissue amino acid profiles are characteristic for normal tissue type, tumor histological type, and pathological lesion, and are representative of the cancer grade or progression stage in multistep carcinogenesis and of malignant characteristics. The TAAI could serve as an independent prognosticator for patients with PDAC.

BACKGROUND We investigated whether patients with out-of-hospital cardiac arrest (OHCA) and sustained ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) or conversion to pulseless electrical activity/asystole (PEA/asystole) benefit more from extracorporeal cardiopulmonary resuscitation (ECPR). Methods and Results: We analyzed data from the Study of Advanced Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan, which was a prospective, multicenter, observational study with 22 institutions in the ECPR group and 17 institutions in the conventional CPR (CCPR) group. Patients were divided into 4 groups by cardiac rhythm and CPR group. The primary endpoint was favorable neurological outcome, defined as Cerebral Performance Category 1 or 2 at 6 months. A total of 407 patients had refractory OHCA with VF/pVT on initial electrocardiogram. The proportion of ECPR patients with favorable neurological outcome was significantly higher in the sustained VF/pVT group than in the conversion to PEA/asystole group (20%, 25/126 vs. 3%, 4/122, P

Neural invasion is one of the malignant features contributing to locally advanced and/or metastatic disease progression in patients with pancreatic ductal adenocarcinoma (PDAC). Few studies exist on the distribution and state of nerve fibers in PDAC tissue and their clinicopathological impacts. The aim of the present study was to investigate the clinicopathological characteristics and prognostic value of intrapancreatic neural alterations in patients with PDAC. We retrospectively analyzed 256 patients with PDAC who underwent macroscopic curative surgery. Nerve fibers, immunolabeled with a specific neural marker GAP‐43, were digitally counted and compared among PDAC, chronic pancreatitis (CP) and normal pancreatic tissues. Interlobular nerve fibers were apparently hypertrophic in both CP and PDAC, although intrapancreatic neural density and nerve number decreased characteristically in PDAC. They tended to decrease toward the center of the tumor. Kaplan‐Meier survival analyses revealed a statistically significant correlation between low neural density and shorter overall survival (OS) (P = 0.014), and between high neural invasion and shorter OS (P = 0.017). Neural density (P = 0.04; HR = 1.496; 95% CI 1.018‐2.199) and neural invasion ratio (P = 0.064; HR = 1.439; 95% CI .980‐2.114) were prognostic factors of shorter OS in the multivariate analysis. These findings suggest low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose a simple, practical and reproducible method (to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC), which has been validated using another cohort (n = 81).

Aim Intentional or unintentional acute drug poisoning occurs even in elderly people, but little is known about the factors influencing the intention to poisoning. A retrospective study was undertaken to describe the characteristics of acute drug poisoning in elderly people according to whether the poisoning was intentional or unintentional and the responsible agents. Methods The study was carried out in a single tertiary hospital in Japan. A total of 145 patients aged ≥65 years who were transferred by an ambulance service and were diagnosed with acute drug poisoning were included. Medical records were used to collect information on the intention behind poisoning and the responsible agents. Patients were divided into two groups according to whether they experienced intentional or unintentional poisoning and were further classified according to the responsible agent. Multivariable logistic regression models were used to estimate the association between hospitalization for acute drug poisoning and the use of benzodiazepine receptor agonists (BzRAs). Results Poisoning was unintentional in 102 (70.3%) patients and intentional in 43 (29.7%) patients. In total, 65 (44.8%) patients required hospitalization. Among patients in the unintentional poisoning group, those using non-BzRAs were more likely to be hospitalized than those using BzRAs (odds ratio, 6.64; 95% confidence interval, 2.56-17.22). The length of hospital stay was significantly longer in the unintentional poisoning group than in the intentional poisoning group (13.9 vs. 6.2 days; P = 0.013). Conclusions The proportion of unintentional poisoning in the elderly is high, and particularly with respect to poisoning with non-BzRAs, the hospitalization rates are high.

The outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors. This retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital. The 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226–10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594–10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0–1 risk factors and those with 2–3 risk factors, respectively (P

Background Whether the portal/superior mesenteric vein (PV) should be resected during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) based on preoperative CT or intraoperative findings is controversial. Methods This was a retrospective study with data of patients who had undergone pancreatoduodenectomy for PDAC between 2002 and 2016 in a tertiary referral centre. Based on the extent of contact between the PV and tumour on CT, patients were categorized into: group 1, no contact; group 2, contact 180° or less; group 3, contact greater than 180°. Extent of pathological PV invasion (pPV) (no invasion, pv0; invasion to tunica adventitia, pv1; invasion to media, pv2; invasion to intima, pv3) was compared with patient survival. To assess the feasibility of performing PV resection (PVR) based on intraoperative findings, the prognosis of patients in groups 1 and 2 with pv0 and no PVR (PVR(-)pv0) was compared with that of patients who had PVR (PVR(+)pv0), selected using propensity score matching. Results Groups 1, 2 and 3 comprised 230, 232 and 38 patients respectively, and PVR was performed in 10·9, 73·3 and 95 per cent of them (P

Background Patients with advanced-stage breast cancer often demonstrate pancreatic metastases. However, pancreatic metastases resection from breast cancer has been rarely performed, with only 20 cases having been reported to date. Case presentation A 49-year-old woman presented to our hospital in September 2003 with complaints of uncontrollable oozing from her left breast tumor. Computed tomography revealed a left breast tumor approximately 9.3 cm in diameter as well as heterogeneously enhanced solid mass lesions with necrotic foci in the pancreatic tail and body, up to 6.2 cm, which were radiologically diagnosed as pancreatic metastases from breast cancer. An emergent left simple mastectomy was performed to control bleeding. After epirubicin and cyclophosphamide hydrate treatment failed to improve her condition, the pancreatic metastases responded to weekly paclitaxel treatment, but eventually regrew. The patient underwent distal pancreatectomy with splenectomy, left adrenalectomy, partial stomach resection, and paraaortic lymph nodes excision in December 2004 after no other metastasis was confirmed. Furthermore, she received radiation therapy for left parasternal lymph node metastasis 6 months later. The patient recovered well. Consequently, she has no evidence of disease > 15 years after pancreatectomy. Conclusions This is the first reported case of pancreatectomy for pancreatic metastases from breast cancer, which was simultaneously diagnosed. Patients with no metastasis other than resectable pancreatic metastases and breast cancer and who possess some sensitivity for chemotherapy may benefit from pancreatectomy.

Background Sickle cell disease (SCD) is a monogenic disease characterized by sickle hemoglobin (HbS). Patients homozygous for HbS experience symptoms resulting from sickled erythrocytes no later than adolescence. However, heterozygous HbS carriers, or those with the so-called sickle cell trait (SCT), may undergo surgery without their hemoglobinopathy being known. Case presentation A 53-year-old Nigerian male with hepatitis C infection underwent radiofrequency ablation therapy for multiple hepatocellular carcinomas (HCCs) 17 months prior. Follow-up computed tomography (CT) revealed a solitary tumor (3.2 cm) in the medial section of the cirrhotic liver. The Child–Pugh score was five, and the indocyanine green retention rate at 15 min was 17.4%. The nontumorous liver of the medial section accounted for 10% of the total liver volume according to CT volumetry. With the diagnosis of recurrent HCC, left medial sectionectomy was performed under intermittent blood flow occlusion by Pringle’s maneuver. Intraoperative ultrasonography confirmed that hepatic blood flow had been preserved after hepatectomy. However, laboratory tests on postoperative day (POD) 1 revealed severe liver damage: aspartate aminotransferase 9250 IU/L, alanine aminotransferase 6120 IU/L, total bilirubin 2.8 mg/dL, and prothrombin time% 20.9%. The patient’s renal and respiratory functions also deteriorated; therefore, continuous hemodiafiltration and plasma exchange were initiated under mechanical ventilation. Whole-body contrast-enhanced CT showed no apparent ischemia of the remnant liver, but diffuse cerebral infarction was detected. Despite intensive treatments, he died of multiple organ failure on POD 20. The pathological examination of the resected specimen revealed that the intrahepatic peripheral vessels were occluded by sickled erythrocytes. Additionally, chromatographic analysis of hemoglobin detected the presence of abnormal hemoglobin, although microscopic examination of the peripheral blood erythrocytes did not show morphological abnormalities. Based on these findings, we determined that he had SCT and developed vaso-occlusive crisis involving multiple organs just after hepatectomy. Conclusion SCD is a rare disease in eastern Asia, but its prevalence is increasing globally. Surgeons should pay increased attention to this disease, especially when performing hepatectomy under blood flow occlusion.

Background: To assess medical procedures, particularly damage control resuscitation, at the time of transfer between hospitals for the purpose of treating massive hemorrhage.Methods: This study used a single-center retrospective observational design, enrolling patients referred to Teine Keijinkai Hospital from another hospital between April 2012 and March 2019 for the treatment of massive hemorrhage. We excluded patients who entered cardiac arrest before arriving at our center. Qualitative or categorical variables were compared using the χ2 or Fisher’s exact test, as appropriate. Quantitative continuous variables were compared using Mann-Whitney nonparametric tests, as appropriate. Risk factors associated with coagulopathy from univariate analyses (fibrinogen level £150 mg/dl; prothrombin time-international normalized ratio ³1.5) were entered into stepwise logistic regression analysis. Significance was defined for values of p < 0.05.Results: Multiple logistic regression analysis revealed trauma (odds ratio (OR) 4.800; 95% confidence interval (CI) 2.016–11.433; p < 0.001) and volume of crystalloid solution (OR 1.001; 95%CI 1.000–1.001; p = 0.008) as independent factors associated with coagulopathy. Patients with coagulopathy showed higher 24-h mortality rates (10.9%) than patients without coagulopathy (1.2%; p = 0.021), and cause of death was hemorrhagic shock for all cases of death within 24 h.Conclusion: In our area, withholding intravenous fluid to achieve permissive hypotension, early administration of fresh frozen plasma, and use of fibrinogen concentrate may improve the prognosis of patients with massive hemorrhage undergoing transfer between hospitals.Trial registration: UMIN, UMIN000041201. Registered 24 July 2020 – Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000047048

Simple Summary Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the serum of PC patients. These specific EVs with O-glycans can act as potential biomarkers in a liquid biopsy for PC patients screening. Abstract Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with O-glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

There is an increasing unmet need for successful immunotherapeutic interventions. Lymphocyte extravasation via tumor tissue endothelial cells (TECs) is required for lymphocyte infiltration into tumor sites. This study aimed to investigate the clinical significance of dysfunctional TECs in pancreatic ductal adenocarcinoma (PDAC) and identify chemical compounds that boost tumor-infiltrating lymphocyte (TIL) numbers. We performed immunohistochemical detection and clinicopathological analysis of VCAM-1 on TECs, which is essential for lymphocyte trafficking. We characterized the gene expression profiles of TECs from fresh PDAC tissues. We isolated compounds that upregulated VCAM-1 and E-selectin expression in TECs and examined their biological activities. Compared to endothelial cells from chronic pancreatitis tissue, TECs showed significantly lower VCAM-1 and E-selectin expression and significant weaknesses in lymphocyte adhesion and transmigration, resulting in decreased T cell infiltration around vessels. Patients with a relatively high percentage of VCAM-1+ vessels among all vessels in PDAC tissue had an improved prognosis. A bioinformatics survey demonstrated that TNFR1 signaling was involved in abnormal VCAM-1 and E-selectin expression in TECs. We screened compounds affecting TNFR1 signaling, and the IAP inhibitor, Embelin, induced these molecules on TECs and enhanced T cell adhesion to TECs and transmigration. Furthermore, in vivo, Embelin enhanced tumor-infiltrating T cell numbers, leading to an antitumor immune response. Embelin accelerates TIL infiltration and the antitumor immune response by recovering VCAM-1 expression in TECs. Our strategy may be a therapeutic approach for accelerating the immunotherapeutic response in immune-quiescent tumors, leading to clinical trials’ success.

Background Definitions of regional lymph nodes for gallbladder cancer differ according to staging system. Hence, the appropriate extent of lymph node dissection has not yet been standardized. Methods Pathological stages and disease-specific survival (DSS) of patients who had undergone surgical resection of gallbladder cancer between 1990 and 2016 were reviewed. Patients with nodal metastases limited to the hepatoduodenal ligament or common hepatic artery, extending to the posterosuperior pancreatic head lymph nodes (PSPLNs), or in nodes along the coeliac axis or superior mesenteric vessels were grouped as having Na, Nb and Nc disease respectively. Metastases beyond these regions were defined as distant metastases (M1). Absence of distant metastasis was expressed as M0. Results A total of 259 patients were evaluated. There were 74, 31 and nine patients respectively in the Na, Nb and Nc groups. Twenty-five, nine and four patients in the respective groups had M1 disease (P = 0·682). The 5-year DSS rate was comparable between patients with Na M0 and those with Nb M0 disease (36 versus 34 per cent respectively; P = 0·950), whereas the rate in patients with Nc M0 status (0 per cent) was worse than that of patients with Nb M0 (P = 0·017) and comparable to that of patients with M1 disease (14 per cent; P = 0·590). Among 22 patients with Nb M0 disease, the 5-year DSS rate did not differ between those who had undergone pancreatoduodenectomy and those who had had dissection of PSPLNs without pancreatoduodenectomy (50 versus 30 per cent respectively; P = 0·499). Conclusion PSPLNs and nodes along the hepatoduodenal ligament and hepatic artery should be considered regional nodes for gallbladder cancer, and should be resected.

Hepatocellular carcinoma (HCC) is the sixth-most common cancer and the third leading cause of cancer-related death in the world. However, 40-70% patients eventually suffer from postoperative recurrence within 5 years. HCC recurrence after surgery severely affects prognosis of the patients. Nevertheless, there is an opportunity to improve patients' prognosis if doctors and researchers can recognize the importance of a standardized perioperative management and study it in clinical and pre-clinical settings. Hence, based on our own experience and published studies from other researchers, we develop this consensus regarding multidisciplinary management of locally recurrent and metastatic hepatocellular carcinoma after resection. This consensus consists of the entire course of recurrent hepatocellular carcinoma (RHCC) management, including prediction of recurrence, prevention, diagnosis, treatment and surveillance of RHCC. Consensus recommendations are presented with grades of evidences (Ia, Ib, IIa, IIb, III and IV), and strength of recommendations (A, B, C, D and E). We also develop a decision-making path for RHCC treatment, which can intuitively demonstrate the management for RHCC. It is hoped that we may make some effort to standardize the management of RHCC and ultimately understand how to improve outcomes.

Background & Aims The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. Methods We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts ( BRAF , CDKN2A , CTNNB1 , GNAS , KRAS , NRAS , PIK3CA , RNF43 , SMAD4 , TP53 , and VHL ); to identify loss of heterozygozity at CDKN2A , RNF43 , SMAD4 , TP53 , and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. Results We identified molecular markers and clinical features that classified cyst type with 90%−100% sensitivity and 92%−98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. Conclusions We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Background Aggressive hepatectomy with venous resection has a higher risk of postoperative liver failure (POLF) than hepatectomy without venous reconstruction; however, venous reconstruction is technically demanding. We performed a novel two-stage hepatectomy (TSH) without venous reconstruction in a patient with bilobar multiple colorectal liver metastases located near the caval confluence, waiting for the development of intrahepatic venous collaterals between procedures. Case presentation A 60-year-old man was referred to our hospital with sigmoid colon cancer accompanied by intraabdominal abscess and two synchronous liver metastases. One of the liver tumors (tumor 1) was located in segment 8 near the caval confluence and was attached to both the right hepatic vein (RHV) and middle hepatic vein (MHV). The other tumor (tumor 2) in the left lobe invaded the umbilical portion of the portal vein. Both liver metastases decreased in size after four cycles of panitumumab/5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) therapy. Radical liver resection was planned because tumor 1 had not invaded the MHV. However, three-dimensional volumetric software showed that the non-congested volume of the future liver remnant was estimated at 354 ml, which corresponded to 26.3% of the total liver volume. TSH was scheduled to avoid POLF. We first performed limited resection of segment 8 with resection of the RHV root. After the first hepatectomy, the development of intrahepatic venous collaterals between the RHV and MHV was seen on computed tomography and magnetic resonance imaging. The estimated non-congested future liver remnant was 1242 ml, 78.5% of the total liver volume. Therefore, the patient underwent left hemihepatectomy 58 days after the first hepatectomy. We saw no adhesions around the porta hepatis, and the left hepatic artery and left branch of the portal vein were safely exposed and divided. Intraoperative Doppler ultrasonography revealed intrahepatic venous collaterals arising from RHV to MHV. The patient’s postoperative course was uneventful, and he underwent eight cycles of panitumumab/FOLFOX therapy for 5 months after the second hepatectomy. Conclusions Our TSH strategy helped avoid POLF by waiting for the development of intrahepatic venous collaterals.

Background Laparoscopic distal pancreatectomy has been shown to be associated with favorable postoperative outcomes using meta-analysis. However, there have been no randomized controlled studies yet. This study aimed to compare laparoscopic and open distal pancreatectomy using propensity score-matching. Methods We retrospectively collected perioperative data of 2,266 patients who underwent distalpancreatectomyin69institutesfrom2006–2013inJapan.Amongthem,2,010patients were enrolled in this study and divided into two groups, laparoscopic distal pancreatectomy and open distal pancreatectomy. Perioperative outcomes were compared between the groups using unmatched and propensity matched analysis. Results After propensity score-matching, laparoscopic distal pancreatectomy was associated with favorable perioperative outcomes compared with open distal pancreatectomy, including higher rate of preservation of spleen and splenic vessels (P

AIM To clarify the histological changes associated with liver atrophy after percutaneous transhepatic portal embolization (PTPE) in pigs and humans. METHODS As a preliminary study, we performed pathological examinations of liver specimens from five pigs that had undergone PTPE in a time-dependent model of liver atrophy. In specimens from embolized lobes (EMB) and nonembolized lobes (controls), we measured the portal vein to central vein distance (PV-CV), the area and number of hepatocytes per lobule, and apoptotic activity using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Immunohistochemical reactivities were evaluated for light chain 3 (LC3) and lysosomal-associated membrane protein 2 (LAMP2) as autophagy markers and for glutamine synthetase and cytochrome P450 2E1 (CYP2E1) as metabolic zonation markers. Samples from ten human livers taken 20-36 d after PTPE were similarly examined. RESULTS PV-CVs and lobule areas did not differ between EMB and controls at day 0, but were lower in EMB than in controls at weeks 2, 4, and 6 (P ≤ 0.001). Hepatocyte numbers were not significantly reduced in EMB at day 0 and week 2 but were reduced at weeks 4 and 6 (P ≤ 0.05). Apoptotic activity was higher in EMB than in controls at day 0 and week 4. LC3 and LAMP2 staining peaked in EMB at week 2, with no significant difference between EMB and controls at weeks 4 and 6. Glutamine synthetase and CYP2E1 zonation in EMB at weeks 2, 4, and 6 were narrower than those in controls. Human results were consistent with those of porcine specimens. CONCLUSION The mechanism of liver atrophy after PTPE has two histological phases: Hepatocellular atrophy is likely caused by autophagy in the first 2 wk and apoptosis thereafter.