堀口 明彦

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) is a standard third-line therapy for unresectable advanced or recurrent colorectal cancer. The standard dosing schedule (5 days of administration followed by 2 days off) is associated with a high incidence of severe neutropenia. Conversely, a biweekly dosing schedule (5 days of administration followed by 9 days off) reportedly reduces this incidence. However, no direct comparison of these regimens has been made. In this study, we retrospectively compared the efficacy and safety of these two dosing schedules. METHODS: We analyzed data from patients who received FTD/TPI + BEV treatment between June 2016 and January 2024 at three hospitals affiliated with Fujita Health University. The effects of the dosing schedules on hematological toxicity, overall survival (OS), and time to treatment failure (TTF) were assessed. RESULTS: Among the 125 patients, 26 and 99 were classified into the standard and biweekly groups, respectively. Grade ≥ 3 neutropenia occurred in 50.0% of patients in the standard group and 29.3% of those in the biweekly group (P = .062), with multivariable analysis confirming the dosing schedule impact (P = .048). Median TTF was 5.4 and 7.0 months, while median OS was 16.4 and 14.5 months (P = .908, 0.947) in the standard and biweekly groups, respectively. CONCLUSION: The biweekly regimen of FTD/TPI + BEV resulted in a lower tendency for severe neutropenia than that in the standard regimen, while maintaining comparable OS and TTF in patients with unresectable advanced or recurrent colorectal cancer.

BACKGROUND: Biliary tract cancer (BTC) is a type of malignancy that is challenging to manage. Further, advanced-stage BTC has poor prognosis. Based on the recent TOPAZ-1 trial, adding durvalumab to gemcitabine and cisplatin significantly improves survival in unresectable BTC, thereby making it the new standard first-line treatment. However, real-world data are essential to validate its efficacy and safety in routine clinical settings, which often involve older patients and those with comorbidities or previous therapies. This study aimed to evaluate the outcomes of combination chemotherapy with gemcitabine, cisplatin, and durvalumab (GCD) in a real-world cohort with BTC. METHODS: This retrospective analysis included patients with unresectable advanced-stage BTC treated with GCD between December 2022 and April 2024 at three institutions. GCD was administered for up to eight cycles, followed by durvalumab monotherapy. Clinical data, including the characteristics of the patients, adverse events, and treatment responses, were collected. The Kaplan-Meier method and the Cox proportional hazards model were used to assess progression-free survival (PFS), overall survival (OS), and other factors affecting outcomes. RESULTS: The current study included 54 patients with a median age of 72 years. Half of the patients had recurrence post-surgery, and many of them had previously received chemotherapy. The median PFS and OS rates were 4.1 and 8.0 months, respectively. Adverse events (AEs) were frequently observed, with 42.1% of patients presenting with grade 3 or higher AEs. However, immune-related AEs were rare and mild. Dose adjustments, which are often caused by renal impairment or fatigue, were common (66.7%). Multivariate analysis revealed that older age, a lower performance status score, and a high neutrophil-to-lymphocyte ratio (NLR) were significant predictors of a shorter PFS. Further, a lower performance status score, and a high NLR were associated with a low OS. CONCLUSIONS: GCD combination chemotherapy is a viable treatment option for advanced-stage BTC in a real-world setting where dose modifications can improve tolerability among elderly patients. Neutrophil-to-lymphocyte ratio can be a prognostic biomarker of OS in patients with BTC receiving immune checkpoint inhibitors. This finding highlights the potential of individualized treatment strategies. Nevertheless, further research should be performed to validate these results in larger cohorts.

BACKGROUND/AIM: Trifluridine/tipiracil (TAS-102) is a standard treatment for unresectable advanced or recurrent colorectal cancer. The incidence of grade 3 or higher neutropenia is high with the standard 5-day-on/2-day-off dosing schedule. Previous studies suggest that a 5-day-on/9-day-off (biweekly) schedule is associated with a lower incidence of neutropenia; however, direct comparative evidence is limited. This study aimed to retrospectively evaluate the impact of TAS-102 dosing schedules on safety. PATIENTS AND METHODS: Patients with colorectal cancer who received TAS-102 with/without bevacizumab with either the standard or biweekly schedule at three Fujita Health University-affiliated hospitals between June 2014 and January 2024 were included. The incidence of neutropenia, anemia, and thrombocytopenia based on the dosing schedule and renal function was retrospectively compared. The effect of dosing schedules on grade ≥3 neutropenia was also evaluated. RESULTS: Among 260 patients, 127 received the standard schedule, and 133 the biweekly schedule. Grade ≥3 neutropenia incidence was significantly lower with the biweekly schedule (26.3%) than with the standard schedule (40.2%) (p=0.0247). Multivariate analysis demonstrated that the standard schedule of TAS-102 was associated with a higher incidence of grade ≥3 neutropenia (p<0.01). Grade ≥3 anemia incidence was also lower with the biweekly schedule (13.5% versus 25.2%) (p=0.0187). Grade ≥3 neutropenia showed a trend towards a higher incidence in patients with estimated glomerular filtration rates ≥60 mL/min, at 29.4% compared with 41.0% in those with rates <60 ml/min (p=0.0679). CONCLUSION: The biweekly schedule of TAS-102 with/without bevacizumab was associated with a significantly lower incidence of grade ≥3 neutropenia than the standard schedule. This schedule may help patients - including those with impaired renal function - adhere to planned treatment regimens.

PURPOSE: This study aimed to clarify the current treatment status for biliary tract cancers based on data from the National Clinical Database (NCD) in Japan. METHODS: Total 3895 cases of biliary tract cancers registered in the NCD during 2021 were included. We identified the rates of resection, R0 resection, postoperative complications, and incidences of lymph node metastasis for gallbladder carcinoma, perihilar cholangiocarcinoma, distal bile duct carcinoma, and ampullary carcinoma. RESULTS: The number of biliary tract cancers registered in the NCD during 2021 was 3895 (1775 in extrahepatic bile duct carcinoma, 1422 in gallbladder carcinoma, and 698 in ampullary carcinoma). In gallbladder carcinoma, the resection (89.59%) and R0 resection rates (87.99%) were favorable, and the complication rate (6.05%) was lower than that of others. However, the postoperative complication rate could be higher in T3-T4 cases and when extrahepatic bile duct resection was performed concomitantly. Lymph node metastasis was frequently seen in 12.60% at the No. 13a lymph node. In perihilar cholangiocarcinoma, the R0 resection (69.82%) and complication rates (16.75%) were significantly lower and higher, respectively. In distal cholangiocarcinoma and ampullary carcinoma, metastasis was observed in approximately 2% and 10% of the dissected No. 16b1 para-aortic lymph nodes, respectively. In conclusion, although short-term surgical outcomes for biliary tract cancers in Japan might be acceptable, the significantly lower R0 resection and higher complication rates of perihilar cholangiocarcinomas indicate additional challenges for surgeons in the future and should continue to be monitored by the Japanese Society of Hepatobiliary and Pancreatic Surgery.

Abstract Aim The Japanese National Clinical Database, which covers more than 95% of the surgeries performed in Japan, is the largest nationwide database. This is the 2021 annual report of the Gastroenterological Section of the National Clinical Database, which aims to present the short‐term outcomes of cases registered in 2021 and discuss significant changes and insights into gastroenterological surgeries observed over the decade. Methods We reviewed the data of patients registered in the National Clinical Database between 2012 and 2021. Results In total, 5 788 093 cases, including 597 780 cases in 2021, were extracted from the National Clinical Database. The number of surgeries resumed its original trend after a uniform decrease due to the coronavirus disease 2019 pandemic. The patient population continues to age, and the proportion of female patients is steadily increasing. The trend of surgeries being conducted in certified institutions with the involvement of board‐certified surgeons is consistently rising. Moreover, the increasing trend of endoscopic surgery rate is still maintained. Although operative mortality is declining, the trend of increasing postoperative complications continues. Surgery on the esophagus, liver, and pancreas has shown substantial improvements in operative mortality, with a high participation rate of board‐certified surgeons. Surgical procedures with a high incidence of emergency surgeries are characterized by low participation rates of board‐certified surgeons, increased morbidity rates, and worse mortality outcomes. Conclusion This overview of surgical patients in Japan, obtained using data extracted from the National Clinical Database, may serve as a critical cornerstone for the future development of gastroenterological surgery.

This study aimed to validate the DFS (direct fast scarlet) staining in the diagnosis of EC (eosinophilic colitis). The study included 50 patients with EC and 60 with control colons. Among the 60 control samples, 39 and 21 were collected from the ascending and descending colons, respectively. We compared the median number of eosinophils and frequency of eosinophil degranulation by HE (hematoxylin and eosin) and DFS staining between the EC and control groups. In the right hemi-colon, eosinophil count by HE was useful in distinguishing between EC and control (41.5 vs. 26.0 cells/HPF, p < 0.001), but the ideal cutoff value is 27.5 cells/HPF (high-power field). However, this method is not useful in the left hemi-colon (12.5 vs. 13.0 cells/HPF, p = 0.990). The presence of degranulation by DFS allows us to distinguish between the groups even in the left hemi-colon (58% vs. 5%, p < 0.001). DFS staining also enabled a more accurate determination of degranulation than HE. According to the current standard to diagnose EC (count by HE staining ≥20 cells/HPF), mucosal sampling from left hemi-colon is problematic since the number of eosinophils could not be increased even in EC. Determination of degranulated eosinophils by DFS may potentiate the diagnostic performance even in such conditions.

BACKGROUND: Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. METHODS: This retrospective multi-institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. RESULTS: Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19-9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un-matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p < 0.001). CONCLUSION: Postoperative AT might benefit selected patients with invasive IPMC, especially those at high risk of poor survival. NAT might improve the survivability of BR invasive IPMC. Any treatment for recurrence after surgery for invasive IPMC might improve survival.

OBJECTIVE: This study was performed to demonstrate the clinical application of duodenum-preserving pancreatic head resection (DPPHR) as a surgical treatment for pancreatic neuroendocrine tumors (PNETs) in terms of both curability and maintenance of postoperative quality of life. METHODS: Seven patients diagnosed with PNETs underwent DPPHR from January 2011 to December 2021 at our institution. We investigated the clinical relevance of DPPHR based on the patients' clinicopathological findings. RESULTS: The median operative time was 492 min, and the median blood loss was 302 g. Postoperative complications were evaluated according to the Clavien-Dindo classification, and postoperative intra-abdominal bleeding was observed in one patient. Pathological examination revealed a World Health Organization classification of G1 in six patients and G2 in one patient. Microvascular invasion was observed in two patients (29%); however, no patients developed lymph node metastasis or recurrence during the follow-up period. A daughter lesion was observed near the primary tumor in one patient. All patients achieved curative resection, and no tumor specimens showed positive margins. CONCLUSIONS: DPPHR facilitates anatomical resection of the pancreatic head in patients with PNETs as well as detailed pathological evaluation of the resected specimen. Therefore, this surgical procedure is an acceptable alternative to pancreaticoduodenectomy or enucleation for patients with PNETs.

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.

PURPOSE: To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan. METHODS: Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed. RESULTS: The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days. CONCLUSIONS: These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy.

症例は68歳男で、19年前に膵体部IPMNに対して膵中央切除+膵管-膵管吻合(Martin手術)を施行された。今回、心窩部痛を主訴に受診し、CTで膵管吻合部から尾側に乏血性腫瘤を認め、残膵癌が疑われた。諸検査の結果から、膵管吻合部に発生したDe novo膵癌が強く疑われたため、残膵切除術を行うこととした。膵切離を行い迅速病理に提出したところ腺癌陽性と診断されたため術式を膵全摘に変更し、術後経過は良好であった。

BACKGROUND: This study aimed to investigate the effect of the use of new lithotomy stirrups-2 on the pressure dispersal on lower limbs, which may lead to the prevention of well-leg compartment syndrome (WLCS) and deep venous thrombosis (DVT), which are the most commonly associated adverse events with laparoscopic and robot-assisted rectal surgery. METHODS: A total of 30 healthy participants were included in this study. The pressure (mmHg) applied on various lower limb muscles when using conventional lithotomy stirrups-1 and new type stirrups-2 was recorded in various lithotomy positions; 1) neutral position, 2) Trendelenburg position (15°) with a 0° right inferior tilt, and 3) Trendelenburg position (15°) with a 10° right inferior tilt. Using a special sensor pad named Palm Q®, and the average values were compared between two types of stirrups. RESULTS: The use of new lithotomy stirrups-2 significantly reduced the pressure applied on the lower limb muscles in various lithotomy positions compared with the use of lithotomy stirrups-1. The most pressured lower limb muscle when using both lithotomy stirrups was the central soleus muscle, which is the most common site for the development of WLCS and DVT. In addition, when using the conventional lithotomy stirrups-1, the pressure was predominantly applied to the proximal soleus muscle; however, when using lithotomy stirrups-2, the pressure was shifted to the more distal soleus muscle. CONCLUSION: These results suggest that the new lithotomy stirrups-2 is useful in reducing the pressure load on leg muscles, especially on the proximal to central soleus, and may reduce the incidence of WLCS and DVT after rectal surgery performed in the lithotomy position. Further clinical studies are needed to determine whether the use of lithotomy stirrups-2 prevents these complications in various clinical settings.

In this review article, we focus on recent papers on organ-preserving pancreatectomy procedures published since 2010. When comparing central pancreatectomy (CP) and distal pancreatectomy (DP), most studies have concluded that the CP group exhibited significantly lower incidence of new-onset diabetes or diabetes exacerbation than the DP group postoperatively. However, because of increased incidence of morbidities such as pancreatic fistula, the surgeon faces a considerable trade-off between increased short-term morbidity and long-term preservation of endocrine function. When the outcomes of two types of spleen-preserving DP (Kimura and Warshaw procedures) are compared, most studies mentioned the low incidence of postoperative gastric varices and splenic infarction with the Kimura procedure. Although there are several reports regarding the effect of spleen preservation on prevention of postoperative infections, no report on the contribution of spleen preservation to the prevention of overwhelming post-splenectomy infection is seen. The advantages of duodenum-preserving pancreatic head resection (DPPHR) concerning endocrine and exocrine functions continue to be subjects of discussion, mainly due to the limited number of institutions that have adopted this approach; however, DPPHR should be presented as an option for patients due to its low incidence of postoperative cholangitis. Organ-preserving pancreatectomy requires meticulous surgical techniques, and postoperative complications may increase with this surgery compared with standard pancreatectomy, which may be influenced by the surgeon's skill and the surgical facility where the procedure is performed. Nonetheless, this technique has significant long-term advantages in terms of endocrine and exocrine functions and its wider adoption in the future is expected.

BACKGROUND/PURPOSE: The aim of this study was to clarify the clinical characteristics of acute cholangitis (AC) after bilioenteric anastomosis and stent-related AC in a multi-institutional retrospective study, and validate the TG18 diagnostic performance for various type of cholangitis. METHODS: We retrospectively reviewed 1079 AC patients during 2020, at 16 Tokyo Guidelines 18 (TG 18) Core Meeting institutions. Of these, the post-biliary reconstruction associated AC (PBR-AC), stent-associated AC (S-AC) and common AC (C-AC) were 228, 307, and 544, respectively. The characteristics of each AC were compared, and the TG18 diagnostic performance of each was evaluated. RESULTS: The PBR-AC group showed significantly milder biliary stasis compared to the C-AC group. Using TG18 criteria, definitive diagnosis rate in the PBR-AC group was significantly lower than that in the C-AC group (59.6% vs. 79.6%, p < .001) because of significantly lower prevalence of TG 18 imaging findings and milder bile stasis. In the S-AC group, the bile stasis was also milder, but definitive-diagnostic rate was significantly higher (95.1%) compared to the C-AC group. The incidence of transient hepatic attenuation difference (THAD) and pneumobilia were more frequent in PBR-AC than that in C-AC. The definitive-diagnostic rate of PBR-AC (59.6%-78.1%) and total cohort (79.6%-85.3%) were significantly improved when newly adding these items to TG18 diagnostic imaging findings. CONCLUSIONS: The diagnostic rate of PBR-AC using TG18 is low, but adding THAD and pneumobilia to TG imaging criteria may improve TG diagnostic performance.

BACKGROUND: Distal pancreatectomy with en bloc coeliac axis resection (DP-CAR) for pancreatic body cancer has been reported increasingly. However, its large-scale outcomes remain undocumented. This study aimed to evaluate DP-CAR volume and mortality, preoperative arterial embolization for ischaemic gastropathy, the oncological benefit for resectable tumours close to the bifurcation of the splenic artery and coeliac artery using propensity score matching, and prognostic factors in DP-CAR. METHODS: In a multi-institutional analysis, 626 DP-CARs were analysed retrospectively and compared with 1325 distal pancreatectomies undertaken in the same interval. RESULTS: Ninety-day mortality was observed in 7 of 21 high-volume centres (1 or more DP-CARs per year) and 1 of 41 low-volume centres (OR 20.00, 95 per cent c.i. 2.26 to 177.26). The incidence of ischaemic gastropathy was 19.2 per cent in the embolization group and 7.9 per cent in the no-embolization group (OR 2.77, 1.48 to 5.19). Propensity score matching analysis showed that median overall survival was 33.5 (95 per cent c.i. 27.4 to 42.0) months in the DP-CAR and 37.9 (32.8 to 53.3) months in the DP group. Multivariable analysis identified age at least 67 years (HR 1.40, 95 per cent c.i. 1.12 to 1.75), preoperative tumour size 30 mm or more (HR 1.42, 1.12 to 1.80), and preoperative carbohydrate antigen 19-9 level over 37 units/ml (HR 1.43, 1.11 to 1.83) as adverse prognostic factors. CONCLUSION: DP-CAR can be performed safely in centres for general pancreatic surgery regardless of DP-CAR volume, and preoperative embolization may not be required. This procedure has no oncological advantage for resectable tumour close to the bifurcation of the splenic artery, and should be performed after appropriate patient selection.