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Background Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients’ prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. Methods We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ≧ 2 or CONUT < 2). Results The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT ≧ 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) ( p  = 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4–6.8; p  = 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien–Dindo classification ≧ III or more). Conclusions CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.

BackgroundBased on the Japan Adjuvant Study Group of Pancreatic Cancer-01 results, S-1 adjuvant chemotherapy has been the standard in resected pancreatic ductal adenocarcinoma (PDAC) patients in Japan and elsewhere, initiated within 10 weeks after surgery. To assess the clinical impact of this timing, we conducted a secondary analysis of a nationwide survey by the Japan Pancreas Society.MethodsA total of 3361 patients were divided into two groups: 2681 (79.8%) initiating the therapy within 10 weeks after surgery (standard) and 680 (20.2%) after 10 weeks (delayed). We compared recurrence-free survival (RFS) and overall survival (OS) using the log-rank test and Cox proportional hazards model with conditional landmark analysis between the groups. Results were verified by adjustment with inverse-probability-of-treatment weighting (IPTW) analysis.ResultsThe median timing of S-1 adjuvant chemotherapy initiation was 50 days (interquartile range: 38–66). In the standard group, 5-year RFS and OS rates were 32.3–48.7%, respectively, compared with 25.0–38.7% in the delayed group. Hazard ratios (HRs) and 95% confidence intervals were 0.84 (0.76–0.93) for RFS (p < 0.001) and 0.77 (0.69–0.87) for OS (p < 0.001). The IPTW analysis yielded 5-year RFS rates of 32.1% and 25.3% in the standard versus delayed group, respectively [HR = 0.86 (0.77–0.96), p < 0.001] and 5-year OS rates of 48.3% and 39.8%, respectively [HR = 0.81 (0.71–0.92), p < 0.001]. ConclusionsInitiation of S-1 adjuvant chemotherapy in resected PDAC patients within 10 weeks after surgery may offer survival benefit over later initiation.

The accumulation of prostaglandin E2 (PGE 2 ) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE 2 , although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all- trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras LSL -G12D /+ ; Ptf1a Cre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE 2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh −/− KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS -driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

PurposeTumor budding is a histological characteristic defined as the presence of small clusters of cancer cells at the invasion front. Its significance in duodenal adenocarcinoma (DA) has not been fully described.MethodsA single-center, retrospective study was conducted. Patients who underwent curative surgery for histologically diagnosed DA from January 2006 to December 2018 at Kansai Medical University Hospital were included. Tumor budding was counted per 0.785 mm2 and classified as low (0–4 buds), intermediate (5–9 buds), or high (≥ 10 buds).ResultsIn total, 47 patients were included. The 5-year overall survival and relapse-free survival rates were 77% and 72%, respectively. High tumor budding was seen in 15 patients (32%). Excluding patients with superficial type (pT1) DA (n = 22), high tumor budding [hazard ratio (HR) 13.4, p = 0.028], regional lymph node metastasis (HR 19.9, p = 0.039), and adjuvant chemotherapy (HR 0.056, p = 0.036) were independent factors related to the overall survival in multivariate analyses. Distant metastases occurred significantly more often in patients who had high tumor budding than in others (p = 0.039).ConclusionThe data suggest that high tumor budding is a predictor of a poor prognosis in resected DA.

Background Portal vein embolization (PVE) can decrease the resection ratio for major hepatectomy. 99m Tc-galactosyl human serum albumin (GSA) scintigraphy is useful for evaluating quantitative functional liver volume. Branched chain amino acids (BCAAs) modulate liver function and regeneration. We analyzed the effects of BCAAs, in terms of liver function and regeneration after PVE, in combination with major hepatectomy. Methods This randomized controlled trial was conducted for patients receiving PVE through to complete hepatectomy from September, 2011 to June, 2013. BCAA granules were added two times a day to a conventional diet in the BCAA administration group (BCAA group). The primary end point was functional liver regeneration of the future remnant liver after PVE followed by hepatic resection. Functional liver regeneration was assessed by the liver uptake value obtained from 99m Tc-GSA scintigraphy single-photon-emission computed tomography/computed tomography fusion images. The secondary end points were volumetric liver regeneration and changes in liver function and laboratory data. Results A BCAA group ( n  = 13) and a non-BCAA group (control group; n  = 15) were included. The primary end point was partially met: the liver uptake value significantly increased in the BCAA group compared with the control group 6 months after hepatic resection (266.7 % vs 77.6 %, P  = 0.04) and marginally increased after PVE (43.8 % vs 17.4 %, P  = 0.079). Following PVE, the increment of the uptake ratio of the liver to the liver plus heart at 15 min was significantly less in the BCAA group than in the control group (0.0 and 0.01, P  = 0.023). Conclusions BCAA supplementation improved functional liver regeneration and function in patients undergoing PVE followed by major hepatic resection.

INTRODUCTION: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, low-grade malignant tumor. Although SPNs generally exhibit indolent behavior, spontaneous regression detected on CT imaging is exceedingly rare, and to the best of our knowledge, regrowth following regression has not been previously reported.CASE PRESENTATION: A 33-year-old woman was referred to Kansai Medical University following the detection of liver dysfunction during a routine medical checkup. Imaging revealed a well-demarcated 20-mm mass in the pancreatic body, and an endoscopic US-guided biopsy confirmed SPN. Surgical resection was initially planned but postponed because of a COVID-19 infection in a fellow inpatient. During follow-up, the tumor showed spontaneous regression and became undetectable on imaging at 4 months. However, MRI at 16 months revealed tumor regrowth, which became clearly visible on T2-weighted imaging by 23 months, measuring 15 mm. At 24 months, a laparoscopic spleen-preserving distal pancreatectomy was performed. Histopathology confirmed SPN with intratumoral hemorrhage and characteristic pseudopapillary architecture. Complete resection was achieved, and the patient’s postoperative course was uneventful.CONCLUSIONS: This case illustrates that SPN can regress spontaneously, yet subsequently regrow, underscoring the need for careful long-term imaging surveillance even after apparent tumor shrinkage.

Aim The incidence of cholelithiasis after gastrectomy is higher than that in the general population; however, the incidence and risk factors for choledocholithiasis have not been well reported. We aimed to assess the association between a history of gastrectomy and choledocholithiasis. Methods A total of 3025 patients who underwent cholecystectomy with or without choledocholithotomy between January 2006 and December 2020 at Kansai Medical University, Japan were included in this study. Patients were divided into a gastrectomy group with a history of gastrectomy (173 patients, 5.7%) and a control group having no history of gastrectomy (2852 patients, 94.3%). Results The incidence of choledocholithiasis was 61.8% and 22.2% in the gastrectomy and control groups, respectively, with a significantly higher incidence in the gastrectomy group (p < 0.0001). Multivariate analysis showed that age, sex, history of gastrectomy, and previous surgery except gastrectomy were risk factors for the development of choledocholithiasis, with a history of gastrectomy being the strongest risk factor (Odds Ratio 3.78, 95% Confidence Interval 2.71–5.27). The incidence values of choledocholithiasis in the Billroth I, Billroth II, and Roux‐en‐Y methods were 44.7%, 70.6%, and 69.7%, respectively, and were significantly lower in the Billroth I group than in the Roux‐en‐Y group (p = 0.009). The median time from gastrectomy to development of choledocholithiasis was 5.5 years for Roux‐en‐Y, which was significantly faster than 20 years for Billroth I and 35 years for Billroth II. Conclusion Gastrectomy is a known risk factor for choledocholithiasis. Concomitant cholecystectomy during gastrectomy may be indicated in older men. This retrospective study suggests that gastrectomy is a risk factor for choledocholithiasis. Especially in terms of the differences in reconstruction methods, the median time from gastrectomy to development of choledocholithiasis was 5.5 years for Roux‐en‐Y, which was significantly faster than 20 years for Billroth I and 35 years for Billroth II.

Preoperative evaluation of resectability of pancreatic cancer (PC) is difficult, so that staging laparoscopy (SL) has come to be used for detecting occult metastases. We aimed to evaluate the prognostic impact of SL in comparison with exploratory laparotomy (EL) in unresectable PC. Between 2010 and 2016, 57 patients with PC underwent SL after conventional tumor staging. Patient characteristics, operative findings and survival rates were compared between SL and EL group. Twenty patients (35%) were identified as having unresectable factors in SL group. In contrast, laparotomy showed unresectable factors in 8 patients who did not receive preoperative SL (EL group). The time between the surgery to the induction of chemotherapy was significantly shorter in the SL group (mean=6 days, range=2-17) than in the EL group (mean=10 days, range=6-15). There was no significant difference in overall survival between the two groups; however, EL was associated with shorter survival in the early postoperative period. SL was associated with a shorter time interval to chemotherapy and lead to the prevention of unnecessary laparotomy.

Background The level of long interspersed nucleotide element-1 (LINE-1) methylation has become regarded as a surrogate marker of global DNA methylation. Previously, we demonstrated that LINE-1 hypomethylation might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as cyclin-dependent kinase 6 ( CDK6 ) in esophageal squamous cell carcinoma. However, the relationship between LINE-1 hypomethylation and clinical outcome in hepatocellular carcinoma (HCC) remains unclear. Methods LINE-1 methylation level in 208 samples of curatively resected HCCs was measured by pyrosequencing assay, and the prognostic value of LINE-1 methylation level in HCC was examined. Results LINE-1 methylation levels in the 208 HCC patients investigated were distributed as follows: mean 64.7; median 64.6; standard deviation (SD) 13.6; range 21.5–99.1; interquartile range 62.9–66.6. Univariate Cox regression analysis revealed a significantly higher cancer recurrence rate in the low-methylation-level group than in the high-methylation-level group (hazard ratio 1.58; 95 % CI 1.05–2.47; p  = 0.028). Interestingly, the influence of LINE-1 hypomethylation on patient outcome was modified by hepatitis virus infection ( p of interaction = 0.023); LINE-1 hypomethylation was associated with a higher cancer recurrence rate in patients without hepatitis virus infection (log-rank p  = 0.0047). CDK6 messenger RNA expression levels were inversely associated with LINE-1 methylation levels ( p  = 0.0075; R = −0.37). Conclusions Genome-wide DNA hypomethylation, as measured by LINE-1 levels, might be associated with poor disease-free survival in HCC patients, suggesting a potential role for LINE-1 methylation level as a biomarker for identifying patients who will experience an unfavorable clinical outcome.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients. IL‐1β derived from activated macrophages down‐regulates 15‐PGDH expression in PDAC cells. Down‐regulation of 15‐PGDH promotes PDAC cell growth and leads to poor prognosis in PDAC patients.