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Lymph node metastasis is considered one of the most significant factors associated with postoperative prognosis in patients with pancreatic cancer. Some prospective studies found no significant differences in survival between patients who underwent pancreatic cancer surgery with extended lymphadenectomy and those who underwent surgery with standard lymphadenectomy. However, recent reports, such as those describing the significance of the metastatic to examined lymph node ratio, suggest the need for some degree of lymphadenectomy. This review describes the findings of published studies and discusses the usefulness of LN dissection in patients with pancreatic cancer.

Mutations in the human ATP13A2 (PARK9), a lysosomal ATPase, cause Kufor-Rakeb Syndrome, an early-onset form of Parkinson’s disease (PD). Here, we demonstrate that ATP13A2 functions as a lysosomal H + ,K + -ATPase. The K + -dependent ATPase activity and the lysosomal K + -transport activity of ATP13A2 are inhibited by an inhibitor of sarco/endoplasmic reticulum Ca 2+ -ATPase, thapsigargin, and K + -competitive inhibitors of gastric H + ,K + -ATPase, such as vonoprazan and SCH28080. Interestingly, these H + ,K + -ATPase inhibitors cause lysosomal alkalinization and α-synuclein accumulation, which are pathological hallmarks of PD. Furthermore, PD-associated mutants of ATP13A2 show abnormal expression and function. Our results suggest that the H + /K + -transporting function of ATP13A2 contributes to acidification and α-synuclein degradation in lysosomes. Mutations in the human ATP13A2, a lysosomal ATPase, is associated with pathogenesis of Parkinson’s disease. Here, the authors show that ATP13A2 functions as H + /K + transporting protein, preventing lysosomal alkalinization and α-synuclein accumulation.

BackgroundAs non-ampullary duodenal cancer is relatively rare, the optimal treatment strategy, including the appropriate surgical procedure and efficacy of adjuvant chemotherapy, remains unclear. This nationwide survey aimed to clarify the actual lymph node spread pattern and determine the optimal treatment strategy for this disease, using a large-scale database.MethodsWe used a questionnaire and a retrospective registry of 1083 patients with non-ampullary duodenal cancer who had undergone surgery during 2008–2017 in 114 high-volume Japanese Society of Hepatobiliary and Pancreatic Surgery-certified training institutions. Propensity score-matched analyses were conducted to minimise background bias. Cox regression was performed to identify covariates associated with recurrence-free survival. There were distinct disparities in the nodal dissection rate according to the predominant tumor location and tumor invasion depth. Metastases were frequently observed in the peripancreatic nodes and those along the superior mesenteric artery, irrespective of tumor location. Their dissection seemed to be beneficial for improved survival. In the overall cohort, no survival benefit was observed in patients who received adjuvant chemotherapy when compared with that in patients who underwent surgery alone. Nevertheless, in the matched cohort, adjuvant chemotherapy for > 6 months was associated with a significant improvement in recurrence-free survival (median: 43.5 vs. 22.5 months, p = 0.016), particularly in patients with tumor invasion of the subserosa or deeper tumor invasion, lymph node metastasis, or elevated serum carbohydrate antigen 19-9 levels.ConclusionPancreatoduodenectomy should be the standard procedure for advanced non-ampullary duodenal cancer. Adjuvant chemotherapy for > 6 months, especially for advanced tumors, significantly improves survival.

BackgroundThe expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC). MethodsSLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters.ResultsThe expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence.ConclusionsSLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients.

Background The efficacy of neoadjuvant therapy (NAT), including neoadjuvant chemotherapy (NAC) and neoadjuvant chemo-radiotherapy (NACRT), for patients with borderline resectable pancreatic cancer (BRPC) has not been elucidated. This study aimed to clarify the efficacy of NAC and NACRT for patients with BRPC. Methods The study analyzed the treatment outcomes of 884 patients treated for BRPC from 2011 to 2013. Treatment results were compared between upfront surgery and NAT and between NAC and NACRT using propensity score-matching analysis. Overall survival (OS) was calculated via intention-to-treat analyses. Results The overall resection rates for the patients who underwent NAT were significantly lower than for the patients who underwent upfront surgery (75.1% vs 93.3%; p  < 0.001). However, the R0 resection rate was significantly higher for NAT than for upfront surgery ( p  < 0.001). Additionally, the OS for the patients who received NAT was significantly longer than for those who underwent upfront surgery (median survival time [MST], 25.7 vs 19.0 months; p  = 0.015). The lymph node rate for the patients with NACRT was significantly lower than for those who underwent NAC ( p  < 0.001). However, the resection rate for the NACRT cases was significantly lower than for the NAC cases ( p  = 0.041). The local recurrence rate for the NACRT cases was significantly lower than for the NAC cases ( p  = 0.002). However, OS did not differ significantly between NAC and NACRT (MST, 29.2 vs 22.5 months; p  = 0.130). Conclusions The study showed that NAT has potential benefit for patients with BRPC. Compared with NAC, NACRT decreased the rates for lymph node metastasis and local recurrence but did not improve the prognosis.

BackgroundLiver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome.ObjectiveIn this study, we aimed to identify novel genes associated with liver metastasis of GC.MethodsGlobal expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis.ResultsAmong 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R.ConclusionsPRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.

Backgroundβ-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC).Patients and MethodsExpression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. ResultsB4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level.ConclusionsB4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

Circulating cancer cells (CCCs) are closely related to the process of distant metastasis. In early step of the metastasis cascade, CCCs must evade the detachment-induced cell death (anoikis) for their survival. Here, we examined whether Na + /K + -ATPase α3-isoform (α3NaK) in CCCs contributes to avoidance of anoikis. In CCCs isolated from gastric cancer patients, α3NaK was predominantly localized in the plasma membrane (PM), but it moved to the cytoplasm when the CCCs were attached to culture dishes. The CCCs showed significant expression of integrin α5 but not fibronectin, one of components of the extracellular matrix (ECM). In human gastric cancer MKN45 cells, digoxin (20 and 50 nM), a cardiac glycoside, significantly inhibited the enzyme activity and translocation (from cytoplasm to PM) of α3NaK, while they had no significant effect on ubiquitous Na + /K + -ATPase α1-isoform (α1NaK) in the PM. The translocation of α3NaK required the loss of ECM components from the cells. Additionally, digoxin significantly enhanced caspase 3/7 activity, as well as the expression of cleaved caspase 3, while reducing the viability of detached (floating) cells. In the MKN45 xenograft mouse model, intraperitoneal administration of digoxin (2 mg/kg/day) significantly decreased the number of CCCs and suppressed their liver metastasis. Our results suggest that α3NaK plays an essential role in the survival of CCCs in gastric cancer, and that digoxin enhances anoikis in detached (metastatic) gastric cancer cells by inhibiting the α3NaK translocation from cytoplasm to PM, thereby reducing CCCs. Targeting α3NaK may be a promising therapeutic strategy against CCC survival.

BackgroundThe clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC.MethodsSamples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated.ResultsPositive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY−). The mutant allele frequency was significantly higher in the CY+ patients than in the CY− patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY− and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity.ConclusionsAs a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

Background The efficacy of neoadjuvant chemoradiotherapy (NACRT) and subset of pancreatic ductal adenocarcinoma (PDAC) patients who are most likely to benefit from this strategy remain elusive. The aim of this study was to investigate the effects of NACRT in patients with resectable (R) or borderline resectable (BR) adenocarcinoma of the pancreatic head. BR diseases were classified into two groups: lesions involving exclusively the portal vein system (BR-PV) and those abutting the major artery (BR-A). Methods A total of 504 patients treated with curative intent for PDAC were analyzed (R, n  = 273; BR-PV, n  = 129; BR-A, n  = 102). Patients who underwent upfront surgery and those who underwent NACRT followed by surgery were compared using propensity score-matched and inverse probability of treatment-weighted analyses (UMIN000019719). Results No significant differences were noted in the incidences of curative resection among the three categories (R, BR-PV and BR-A). Propensity score-weighted logistic regression analysis revealed that the incidence of pathologically positive resection margins was reduced by NACRT only for BR patients. Among the propensity score-matched patients, NACRT rather than upfront surgery significantly prolonged the median survival time of BR-PV patients (28.4 vs. 20.1 months; P  = 0.044) but not that of R-PDAC patients (28.6 vs. 33.7 months; P  = 0.960). NACRT prolonged the median survival time of BR-A patients (18.1 vs. 10.0 months; P  = 0.046), but the results remained unsatisfactory. Conclusions These findings suggest that NACRT improves R0 rates and increases the survival of patients with BR-PV adenocarcinoma of the pancreatic head but not that of patients with R-PDAC.