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We report a rare case of a patient with initially unresectable gallbladder cancer who underwent conversion surgery with durvalumab in combination with gemcitabine plus cisplatin and achieved an R0 resection. A 68 year-old woman was found to have gallbladder cancer and multiple enlarged lymph nodes around the suprapancreatic rim and hepatic hilum invading the proper hepatic artery on computed tomography. The diagnosis was cT3cN2cM0, cStage IVB. After eight cycles of durvalumab in combination with gemcitabine plus cisplatin, all tumor markers became negative, and lymph node invasion of the hepatic artery disappeared. The patient underwent conversion surgery with gallbladder bed resection and regional lymph node dissection. There was no need for hepatic artery reconstruction. Pathology revealed ypT2aypN0ycM0, ypStage IIA, and radical resection was considered. Immunostaining of tissue collected at the time of endoscopic ultrasound-guided tissue acquisition revealed less than 1% programmed death ligand-1 expression. The patient continued adjuvant chemotherapy with single-agent durvalumab every 4 weeks and maintained a relapse-free survival of 8 months postoperatively. The utility of durvalumab in combination with gemcitabine plus cisplatin in unresectable gallbladder cancer independent of programmed death ligand-1 expression has been confirmed and may be an important option in future multimodal treatment, including conversion surgery., (© 2024. Japanese Society of Gastroenterology.)

Background: Postoperative pancreatic fistula (POPF) continues to be the most common complication after distal pancreatectomy (DP). Recent advancements in surgical techniques have established minimally invasive distal pancreatectomy (MIDP) as the standard treatment for various conditions, including pancreatic cancer. However, MIDP has not demonstrated a clear advantage over open DP in terms of POPF rates, indicating the need for additional strategies to prevent POPF in MIDP. This trial (WRAP study) aims to evaluate the efficacy of wrapping the pancreatic stump with polyglycolic acid (PGA) mesh and fibrin glue in preventing clinically relevant (CR-) POPF following MIDP., Methods: This multicenter, randomized controlled trial will include patients scheduled for laparoscopic or robotic DP for tumors in the pancreatic body and/or tail. Eligible participants will be centrally randomized into either the control group (Group A) or the intervention group (Group B), where the pancreatic stump will be reinforced by PGA mesh and fibrin glue. In both groups, pancreatic transection will be performed using a bioabsorbable reinforcement-attached stapler. A total of 172 patients will be enrolled across 14 high-volume centers in Japan. The primary endpoint is the incidence of CR-POPF (International Study Group of Pancreatic Surgery grade B/C)., Discussion: The WRAP study will determine whether the reinforcement of the pancreatic stump with PGA mesh and fibrin glue, a technique whose utility has been previously debated, could become the best practice in the era of MIDP, thereby enhancing its safety., Trial Registration: This trial was registered with the Japan Registry of Clinical Trials on June 15, 2024 (jRCTs032240120)., (© 2024. The Author(s).)

A 72-year-old woman was diagnosed with unresectable pancreatic body-tail cancer (cT4N1M1, cStage IV) with para-aortic lymph node metastasis. She underwent six courses of gemcitabine + nab-paclitaxel as first-line chemotherapy, 12 courses of oxaliplatin + irinotecan + levofolinate + fluorouracil as second-line chemotherapy, and five courses of albumin-suspended irinotecan + levofolinate + fluorouracil as third-line chemotherapy. After each chemotherapy regimen, the disease was determined to be progressive. Analyses of endoscopic ultrasound-fine needle aspiration specimens and peripheral blood samples revealed microsatellite-instability (MSI)-high pancreatic cancer. The patient underwent 19 courses of pembrolizumab and achieved a partial response. She then underwent conversion surgery, including distal pancreatectomy, lymph node dissection, local gastrectomy and partial mesenteric resection of transverse colon. She is currently alive without recurrence at 18 months postoperatively. It is extremely rare for patients with unresectable and MSI-high pancreatic cancer to successfully undergo conversion surgery after pembrolizumab treatment., (© 2024. Japanese Society of Gastroenterology.)

Pancreatic acinar cell carcinoma (PACC) is a rare type of pancreatic cancer; further, its pathogenesis and treatment strategies remain unclear. We report the case of a 70-year-old man who presented with a chief complaint of abdominal distention. Computed tomography scans revealed a large lobulated mass (tumor diameter: 150 mm) in the pancreatic body tail, which was diagnosed as a PACC through endoscopic ultrasonography fine needle aspiration. The other imaging modalities did not reveal distant metastases, and the tumor was classified as resectable. Neoadjuvant chemotherapy was planned after staging laparoscopy ruled out microscopic distant metastasis. First-line chemotherapy with gemcitabine + nab-paclitaxel failed due to tumor growth and worsening abdominal distention. Evaluation using the BRACAnalysis ® device indicated that the patient was positive for BRCA1 mutation. Second-line modified FOLFIRINOX (mFFX) resulted in a marked decrease in elastase 1 levels; moreover, a partial antitumor response was observed, which prompted radical resection. After distal pancreatectomy, the patient has survived for 3.5 years without recurrence. BRCA-mutated pancreatic cancer is more likely to respond to mFFX, including platinum, and BRCA mutations have been reported to be highly prevalent in PACC. It is important to evaluate the presence of BRCA mutations in patients with PACC prior to treatment., (© 2024. Japanese Society of Gastroenterology.)

Background: The aim of this study was to determine the optimal treatment for patients with pancreatic cancer (PaCa) having positive peritoneal cytology (PPC)., Methods: This multicenter retrospective study included patients with PPC treated at 78 high-volume centers between January 2012 and December 2020. Prognoses after resection (S-group) and initiation of nonsurgical treatment (N-group) were compared. Prognostic factors for survival in both groups were analyzed. Detailed characteristics of conversion surgery (CS) in the N-group were evaluated., Results: In total, 568 enrolled patients were classified into an S-group (n = 445) or an N-group (n = 123). Median survival times (MSTs) were 19.0 months and 19.3 months, respectively, with no significant difference in prognosis (p = .845). The intervenable prognostic factors for survival were adjuvant treatment in the S-group (p < .001) and CS in the N-group (p < .001). Following CS, the MST was prolonged to 45.6 months, and peritoneal or liver recurrence decreased considerably. CS can be expected if PPC is diagnosed before neoadjuvant treatment and when combination treatment is initiated., Conclusion: Surgical resection may not be beneficial for improving survival when PPC is evident. Chemotherapy aiming for CS may be the optimal treatment for such patients., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Background: Chylothorax, a rare but serious complication following esophagectomy, can lead to dehydration, malnutrition, and even mortality. Surgical intervention is considered when conservative treatment is ineffective; however, in some refractory cases, the cause of chylothorax remains unclear. We report a case of refractory chylothorax caused by abdominal chyle leakage into the pleural space via an unenclosed esophageal hiatus., Case Presentation: A 66-year-old man was diagnosed with advanced esophageal squamous cell carcinoma. The patient underwent robot-assisted thoracoscopic subtotal esophagectomy in the prone position with retrosternal gastric tube reconstruction following neoadjuvant chemotherapy. The thoracic duct was ligated and resected because of tumor invasion. Chylothorax and chylous ascites were observed 2 weeks after surgery but did not improve despite conservative management with medications and drainage. Lymphoscintigraphy through the inguinal lymph node showed tracer accumulation in the fluid in both the abdominal and pleural spaces. Lipiodol lymphangiography revealed abdominal lymphoid leakage, but no leakage was detected from the thoracic duct or mediastinum. We considered that the chylothorax was caused by chylous ascites flowing into the pleural space via an unenclosed esophageal hiatus, and we performed surgical intervention. Laparotomy revealed abdominal chyle leakage and a fistula at the esophageal hiatus with the inflow of ascites into the thoracic cavity. Lipiodol lymphangiography was additionally performed for treating abdominal lymphorrhea after surgery, and resulted in the improvement of the chylothorax and ascites. The patient was discharged with no recurrence of chylothorax or chylous ascites., Conclusions: Refractory chylothorax can occur due to chylous ascites flowing into the pleural space via an unenclosed esophageal hiatus. When the site of chylothorax leakage is unclear, the possibility of inflowing chylous ascites via the unenclosed esophageal hiatus should be explored. Esophageal hiatus closure and lipiodol lymphangiography could be effective in treating refractory chylothorax of unknown cause after esophagectomy., (© 2024. The Author(s).)

Pancreatic cancer, one of the deadliest cancers with the lowest 5-year survival rate, often develops resistance to gemcitabine-based chemotherapies. The hypovascular nature of pancreatic tumors forces cancer cells to adapt to nutrient-depleted tumor microenvironments. Conventional anticancer agents targeting rapidly dividing cancer cells under nutrient-rich conditions are largely ineffective against adapted pancreatic cancer cells. Thus, targeting cancer cells under nutrient starvation, termed the "antiausterity strategy", may be effective for pancreatic cancer. This study examined nicolaioidesin C (Nic-C) derivatives as antiausterity agents. Among the 32 derivatives, Nic-15 ( 4n ) exhibited superior cytotoxicity against MIA PaCa-2 and PANC-1 pancreatic cancer cells, inhibited MIA PaCa-2 cell migration and colony formation, and modulated the PI3K/Akt/mTOR pathway, while reducing the ER stress markers induced by gemcitabine. Nic-15 was found to inhibit tumor growth and enhance the efficacy of gemcitabine in an in vivo xenograft model. Nic-15 in combination with gemcitabine may be an effective strategy for the treatment of pancreatic cancer.

In 2023, the Japan Pancreas Society (JPS) published the new eighth edition of the Japanese classification of pancreatic carcinoma. We present here an excerpted version in English, based on the latest edition. The major changes in this revision are as follows: In the eighth edition of the Union for International Cancer Control (UICC), the T category was changed to be based on tumor size; however, the eighth edition of the Japanese classification retains the previous T category based on local invasion factors. Lymph nodes have been renamed, and regional lymph nodes have been defined by location. Peritoneal cytology, which was not previously included in distant metastasis (M), has now been included in the M category. Moreover, significant additions have been made regarding the pathological diagnosis of endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) and criteria for histological assessment of the effects after chemotherapy and radiation therapy. Although this classification is aimed at carcinoma originating in the pancreas, not in the bile duct or duodenum, if the differentiation of the primary organ is difficult, this classification should be applied. It is also desirable to describe tumors other than carcinoma and metastatic tumors to the pancreas in accordance with this classification., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Objective: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection., Summary Background Data: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown., Methods: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated., Results: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways., Conclusion: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs., Competing Interests: Disclosures: All authors disclose no personal and financial conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs., Methods: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort., Results: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate., Conclusions: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Glomus tumors (GT) generally occur in the skin. However, esophageal GT, an extremely rare condition, has no established standardized treatment guidelines. Herein, we report the case of an esophageal GT successfully removed by thoracoscopic enucleation in the prone position using intra-esophageal balloon compression., Case Presentation: A 45-year-old man underwent an annual endoscopic examination and was found to have a submucosal tumor in the lower esophagus. Endoscopic ultrasound (EUS) revealed a hyperechoic mass originating from the muscular layer. Contrast-enhanced computed tomography identified a 2 cm mass lesion with high contrast enhancement in the right side of the lower esophagus. Pathologic findings of EUS-guided fine needle aspiration biopsy (EUS-FNA) revealed round to spindle shaped atypical cells without mitotic activity. Immunohistochemically, the tumor was positive for alpha-smooth muscle actin, but negative for CD34, desmin, keratin 18, S-100 protein, melan A, c-kit, and STAT6. He was diagnosed with an esophageal GT and a thoracoscopic approach to tumor resection was planned. Under general anesthesia, a Sengstaken-Blakemore (SB) tube was inserted into the esophagus. The patient was placed in the prone position and a right thoracoscopic approach was achieved. The esophagus around the tumor was mobilized and the SB tube balloon inflated to compress the tumor toward the thoracic cavity. The muscle layer was divided and the tumor was successfully enucleated without mucosal penetration. Oral intake was initiated on postoperative day (POD) 3 and the patient discharged on POD 9. No surgical complications or tumor metastasis were observed during the 1-year postoperative follow-up., Conclusions: As malignancy criteria for esophageal GT are not yet established, the least invasive procedure for complete resection should be selected on a case-by-case basis. Thoracoscopic enucleation in the prone position using intra-esophageal balloon compression is useful to treat esophageal GT on the right side of the esophagus., (© 2024. The Author(s).)

Hineka is a type of off-flavor of sake and is attributed to the presence of several compounds, including a major one called dimethyl trisulfide (DMTS). The production of the main precursor of DMTS involves yeast methionine salvage pathway. The DMTS-producing potential (DMTS-pp) of sake brewed using the Km67 strain, a non-Kyokai sake yeast, is lower than that of sake brewed using Kyokai yeast; however, the detailed mechanism is unclear. We focused on S-adenosyl-methionine (SAM) and aimed to elucidate the mechanism that prevents DMTS production in sake brewed using the Km67 strain. We revealed that SAM is involved in DMTS production in sake, and that the conversion of SAM to the DMTS precursor occurs through an enzymatic reaction rather than a chemical reaction. Based on previous reports on ADO1 and MDE1 genes, sake brewing tests were performed using the Km67 Δmde1, Δado1, and Δmde1Δado1 strains. A comparison of the SAM content of pressed sake cakes and DMTS-pp of sake produced using the Km67 Δado1 strain showed an increase in both SAM content and DMTS-pp compared to those produced using the parent strain. However, the Km67 Δmde1Δado1 strain showed little increase in DMTS-pp compared to the Km67 Δmde1 strain, despite an increase in SAM content. These results suggest that SAM accumulation in yeast plays a role in the production of DMTS in sake through the methionine salvage pathway. Moreover, the low SAM-accumulation characteristic of the Km67 strain contributes to low DMTS production in sake., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Myolipomas are rare tumors that are often difficult to differentiate from liposarcoma. Herein, we report a case of resected giant myolipoma preoperatively diagnosed as liposarcoma. A 63-year-old woman was suspected of having a large retroperitoneal liposarcoma on October 202X. The patient was referred to our department for tumor resection and a histological diagnosis. After consultation with the urology, obstetric and gynecology, and vascular surgery departments, tumor resection was planned, including the potential resection of other organs. Intraoperative findings revealed a large, elastic, soft tumor with a smooth surface and a capsule occupying the entire abdominal cavity. The tumor was adherent to the stomach, left colon, and uterine adnexa, and no invasion was observed. The tumor was completely resected, and organ resection was not necessary. The tumor was 40 cm in diameter and 4.0 kg in weight. Pathological examination and immunostaining confirmed a diagnosis of myolipoma. The patient's postoperative course was uneventful, and she was discharged on postoperative day 10 with no complications. Twelve months after surgery, the patient was doing well. To the best of our knowledge, we report a complete resection of the largest retroperitoneal myolipoma reported to date. Physicians should consider surgery, even for suspected large sarcomas that may be difficult to resect completely., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Introduction: We aimed to evaluate the safety and short-term outcomes of robotic-assisted transabdominal preperitoneal repair for inguinal hernia in 12 pioneering hospitals in Japan., Methods: Clinical data of patients who underwent robotic-assisted transabdominal preperitoneal repair between September 1, 2016, and December 31, 2021 were collected. Primary outcome measures were intra-operative adverse events and post-operative complications, whereas secondary outcomes were surgical outcomes, including chronic pain, recurrence, and learning curve., Results: In total, 307 patients were included. One case of inferior epigastric arterial injury was reported; no cases of bowel or bladder injury were reported. Thirty-five seromas were observed, including four (1.3%) cases that required aspiration. The median operative time of a unilateral case was 108 minutes (interquartile range: 89.8-125.5), and post-operative pain was rated 1 (interquartile range: 0-2) on the numerical rating scale. In complicated cases, such as recurrent inguinal hernias and robotic-assisted radical prostatectomy-associated hernias, dissection and suture were safely achieved, and no complications were observed, except for non-symptomatic seroma. All patients underwent robotic procedures, and there was no chronic post-operative inguinal pain, although one case of hernia recurrence was reported. Regarding the learning curve, plateau performance was achieved after 7-10 cases in terms of operative time (P < .001)., Conclusion: Robotic-assisted transabdominal preperitoneal repair can be safely introduced in Japan. Regardless of the involvement of many surgeons, the mastery of robotic techniques was achieved relatively quickly. The advantage of robotic technology such as wristed instruments may expand the application of minimally invasive hernia repair for complicated cases., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

We evaluated the effects of long-term glycerophosphocholine (GPC) intake on microglia, the blood-brain barrier (BBB), and neurogenesis in senescence-accelerated mice prone 8 (SAMP8). The GPC intake suppressed microglial activation and BBB disruption and sustained doublecortin-positive cells in the hippocampus. The results indicate that GPC intake exerts anti-inflammatory and neuroprotective effects in the brain of aged mice., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: The frequency and prognosis of positive peritoneal washing cytology (CY1) in resectable pancreatic ductal adenocarcinoma (R-PDAC) remains unclear. The objective of this study was to identify the clinical implications of CY1 in R-PDAC and staging laparoscopy (SL)., Methods: We retrospectively analyzed 115 consecutive patients with R-PDAC who underwent SL between 2018 and 2022. Patients with negative cytology (CY0) received radical surgery after neoadjuvant chemotherapy, while CY1 patients received systemic chemotherapy and were continuously evaluated for cytology., Results: Of the 115 patients, 84 had no distant metastatic factors, 22 had only CY1, and nine had distant metastasis. Multivariate logistic regression revealed that larger tumor size was an independent predictor of the presence of any distant metastatic factor (OR: 6.30, p = .002). Patients with CY1 showed a significantly better prognosis than patients with distant metastasis (MST: 24.6 vs. 18.9 months, p = .040). A total of 11 CY1 patients were successfully converted to CY-negative, and seven underwent conversion surgery. There was no significant difference in overall survival between patients with CY0 and those converted to CY-negative., Conclusion: SL is effective even for R-PDAC. The prognosis of CY1 patients converted to CY-negative is expected to be similar to that of CY0 patients., (© 2023 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

We present the case of a 100-year-old man with no specific symptoms. Computed tomography (CT) revealed a 34 mm tumor in the pancreatic tail, which was diagnosed as pancreatic cancer by biopsy. CT and magnetic resonance imaging showed that the tumor was resectable, and there were no noncurative factors on staging laparoscopy (cT3N0M0: cStage IIA). His performance status was good, and hypertension was the only comorbidity. A cardiologist, respiratory physician, and anesthesiologist examined the patient and determined that his condition was suitable for surgery. His postoperative predicted mortality rate was 0.9% using the American College of Surgeons risk calculator. We administered synbiotics and nutrients before surgery and introduced preoperative rehabilitation to improve his activities of daily living (ADL) as well as respiratory training to prevent postoperative pneumonia. Regarding the invasiveness of the surgery, we performed laparoscopic distal pancreatectomy with D1 lymphadenectomy. The patient was discharged on postoperative day 17, without any major complications. When performing pancreatectomy in older adults, it is important to fully assess preoperative tolerance and perioperative risk and prevent worsening of ADL by introducing nutritional therapy and rehabilitation., (© 2023. Japanese Society of Gastroenterology.)

Background: There have been few studies of countermeasures against postoperative cholangitis, a serious complication after pancreaticoduodenectomy (PD) that impairs quality of life., Objective: To evaluate our recently developed, novel method of choledochojejunostomy with a larger anastomotic diameter, the "T-shaped anastomosis.", Methods: The study included 261 cases of PD. The T-shaped choledochojejunostomy technique was performed with an additional incision for a distance greater than half the diameter of the bile duct at the anterior wall of the bile duct and the anterior wall of the elevated jejunum. To compensate for potential confounding biases between the standard anastomosis group ( n  = 206) and the T-shaped anastomosis group ( n  = 55), we performed propensity score matching (PSM). The primary endpoint was the incidence of medium-term postoperative cholangitis adjusted for PSM., Results: In the PSM analysis, 54 patients in each group were matched, and the median bile duct diameter measured by preoperative CT was 8.8 mm versus 9.3 mm, the rate of preoperative biliary drainage was 31% versus 37%, the incidence of cholangitis within 1 month before surgery was 9% versus 13%, and the incidence of postoperative bile leakage was 2% versus 2%, with no significant differences. The incidence of medium-term postoperative cholangitis was 15% versus 4%, and multivariate logistic regression revealed that T-shaped choledochojejunostomy was an independent predictor of a reduced incidence of cholangitis (odds ratio, 0.17, 95% CI 0.02-0.81; p  = 0.024)., Conclusions: The T-shaped choledochojejunostomy technique was shown to be effective with a significant reduction in the incidence of medium-term postoperative cholangitis. Clinical trial identification: UMIN000050990., Competing Interests: The authors declare no conflicts of interest for this article., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Purpose: The efficiency and safety of routine intravenous administration of acetaminophen after highly invasive hepatobiliary pancreatic surgery remain unclear. In particular, there have been no studies focusing on pancreatoduodenectomy. The present study clarified its clinical utility for patients undergoing pancreatoduodenectomy., Methods: We retrospectively collected 179 patients who underwent open pancreatoduodenectomy from 2015 to 2020. The analgesic effects and adverse events in patients with scheduled intravenous administration of acetaminophen were evaluated using propensity score matching., Results: After 40 patients from each group were selected by propensity score matching, the postoperative liver function tests were not significantly different between the control and acetaminophen groups. No significant differences were found in the self-reported pain intensity score or postoperative nausea and vomiting; however, the rate of pentazocine use and the total number of additional analgesics were significantly lower in the acetaminophen group than in the control group (p = 0.003 and 0.002, respectively)., Conclusion: The scheduled intravenous administration of acetaminophen did not affect the postoperative liver function and had a good analgesic effect after pancreatoduodenectomy., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Pancreatic ductal adenocarcinoma (PDAC) is a typical refractory malignancy, and many patients have distant organ metastases at diagnosis, such as liver metastasis and peritoneal dissemination. The standard treatment for unresectable PDAC with distant organ metastasis (UR-M) is chemotherapy, but the prognosis remained poor. However, with recent dramatic developments in chemotherapy, the prognosis has gradually improved, and some patients have experienced marked shrinkage or disappearance of their metastatic lesions. With this trend, attempts have been made to resect a small number of metastases (so-called oligometastases) in combination with the primary tumor or to resect the primary and metastatic tumor in patients with a favorable response to anti-cancer treatment after a certain period of time (so-called conversion surgery). An international consensus meeting on surgical treatment for UR-M PDAC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of the Japan Pancreas Society (JPS) in Kyoto in July 2022. The presenters showed their indications for and results of surgical treatment for UR-M PDAC and discussed their advantages and disadvantages with the experts. Although these reports were limited to a small number of patients, findings suggest that these surgical treatments for patients with UR-M PDAC who have had a significant response to chemotherapy may contribute to a prognosis of prolonged survival. We hope that this article summarizing the discussion and agreements at the meeting will serve as the basis for future trials and guidelines., Competing Interests: Declaration of competing interest Sohei Satoi received grants for research on pancreas cancer from Nihon Servier and Amino Up. Other authors report no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Squamous cell carcinoma (SCC) of the breast is a rare form of breast cancer, accounting for approximately 0.1% of all breast cancers. It is known for its rapid tumor growth and poor prognosis with no established treatment., Case Presentation: A 56-year-old woman was diagnosed with breast SCC with axillary, supraclavicular and internal thoracic lymph node metastases. She received neoadjuvant chemotherapy (NAC) with dose-dense doxorubicin and cyclophosphamide (AC) followed by dose-dense paclitaxel (PTX). This treatment resulted in a pathological complete response (pCR) after breast-conserving surgery. The patient was then treated with radiotherapy. She remained free of recurrence for three years postoperatively., Conclusions: We report a rare case of breast SCC treated with preoperative dose-dense chemotherapy, resulting in pCR and allowing breast-conserving surgery., (© 2023. The Author(s).)

Introduction: The prognosis of pancreatic ductal adenocarcinoma (PDAC) in patients with positive peritoneal washing cytology (CY1) is poor. We aimed to evaluate the results of staging laparoscopy (SL) and treatment efficacy in CY1 patients based on a resectability classification., Methods: We retrospectively reviewed 250 patients with PDAC who underwent SL before the initial treatment between 2017 and 2023 at the University of Toyama., Results: The breakdown of cases by resectability classification was resectable (R):borderline resectable (BR):unresectable locally advanced (UR-LA) = 131:48:71 cases. The frequency of CY1 increased in proportion to the degree of local progression (R:BR:UR-LA = 20:23:34%), but the frequencies of liver metastasis or peritoneal dissemination were comparable (R:BR:UR-LA = 6.9:6.3:8.5%). Most CY1 patients received gemcitabine along with nab-paclitaxel therapy. The CY-negative conversion rates (R:BR:UR-LA = 70:64:52%) and conversion surgery rates (R:BR:UR-LA = 40:27:9%) were inversely proportional to the degree of local progression.Comparing H0P0CY1 factors for each classification, patients with H0P0CY1 had significantly more pancreatic body or tail carcinoma and tumor size ≥32 mm in R patients, whereas in BR patients, duke pancreatic monoclonal antigen type 2 (DUPAN-2) ≥ 230 U/mL was a significant factor. In contrast, no significant factors were observed in UR-LA patients., Conclusion: The CY1 rates, CY-negative conversion rates, and conversion surgery rates varied according to local progression. In the case of R and BR, SL could be considered in patients with pancreatic body or tail carcinoma, large tumor size, or high DUPAN-2 level. In UR-LA, SL might be considered for all patients., Competing Interests: The authors have no conflicts of interest to declare for this study., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Human pancreatic tumors are hypovascular in nature, and their tumor microenvironment is often characterized by hypoxia and severe nutrient deprivation due to uncontrolled heterogeneous growth, a phenomenon known as "austerity". However, pancreatic tumor cells have the inherent ability to adapt and thrive even in such low nutrient and hypoxic microenvironments. Anticancer drugs such as gemcitabine and paclitaxel, which target rapidly proliferating cells, are often ineffective against nutrient-deprived pancreatic cancer cells. In order to overcome this limitation, the search for novel agents that can eliminate cancer cells' adaptations to nutrition starvation, also known as "antiausterity" agents, represents a promising strategy to make the cancer cells susceptible to treatment. The natural product (+)-nicolaioidesin C (Nic-C) was found to have potent antiausterity activity against the PANC-1 human pancreatic cancer cell line in a nutrient-deprived condition. However, its efficacy in vivo remained untested. To address this, we synthesized Nic-C in its racemic form and evaluated its antitumor potential in a human pancreatic cancer xenograft model. Nic-C inhibited pancreatic cancer cell migration and colony formation and significantly inhibited tumor growth in MIA PaCa-2 xenografts in a dose-dependent manner. Furthermore, Nic-C inhibited the Akt/mTOR and autophagy signaling pathways in both in vitro and in vivo studies. Metabolomic profiling of in vivo tumor samples suggests that Nic-C downregulates amino acid metabolism while upregulating sphingolipid metabolism.

Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin ( 3f ) was the most promising compound with a PC 50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f , demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.

Despite recent advances in multidisciplinary treatments of esophageal squamous cell carcinoma (ESCC), patients frequently suffer from distant metastasis after surgery. For numerous types of cancer, circulating tumor cells (CTCs) are considered predictors of distant metastasis, therapeutic response and prognosis. However, as more markers of cytopathological heterogeneity are discovered, the overall detection process for the expression of these markers in CTCs becomes increasingly complex and time consuming. In the present study, the use of a convolutional neural network (CNN)-based artificial intelligence (AI) for CTC detection was assessed using KYSE ESCC cell lines and blood samples from patients with ESCC. The AI algorithm distinguished KYSE cells from peripheral blood-derived mononuclear cells (PBMCs) from healthy volunteers, accompanied with epithelial cell adhesion molecule (EpCAM) and nuclear DAPI staining, with an accuracy of >99.8% when the AI was trained on the same KYSE cell line. In addition, AI trained on KYSE520 distinguished KYSE30 from PBMCs with an accuracy of 99.8%, despite the marked differences in EpCAM expression between the two KYSE cell lines. The average accuracy of distinguishing KYSE cells from PBMCs for the AI and four researchers was 100 and 91.8%, respectively (P=0.011). The average time to complete cell classification for 100 images by the AI and researchers was 0.74 and 630.4 sec, respectively (P=0.012). The average number of EpCAM-positive/DAPI-positive cells detected in blood samples by the AI was 44.5 over 10 patients with ESCC and 2.4 over 5 healthy volunteers (P=0.019). These results indicated that the CNN-based image processing algorithm for CTC detection provides a higher accuracy and shorter analysis time compared to humans, suggesting its applicability for clinical use in patients with ESCC. Moreover, the finding that AI accurately identified even EpCAM-negative KYSEs suggested that the AI algorithm may distinguish CTCs based on as yet unknown features, independent of known marker expression., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Akashi et al.)

Background: The pectoralis major musculocutaneous flap (PMMF) is a pedicled flap often used as a reconstruction option in head and neck surgery, especially in cases with poor wound healing. However, applying PMMF after esophageal surgery is uncommon. We report here, the case of a successfully repaired refractory anastomotic fistula (RF) after total esophagectomy, by PMMF., Case Presentation: A 73-year-old man had a history of hypopharyngolaryngectomy, cervical esophagectomy, and reconstruction using a free jejunal graft for hypopharyngeal carcinosarcoma at the age of 54. He also received conservative treatment for pharyngo-jejunal anastomotic leakage (AL), then postoperative radiation therapy. This time, he was diagnosed with carcinosarcoma in the upper thoracic esophagus; cT3rN0M0, cStageII, according to the Japanese Classification of Esophageal Cancer 12th Edition. As a salvage surgery, thoracoscopic total resection of the esophageal remnant and reconstruction using gastric tube via posterior mediastinal route was performed. The distal side of the jejunal graft was cut and re-anastomosed with the top of the gastric tube. An AL was observed on the 6th postoperative day (POD), and after 2 months of conservative treatment was then diagnosed as RF. The 3/4 circumference of the anterior wall of the gastric tube was ruptured for 6 cm in length, and surgical repair using PMMF was performed on POD71. The edge of the defect was exposed and the PMMF (10 × 5 cm) fed by thoracoacromial vessels was prepared. Then, the skin of the flap and the wedge of the leakage were hand sutured via double layers with the skin of the flap facing the intestinal lumen. Although a minor AL was observed on POD19, it healed with conservative treatment. No complications, such as stenosis, reflux, re-leakage, were observed over 3 years of postoperative follow-up., Conclusions: The PMMF is a useful option for repairing intractable AL after esophagectomy, especially in cases with large defect, as well as difficulties for microvascular anastomosis due to previous operation, radiation, or wound inflammation., (© 2023. The Author(s).)

Esophageal neuroendocrine carcinoma (E-NEC) is an aggressive disease with a poor prognosis. The present study aimed to assess the role of surgery in the treatment of patients with resectable E-NEC, and identify a microRNA (miRNA/miR) signature in association with positive postoperative outcomes. Between February 2017 and August 2019, 36 patients with E-NEC who underwent curative surgery at the Japan Neuroendocrine Tumor Society partner hospitals were enrolled in the study. A total of 16 (44.4%) patients achieved disease-free survival (non-relapse group), whereas 20 (55.6%) patients developed tumor relapse (relapse group) during the median follow-up time of 36.5 months (range, 1-242) after surgery with a 5-year overall survival rate of 100 and 10.8%, respectively (P<0.01). No clinicopathological parameters, such as histological type or TNM staging, were associated with tumor relapse. Microarray analysis of 2,630 miRNAs in 11 patients with sufficient quality RNA revealed 12 miRNAs (miR-1260a, -1260b, -1246, -4284, -612, -1249-3p, -296-5p, -575, -6805-3p, -12136, -6822-5p and -4454) that were differentially expressed between the relapse (n=6) and non-relapse (n=5) groups. Furthermore, the top three miRNAs (miR-1246, -1260a and -1260b) were associated with overall survival (P<0.01). These results demonstrated that surgery-based multidisciplinary treatment is effective in a distinct subpopulation of limited stage E-NEC. A specific miRNA gene set is suggested to be associated with treatment outcome., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Okumura et al.)

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., (© 2023. The Author(s).)

Background: Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated α 1 -acid glycoprotein (fAGP) level markedly elevated along with disease progression in large cohorts of patients with various cancers., Methods: The fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard., Results: The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P = .0012). At a cutoff value of 27.04 U/μg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61%, 65.96%, and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level and 18 F-fluorodeoxyglucose uptake on the PET/CT imaging in the lesions seemed to offer the best diagnosis of IPMN. Accordingly, 27 of the 28 patients who were positive in both tests had IPMC, while patients who are negative had benign IPMN., Conclusions: The fAGP level appeared to be a relevant biomarker for malignant potential of IPMN., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC., Methods: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days., Results: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis., Conclusions: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment., (© 2022 American Cancer Society.)

Solitary colonic metastasis from esophageal cancer is rare. The prognosis of patients with distant metastases from esophageal cancer is extremely poor. A case of long-term survival with colonic metastasis from esophageal cancer treated by multimodal therapy is reported. A 67-year-old man was diagnosed with middle thoracic esophageal squamous cell carcinoma. The patient received neoadjuvant chemotherapy and then underwent subtotal esophagectomy. Approximately 1 year after esophagectomy, an asymptomatic, solitary colonic mass was detected on the follow-up computed tomography for esophageal cancer. Preoperative colonoscopy showed a 5-cm type 3 tumor at the ascending colon, and histological findings of the biopsy specimen indicated possible metastasis from primary esophageal squamous cell carcinoma. The patient underwent laparoscopic ileocolic resection with D3 lymph noddle dissection. Histologically, the colonic tumor was confirmed to be a metastasis from the esophageal squamous cell carcinoma. To the best of our knowledge, only eight cases with resected solitary colonic metastasis, including the present case, have been reported, and the present patient achieved greater than 3-year survival after esophagectomy. Resection of an asymptomatic solitary organ metastasis from primary esophageal cancer appears to be a good therapeutic option, even following esophagectomy., (© 2022. Japanese Society of Gastroenterology.)

Bevacizumab and eribulin are novel agents for the treatment of HER2-negative metastatic breast cancer (MBC); however, the choice between bevacizumab and eribulin for MBC can be difficult. The present study aimed to compare two treatment strategies, eribulin followed by bevacizumab and paclitaxel (BEV + PTX) versus BEV + PTX followed by eribulin, to determine whether the order of administration affects the outcome of MBC in the real world. A total of 180 patients who started BEV + PTX and eribulin treatment for HER2-negative MBC from August 2011 to June 2018 were selected. Of these, 84 patients were treated with both BEV + PTX and eribulin sequentially. To evaluate the influence of the sequential order, the efficacy of BEV + PTX followed by eribulin (B-E arm) was compared to treatment with the reverse sequence (E-B arm). The propensity score matching method (PSMA) was used to improve the robustness of the findings from the present study. A total of 60 cases analyzed received BEV + PTX or eribulin as either first- or second-line treatment. In the entire cohort, the median time to failure of strategy (TFS) was 16.8 and 9.9 months in the B-E and E-B arms, respectively [hazard ratio (HR)=0.515, 95% CI 0.298-0.889, P=0.017). A similar HR was derived from PSMA for TFS. Using PSMA, TFS was 16.9 and 9.9 months in the B-E and E-B arms, respectively (HR=0.491, 95% CI 0.253-0.952, P=0.031). These results suggested that when both bevacizumab and eribulin are administered, bevacizumab should be administered first and eribulin should be administered later to ensure the most effective use of each drug., Competing Interests: SM received honoraria from Chugai Pharmaceutical Co., Ltd., and Eisai Co., Ltd., and received research funding (institution) from Eisai Co., Ltd., outside the submitted work., (Copyright: © Matsui et al.)

Sake yeasts have a range of brewing characteristics that are particularly beneficial for sake making including high ethanol fermentability, high proliferative capacity at low temperatures, lactic acid tolerance, and high ester productivity. On the other hand, sake yeasts also accumulate a diverse range of functional components. For example, significantly greater accumulation of S-adenosylmethionine (SAM), a compound that plays important regulatory roles in a range of biological processes as a major donor of methyl groups, occurs in sake yeasts compared to other microorganisms. Significantly greater accumulation of folate, a bioactive water-soluble vitamin (vitamin B9), also occurs in sake yeasts compared to laboratory yeasts, and the methyl group on SAM is supplied by folate. Accordingly, fully characterizing 'sake yeast identity' requires detailed understanding of the mechanisms underlying both the nutritional characteristics (functional components) and the brewing characteristics in sake yeasts. Therefore, this mini-review focuses on the accumulation of SAM and folate in sake yeast including descriptions of the genes known to contribute to SAM and folate accumulation and the underlying mechanisms., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Background/aim: MicroRNAs (miRNAs) are abnormally expressed and involved in the pathogenesis of various carcinomas. The present study aimed to identify novel miRNA genes associated with the pathogenesis and prognosis of oesophageal squamous cell carcinoma (ESCC)., Materials and Methods: The miRNA profiling of 873 genes was performed using surgically resected oesophageal tissues from 35 patients with ESCC to identify candidate miRNAs. To examine the biological activities of candidate miRNAs, their proliferative, invasive, and migratory abilities were evaluated in ESCC cells subjected to miRNA mimic-mediated over-expression. The miRNA expression levels of the selected candidate miRNAs were analysed in the resected oesophageal tissues of 76 patients with ESCC from the two cohorts and correlated with the clinicopathological parameters., Results: Among the four candidate miRNAs identified by miRNA profiling, miR-877-3p was selected for subsequent analyses. In vitro analyses showed that the over-expression of miR-877-3p significantly suppressed the proliferation, invasion, and migration of ESCC cell lines compared with those of control cells. In the analyses of clinical specimens, the expression of miR-877-3p was down-regulated in ESCC tissues compared with that in adjacent normal oesophageal tissues. The down-regulation of miR-877-3p expression in ESCC tissues was significantly associated with advanced local progression and lymphatic involvement. The miR-877-3p down-regulation was also significantly associated with poor disease-free and disease-specific survival., Conclusion: miR-877-3p acts as a tumour suppressor gene in ESCC cells, and its down-regulation in ESCC tissues is associated with a poor prognosis. Thus, miR-877-3p may serve as a novel prognostic marker and promising therapeutic target., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Third-line chemotherapy has been suggested to improve survival in patients with gastric cancer. This study aimed to identify factors associated with the induction of third-line chemotherapy for advanced gastric cancer, focusing on patient eligibility for clinical trial., Methods: We retrospectively analyzed 335 patients treated for unresectable or recurrent gastric cancer between April 2009 and May 2020. The patients were grouped into those that met the key eligibility criteria for clinical trial (136 patients, 40.6%) and those that did not (199 patients, 59.4%) before receiving first-line chemotherapy., Results: The overall survival (OS) was 16.8 months (95% CI: 14.0-19.6) and 9.3 months (95% CI: 7.8-11.0) in the eligible and ineligible group, respectively. Multivariate analyses to identify the risk factors associated with the induction of third-line chemotherapy revealed ineligibility of clinical trial (OR 1.95; 95% CI: 1.15-3.31), number of metastatic sites (OR 1.99; 95% CI: 1.23-3.22), low albumin concentration (OR 2.24; 95% CI: 1.14-4.38), and a lack of complete or partial response to first-line treatment (OR 1.85; 95% CI: 1.05-3.26). Indeed, in responders to first-line treatment for ineligible patients, the median OS was 17.7 months (95% CI: 10.6-27.9), respectively., Conclusions: Treatment outcomes were different for those eligible for clinical trials and those who were not. However, this study suggested that patients who responded to first-line treatment have more favorable prognosis when treated with salvage chemotherapy, even if they were deemed ineligible for clinical trials., (© 2022 S. Karger AG, Basel.)

Background: The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear., Methods: We analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs., Results: Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P < 0.01, P < 0.01) and validation cohort (P < 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P < 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells., Conclusion: We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms., Methods: We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients., Results: Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255)., Conclusions: A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety., Methods: We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary., Results: Highly advanced HBPS was performed in 121 518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (P < .001). Ninety-day mortality rates were 2.1%, 1.82%, 1.62%, 1.28%, 1.46%, 1.22%, 1.19%, and 0.98%, respectively (P < .001). Summary reports were submitted by 20 hospitals between 2015 and 2019. Mortality rates before and after the start of report submission and audit were 5.72% and 2.79%, respectively (odds ratio 0.690, 95% confidence interval 0.487-0.977; P = .037)., Conclusions: Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC., Summary of Background Data: Pretreatment risk stratification is essential for offering individualized treatments to patients with PDAC, but predicting recurrence following surgery remains clinically challenging., Methods: We analyzed 210 plasma and serum specimens from 4 cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation., Results: We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence [area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.70-0.89] and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65- 0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (hazard ratio: 2.84, 95% CI: 1.30-6.20)., Conclusions: We identified a novel, noninvasive exo-miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient)., (© 2022. The Author(s).)

Aims/introduction: This study aimed to identify the clinical factors affecting postoperative residual pancreatic β-cell function, as assessed by the C-peptide index (CPI), and to investigate the association between perioperative CPI and the status of diabetes management after pancreatectomy., Materials and Methods: The associations between perioperative CPI and clinical background, including surgical procedures of pancreatectomy, were analyzed in 47 patients who underwent pancreatectomy, and were assessed for pre-and postoperative CPI. The association between perioperative CPI and glycemic control after pancreatectomy was investigated., Results: The low postoperative CPI group (CPI <0.7) had longer duration of diabetes (17.5 ± 14.5 vs 5.5 ± 11.0 years, P = 0.004), a higher percentage of sulfonylurea users (41.7 vs 8.7%, P = 0.003) and a greater number of drug categories used for diabetes treatment (1.9 ± 1.1 vs 0.8 ± 0.8, P <0.001) than did the high postoperative CPI group. Postoperative CPI was higher (1.4 ± 1.2 vs 0.7 ± 0.6, P = 0.039) in patients with low glycosylated hemoglobin (<7.0%) at 6 months after pancreatectomy; preoperative (2.0 ± 1.5 vs 0.7 ± 0.5, P = 0.012) and postoperative CPI (2.5 ± 1.4 vs 1.4 ± 1.1, P = 0.020) were higher in non-insulin users than in insulin users at 6 months after surgery., Conclusions: The duration of diabetes and preoperative diabetes treatment were associated with residual pancreatic β-cell function after pancreatectomy. Furthermore, perioperative β-cell function as assessed by CPI was associated with diabetes management status after pancreatectomy., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

BACKGROUND Distal pancreatectomy with en bloc celiac artery resection (DP-CAR) is a curative surgical method for locally advanced pancreatic body cancer; however, arterial reconstruction remains controversial in this procedure. This report presents the case of a 47-year-old man with advanced distal pancreatic carcinoma and initial partial response to chemotherapy who required celiac axis reconstruction of the common hepatic artery and left gastric artery. CASE REPORT A 47-year-old man had loss of appetite. He had a 40-mm hypovascular tumor extending from the pancreatic body to the tail, invading around the celiac artery, common hepatic artery, left gastric artery, and splenic artery. We initiated chemotherapy concurrent with chemo-radiotherapy with S-1 administration. After chemo-radiotherapy, computed tomography (CT) showed tumor shrinkage, indicating partial response, but soft tissue CT density surrounding the celiac axis arteries persisted. We conducted conversion surgery. When the common hepatic artery was clamped during surgery, the intrahepatic arterial blood flow reduced; thus, we reconstructed the middle hepatic artery to the common hepatic artery. The left gastric artery was also reconstructed using the second jejunal artery to prevent ischemic gastropathy. Histopathologic examination showed no tumor cells in the specimen; thus, R0 resection was achieved. CONCLUSIONS Arterial reconstruction can be an option for R0 resection in DP-CAR when hepatic arterial blood flow is reduced due to an intraoperative common hepatic artery clamping test.

Background: Local duodenectomy and primary closure is a simple option for some nonampullary duodenal neoplasms. Minimizing the resection area while ensuring curability is necessary for safe primary duodenal closure. However, it is often difficult to determine the appropriate resection line from the serosal side. We developed clip-guided local duodenectomy to easily determine the resection range and perform local duodenectomy safely, then performed a retrospective observational study to confirm the safety of clip-guided local duodenectomy., Methods: The procedure is as follows: placing endoscopic metal clips at four points on the margin around the tumor within 3 days before surgery, identifying the tumor extent with the clips under X-ray imaging during surgery, making an incision to the duodenum just outside of the clips visualized by X-ray imaging, full-thickness resection of the duodenum with the clips as guides of tumor demarcation, and transversely closure by Gambee suture. We evaluated clinicopathological data and surgical outcomes of patients who underwent clip-guided local duodenectomy at two surgical centers between January 2010 and May 2020., Results: Eighteen patients were included. The pathological diagnosis was adenoma (11 cases), adenocarcinoma (6 cases), and GIST (1 case). The mean ± SD tumor size was 18 ± 6 mm, and the tumor was mainly located in the second portion of the duodenum (66%). In all cases, the duodenal defect was closed with primary sutures. The mean operation time and blood loss were 191 min and 79 mL, respectively. The morbidity was 22%, and all complications were Clavien-Dindo grade II. No anastomotic leakage or stenosis was observed. In the 6 adenocarcinoma patients, all were diagnosed with pT1a, and postoperative recurrence was not observed. The 1-year overall and recurrence free survival rate was 100%., Conclusions: Clip-guided local duodenectomy is a safe and useful surgical option for minimally local resection of nonampullary duodenal neoplasms such as duodenal adenoma, GIST, and early adenocarcinoma., (© 2022. The Author(s).)

Background: In pancreatic ductal adenocarcinoma (PDAC), only radical surgery improves long-term survival. We focused on surgical outcome after induction gemcitabine along with nab-paclitaxel (GnP) and subsequent chemoradiotherapy (CRT) with S-1 administration for unresectable locally advanced (UR-LA) PDAC., Methods: We retrospectively analyzed 144 patients with UR-LA PDAC between 2014 and 2020. The first-line regimen of induction chemotherapy was GnP for 125 of the 144 patients. Of the 125 patients who received GnP, 41 who underwent radical resection after additional preoperative CRT were enrolled. We evaluated the prognostic factors for this treatment strategy., Results: The median length of preoperative GnP was 8.8 months, and 30 (73%) patients had normalized CA19-9 levels. R0 resection was achieved in 36 (88%) patients. Postoperative major complications of ≥Clavien-Dindo grade IIIa developed in 16 (39%) patients. With a median follow-up of 35.2 months, 14 (34%) patients developed distant metastasis postoperatively. Using the Kaplan-Meier method, prognostic analysis of the 41 cases revealed the 3-y overall survival rate (OS) was 77.4% and the 5-y OS was 58.6%. In univariate analysis, length of preoperative GnP (≥8 months), CA19-9 normalization, and good nutritional status at operation (prognostic nutritional index ≥41.7) were significantly associated with favorable prognosis. Multivariate analysis revealed CA19-9 normalization (hazard ratio [HR] 0.23; P  = .032) and prognostic nutritional index ≥41.7 (HR 0.05; P  = .021) were independent prognostic factors., Conclusion: For surgical outcome after induction GnP and subsequent CRT for UR-LA PDAC, CA19-9 normalization and maintenance of good nutritional status during treatment until surgery were important for prolonged prognosis., (© 2022 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Background: In some breast cancer patients with a contralateral unaffected hypertrophic and ptotic breast, autologous small-breast reconstruction with contralateral breast reduction is a good option. The current study is aimed to assess the efficacy of the double-pedicle unaffected split-breast (USB) flap harvested from the central half of the unaffected breast for unilateral breast reconstruction with contralateral transverse scar reduction mammoplasty., Methods: Between February 2003 and May 2020, 14 patients underwent breast reconstruction using the USB flap. The mean patient age was 59.1 (range: 48-76) years, and the mean body mass index was 24.2 (range: 19.5-33.3) kg/m 2 . This flap comprised half of the contralateral breast tissues with the 3rd or 4th internal mammary perforator (IMAP) and the lateral thoracic vessel (LTA/V). After USB flap elevation and LTA/V resection, flap perfusion from the IMAP was evaluated on indocyanine green (ICG) angiography. The medial pedicle USB flap was rotated 180° and was transferred to the affected site via the midline. The LTA/V was anastomosed to the recipient vessel to supercharge the distal part of the USB flap, which was then used for breast reconstruction. Then, the remaining contralateral upper and lower breast poles were used for transverse scar reduction mammoplasty., Results: The mean flap size was 13.3 × 26.9 (range: 9.5 × 22 to 16 × 29) cm. All flaps and reduced breasts survived without serious complications such as flap necrosis, although there was one patient with hematoma and one patient with hypertrophic scar. ICG revealed poor perfusion in the distal, lateral part of the flap, ranging from 22.0% to 48.5% of the overall flap area. Final aesthetic evaluation was high, with 11 cases (78.6%) being "good" or "excellent" and 3 cases (21.4%) that were either poor or fair. The mean follow-up period for the patients was 53.8 (range: 15-84) months, with none of the patients presenting second primary breast cancer or recurrence in both breasts., Conclusion: USB flap breast reconstruction with contralateral reduction mammoplasty is a valuable option in breast cancer patients with a hypertrophic and ptotic breast., (© 2022 Wiley Periodicals LLC.)

Musty or moldy off-odor in sake severely reduces its quality. Such off-odor is caused by 2,4,6-trichloroanisole (TCA), a compound that is produced by Aspergillus oryzae during sake production by O-methylating the precursor 2,4,6-trichlorophenol (TCP). TCP suppresses the growth of fungi, including A. oryzae, although TCA does not. Therefore, strains that are unable to convert TCP to TCA should be sensitive to TCP in the medium. Nevertheless, A. oryzae with a disrupted O-methyltransferase gene (ΔomtT) grew in a medium containing TCP. In agar medium, we observed no growth difference between the ΔomtT strain and a non-disrupted transformant; however, a significant growth delay was observed with the ΔomtT strain grown in liquid medium containing 0.5 µg/mL of TCP. This strain was more sensitive to low concentrations of TCP, suggesting that omtT contributes to the conversion (detoxification) of TCP in liquid culture. We generated A. oryzae RIB 40 mutants by ultraviolet irradiation and then cultured them in liquid medium containing TCP to obtain strains that did not produce moldy odor. The slow-growing strains were cultured in agar plates and then used to make koji with added TCP. We obtained three strains with lower TCA-producing ability and with sufficient hydrolase activities for sake brewing.

An ethanolic extract of the stem of Abies spectabilis exhibited strong cytotoxicity against MIA PaCa-2 human pancreatic cancer cells preferentially under nutrient-deprived conditions. Therefore, phytochemical investigation of this bioactive extract was carried out, and that led the isolation of ten compounds (1-10) including a new abietane-type diterpene (1). The structure of the new compound (1) was elucidated by combined spectroscopic techniques, including HRFABMS, NMR and quantum ECD calculation. All the isolated compounds were evaluated for their efficacy against MIA PaCa-2 human pancreatic cancer cell line by employing an anti-austerity strategy. Among the tested compounds, dehydroabietinol (5) displayed the most potent activity with a PC 50 value of 6.6 μM. Dehydroabietinol (5) was also found to retard the MIA PaCa-2 cell migration under normal nutrient-rich conditions displaying its anti-metastatic potential. Investigation on the mechanism suggested that dehydroabietinol (5) is an inhibitor of the key cancer cell survival Akt/mTOR/autophagy signaling pathway., (Copyright © 2022 Elsevier Ltd. All rights reserved.)