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Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

Purpose Acute liver failure is a life-threatening condition for which ABO-incompatible living donor liver transplantation (ABOi-LDLT) is sometimes the only life-saving treatment option. We reviewed a single-center experience of adult ABOi-LDLT treatment for acute liver failure (ALF). Methods Preoperative treatment, immune indices (B cell marker, anti-donor blood-type antibody), and postoperative outcomes were compared between ALF and non-ALF groups. Results There were 5 and 33 patients in the ALF and non-ALF groups, respectively. The ALF group received higher doses of steroids, underwent more rounds of plasma exchange (PE), and underwent transplantation for ALF with a shorter interval following preoperative rituximab (RTx) administration (median: 2 vs 13 days; P  < 0.05) than the non-ALF group. Preoperatively, CD19-positive lymphocytes in the peripheral blood were sufficiently depleted in all of the non-ALF group patients, whereas they were poorly depleted in the ALF group. Postoperatively, neither group suffered anti-donor blood-type antibody titer rebound or antibody-mediated rejection. The ALF group had a comparable 5-year survival rate to the non-ALF group (80.0% vs 77.9%). Conclusions Despite the delayed preoperative administration of RTx, the ALF group showed an uneventful immunological response and acceptable long-term survival rate. Thus, ABOi-LDLT seems a viable treatment option for ALF.

Aims/hypothesisType 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes.MethodsPancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined.ResultsBoth beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = −0.45, p < 0.01).Conclusions/interpretationBoth beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes.

The resectable liver volume is strictly limited and this reduces the number of patients who may be treated. Recently, “tissue/organ decellularization”, a new approach in bioengineering, has been investigated for its ability to produce a native organ scaffold by removing all the viable cells. Such a scaffold may support the repair of damaged or injured tissue. The purpose of this study was to evaluate the potential contribution of liver scaffolds to hepatic regeneration after hepatectomy. We sutured the partial liver scaffolds onto the surfaces of partially hepatectomized porcine livers and assessed their therapeutic potential by immune histological analysis at various time points. Animals were sacrificed after surgery and the implanted scaffolds were evaluated for the infiltration of various types of cells. Immune histochemical study showed that blood vessel-like structures, covered with CD31 positive endothelial cells and ALB positive cells, were present in all parts of the scaffolds at days 10 and 28. Blood inflow was observed in some of these ductal structures. More interestingly, CK19 and EpCAM positive cells appeared at day 10. These results suggest that the implantation of a decellularized organ scaffold could promote structural reorganization after liver resection.

The abundance of cytotoxic T-cell infiltrates has important implications for patient outcome and therapeutic design for pancreatic ductal adenocarcinoma. However, intratumoral heterogeneity remains a challenge to understanding the complex immune microenvironment. We hypothesized that characterizing CD8 + cell distribution within pancreatic adenocarcinoma tissues might refine the prognostic value of tumor-infiltrating CD8 + lymphocytes. Using multiplex immunohistochemistry-based image analysis on whole-tissue sections of 214 pancreatic ductal adenocarcinomas, we measured CD8 + cell densities in the tumor center, the tumor margin, and the whole tumor, along with the proximity of CD8 + cells to carcinoma cells. Multivariable Cox regression analysis was performed to assess the associations of CD8 + cell densities with pancreatic cancer-specific survival, adjusting for clinicopathologic and immune-related features, including tumor expressions of TP53, SMAD4, and the programmed cell death 1 ligand 1 (CD274, PD-L1) and the extent of tertiary lymphoid structures. There was substantial heterogeneity in CD8 + cell density, with the mean density in the tumor center less than half that in the tumor margin. Tumor CD274 expression and extensive tertiary lymphoid structures were appeared to be associated with higher CD8 + cell density in the tumor margin ( P  = 0.037 and P  = 0.005, respectively), but not with that in the tumor center ( P  > 0.50). The association of higher CD8 + cell density with prolonged survival was significant for the whole tumor ( P trend  = 0.009); however, the association was stronger for the tumor center ( P trend  = 0.002) and insignificant for the tumor margin ( P trend  = 0.07). Tumor cell–CD8 + cell distance correlated strongly with CD8 + cell density, whereas the density of CD8 + cells proximate to cancer cells exhibited no prognostic association. In conclusion, spatial computational analysis on pancreatic ductal adenocarcinoma reveals the prognostic validity of CD8 + cell density in the tumor center, where CD8 + cell infiltration is ununiformly restricted, likely suggesting pro-tumorigenic roles of the immunosuppressive tumor microenvironment of pancreatic cancer.

Pancreatic cancer (PC) is a lethal disease that requires innovative therapeutic approaches to enhance the survival outcomes. Neoadjuvant treatment (NAT) has gained attention for resectable and borderline resectable PC, offering improved resection rates and enabling early intervention and patient selection. Several retrospective studies have validated its efficacy. However, previous studies have lacked intention-to-treat analyses and appropriate resectability classifications. Randomized comparative trials may help to enhance the clinical applicability of evidence. Therefore, after searching the MEDLINE database, this scoping review presents a comprehensive summary of the evidence from published (n = 14) and ongoing (n = 12) randomized Phase II and III trials. Diverse regimens and their outcomes were explored for both resectable and borderline resectable PC. While some trials have supported the efficacy of NAT, others have demonstrated no clear survival benefits for patients with resectable PC. The utility of NAT has been confirmed in patients with borderline resectable PC, but the optimal regimens remain debatable. Ongoing trials are investigating novel regimens, including immunotherapy, thereby highlighting the dynamic landscape of PC treatment. Studies should focus on biomarker identification, which may enable precision in oncology. Future endeavors aim to refine treatment strategies, guided by precision oncology.

Background:Pancreatic ductal adenocarcinoma (PDAC) has very poor prognosis despite existing multimodal therapies. This study aimed to investigate whether KRAS mutations at codons 12/13 in cell-free DNA (cfDNA) from preoperative and postoperative sera from patients with PDAC can serve as a predictive biomarker for treatment response and outcomes after surgery.Methods:Preoperative and postoperative serum samples obtained from 45 patients with PDAC whom underwent curative pancreatectomy at our institution between January 2013 and July 2016 were retrospectively analysed. Peptide nucleic acid-directed PCR clamping was used to identify KRAS mutations in cfDNA.Results:Among the 45 patients enrolled, 11 (24.4%) and 20 (44.4%) had KRAS mutations in cfDNA from preoperative and postoperative sera, respectively. Multivariate analysis revealed that KRAS mutations in postoperative serum (hazard ratio (HR)=2.919; 95% confidence interval (CI)=1.109-5.621; P=0.027) are an independent prognostic factor for disease-free survival. Furthermore, the shift from wild-type KRAS in preoperative to mutant KRAS in postoperative cfDNA (HR=9.419; 95% Cl=2.015-44.036; P=0.004) was an independent prognostic factor for overall survival.Conclusions:Changes in KRAS mutation status between preoperative and postoperative cfDNA may be a useful predictive biomarker for survival and treatment response.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy due to the difficulty in diagnosis and poor prognosis because of the high recurrence rate, necessitating reliable biomarkers to improve the diagnosis and prognosis. However, the existing markers have limitations. We previously identified extracellular vesicles (EVs) recognized by O‐glycan‐binding lectins (Amaranthus caudatus agglutinin [ACA]) as a novel diagnostic biomarker for PDAC using an EV‐counting system (ExoCounter). This retrospective study analyzed changes in ACA‐positive EVs in perioperative PDAC serum and its association with prognosis using ExoCounter. Absolute EV levels in the pre‐ and postoperative sera of 44 patients who underwent curative pancreatectomy for PDAC were quantified using ExoCounter. The carbohydrate antigen 19‐9 levels declined in most samples postoperatively, and presented no correlation with poor prognosis. In contrast, ACA‐positive EVs increased in serum at 7 days postoperatively in 27 of 44 patients (61.4%). We therefore divided participants with ACA‐positive EVs before and after surgery into elevation and decline groups. The overall survival (OS) and recurrence‐free survival (RFS) of patients with higher ACA‐positive EVs were significantly shorter than those with lower ACA‐positive EVs (26.1 months vs. not reached, P = 0.018; 11.9 vs. 38.6 months, P = 0.013). Multivariable analysis revealed that ACA‐positive EV elevation in postoperative serum was an independent prognostic factor for poor OS (hazard ratio [HR] = 3.891, P = 0.023) and RFS (HR = 2.650, P = 0.024). The detection of ACA‐positive EVs in perioperative serum may be used to predict the prognosis of PDAC in the early postoperative period. This retrospective, observational study developed a system to predict poor prognosis of pancreatic ductal adenocarcinoma after surgery based on the change in Amaranthus caudatus agglutinin‐positive extracellular vesicles in patients' sera before surgery and after surgical resection.

BackgroundDespite the increasing number of laparoscopic liver resection (LLR) procedures, postoperative bile leakage (POBL) remains a major complication. We occasionally experienced intraoperative bile leakage (IOBL) during LLR and managed it within the restrictions of laparoscopic surgery. However, there have been no reports about IOBL in LLR. We therefore investigated the impact of IOBL on postoperative outcomes and its predictive factors.MethodsWe reviewed 137 patients who underwent LLR from April 2016 to March 2019 at our institute and assigned them to IOBL-positive or IOBL-negative groups. We compared clinicopathological characteristics and perioperative outcomes. Patients were further divided into four groups according to IOBL pattern, and the frequency of POBL in each was calculated. Predictors of IOBL were identified using multivariate logistic regression analysis.ResultsThere were 30 and 107 patients in the IOBL-positive and IOBL-negative groups, respectively. In the IOBL-positive group, operative time and postoperative hospital stays were significantly longer (P < 0.001). The frequency of POBL was significantly higher in the IOBL-positive group (P = 0.006). The IOBL-positive group was divided into two subgroups: IOBL from the transected parenchyma (IOBL-TP, n = 18) and from the main Glissonean pedicle (IOBL-mGP, n = 12). The IOBL-negative group was divided into two subgroups: bile staining in the mGP (BS-mGP, n = 9) and no change (NC, n = 98). POBL occurred in 11% (n = 2/18) of patients with IOBL-TP, 25% (n = 3/12) of those with IOBL-mGP, 11% (n = 1/9) of those with BS-mGP, and 1% (n = 1/98) of those with NC. Age, diabetes mellitus, indocyanine green retention rate, and Glissonean approach were predictors of IOBL (P < 0.05).ConclusionsIOBL was relatively common during LLR and resulted in a higher incidence of POBL. Depending on the predictive factors, IOBL must be promptly identified and appropriately managed.

Purpose Hepatic veno-occlusive disease (HVOD) after liver transplantation (LT) is almost always a fatal complication. We assessed the outcomes of HVOD in a single institute and analyzed a literature-based cohort. Methods We reviewed the medical records of recipients of LT performed between 1995 and 2020 at our institute and the literature on HVOD after LT. We then analyzed the clinical features based on a “pooled” cohort of cases identified in our institute and reported in the literature. Results HVOD was diagnosed in 3 of 331 LT recipients, all of whom died in hospital, on days 164, 12, and 13, respectively. Our comprehensive review of the literature, as well as our cases, identified eight cases of HVOD that developed within 14 days after LT (early-onset type). Early-onset HVOD had a significantly worse prognosis than HVOD that developed beyond 2 weeks after LT (non-early-onset type), which was identified in 22 cases (25.0% vs. 86.1% of the 3-month graft survival rate). The most common causes of early-onset and non-early-onset types were acute cellular rejection (50%) and drug-induced disease (50%), respectively. Conclusion Early-onset HVOD developing within 14 days after LT has a poor prognosis.