加藤 宏之

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.

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: Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. METHODS: The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. RESULTS: A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). CONCLUSION: Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov).

OBJECTIVES: Heterotopic ossification (HO), which occurs when bone tissue forms outside the skeleton, is extremely rare in rectal cancer. Adenocarcinoma is the histological type of all reported primary colorectal cancers with HO. However, in the present case, we observed areas of adenocarcinoma with squamous cell carcinoma-like differentiation. Here we conducted histopathological and immunohistochemical analyses to identify the mechanisms of HO development, to differentiate between adenocarcinoma and squamous cell carcinoma-like phenotypes, and to understand the associated prognostic implications. CASE REPORT: A 62-year-old woman was admitted to our hospital with symptoms of intermittent hematochezia without abdominal pain. Colonoscopy revealed stenosis with a protuberant mass in the rectum. Abdominopelvic contrast-enhanced computed tomography showed irregular wall thickness of the rectum, multiple lymph node metastases, and liver metastases. The rectal tumor exhibited calcified deposits with marked hyperintensity. We then performed Hartmann's operation and D3 lymph node resection. The biopsy specimen revealed tubular and solid adenocarcinoma nests and squamous carcinoma-like components over a necrotic extent without secreted mucin. She received chemotherapy (mFOLFOX6 with bevacizumab) as the first option and is alive 5 months after surgery. CONCLUSION: To the best of our knowledge, this is the first case of heterotopic ossification in a primary rectal cancer with squamous cell carcinoma-like differentiation that was surgically resected. This case suggests that BMP-2 transformed fibroblasts and pluripotent stem cells into osteocytes. We conclude that the squamous cell carcinoma-like lesion was squamous metaplasia of adenocarcinoma.

The case was a 72-year-old man who had been on medication due to chronic pancreatitis since 2009 and was referred to our hospital because dilation of the main pancreatic duct was shown by abdominal ultrasonography. The contrast CT scan of the abdomen showed a 30 mm in size, poorly enhanced tumor at the body of the pancreas, which was suspected to invasion the celiac artery, common hepatic artery, and splenic artery. EUS showed a hypoechoic tumor with a diameter of 29× 24 mm. ERCP showed disruption of the pancreatic duct in the body of the pancreas, and cytological examination of the pancreatic juice showed a suspicious positive result. We diagnosed unresectable locally advanced pancreatic cancer in the body of the pancreas and underwent chemotherapy(gemcitabine plus nab-paclitaxel: GnP). Contrast-enhanced CT after 6 courses of GnP showed tumor shrinkage. FDG-PET/CT revealed a slightly in fluorine-18-deoxyglucose(FDG)accumulation in the tumor, but no accumulation around the blood vessels. Based on the above, it was judged that the tumor was possible radical resection, and surgery was performed. Intraoperative frozen section examination revealed no malignant findings in the tissues surrounding the main artery near the pancreatic body cancer, and distal pancreatectomy was performed. Histopathologically, the tumor showed findings of tubular adenocarcinoma, and the histological response to neoadjuvant therapy was Grade 2. We report a case in which conversion surgery was possible by chemotherapy.

In performing PD, it is very important to understand the running and anatomy of the hepatic artery and the positional relation with the tumor before surgery, leading to planning a proper surgical procedure. In this case series, we report 2 cases in which radical resection was achieved by pancreaticoduodenectomy(PD)with combined hepatic artery resection(without reconstruction)while paying attention to the positional relationship between the bifurcated hepatic artery and the tumor in the head of the pancreas. Case 1: A 73-year-old man. He visited the hospital with jaundice and was diagnosed with distal bile duct cancer. Preoperative contrast-enhanced CT showed that the replaced right hepatic artery(RRHA)was involved by the tumor. Intraoperatively, it was confirmed by ultrasonography that the arterial blood flow in the right lobe of the liver was flowing from the left hepatic artery through the hepatic hilar plate after clamping the right hepatic artery. Thus, PD with combined RRHA resection(without reconstruction)was performed. After the operation, there was no problem with hepatic artery blood flow, and R0 resection was achieved. Case 2: A 65-year-old man. He visited the hospital with jaundice as the chief complaint and was diagnosed with pancreatic head cancer with encasement in the proper hepatic artery(PHA). In this case, the right hepatic artery branches from the SMA and the left hepatic artery branches from the left gastric artery. Intraoperative findings showed no problem with hepatic artery blood flow even after test-clamping the common hepatic artery, and the common hepatic artery was not reconstructed. There is no postoperative complication, and R0 resection was achieved pathologically. Conclusion: For pancreatic head tumors with hepatic artery infiltration, it is important to understand the anatomy of hepatic artery preoperatively and to confirm the intraoperative blood flow. In such cases, pancreaticoduodenectomy with hepatic artery resection may contribute to achieving R0.

BACKGROUND/PURPOSE: This study aimed to prospectively assess the current prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) after total pancreatectomy (TP). METHODS: Between August 2015 and December 2017, we prospectively collected data from 68 Japanese centers on 148 consecutive patients who underwent TP whose computed tomography (CT) attenuation values were evaluated for 12 months. We defined post-TP NAFLD as a liver parenchyma CT value of less than 40 Hounsfield units (HU). Data on perioperative variables were retrieved from all patients and evaluated using univariate and multivariate analyses to identify the perioperative risk factors of NAFLD. RESULTS: In this prospective cohort study, supplementation of pancreatic exocrine enzymes was provided to all 148 patients, and 97% of them were treated with high-titer pancrelipase (median dosage: 1800 mg) postoperatively. Indeed, 29 patients (19.6%) developed NAFLD within a year after TP. Multivariate analysis revealed that female sex (p=0.002), higher body mass index (BMI) (p=0.001), and postoperative diarrhea (p=0.038) were independent risk factors for post-TP NAFLD. However, post-TP NAFLD ameliorated in 11 patients (37.9%) at 12 months after surgery. CONCLUSIONS: Among patients with risk factors such as female sex, higher BMI, and postoperative diarrhea, attention should be paid to the occurrence of NAFLD after TP.

BACKGROUND: Socratic method, which is an educational method to promote critical thinking through a dialogue, has never been practiced in a large number of people at the academic societies. METHODS: Modified Socratic method was performed for the first time as an educational seminar using an example case of moderate acute cholecystitis based on the evidence described in Tokyo Guidelines 2018. We adopted a method that Takada had been modifying for many years: the instructor first knows the degree of recognition of the audience, then the instructor gives a lecture in an easy-to-understand manner and receives questions from the audience, followed by repeated questions and answers toward a common recognition. RESULTS: Using slides, video, and an answer pad, 281 participants including the audience, instructors and moderators came together to repeatedly ask and answer questions in the five sessions related to the case scenario. The recognition rate of the topic of Critical View of Safety increased significantly before vs after this method (53.0% vs 90.3%). The seminar had been successfully performed by receiving a lot of praise from the participants. CONCLUSION: This educational method is considered to be adopted by many academic societies in the future as an effective educational method.

PURPOSE: To investigate whether proximal subtotal pancreatectomy (PSTP) is superior to total pancreatectomy (TP) for preserving postoperative endocrine function, and to identify the pre-operative risk factors influencing prognosis after TP and PSTP. METHODS: The subjects of this retrospective study were patients who underwent TP (n = 15) or PSTP (n = 16) between 2008 and 2018 in our hospital. First, we compared the incidence of hypoglycemia within 30 days after surgery and the total daily amount of insulin needed in the 30 days after TP vs. PSTP. Then, we compared the prognoses between the groups. RESULTS: The incidence of hypoglycemia in the 30 days after surgery was significantly lower in the PSTP group than in the TP group (n = 0 vs. n = 5; p < 0.001). The total amount of daily insulin given was also significantly lower after PSTP than after TP: (0 units vs. 18 units, p = 0.001). Lower lymphocyte counts (p = 0.014), lower cholinesterase (p = 0.021), and lower prognostic nutrition index (p = 0.021) were identified as significant risk factors for hypoglycemia in the TP group. Low cholinesterase (p = 0.015) and a low prognostic nutrition index (p = 0.048) were significantly associated with an unfavorable prognosis in the TP group, but not in the PSTP group. CONCLUSIONS: PSTP may be a feasible alternative to TP to preserve endocrine function, especially for malnourished patients.

PURPOSE: The aim of this study was to elucidate the association between pancreatic fistula (PF) and the sequential changes in the perioperative exocrine function after pancreatectomy. METHODS: The subjects were 96 patients who underwent a 13C-trioctanoin breath test before and 1 month after pancreatectomy, between 2006 and 2018. We retrospectively compared the pre- and postoperative fat absorption levels between patients with PF (PF group; n = 17) and without PF (non-PF group; n = 79) using the breath test. RESULTS: The preoperative level of 13C-trioctanoin absorption (%dose/h) was comparable between the non-PF and PF groups (36.5 vs. 36.9). In the non-PF group, 13C-trioctanoin absorption was significantly decreased after surgery in comparison to the preoperative setting (post-operative 28.5; pre-operative 36.5; p < 0.0001), whereas these values were comparable (post-operative 36.9; pre-operative 34.5; p = 0.129) in the PF group. Moreover, postoperative absorption in the PF group was significantly better than that in the non-PF group (34.5 vs. 28.5%, p = 0.0003). The maximum drain amylase level was significantly higher in patients with a 13C-trioctanoin absorption level (%dose/h) of ≥ 30 in comparison to patients with levels of < 30 (2502 vs. 398 U/L, p = 0.001). CONCLUSION: PF did not exacerbate the pancreatic exocrine function in the early postoperative period, and the acceleration or preservation of the exocrine function after surgery may be an important cause of PF.

OBJECTIVE: The aim of this study was to evaluate how often left-sided portal hypertension (LPH) develops and how LPH affects the long-term outcomes of patients with pancreatic cancer treated with pancreaticoduodenectomy (PD) and resection of the portal vein (PV)/superior mesenteric vein (SMV) confluence. SUMMARY BACKGROUND DATA: Little is known about LPH after PD with resection of the PV/SMV confluence. METHODS: Overall, 536 patients who underwent PD with PV/SMV resection were enrolled. Among them, we mainly compared the SVp group [n=285; the splenic vein (SV) was preserved] and the SVr group (n = 227; the SV was divided and not reconstructed). RESULTS: The incidence of variceal formation in the SVr group increased until 3 years after PD compared with that in the SVp group (38.7% vs 8.3%, P < 0.001). Variceal bleeding occurred in the SVr group (n = 9: 4.0%) but not in the SVp group (P < 0.001). In the multivariate analysis, the risk factors for variceal formation were liver disease, N factor, conventional PD, middle colic artery resection, and SV division. The only risk factor for variceal bleeding was SV division. The platelet count ratio at 6 months after PD was significantly lower in the SVr group than in the SVp group (0.97 vs 0.82, P < 0.001), and the spleen-volume ratios at 6 and 12 months were significantly higher in the SVr group than in the SVp group (1.38 vs 1.00 and 1.54 vs 1.09; P < 0.001 and P < 0.001, respectively). CONCLUSIONS: PD with SV division causes variceal formation, bleeding, and thrombocytopenia.

The spread of the new coronavirus (COVID-19) infection in 2020 has had a significant impact on the treatment of cancer worldwide. During the COVID-19 pandemic, the biggest challenge for pancreatic surgeons is the difficulty in providing oncological care. In this review article, from the standpoint of surgeons, we explain the concept of triaging of patients with pancreatic tumors under the COVID-19 pandemic, and the actual impact of COVID-19 on the treatment of patients with pancreatic tumors. The most vital points in selecting the best therapeutic approach for patients with pancreatic tumors during this pandemic are (1) Oncologists need to tailor the treatment plan based on the COVID-19 phase, tumor malignant potential, and patients' comorbidities; and (2) Optimal treatment for pancreatic cancer should be planned according to the condition of each patient and tumor resectability based on national comprehensive cancer network resectability criteria. To choose the best therapeutic approach for patients with pancreatic tumors during this pandemic, we need to tailor the treatment plan based on elective surgery acuity scale (ESAS). Newly established ESAS for pancreatic tumor and flowchart indicating the treatment strategy of pancreatic cancer, are feasible to overcome this situation.

当科では膵癌治療において2005年から切除可能性分類に基づいた術前治療を導入し、現在では標準的治療として大きな役割を果たしている。2010年からは肝門部領域胆管癌についても切除可能性分類を確立し、同分類に加え、予後不良因子であるリンパ節転移の有無に基づいて積極的に術前化学療法を行っている。今回、その成績と有用性について検討した。対象は2010年9月〜2020年3月に当科に紹介された肝門部領域胆管癌患者のうち遠隔転移例を除く97例とし、切除可能性分類に基づいてResectable群41例、Borderline resettable(以下BR)群31例、Locally advanced(LA)群25例に分け、このうちBR群とLA群および術前リンパ節転移が強く疑われた症例に対して術前化学療法を行った。化学療法の内容は、Gemcitabine(800mg/m2 on days 7 and 21)+S1(80mg/body daily on days 1〜21 every 4 weeks)を2サイクル施行し、その後再評価を行い、根治切除が可能と判断されれば実施した。検討の結果、切除可能性分類とリンパ節転移の有無に基づいた術前治療の有用性が示された。予後因子の解析を行った結果、最も強い予後不良因子として「術前CEA値8.5ng/ml以上」が抽出された。

Overall survival of patients with localized pancreatic ductal adenocarcinoma (PDAC) is extremely poor. Therefore, the establishment of multimodal treatment strategies is indispensable for PDAC patients because surgical treatment alone could not contribute to the improvement of survival. In this review article, we focus on the current topics and advancement of the treatments for localized PDAC including resectable, borderline resectable, and locally advanced PDAC in accordance with the articles mainly published from 2019 to 2020. Reviewing the articles, the recent progress of multimodal treatments notably improves the prognosis of patients with localized PDAC. For resectable PDAC, neoadjuvant chemo or chemoradiation therapy, rather than upfront surgery, plays a key role, especially in patients with a large tumor, poor performance status, high tumor marker levels, peripancreatic lymph nodes metastasis, or neural invasion suspected on preoperative imaging. For borderline resectable PDAC, neoadjuvant treatments followed by surgery is a desirable approach, and maintenance of immunonutritional status during the treatments are also important. For locally advanced disease, conversion surgery has a central role in improving a survival outcome; however, its indication should be standardized.