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BackgroundThe 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.MethodsWe 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).ResultsThe 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.ConclusionThese results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.

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 The prevalence of extracorporeal cardiopulmonary resuscitation (ECPR) in patients with out-of-hospital cardiac arrest (OHCA) has been increasing rapidly worldwide. However, guidelines or clinical studies do not provide sufficient data on ECPR practice. The aim of this study was to provide real-world data on ECPR for patients with OHCA, including details of complications. Methods We did a retrospective database analysis of observational multicenter cohort study in Japan. Adult patients with OHCA of presumed cardiac etiology who received ECPR between 2013 and 2018 were included. The primary outcome was favorable neurological outcome at hospital discharge, defined as a cerebral performance category of 1 or 2. Results A total of 1644 patients with OHCA were included in this study. The patient age was 18–93 years (median: 60 years). Shockable rhythm in the initial cardiac rhythm at the scene was 69.4%. The median estimated low flow time was 55 min (interquartile range: 45–66 min). Favorable neurological outcome at hospital discharge was observed in 14.1% of patients, and the rate of survival to hospital discharge was 27.2%. The proportions of favorable neurological outcome at hospital discharge in terms of shockable rhythm, pulseless electrical activity, and asystole were 16.7%, 9.2%, and 3.9%, respectively. Complications were observed during ECPR in 32.7% of patients, and the most common complication was bleeding, with the rates of cannulation site bleeding and other types of hemorrhage at 16.4% and 8.5%, respectively. Conclusions In this large cohort, data on the ECPR of 1644 patients with OHCA show that the proportion of favorable neurological outcomes at hospital discharge was 14.1%, survival rate at hospital discharge was 27.2%, and complications were observed during ECPR in 32.7%.

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). Neural invasion is one of the malignant features in patients with pancreatic ductal adenocarcinoma (PDAC), but few studies exist on the distribution and state of nerve fibers in PDAC tissue. Here we investigated the clinicopathological characteristics of intrapancreatic neural alterations in patients with PDAC and we concluded that low intrapancreatic neural density was an independent prognosticator. We also propose a simple, practical and reproducible method to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC.

Purpose This study aimed to establish a reliable criterion for early drain removal after pancreaticoduodenectomy (PD) based on predictive factors of clinically relevant postoperative pancreatic fistula (CR-POPF) available on postoperative day 3 (POD3). Methods A total of 300 consecutive patients who underwent PD with pancreaticojejunostomy at our hospital from 2011 to 2015 were analyzed retrospectively. CR-POPF was defined as POPF grade B or C according to the definition by ISGPF. Clinicopathological factors available on or before POD3 were analyzed to identify predictors of CR-POPF. Using obtained predictors, we developed a criterion for no CR-POPF and internally validated its relevance in 100 consecutive patients. Results The incidence rates of CR-POPF, severe complications (Clavien–Dindo ≥ grade IIIa), and postoperative mortality were 35%, 9.6%, and 0.3%, respectively. Multivariate analysis showed that drain amylase (d-AMY) levels ≥ 350 IU/l on POD3, C-reactive protein (CRP) levels ≥ 14 mg/dl on POD3, preoperative endoscopic retrograde biliary drainage, and no portal vein resection were significant predictors of CR-POPF. Using the strongest predictors (i.e., d-AMY and CRP), we established a criterion for no CR-POPF: d-AMY levels < 350 IU/l and CRP levels < 14 mg/dl on POD3. The incidence rates of CR-POPF were 6%, 38%, and 88% in patients who fulfilled both of ( n  = 149), each of ( n  = 74), and none of ( n  = 77) the two factors, respectively. In the internal validation cohort, the positive predictive value of CR-POPF was 89%. Conclusions A simple two-factor criterion available on POD3 after PD has a reliable predictive ability. In patients who fulfill this criterion, early drain removal is considered safe.

BackgroundWe have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the clinical development of apoA2-is.MethodsWe established a new enzyme-linked immunosorbent sandwich assay for apoA2-is under the Japanese medical device Quality Management System requirements and performed in vitro diagnostic tests with prespecified end points using 2732 plasma samples. The clinical equivalence and significance of apoA2-is were compared with CA19-9.ResultsThe point estimate of the area under the curve to distinguish between pancreatic cancer (n = 106) and healthy controls (n = 106) was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832–0.925] than for CA19-9 (0.849, 95% CI 0.793–0.905) and achieved the primary end point. The cutoff apoA2-ATQ/AT of 59.5 μg/mL was defined based on a specificity of 95% in 2000 healthy samples, and the reliability of specificities was confirmed in two independent healthy cohorts as 95.3% (n = 106, 95% CI 89.4–98.0%) and 95.8% (n = 400, 95% CI 93.3–97.3%). The sensitivities of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) pancreatic cancers were higher than those of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cutoff, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. The clinical performance of apoA2-is was blindly confirmed by the National Cancer Institute Early Detection Research Network.ConclusionsThe clinical performance of ApoA2-ATQ/AT as a blood biomarker is equivalent to or better than that of CA19-9.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes ( KRAS , CDKN2A , TP53 and SMAD4 ) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.

Background The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. Methods A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu’s nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensity score matching analysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. Results Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS ( n  = 139) and bBR-NAC ( n  = 101). Ten (10%) in the bBR-NAC group ( n  = 101) experienced biological status change from unfavorable to favorable after NAC (Biological Conversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37–23.1; P  = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups ( n  = 67 for each) was found in long-term outcomes. Conclusions NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the Biological Conversion.

Background Postoperative pancreatic fistula (POPF) remains a leading cause of morbidity after pancreaticoduodenectomy (PD). In the present study we sought to establish a preoperative scoring system with which to predict this complication. Patients and methods The clinical records of 387 consecutive patients who underwent PD for periampullary tumor between 2004 and 2009 were reviewed retrospectively. Patients were divided into two groups; 279 consecutive patients constituted the study group and the next 108 patients constituted the validation group. Univariate and multivariate logistic regression analyses were performed using preoperative and surgical factors potentially influencing grade B or C POPF in the study group, and a score to predict POPF was constructed. This score was confirmed in the validation group. Results In the study group, grade A POPF was recognized in 45 patients (16%), grade B in 98 (35%), and grade C in 5 (2%). A preoperative predictive scoring system for POPF (0-7 points) was constructed using the following 5 factors; main pancreatic duct index <0.25 (2 points), away from portal vein on computed tomography (2 points), disease other than pancreatic cancer (1 point), male (1 point), and intra-abdominal thickness >65 mm (1 point). The nomogram showed an area under the curve (AUC) of 0.808. This scoring system was highly predictive for grade B or C POPF in the validation group (AUC = 0.834). Conclusions The present scoring system satisfactorily predicted the occurrence of POPF and thus will be useful for the perioperative risk management of patients undergoing PD in a high-volume center hospital.

BackgroundSplenic artery (SpA) involvement heralds poor prognosis in pancreatic ductal adenocarcinoma (PDAC) of the body and tail but is not included in the resectability criteria. This study evaluated the prognostic impact of radiological SpA involvement in PDAC of the body and tail.MethodsPreoperative computed tomography images of patients who underwent distal pancreatectomy for resectable PDAC of the body and tail (n = 242) at our hospital between 2004 and 2018 were graded according to splenic vessel involvement status as clear, abutment, or encasement. Clinicopathological prognostic factors and overall survival (OS) and recurrence-free survival (RFS) rates were compared between the three groups. The prognostic value of radiological involvement status was assessed using Harrell’s concordance statistic (C-index) and time-dependent receiver-operating characteristic curve analysis and compared with pathological findings.ResultsThe diagnostic concordance rate was 0.87 (weighted κ statistic). Prognosis worsened with progression from clear, abutment, to encasement status. SpA encasement (hazard ratio [HR] 1.97, p = 0.04) predicted poor OS in multivariate Cox hazard regression analysis. SpA abutment (HR 1.77, p = 0.017) and encasement (HR 1.86, p = 0.034) independently predicted poor RFS. Splenic vein abutment and encasement were not significant predictors of poor OS or RFS. SpA encasement without adjuvant chemotherapy had the poorest prognosis because of early distant metastasis. The prognostic value was higher for radiological SpA involvement than for pathological SpA invasion.ConclusionsRadiological SpA involvement status is a meaningful and reproducible prognostic indicator that can be used preoperatively for determining the treatment strategy in PDAC of the body and tail.