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The element magnesium (Mg) is involved in various metabolic reactions within the human body, and its deficiency is considered a risk factor for several diseases. In this study, we investigated the relationship between serum Mg levels and mortality in a community-based population. We prospectively assessed the association between serum Mg levels at enrollment and all-cause mortality in 1,314 participants who underwent a community health examination. The mean serum Mg level was 2.4 (±0.2) mg/dL. Patients with serum Mg levels ≤2.3 mg/dL constituted the low Mg group, while those with serum Mg ≥2.4 mg/dL constituted the high Mg group. Ninety-three (7.1%) patients died during the 10-y follow-up period. Kaplan-Meier analysis revealed that all-cause mortality was significantly higher in the low Mg group (log-rank p0.05). Cox proportional hazards analysis revealed a significant association in the unadjusted model (hazard ratio [HR] 1.72, 95% confidence intervals [CI] 1.14-2.58, p0.01) and in the fully adjusted model (HR 1.73, 95% CI 1.09-2.76, p0.05). This association was particularly strong in males (HR 2.08, 95% CI 1.19-3.63, p0.05). Low serum Mg levels were significantly associated with the risk of all-cause mortality among males in a community-based Japanese population.

Cripto-1 is a plasma membrane protein which is not expressed in adult tissue, but some tumors are accompanied by re-activation. We studied the clinical and biological significance of Cripto-1 in colorectal cancer. Cripto-1 was positive in 68 out of 192 cases (35%) by immunohistochemistry. Cripto-1 expression was correlated with worse prognosis and was an independent prognostic factor. Cripto-1-silenced colorectal cancer cell lines had reduced cell proliferation, migration, and activation of Akt and MAPK signaling pathways

A 64-year-old man with gastric tumor in the antrum had been diagnosed with gastric neuroendocrine carcinoma(NEC) by biopsy and multiple lymph node metastases(#3 and #6)by abdominal computed tomography. After staging laparoscopy showed that there were no non-curative factors, neoadjuvant chemotherapy(S-1/cisplatin[CDDP]: 2 courses)and distal gastrectomy and D2 lymph node dissection were performed. The pathological diagnosis was shown as pathological complete response(pCR). After adjuvant chemotherapy(S-1/CDDP: 2 courses, S-1: 6 courses)was administered, the patient is alive at 8 years without recurrence.

A 75-year-old man with a Type 3 advanced gastric cancer in the middle gastric body and paraaortic lymph node swelling was treated chemotherapy. After treatment, we performed an exploratory laparotomy and curative total gastrectomy. As adjuvant chemotherapy, S-1 treatment was administrated for 4 courses but multiple metastases from left supraclavicular to paraaortic lymph nodes. First, Cape plus CDDP plus T-mab therapy treated. Because of acute renal failure, Cape plus L-OHP plus T-mab was administrated but response evaluation was PD. In the second-line therapy, Ramucirumab plus paclitaxel was performed 4 courses. Third, we administrated Nivolumab. After 6 courses, response evaluation was PR and we continued 24 courses. At the same time, there was acute-onset Nivolumab-induced organizing pneumonia and we treated steroid pulse, azithromycin and introduced home oxygen therapy. At the present, 47 months long-term survival achieved after Nivolumab treatment.

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.

To investigate the impact of early postoperative drainage fluid culture positivity on the development of clinically relevant postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD). We assessed the positive prevalence, distribution, and drug sensitivity of microorganisms in drainage fluid collected on postoperative day (POD) 1 after PD from 465 patients. Culture results were positive in pancreaticojejunostomy (PJ) drainage fluid from 26.0% of patients. Similar distributions of microorganisms were observed in the bile juice and PJ/hepaticojejunostomy (HJ) drainage fluid from these patients. PJ drain culture positivity was associated with an elevated drainage amylase level and with preoperative biliary drainage. No associations were seen between HJ drainage culture positivity and the drainage amylase and bilirubin levels. PJ drainage culture positivity was found to be an independent predictor of grade B/C POPF. According to the antibiogram, the bacteria identified were likely to be resistant to prophylactic antibiotics. PJ drainage culture positivity on POD 1 in combination with an elevated drainage amylase level is an early predictor of grade B/C POPF. PJ drainage culture positivity may be attributable to bile juice contamination caused by intraoperative spillage and early postoperative leakage from the PJ anastomotic sites.

The neoadjuvant therapy against locally advanced pancreatic cancer(LAPC)have been developed by combining radiation with chemotherapy. We experienced a case of LAPC performed R0 resection and obtained high histopathological effect by carbon-ion radiotherapy with gemcitabine(GEM).A 65-year-old male with epigastric and back pain was suspected as pancreas cancer by FDG-PET/CT scan, and was referred to our hospital. CT scan revealed a tumor in pancreatic body with poor contrast effect and with invasion to celiac artery, common hepatic artery and portal vein, and diagnosed as pancreatic adenocarcinoma by endoscopic ultrasound-fine needle aspiration(EUS-FNA). Therefore we diagnosed the tumor as pancreatic body cancer, cT4, cN1a, cM0, cStage Ⅲ, UR-LA. GEM plus nab-paclitaxel(GnP)were administered for 4 months followed by carbon-ion radiotherapy with GEM at other hospital. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed 3 months after irradiation. High therapeutic effect was obtained histopathologically( Evans grade Ⅲ), and lesions outside the pancreas disappeared except for metastasis to one lymph node (ypT1c, ypN1a, ycM0, ypStage ⅡB), and R0 resection was performed.Carbon-ion radiotherapy with chemotherapy for LAPC may improve curative resection rate.

Patients with pancreatic cancer have a poor prognosis, therefore identifying particular tumor characteristics associated with prognosis is important. This study aims to investigate the utility of radiomics with machine learning using 18F-fluorodeoxyglucose (FDG)-PET in patients with pancreatic cancer. We enrolled 161 patients with pancreatic cancer underwent pretreatment FDG-PET/CT. The area of the primary tumor was semi-automatically contoured with a threshold of 40% of the maximum standardized uptake value, and 42 PET features were extracted. To identify relevant PET parameters for predicting 1-year survival, Gini index was measured using random forest (RF) classifier. Twenty-three patients were censored within 1 year of follow-up, and the remaining 138 patients were used for the analysis. Among the PET parameters, 10 features showed statistical significance for predicting overall survival. Multivariate analysis using Cox HR regression revealed gray-level zone length matrix (GLZLM) gray-level non-uniformity (GLNU) as the only PET parameter showing statistical significance. In RF model, GLZLM GLNU was the most relevant factor for predicting 1-year survival, followed by total lesion glycolysis (TLG). The combination of GLZLM GLNU and TLG stratified patients into three groups according to risk of poor prognosis. Radiomics with machine learning using FDG-PET in patients with pancreatic cancer provided useful prognostic information.

Pancreatic cystic neoplasms (PCNs) are a heterogeneous group with varying risks of malignancy. To explore the clinical utility of liquid biopsy in cyst type classification, we analyzed the GNAS/KRAS mutations in circulating cell-free DNA (cfDNA) obtained from 57 patients with histologically diagnosed PCNs, including 34 with intraductal papillary mucinous neoplasms (IPMNs) and compared the mutant allele prevalence and variant patterns with the paired resected specimens using next-generation sequencing. The positive prevalence of GNAS mutations in cfDNA of patients with IPMN (n = 11, 32%) was significantly higher than that in those with other PCNs (0%, P = 0.002). Conversely, KRAS mutations were detected in cfDNA of only 2 (6%) IPMN patients. The paired-sample comparison revealed highly concordance between the GNAS mutation status of cfDNA and resected IPMN specimens. Similar distributions of GNAS mutation positivity in cfDNA were observed across the different histological grades, whereas IPMNs with intestinal subtype showed a significantly higher prevalence of GNAS mutations than other subtypes (P = 0.030). GNAS mutation positivity in cfDNA was significantly associated with the acellular mucin pool of histological findings in primary IPMN lesions (P = 0.017). Detection of GNAS mutation in cfDNA can serve as a novel biomarker for cyst type classification and differentiation of intestinal subtype IPMN from the other PCNs.

Objective The aim of the study was to clarify the diagnostic impact of measuring serum anti-p53 antibody (S-p53Ab) in predicting the histological grades of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Methods We compared the measured values and positive prevalence of S-p53Ab across the different histological grades of 111 resected IPMN cases. We also evaluated the TP53 alterations using immunohistochemistry and next-generation sequencing. Results Serum anti-p53 antibody were detected in 6 of 111 cases, all of their histological grades were high-grade dysplasia (HGD) and invasive carcinoma (INV). Positive prevalence of S-p53Ab was higher in cases with INV (4/35 cases, 11.4%) than those with HGD (2/38 cases, 5.3%), whereas S-p53Abs were undetectable in cases with low-grade dysplasia. Measured S-p53Ab values were not correlated with either carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9). In 4 of 6 S-p53Ab-positive cases, the TP53 alterations-somatic pathogenic mutations or aberrant immunoreactivity-were identified in their IPMN lesions. A combination assay of S-p53Ab, CEA, and CA 19-9 revealed a 38.4% sensitivity and 81.6% specificity for predicting HGD/INV. Conclusions Serum anti-p53 antibody can serve as a surrogate marker for TP53 alterations and help predict the presence of HGD/INV in cases with IPMN, in combination with CEA and CA 19-9.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, mainly because of its invasive and metastatic characteristics. Pancreatic intraepithelial neoplasia (PanIN) is one of the major precursor lesions of PDAC. Although epithelial‐to‐mesenchymal transition (EMT) is known to play an important role for these malignant behaviors, the association between PanIN and EMT has not been clearly understood. Therefore, we explored possible molecules for regulation of EMT immunohistochemically. Using surgically resected specimens from 71 PDAC patients, expressions of SNAIL, SLUG, TWIST1, and ZEB1 were investigated in high‐grade PanIN (HG‐PanIN) and PDAC. Results demonstrated that PDAC accompanied by SNAIL‐positive HG‐PanIN showed a significantly better relapse‐free survival (RFS) (median survival time (MST) of 11.3 months vs 4.4 months, P

Supplemental digital content is available in the text., Objectives The aim of this study was to identify an association of pancreatic anaplastic carcinoma (APC) with the epithelial-mesenchymal transition (EMT). Methods Resected APCs (n = 24) were examined to assess components of APCs, including carcinomatous, transitional, and sarcomatous regions. Analysis was performed based on the immunoreactivity of E-cadherin and 3 EMT-related proteins: Slug (zinc finger protein SNAI2), Twist (Twist-related protein 1), and Zeb1 (zinc finger E-box–binding homeobox 1). Expression score was determined based on staining intensity and stained area of the target cells. Finally, we performed a hierarchical clustering based on the expression pattern of E-cadherin and EMT-related proteins of the sarcomatous component. Results The expression score of E-cadherin decreased in the order of sarcomatous > transitional > carcinomatous components (P < 0.01). Although there were significant differences in the immunohistochemical scores of Slug, Twist, and Zeb1 between carcinomatous and transitional components (P < 0.01), the significant difference in immunohistochemical score of Zeb1 between transitional and sarcomatous components was found (P < 0.05). Furthermore, APCs were divided into 2 subgroups based on the expression patterns of E-cadherin and EMT-related proteins (hierarchical clustering analysis). Consequently, these subgroups were distinguished by Twist expression. Conclusions Epithelial-mesenchymal transition plays an essential role in the pathogenesis of APC.

Objectives The aim of this study was to evaluate the diagnostic and prognostic impact of systemic inflammatory markers for IPMN with high-grade dysplasia (HGD)/invasive carcinoma. Methods Neutrophil-to-lymphocyte ratio (NLR), derived NLR, platelet-to-lymphocyte ratio, and C-reactive protein-to-albumin ratio were compared across the different histological grades of 205 IPMN cases. We also tested the diagnostic performance for IPMN with HGD/invasive carcinoma. Results The median (interquartile range) preoperative NLR was higher in IPMN with HGD/invasive carcinoma (2.03 [1.48-2.93]) than IPMN with low-grade dysplasia (1.74 [1.42-2.24], P = 0.0137). The C-reactive protein-to-albumin ratio and derived NLR values were also significant higher in cases with HGD/invasive carcinoma. A combination assay of NLR, carcinoembryonic antigen, and carbohydrate antigen 19-9 revealed a 58.8% sensitivity and 76.8% specificity. Among the cases with worrisome features, the high NLR values increased the positive predictive value (68.8%) compared with low values (31.8%). In IPMN cases with the associated invasive carcinoma, high NLR values showed association with the deeper vertical invasion and shorter survival periods. Conclusions Preoperative NLR, combined with tumor markers and image findings, can be a useful predictive marker for the presence of HGD/invasive carcinoma in IPMNs. Preoperative NLR also predicts the long-term outcomes in IPMN cases with invasive carcinoma.

A 69-year-old man was referred to our institute for the surgical resection of focal resistant peritoneal GIST during imatinib administration. He had been diagnosed with GIST of the small intestine with liver and peritoneal metastases, and imatinib treatment was initiated. Shortly after imatinib administration, the primary lesion perforated, and thus, partial resection of the small intestine was performed. Imatinib treatment was resumed after the first surgery, and he achieved partial response. However, computed tomography scans obtained 7 months after the first surgery showed focal progression, a peritoneal metastasis near the right kidney. Under the diagnosis of focally imatinib-resistant GIST, local resection of the metastatic tumor was performed. In this case, an exon 11 mutation of c-kit was noted initially. After the imatinib treatment, an additional point mutation was observed in exon 18 that caused resistance to imatinib. Therefore, imatinib treatment was reinitiated after the second surgery, and other metastases were well controlled. In case of GIST with multiple metastases, appropriate treatment should be selected based on the resistance of each lesion.

Survival after surgery for pancreatic adenocarcinoma (PA) is poor and heterogeneous, even for curative (R0) resection. Serum carbohydrate antigen (CA) 19-9 levels are important prognostic markers for resected PA. However, sustained elevation of CA19-9 in association with the patterns of recurrence has been rarely investigated. Patients who underwent R0 resection (n = 539) were grouped according to postoperative serum CA19-9 levels (Group E: sustained elevation; Group N: no elevation). Clinicopathological factors, patterns of recurrence, and survival were compared between the groups. Group E (n = 159) had significantly shorter median overall survival (17.1 vs. 35.4 months, p

The Frey procedure is an effective surgery for chronic pancreatitis (CP) patients who have pancreatic head lesions with dilation of the main pancreatic duct. However, pancreatic tail lesions can cause relapsing pancreatitis after the procedure. Therefore, additional distal pancreatectomy (DP) might complement the therapeutic effect of the Frey procedure in controlling inflammation of the pancreatic tail. The Frey procedure with DP (Frey + DP) is indicated for inflammatory lesions in the pancreatic head and tail. In this study, we assessed the usefulness of Frey + DP using the retrospective clinical data of our cases. The clinical outcomes were compared between CP patients who underwent the Frey procedure (N = 44) and Frey + DP (N = 13) from January 2005 to April 2016. Frey + DP showed similarly good therapeutic effects to the Frey procedure with regard to the postoperative stay, morbidity, mortality, pain relief and nutrition, although the Frey + DP had a longer operative time, more bleeding and higher incidence of diabetes mellitus than the Frey procedure because of the additional DP. One patient in the Frey group received additional DP because of recurrent pain due to the tail lesion. Frey + DP can be a promising treatment for CP patients with pancreatic head and tail lesions.

Objectives We retrospectively investigated the operative outcomes of patients who underwent distal pancreatectomy (DP) for invasive pancreatic ductal adenocarcinoma (PDAC) located at the body and tail. Methods Data from 395 patients with PDAC who underwent DP with margin-negative resection (R0 or R1) were collected from seven high-volume centers in Japan from 2001 to 2012. Among them, 72 patients underwent DP with en-bloc celiac axis resection (DP-CAR). The remaining 323 patients underwent conventional DP with splenectomy (DP-S). To determine the efficacy of DP-CAR, clinicopathological data were compared between the DP-CAR and the DP-S groups. Results The DP-S group consisted mainly of patients with resectable disease (93%), and conversely, all patients in the DP-CAR group had borderline resectable or unresectable disease. The overall morbidity was significantly higher in the DP-CAR group than in the DP-S group (63% vs 47%, respectively; P = 0.017). The median survival time (MST) of the DP-CAR group was significantly shorter than that of the DP-S group (17.5 vs 28.6 months, respectively; P = 0.004). However, the MST of patients in the DP-CAR group (n = 61, 85%) who received adjuvant therapy was significantly longer than that of patients in the DP-S group (n = 65, 20%) who underwent R1 resection (21.9 vs 16.7 months, respectively; P = 0.024). Conclusion DP-CAR followed by adjuvant chemotherapy provided an acceptable overall survival rate in patients with highly advanced PDAC, but should be performed with great caution because of high morbidity. Patients with a high risk of positive surgical margins with DP-S may be candidates for DP-CAR.

We aimed to determine whether treatment should be stratified according to 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) maximum standardized uptake values (SUVmax) in pancreatic ductal adenocarcinoma. Patients who underwent preoperative 18F-FDG PET/CT between 2006 and 2014 (n = 138) were stratified into high (≥ 4.85) and low (

Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study is to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed with CA-containing diet for 5 days (CA1) and mice fed with CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non-CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase in apoptosis. Quantitative targeted absolute proteomics revealed (1) decreases in basolateral bile acid transporters Na+-taurocholate cotransporting polypeptide, anion transporting polypeptide (oatp) 1a1, and oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters breast cancer resistance protein, multidrug resistance-associated protein 6, ent1, and oatp2b1; and (2) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, whereas the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.

The aim of surgical intervention for chronic pancreatitis (CP) is to relieve symptoms and improve quality of life. However, the precise effect of surgery on the nutritional status of CP patients, which is often impaired by exocrine and endocrine pancreatic dysfunction, has not been elucidated. We conducted this study to evaluate whether Frey’s procedure improves the nutritional status of CP patients. The nutritional status of 35 patients who underwent Frey’s procedure for CP at our institute between April 2005 and December 2014, was assessed by the controlling nutritional status (CONUT) scoring before and 1 year after the surgery, and compared with that of seven CP patients who underwent pancreatoduodenectomy. The occurrence of postoperative hepatic steatosis was also monitored. The nutritional status improved after Frey’s procedure, but not after pancreatoduodenectomy. The median postoperative CONUT score after Frey’s procedure was significantly lower than the preoperative score (1.0 ± 0.5 vs. 4.0 ± 2.5; p

Background Even though most patients who undergo resection of pancreatic adenocarcinoma have T3 disease with extra-pancreatic tumor extension, T3 disease is not currently classified by tumor size. The aim of this study was to modify the current TNM classification of pancreatic adenocarcinoma to reflect the influence of tumor size., Methods A total of 847 consecutive pancreatectomy patients were recruited from multiple centers. Optimum tumor size cutoff values were calculated by receiver operating characteristics analysis for tumors limited to the pancreas (T1/2) and for T3 tumors. In our modified TNM classification, stage II was divided into stages IIA (T3aN0M0), IIB (T3bN0M0), and IIC (T1-3bN1M0) using tumor size cutoff values. The usefulness of the new classification was compared with that of the current classification using Akaike’s information criterion (AIC)., Results The optimum tumor size cutoff value distinguishing T1 and T2 was 2 cm, while T3 was divided into T3a and T3b at a tumor size of 3 cm. The median survival time of the stages IIA, IIB, and IIC were 44.7, 27.6, and 20.3 months, respectively. There were significant differences of survival between stages IIA and IIB (P = 0.02) and between stages IIB and IIC (P = 0.03). The new classification showed better performance compared with the current classification based on the AIC value., Conclusions This proposed new TNM classification reflects the influence of tumor size in patients with extra-pancreatic tumor extension (T3 disease), and the classification is useful for predicting mortality.

Background The morbidity rate after pancreaticoduodenectomy remains high. The objectives of this retrospective cohort study were to clarify the risk factors associated with serious morbidity (Clavien–Dindo classification grades IV–V), and create complication risk calculators using the Japanese National Clinical Database. Methods Between 2011 and 2012, data from 17,564 patients who underwent pancreaticoduodenectomy at 1,311 institutions in Japan were recorded in this database. The morbidity rate and associated risk factors were analyzed. Results The overall and serious morbidity rates were 41.6% and 4.5%, respectively. A pancreatic fistula (PF) with an International Study Group of Pancreatic Fistula (ISGPF) grade C was significantly associated with serious morbidity (P

Background Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. Methods The frequencies of dose‐limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom‐relieving effects, safety and overall survival. Results The recommended doses of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0–22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1‐year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3–4 haematological toxicities developed in 35 of 46 patients, whereas non‐haematological adverse events occurred in seven patients. Conclusion Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability., This multicentre phase I/II study was undertaken to determine the recommended dose of the combination of intravenous gemcitabine, intravenous nab‐paclitaxel and intraperitoneal paclitaxel in patients with pancreatic ductal adenocarcinoma and peritoneal metastasis, and to evaluate its clinical efficacy and safety. This regimen exhibited promising clinical efficacy, with acceptable tolerability. Effective and safe in pancreatic cancer

Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.

To clarify the usefulness of cancer-related inflammation, hypermetabolism, and subsequent host malnutrition biomarkers for predicting the histological grades of intraductal papillary mucinous neoplasms of the pancreas (IPMNs). The systemic immune-inflammation index (SII), prognostic nutritional index (PNI), and maximum standardized uptake value (SUVmax) on fluorodeoxyglucose-positron emission tomography were compared across 171 resected IPMN cases of different histological grades. The diagnostic performance of each marker and of their combinations for predicting IPMN with high-grade dysplasia (HGD)/associated invasive carcinoma (INV) was also tested. Of the 171 IPMNs, the IPMN cases with HGD showed significantly higher values of SII (median 406 vs. 340; P = 0.041) and SUVmax (median 2.5 vs. 2.0; P = 0.001) than those with low-grade dysplasia (LGD). On a multivariate analysis, the SII and SUVmax were both independent markers for predicting HGD/INV. A combination analysis including the tumor- and host-derived markers in combination with imaging findings showed an improved diagnostic performance (area under the curve 0.824; sensitivity 75.9%; specificity 80.0%). The combination of multiple markers of host-derived inflammation and tumor-derived focal hypermetabolism can serve as a predictor for the presence of HGD/INV.

To evaluate the long-term outcomes of total pancreatectomy in a modern cohort of pancreatic cancer patients and to establish whether any factors identified prior to pancreatic resection were related to poor survival. We analyzed, retrospectively, patients who underwent total pancreatectomy for pancreatic cancer between 2007 and 2016. The short- and long-term outcomes were investigated and Cox regression analysis was used to evaluate the prognostic factors identified before resection. The subjects were 49 patients with a mean age of 65 years, who underwent total pancreatectomy in our hospital during the study period. Peritoneal washing cytology was performed in 48 patients, with positive results in 4 (8.3%). There was no 30-day mortality. The median overall survival was 22.5 months, with a 5-year survival rate of 28.5%. Univariate analyses of the pre-resection variables revealed that overall survival was associated with tumor location, resectability classification, maximum standardized uptake value of positron emission tomography, the preoperative carbohydrate antigen 19–9 level, and peritoneal washing cytology status. Multivariate analysis revealed that positive peritoneal washing cytology status and the maximum standardized uptake value were independent predictors of poor survival. Total pancreatectomy for pancreatic cancer is appropriate for selected patients, but peritoneal washing cytology and positron emission tomography should be performed preoperatively.

Background The differentiation between pancreatic head cancer (PHC) and distal cholangiocarcinoma (DCC) can be challenging because of their anatomical and histopathological similarity. This is an important problem, because the distinction has important implications for the treatment of these malignancies. However, there are no biomarkers for the differential diagnosis of PHC and DCC. The present study aimed to identify novel diagnostic immunohistochemical biomarkers to distinguish PHC from DCC. Methods Liquid chromatography tandem mass spectrometry (LC-MS/MS) was employed to detect candidate proteins. Ten PHC and 8 DCC specimens were analyzed by LC-MS/MS. Selected proteins were evaluated, using immunohistochemical analysis, to determine whether they would be appropriate biomarkers. Finally, we generated biomarker panels to improve diagnostic accuracy. We applied these panels to clinically difficult cases (cases in which different diagnoses were made before and after operation). Results Consequently, 1820 proteins were detected using LC-MS/MS. Fifteen differentially expressed proteins were selected as candidates based on semi-quantitative comparison. We first performed immunohistochemical staining on samples from the small cohort group (12 PHCs and 12 DCCs) using 15 candidates. KRT17, ANXA10, TMEM109, PTMS, and ATP1B1 showed favorable performances and were tested in the next large cohort group (72 PHCs and 74 DCCs). Based on immunohistochemical analysis, KRT17 performed best for the diagnosis of PHC as a single marker; additionally, PTMS exhibited good performance for the diagnosis of DCCs. Moreover, we indicated the KRT17+/ANXA10+/PTMS- staining pattern as a biomarker panel for the correct diagnosis of PHC and KRT17−/ANXA10−/PTMS+ for the diagnosis of DCC. After immunohistochemical staining for examining samples from the clinically difficult cases, these panels showed satisfactory diagnostic performance with 85.7% (6/7) accuracy. Conclusions We conclude that 5 proteins and 2 biomarker panels are promising for distinguishing PHC from DCC, and patients with an equivocal diagnosis would benefit from the application of these biomarkers. Confirmatory studies are needed to generalize these findings to other populations. Electronic supplementary material The online version of this article (10.1186/s12885-019-5548-x) contains supplementary material, which is available to authorized users.

OBJECTIVE: To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, "an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium" in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis. BACKGROUND: PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive. METHODS: Paclitaxel was administered i.v. at 50 mg/m and i.p. at 20 mg/m on days 1 and 8. S-1 was administered at 80 mg/m/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446). RESULTS: Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47-22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery. CONCLUSIONS: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.

Background Postoperative pancreatic fistula (POPF) remains a major cause of morbidity after distal pancreatectomy. The aim of this study was to investigate whether duct-to-mucosa pancreaticogastrostomy of the pancreatic stump decreased clinical POPF formation compared with handsewn closure after distal pancreatectomy. Methods This multicentre RCT was performed between April 2012 and June 2014. Patients undergoing distal pancreatectomy were assigned randomly to either duct-to-mucosa pancreaticogastrostomy or handsewn closure. The primary endpoint was the incidence of clinical POPF. Secondary endpoints were rates of other complications and length of hospital stay. Results Some 80 patients were randomized, and 73 patients were evaluated in an intention-to-treat analysis: 36 in the pancreaticogastrostomy group and 37 in the handsewn closure group. The duration of operation was significantly longer in the pancreaticogastrostomy group than in the handsewn closure group (mean 268 versus 197 min respectively; P < 0·001). The incidence of clinical POPF did not differ between groups (7 of 36 versus 7 of 37; odds ratio (OR) 1·03, 95 per cent c.i. 0·32 to 3·10; P = 1·000). The rate of intra-abdominal fluid collection was significantly lower in the pancreaticogastrostomy group (6 of 36 versus 21 of 37; OR 0·15, 0·05 to 0·45; P < 0·001). There were no statistically significant differences in the rates of other complications or length of hospital stay. Conclusion Duct-to-mucosa pancreaticogastrostomy did not reduce the incidence of clinical POPF compared with handsewn closure of the pancreatic stump after distal pancreatectomy. Registration number UMIN000007426 (http://www.umin.ac.jp).

Several studies have demonstrated that postoperative complications after pancreatectomy for pancreatic cancer adversely affect survival. The impact on survival of a pancreatic fistula according to the classification of the International Study Group for Pancreatic Surgery has not been fully evaluated. The aim of this multicenter, observational study was to evaluate the impact of pancreatic fistula on pancreatic cancer patients who had undergone pancreatectomy.Between 2001 and 2012, 1,397 patients who underwent pancreatectomy for pancreatic cancer at 7 high-volume centers in Japan were reviewed retrospectively. The impact of pancreatic fistula on survival was evaluated by univariate and multivariate analysis.Pancreatic fistula occurred in 327 of 1,397 patients (23.4%) and was classified based on the International Study Group for Pancreatic Surgery as follows: grade A in 9.9%, grade B in 10.6%, and grade C in 2.9% of the patients. Median survival time in no fistula/grade A, grade B, and grade C were 23.6, 26.0, and 9.0 months, respectively. There was no significant difference in overall survival between patients with no fistula/grade A and those with grade B (P = .403); in contrast, overall survival in patients with grade C was worse than in patients without grade C (P .001). The multivariate Cox proportional hazard analysis demonstrated that grade C pancreatic fistula was an independent prognostic factor (hazard ratio 1.59; 95% confidence interval, 1.03-2.45; P = .035).Grade B pancreatic fistula after pancreatectomy does not adversely affect long-term survival, but a grade C pancreatic fistula has a negative impact on long-term survival of patients with pancreatic cancer.

Mucinous cystic neoplasms (MCNs) are generally defined as cyst-forming epithelial neoplasms that arise in the pancreas and harbor characteristic ovarian-type stroma beneath the epithelium. In this study, we compared the immunoreactivity of steroid-related factors in these subepithelial stromal cells in MCNs to those in intraductal papillary mucinous neoplasms (IPMNs) to further characterize this unique MCN ovarian-type stroma through evaluation of sex steroid biosynthesis. Twenty MCNs and twenty IPMNs were examined. Immunoreactivity of steroid hormone receptors, including estrogen receptor (ERα and ERβ), progesterone receptor (PR, PR-A, and PR-B), and androgen receptor (AR), was more frequently detected in MCN ovarian-type stromal cells than in IPMN stromal cells (P < 0.01). The H-scores (mean ± SD) of steroidogenic factor (SF)-1 were also significantly higher in MCNs (112.3 ± 33.1) than in IPMNs (0.9 ± 1.2) (P < 0.01). The steroidogenic enzymes cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), cytochrome P450 17 alpha-hydroxylase (P450c17) and 3β-hydroxysteroid dehydrogenase (3β-HSD) showed immunoreactivity in 9/20 (45.0 %), 15/20 (75.0 %) and 13/20 (65.0 %), respectively, of ovarian-type stroma from MCN cases. These results demonstrate that the ovarian-type stroma of MCNs can express steroidogenic enzymes. Thus, the ovarian-type stroma of MCNs can produce sex steroids that may also act on these cells.

Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.

Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces β-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Ins

Duodenal–jejunal bypass (DJB) shows great effects on weight loss and diabetes improvement. Previously, we reported that the bilio-pancreatic (BP) limb plays an important role in glycemic improvement and in serum bile acid (BA) level increase as reported by Miyachi et al. (Surgery 159(5):1360–71, 2016). This study aimed to investigate the mechanism of BA elevation after DJB and the relationship between these effects and BP-limb length. Otsuka Long-Evans Tokushima Fatty rats with diabetes were randomly assigned into four groups: one sham group and three DJB groups. Three DJB groups were defined according to the BP-limb length: 0 cm, 15 cm, and 30 cm. The lengths of the alimentary limb and common channel were set equally in each DJB groups. Body weight, glucose tolerance, and BA levels in the liver, bile juice, portal vein, and intestinal contents were assessed postoperatively. Changes in enterohepatic circulation of BAs were assessed using labeled BA. BA elevation after DJB was higher with longer BP-limb. In the 30-cm group, the serum total BA level and BA levels in the portal vein, liver, and bile juice were greater than those in other groups. The enterohepatic circulation was shortened in the 15-cm and 30-cm groups. Shortening of the “enterohepatic circulation” by early reabsorption of BAs in the BP-limb, not by the early influx of bile juice into the ileum, was the main cause of BA elevation after DJB. Thus, glycemic improvement and elevation of BA concentration after DJB depend on the BP-limb length.

Here we report a case treated with conversion surgery combined with preoperative coil embolization of the hepatic artery after chemoradiation therapy for locally advanced unresectable pancreatic head cancer with hepatic artery invasion. A 63- year-old man was referred to our hospital for treatment of pancreatic cancer. Abdominal CT scan revealed a 30mm pancreatic head tumor with involvement of the common hepatic artery(CHA)and proper hepatic artery(PHA). The left hepatic artery diverged from the left gastric artery. Although S-1 with concurrent radiation therapy was performed, a follow-up CT scan revealed the progression of soft tissue shadow around the CHA. Subsequently, gemcitabine plus nab-paclitaxel(GnP)was administered 13 times. GnP helped achieve normalization of the tumor markers and long stable disease(SD)based on the Response Evaluation Criteria in Solid Tumors(RECIST). For the conversion surgery, embolization of the middle hepatic artery (MHA)was performed. Twelve days after, the right hepatic artery was embolized. Subtotal stomach-preserving pancreaticoduodenectomy was performed with resection of the CHA and PHA without arterial reconstruction 16 days after the hepatic arterial embolization. The patient was discharged from our hospital 33 days after surgery without complications related to hepatic ischemia. The patient is alive without recurrence 42 months after the initial diagnosis and 26 months after surgery.

According to the treatment guideline for rectal neuroendocrine tumor(NET), tumor with a diameter ofC10mm should be resected endoscopically, while tumor with a diameter of10mm should be resected surgically with lymph node dissection. We experienced a case of a rectal NET with a diameter of 5mm with lymph node metastasis. A 69-year-old man underwent colonoscopy for positive fecal occult blood test. The colonoscopy revealed a submucosal tumor(SMT)with a diameter of 5 mm in the lower rectum. An endoscopic mucosal resection(EMR)was performed after SMT was diagnosed as NET by biopsy. Histopathological findings were NET-G1, 4.5×2.5 mm, v(+), ly(+). Then, laparoscopically assisted rectal resection with D2 lymph node dissection was performed. In histopathological examination, no tumor residue was observed in the specimu; however, a regional lymph node metastasis was detected. Risk factors of lymph node metastasis with rectal NET are a diameter of10 mm, recessed or ulcerated surface, and lymphovascular invasion. However, we have to keep in mind that lymph node metastasis may occur even in small rectal NET with a diameter of ≤10mm.

A randomized, controlled trial has begun to compare neoadjuvant chemotherapy using gemcitabine and S-1 with upfront surgery for patients planned resection of pancreatic cancer. Patients were enrolled after the diagnosis of resectable or borderline resectable by portal vein involvement pancreatic cancer with histological confirmation. They were randomly assigned to either neoadjuvant chemotherapy or upfront surgery. Adjuvant chemotherapy using S-1 was administered for 6 months to patients with curative resection who fully recovered within 10 weeks after surgery in both arms. The primary endpoint is overall survival; secondary endpoints include adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases and tumor marker kinetics. The target sample size was required to be at least 163 (alpha-error 0.05; power 0.8) in both arms. A total of 360 patients were required after considering ineligible cases. This trial began in January 2013 and was registered with the UMIN Clinical Trials Registry (UMIN000009634).

Neoadjuvant chemotherapy (NAC) represents a promising alternative to pancreatic ductal adenocarcinoma (PDAC) planned resection, but the survival impact remains undefined. To assess the feasibility and survival outcomes of NAC with gemcitabine and S1 (GS) for PDAC planned resection by prospective study. Patients with resectable or borderline resectable PDAC received 2 cycles of NAC-GS and were offered curative resection followed by gemcitabine adjuvant. The primary endpoint was 2-year overall survival (OS). Adverse events during NAC, radiological and tumor marker responses, resection rate, and surgical safety were evaluated as secondary endpoints (UMIN000004148). We enrolled 104 patients between 2010 and 2012, with 101 patients treated using NAC-GS as the full analysis set (FAS). Of the 101 patients, 88% received the planned 2 cycles of NAC. Grade 3 neutropenia was common (35%). Radiological partial response and decreased carbohydrate antigen 19-9 concentration (> 50% decrease) were noted in 13% and 41%, respectively. R0/1 resections with M0 were performed in 65 patients without surgical mortality. Of the 65 patients, 44 received planned gemcitabine adjuvant for 6 months as the on-protocol cohort. The primary endpoint for the 2-year OS rate was 55.9% in the FAS (n = 101) and 74.6% in the on-protocol cohort (n = 44). NAC-GS was feasible and actively prolonged survival following PDAC planned resection. Randomized control trials are needed to further clarify the survival benefit of NAC-GS in addition to surgery followed by adjuvant therapy.

The aim of this study was to compare the clinical outcomes between laparoscopic partial liver resection and open partial hepatectomy for tumors in the posterosuperior segments. The clinical outcomes of patients who underwent either laparoscopic (n = 20) or open (n = 44) resection in segments 7/8 of the liver were initially evaluated. Because of disparities in the background characteristics, a case-matched study (1:1) was conducted. In addition, a comparative study of the patients who met the institutional criteria for laparoscopic partial hepatectomy was performed. In the case-matched study, the laparoscopic technique required a longer operation time (p = 0.001), but was associated with less intraoperative blood loss (p = 0.021), a lower incidence of major complications (p = 0.014), higher levels of serum albumin on postoperative days 3 and 7 (p = 0.031 and p = 0.035), and earlier discharge (p = 0.001) than open resection. The results of the latter study were similar to those of the case-matched analysis. Laparoscopic partial hepatectomy was a feasible procedure for treating tumors in the posterosuperior segments without compromising oncological safety and yielded better short-term outcomes than open techniques. In addition, this study provides concrete selection criteria for laparoscopic partial hepatectomy for difficult lesions.

We here report a case of endoscopy-assisted partial duodenal resection for duodenal adenoma in a patient with familial adenomatous polyposis(FAP). A male underwent total proctocolectomy with ileal pouch anal anastomosis in 1997. Since 2004, duodenal adenomas occurred and the atypical grade of adenoma was gradually aggravated. Therefore, he underwent endoscopy-assisted partial duodenal resection in 2013. The pathological finding of the specimen showed well-differentiated tubular adenocarcinoma(pM, ly0, v0). No recurrence has been observed at 4 years after the operation. Endoscopy-assisted partial duodenal resection was minimum invasive surgery and considered to be useful for the patients with duodenal adenoma.

Background The optimal therapeutic strategy for very elderly pancreatic cancer patients remains to be determined. The aim of this study was to clarify the role of pancreatic resection in patients 80 years of age or older. Methods A retrospective multicenter analysis of 1401 patients who had undergone pancreatic resection for pancreatic cancer was performed. The patients aged ≥80 years (n = 99) were compared with a control group

We report a case of the pancreas head cancer with peritoneal metastasis, which was resected curatively after chemotherapy. A6 6-year-old male was referred to our hospital for the treatment of biliary stenosis. The serum CA19-9 level was elevated and abdominal CT scan showed stenosis of distal bile duct. By laparotomy, we noticed mass in the head of the pancreas with 8mm of the seeding nodule in a diameter at jejunal mesentery which was diagnosed as adenocarcinoma by intraoperative frozen sections. Therefore, the patient was diagnosed as pancreas head cancer with peritoneal metastasis. After hepaticojejunostomy, we started chemotherapy planning adjuvant surgery if the clinical response was observed. Systemic chemotherapy with gemcitabine and nab-paclitaxel was administrated on days 1, 8 and 15 every 4 weeks. After 5 courses, therapeutic effect was stable disease(SD)in response evaluation criteria in solid tumor(RECIST). All of tumor markers were normalized. Subtotal stomach-preserving pancreatoduodenectomy(SSPPD)was performed 6 months after the initial surgery. Histopathologically, most cancer cells showed degeneration and eliminated in the head of the pancreas. R0 resection was achieved with diagnosis of ypT3, ypN1, pM1(PER), Stage IV . Histological therapeutic effect was Grade III according to the Evans classification. The patient is alive, with no sign of recurrence 8 months after surgery. Adjuvant surgery was suggested to be one of the therapeutic options for pancreatic cancer with peritoneal metastasis.

A 40-year-old man was referred to our hospital because of severe anemia and small intestinal tumor revealed by computed tomography. The enteroscopy exam showed the intraluminal penetration of the tumor, which was considered as a cause of anemia. Although emergency operation was performed laparoscopically, intraoperative findings indicated tumor invasion into peritoneum, and we converted from laparoscopic surgery to open surgery that included concomitant peritoneum resection. Histopathological findings showed spindle-shaped tumor cells with severe atypia. Immunohistochemical study showed tumor cells to be positive for aSMA, but negative for c-kit and CD34, then we diagnosed the tumor as leiomyosarcoma of the ileum. Since leiomyosarcoma of the small intestine is a rare entity, we have reported with literature consideration.

Gemcitabine with nab-paclitaxel(GN)shows promisinganti -tumor effect and has been established standard regimen for metastatic pancreatic cancer(PC). Conversion surgery(CS), recently reported about initially unresectable PC with favorable response to non-surgical treatment, might provide long-term survival. The aim of this study is to evaluate the efficacy of multi-modal treatment includingCS after GN therapy for initially unresectable PC. From 2015 to 2016, 29 initially unresectable PC treated with chemotherapy includingGN were eligible for the retrospective analysis. Unresectability was defined over 180- degree abutment to major arteries(UR-LA)or suspicious small metastases(UR-M). CS was planed after clinical favorable response over 6 months of treatment duration. Median age of the patients was 62.5 years old, including 18 males and 11 females. Tumor in the pancreas head(n=20)was dominant. Eighteen patients were UR-LA and remaining1 1 were UR-M. CS was performed in 9 cases(31%)with no significant difference between UR-LA and UR-M. CS showed significant better survival with 67%of 2-year survival rate, compared to without CS(p=0.039). GN regimen effectively induced CS for initially unresectable PC. Multidisciplinary therapy includinginduction GN and CS might have survival impact on unresectable PC.

Background: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. Methods: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. Results: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). Conclusion: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.

The increasing incidence of non-alcoholic steatohepatitis (NASH) has resulted in it becoming a common cause of liver-related mortality; however, no efficient treatment has been established. It has been reported that bariatric surgery improves metabolic comorbidities, such as diabetes mellitus and NASH. Although the mechanism is unclear, it is thought that the changes in bile acid (BA) signaling via its nuclear receptor, farnesoid X receptor (FXR), produce various metabolic effects. We sought to investigate the effects and mechanisms of bariatric surgery on NASH improvement. Male Sprague-Dawley rats were fed by a high-fat and high-fructose diet, which results in obesity, insulin resistance, and NASH. Rats underwent duodenal-jejunal bypass (DJB), which is a main component of bariatric procedures. The liver pathological findings and the expression level of mRNA of FXR were investigated. The plasma BA level was measured in peripheral and portal vein blood. DJB suppressed weight gain, improved insulin resistance, and ameliorated NASH mainly in a point of inflammation. The plasma BA level along with the expression of FXR and its target transcriptional factor, small heterodimer partner (SHP), in the liver were elevated. DJB has a direct effect on NASH improvement, and there is a possibility that an anti-inflammatory effect is functioning as a part of the mechanism. The increase of plasma bile acid level followed by the stimulation of FXR signaling may contribute to this phenomenon.

Purpose To assess recent trends in pancreaticoduodenectomy (PD) and the role of institutional standardization on the development of post-operative complications in 3,378 patients who underwent PD in Japan. Methods Data were collected from 3,378 patients who underwent PD in 2006, 2010, and 2014 at 53 institutions. A standardized institution (SI) was defined as one that implements ≥7 of 13 quality initiatives according to departmental policy. There were 1,223 patients in the SI group and 2,155 in the non-SI group. Clinical parameters were compared over time, and between groups. Risk factors for morbidity and mortality were assessed by logistic regression analysis with a mixed-effects model. Results The number of patients who underwent PD in standardized institutions increased from 16.5% in 2006 to 46.4% in 2014. The SI group experienced an improved process of care and a lower frequency of severe complications vs. the non-SI group (p

Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

The prognosis of pancreatic cancer patients with metastatic para-aortic lymph node (PALN) has been reported to be extremely poor. In general, PALN metastasis has been considered as a contraindication for pancreatic resection. The aim of this study was to reevaluate the postoperative prognostic value of PALN metastasis in pancreatic cancer and to determine the validity of pancreatic surgery. Retrospective multicenter analysis of 882 patients who have undergone curative-intent pancreatic resection with pathological evaluation of PALNs for pancreatic ductal adenocarcinoma between 2001 and 2012 was conducted. Clinicopathological data and outcomes were evaluated with univariate and multivariate analysis. In total, 102 (12.4 %) patients had positive metastasis in PALN. Patients with metastatic PALN had significantly poorer survival than those without (17 vs. 23 months; p

Adenosquamous carcinoma of the pancreas is a rare subtype of pancreatic cancer. We herein describe the clinicopathological features of surgically resected cases of adenosquamous carcinoma of the pancreas.From 2001 to 2011, 132 patients underwent R0 resection for Stage IIA or IIB pancreatic cancer. The survival rate, pathological features and recurrence status were reviewed.Out of 132 patients, 121 patients had tubular adenocarcinoma, and only seven had adenosquamous carcinoma (ASC). The incidence of ASC increased with the tumor size. The overall survival and disease-free survival periods of the patients with ASC were significantly shorter than those of patients with tubular adenocarcinoma (p = 0.0153 and p = 0.0045). The histological findings revealed more marked venous invasion in ASC compared to tubular adenocarcinoma (G1, G2 and G3). The proportion of v3 cases, which denotes the most severe venous invasion, was 31.3 % in G1, 47.3 % in G2, 60.0 % in G3 and 71.4 % in ASC cases, respectively. Other factors, including lymphatic and nerve invasion, were not correlated with the histological subtypes. The incidence of ASC was 11.1 % in the tumors more than 6 cm in diameter, and 0 % in those less than 2 cm in diameter.We revealed that adenosquamous carcinoma of the pancreas is associated with a poor outcome, and also clarified its clinicopathological features.