研究者詳細 - 北郷　実

論文 - 北郷　実

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Preoperative platelet count as an independent predictor of long-term outcomes among patients undergoing resection for intrahepatic cholangiocarcinoma.

Chatzipanagiotou OP, Tsilimigras DI, Catalano G, Ruzzenente A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Kitago M, Pawlik TM

Journal of surgical oncology 130 （ 5 ） 1042 - 1050 2024年10月

ISSN 0022-4790

Background and Objectives: An elevated platelet count may reflect neoplastic and inflammatory states, with cytokine-driven overproduction of platelets. The objective of this study was to evaluate the prognostic utility of high platelet count among patients undergoing curative-intent liver surgery for intrahepatic cholangiocarcinoma (ICC). Methods: An international, multi-institutional cohort was used to identify patients undergoing curative-intent liver resection for ICC (2000–2020). A high platelet count was defined as platelets >300 *109/L. The relationship between preoperative platelet count, cancer-specific survival (CSS), and overall survival (OS) was examined. Results: Among 825 patients undergoing curative-intent resection for ICC, 139 had a high platelet count, which correlated with multifocal disease, lymph nodes metastasis, poor to undifferentiated grade, and microvascular invasion. Patients with high platelet counts had worse 5-year (35.8% vs. 46.7%, p = 0.009) CSS and OS (24.8% vs. 39.8%, p < 0.001), relative to patients with a low platelet count. After controlling for relevant clinicopathologic factors, high platelet count remained an adverse independent predictor of CSS (HR = 1.46, 95% CI 1.02–2.09) and OS (HR = 1.59, 95% CI 1.14–2.22). Conclusions: High platelet count was associated with worse tumor characteristics and poor long-term CSS and OS. Platelet count represents a readily-available laboratory value that may preoperatively improve risk-stratification of patients undergoing curative-intent liver resection for ICC.

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Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma.

Tamagawa H, Fujii M, Togasaki K, Seino T, Kawasaki S, Takano A, Toshimitsu K, Takahashi S, Ohta Y, Matano M, Kawasaki K, Machida Y, Sekine S, Machinaga A, Sasai K, Kodama Y, Kakiuchi N, Ogawa S, Hirano T, Seno H, Kitago M, Kitagawa Y, Iwasaki E, Kanai T, Sato T

Nature cell biology 26 （ 10 ） 1759 - 1772 2024年10月

ISSN 1465-7392

Human pancreatic cancer is characterized by the molecular diversity encompassing native duct-like and squamous cell-like identities, but mechanisms underlying squamous transdifferentiation have remained elusive. To comprehensively capture the molecular diversity of human pancreatic cancer, we here profiled 65 patient-derived pancreatic cancer organoid lines, including six adenosquamous carcinoma lines. H3K27me3-mediated erasure of the ductal lineage specifiers and hijacking of the TP63-driven squamous-cell programme drove squamous-cell commitment, providing survival benefit in a Wnt-deficient environment and hypoxic conditions. Gene engineering of normal pancreatic duct organoids revealed that GATA6 loss and a Wnt-deficient environment, in concert with genetic or hypoxia-mediated inactivation of KDM6A, facilitate squamous reprogramming, which in turn enhances environmental fitness. EZH2 inhibition counterbalanced the epigenetic bias and curbed the growth of adenosquamous cancer organoids. Our results demonstrate how an adversarial microenvironment dictates the molecular and histological evolution of human pancreatic cancer and provide insights into the principles and significance of lineage conversion in human cancer.

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Molecular diagnosis for detecting KRAS mutation in peritoneal washing fluid of pancreatic ductal adenocarcinoma.

Shimane G, Nakano Y, Matsuda S, Kitago M, Masugi Y, Nakamura K, Nakamura Y, Yagi H, Abe Y, Hasegawa Y, Hori S, Tanaka M, Takemura R, Nishihara H, Kitagawa Y

Scientific reports 14 （ 1 ） 21732 2024年09月

Positive peritoneal washing cytology is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC); however, its sensitivity is relatively low. This study evaluated the performance of peptide nucleic acid (PNA)-directed PCR clamping as a molecular-based peritoneal washing cytology for sensitive detection of KRAS mutation in PDAC. Intraoperative peritoneal washing fluid (IPWF) obtained from patients with PDAC who underwent surgery was analyzed. PNA-directed PCR clamping was performed on DNA extracted from IPWF. Among 54 patients enrolled, threshold cycle (Ct) was significantly lower in patients with positive peritoneal washing cytology than in those with negative peritoneal washing cytology (P < 0.001) and in patients with peritoneal dissemination than in those without peritoneal dissemination (P < 0.01). The optimal Ct cut-off to predict KRAS mutations in IPWF was 36.42 based on a receiver operating characteristic curve. The sensitivity, specificity, and accuracy for molecular diagnosis were 100%, 80.0%, and 85.2%, respectively. Peritoneal dissemination recurrence was significantly more frequent in patients with a positive molecular diagnosis than in those with a negative diagnosis (38.9 vs. 8.0%, P = 0.013). The genomic approach might be clinically valuable for a more precise tumor cell detection in IPWF.

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Development and Validation of a Predictive Risk Score for Blood Transfusion in Patients Undergoing Curative-Intent Surgery for Intrahepatic Cholangiocarcinoma.

Catalano G, Alaimo L, Endo Y, Chatzipanagiotou OP, Ruzzenente A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Kitago M, Pawlik TM

Journal of surgical oncology 2024年09月

ISSN 0022-4790

Background and Objectives: Among patients undergoing liver resection for intrahepatic cholangiocarcinoma (ICC), perioperative bleeding requiring blood transfusion is a common complication, yet preoperative identification of patients at risk for transfusion remains challenging. The objective of this study was to develop a preoperative risk score for blood transfusion requirement during surgery for ICC. Methods: Patients undergoing curative-intent liver surgery for ICC (1990–2020) were identified from a multi-institutional database. A predictive model was developed and validated. An easy-to-use risk calculator was made available online. Results: Among 1420 patients, 300 (21.1%) received an intraoperative transfusion. Independent predictors of transfusion included severe preoperative anemia (OR = 1.65, 95% CI 1.10–2.47), T2 category or higher (OR = 2.00, 95% CI 1.36–3.02), positive lymph nodes (OR = 1.75, 95% CI 1.32–2.32) and major resection (OR = 2.56, 95%CI 1.85–3.58). Receipt of blood transfusion significantly correlated with worse outcomes. The model showed good discriminative ability in both training (AUC = 0.68, 95% CI 0.66–0.72) and bootstrapping validation (C-index = 0.67, 95% CI 0.65–0.70) cohorts. An online risk calculator of blood transfusion requirement was developed (https://catalano-giovanni.shinyapps.io/TransfusionRisk). Conclusions: Intraoperative blood transfusion was significantly associated with poor postoperative outcomes among patients undergoing surgery for ICC. The identification of patients at high risk of transfusion could improve perioperative patient care and blood resources allocation.

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Preoperative and postoperative predictive models of early recurrence for colorectal liver metastases following chemotherapy and curative-intent one-stage hepatectomy.

Kawashima J, Chatzipanagiotou OP, Tsilimigras DI, Khan MMM, Catalano G, Rashid Z, Khalil M, Altaf A, Munir MM, Endo Y, Woldesenbet S, Guglielmi A, Ruzzenente A, Aldrighetti L, Alexandrescu S, Kitago M, Poultsides G, Sasaki K, Aucejo F, Endo I, Pawlik TM

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 50 （ 9 ） 108532 2024年09月

ISSN 0748-7983

Introduction: Accurate prediction of patients at risk for early recurrence (ER) among patients with colorectal liver metastases (CRLM) following preoperative chemotherapy and hepatectomy remains limited. Methods: Patients with CRLM who received chemotherapy prior to undergoing curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with ER, and an online calculator was developed and validated. Results: Among 768 patients undergoing preoperative chemotherapy and curative-intent resection, 128 (16.7 %) patients had ER. Multivariable Cox analysis demonstrated that Eastern Cooperative Oncology Group Performance status ≥1 (HR 2.09, 95%CI 1.46–2.98), rectal cancer (HR 1.95, 95%CI 1.35–2.83), lymph node metastases (HR 2.39, 95%CI 1.60–3.56), mutated Kirsten rat sarcoma oncogene status (HR 1.95, 95%CI 1.25–3.02), increase in tumor burden score during chemotherapy (HR 1.51, 95%CI 1.03–2.24), and bilateral metastases (HR 1.94, 95%CI 1.35–2.79) were independent predictors of ER in the preoperative setting. In the postoperative model, in addition to the aforementioned factors, tumor regression grade was associated with higher hazards of ER (HR 1.91, 95%CI 1.32–2.75), while receipt of adjuvant chemotherapy was associated with lower likelihood of ER (HR 0.44, 95%CI 0.30–0.63). The discriminative accuracy of the preoperative (training: c-index: 0.77, 95%CI 0.72–0.81; internal validation: c-index: 0.79, 95%CI 0.75–0.82) and postoperative (training: c-index: 0.79, 95%CI 0.75–0.83; internal validation: c-index: 0.81, 95%CI 0.77–0.84) models was favorable (https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/). Conclusions: Patient-, tumor- and treatment-related characteristics in the preoperative and postoperative setting were utilized to develop an online, easy-to-use risk calculator for ER following resection of CRLM.

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Anatomic, isolated complete caudate lobectomy using an anterior transhepatic approach with glissonian pedicle approach and indocyanine green fluorescence guidance: a case report.

Endo Y, Abe Y, Kitago M, Hasegawa Y, Hori S, Tanaka M, Nakano Y, Shimazu M, Kitagawa Y

Journal of surgical case reports 2024 （ 8 ） rjae505 2024年08月

ISSN 2042-8812

Hepatocellular carcinoma (HCC) in the caudate lobe presents surgical challenges due to the lack of distinct anatomical landmarks. This case report introduces a novel surgical approach combining Takasaki’s classification and indocyanine green negative counterstaining for precise anatomical caudate lobectomy. A 78-year-old patient with hepatocellular carcinoma in the caudate lobe underwent surgery following preoperative volumetric assessment. The method involved a glissonian approach for both left and right pedicles, coupled with meticulous dissection of hepatic pedicles of the caudate lobe guided by taping of left and right glissonian pedicles, followed by indocyanine green administration for improved visualization of caudate lobe boundaries. The procedure enabled complete tumor resection with minimal blood loss. At 50 months postsurgery, the patient maintains favorable liver function and performance status. This innovative approach offers a promising solution for precise resection of caudate lobe hepatocellular carcinoma, potentially improving surgical outcomes and long-term prognosis.

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Impact of an artificial intelligence based model to predict non-transplantable recurrence among patients with hepatocellular carcinoma.

Altaf A, Endo Y, Munir MM, Khan MMM, Rashid Z, Khalil M, Guglielmi A, Ratti F, Marques H, Cauchy F, Lam V, Poultsides G, Kitago M, Popescu I, Martel G, Gleisner A, Hugh T, Shen F, Endo I, Pawlik TM

HPB : the official journal of the International Hepato Pancreato Biliary Association 26 （ 8 ） 1040 - 1050 2024年08月

ISSN 1365-182X

Objective: We sought to develop Artificial Intelligence (AI) based models to predict non-transplantable recurrence (NTR) of hepatocellular carcinoma (HCC) following hepatic resection (HR). Methods: HCC patients who underwent HR between 2000-2020 were identified from a multi-institutional database. NTR was defined as recurrence beyond Milan Criteria. Different machine learning (ML) and deep learning (DL) techniques were used to develop and validate two prediction models for NTR, one using only preoperative factors and a second using both preoperative and postoperative factors. Results: Overall, 1763 HCC patients were included. Among 877 patients with recurrence, 364 (41.5%) patients developed NTR. An ensemble AI model demonstrated the highest area under ROC curves (AUC) of 0.751 (95% CI: 0.719–0.782) and 0.717 (95% CI:0.653–0.782) in the training and testing cohorts, respectively which improved to 0.858 (95% CI: 0.835–0.884) and 0.764 (95% CI: 0.704–0.826), respectively after incorporation of postoperative pathologic factors. Radiologic tumor burden score and pathological microvascular invasion were the most important preoperative and postoperative factors, respectively to predict NTR. Patients predicted to develop NTR had overall 1- and 5-year survival of 75.6% and 28.2%, versus 93.4% and 55.9%, respectively, among patients predicted to not develop NTR (p < 0.0001). Conclusion: The AI preoperative model may help inform decision of HR versus LT for HCC, while the combined AI model can frame individualized postoperative care (https://altaf-pawlik-hcc-ntr-calculator.streamlit.app/).

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Prognostic significance of postoperative complications for patients with hepatocellular carcinoma relative to alpha-feto protein and tumor burden score.

Endo Y, Tsilimigras DI, Munir MM, Woldesenbet S, Yang J, Guglielmi A, Ratti F, Marques HP, Cauchy F, Lam V, Poultsides GA, Kitago M, Popescu I, Alexandrescu S, Martel G, Gleisner A, Hugh T, Aldrighetti L, Shen F, Endo I, Pawlik TM

HPB : the official journal of the International Hepato Pancreato Biliary Association 26 （ 8 ） 998 - 1006 2024年08月

ISSN 1365-182X

Background: We sought to elucidate the impact of postoperative complications on patient outcomes relative to differences in alpha-fetoprotein-tumor burden score (ATS) among patients with hepatocellular carcinoma (HCC). Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. Moderate/severe complications were defined using the optimal cut-off value of the comprehensive complication index (CCI) based on the log-rank test. Results: A total of 1124 patients was included. CCI cut-off value of 16.6 was identified as the optimal prognostic threshold. Patients who experienced moderate/severe complications were more likely to have worse recurrence free survival [RFS] versus individuals who had no/mild complications (2-year RFS; no/mild complication: 55.9% vs. moderate/severe complication: 38.1% p < 0.001). Of note, low and medium ATS patients who experienced moderate/severe complications had a higher risk of recurrence (2-year RFS; no/mild complication: postoperative complications 70.0% vs. moderate/severe complication: 51.1%, p = 0.006; medium: no/mild complication: 50.8% vs moderate/severe complication: 56.7%, p = 0.01); however, postoperative complications were not associated with worse outcomes among patients with high ATS (no/mild complication: 39.1% vs. moderate/severe complication: 29.2%, p = 0.20). Conclusion: These data serve to emphasize how reduction in postoperative complications may be crucial to improve prognosis, particularly among patients with favorable HCC characteristics.

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Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

Suzuki S, Omori Y, Ono Y, Hirose K, Itoh T, Karasaki H, Shimoda M, Nagakawa Y, Higuchi R, Endo I, Rikiyama T, Unno M, Fujii T, Sunagawa Y, Eguchi H, Sasanuma H, Akahori T, Okano K, Tani M, Hirano S, Shimizu Y, Kitago M, Mizuno S, Yamamoto T, Furukawa M, Ohtsuka M, Sugimoto M, Matsushita A, Hakamada K, Igarashi H, Kuroki T, Tanno S, Tsuji Y, Masamune A, Mizumoto K, Hirooka Y, Yamaue H, Okazaki K, Satoi S, Takeyama Y, Mizukami Y, Furukawa T

Annals of surgery 2024年07月

ISSN 0003-4932

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.

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MUC1-C Dependence for the Progression of Pancreatic Neuroendocrine Tumors Identifies a Druggable Target for the Treatment of This Rare Cancer.

Ozawa H, Haratake N, Nakashoji A, Daimon T, Bhattacharya A, Wang K, Shigeta K, Fushimi A, Fukuda K, Masugi Y, Yamaguchi R, Kitago M, Kawakubo H, Kitagawa Y, Kufe D

Biomedicines 12 （ 7 ） 2024年07月

ISSN 2227-9059

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

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Adjuvant 5-fluorouracil and portal vein infusion chemotherapy followed by gemcitabine for pancreatic cancer.

Kitago M, Endo Y, Aiura K, Takigawa Y, Tani N, Matsui J, Suzuki K, Nishiyama R, Nakano Y, Abe Y, Yagi H, Shinoda M, Itano O, Tanabe M, Kitagawa Y

Cancer medicine 13 （ 14 ） e7459 2024年07月

Background: Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. Methods: 5-fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were OS and treatment completion. Results: Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1-, 3-, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1-, 3-, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). Conclusion: Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

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Early-onset hepatic veno-occlusive disease after liver transplantation: an institutional experience and analysis of a literature-based cohort.

Endo Y, Shinoda M, Maehara J, Hibi T, Hasegawa Y, Obara H, Kitago M, Ojima H, Tanabe M, Kitagawa Y

Surgery today 54 （ 7 ） 670 - 682 2024年07月

ISSN 0941-1291

Purpose: Hepatic veno-occlusive disease (HVOD) after liver transplantation (LT) is almost always a fatal complication. We assessed the outcomes of HVOD in a single institute and analyzed a literature-based cohort. Methods: We reviewed the medical records of recipients of LT performed between 1995 and 2020 at our institute and the literature on HVOD after LT. We then analyzed the clinical features based on a “pooled” cohort of cases identified in our institute and reported in the literature. Results: HVOD was diagnosed in 3 of 331 LT recipients, all of whom died in hospital, on days 164, 12, and 13, respectively. Our comprehensive review of the literature, as well as our cases, identified eight cases of HVOD that developed within 14 days after LT (early-onset type). Early-onset HVOD had a significantly worse prognosis than HVOD that developed beyond 2 weeks after LT (non-early-onset type), which was identified in 22 cases (25.0% vs. 86.1% of the 3-month graft survival rate). The most common causes of early-onset and non-early-onset types were acute cellular rejection (50%) and drug-induced disease (50%), respectively. Conclusion: Early-onset HVOD developing within 14 days after LT has a poor prognosis.

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【Precision medicine時代における肝胆膵癌外科切除の役割】膵癌における腹腔洗浄腹水中のKRAS変異の臨床的意義と今後の応用

田中真之, 北郷実, 中野容, 萩原克洋, 北川雄光

癌の臨床（(株)篠原出版新社） 68 （ 3 ） 189 - 194 2024年07月

ISSN 0021-4949

当科では膵癌患者の腹腔洗浄腹水検体からperitoneal tumor DNA(ptDNA)を抽出しKRAS変異について研究してきた。今回、2020～2022年に当科で膵癌に対して根治切除術を施行した症例のうちゲノムDNA検索が行えた60例を対象とし、ptDANのKRAS変異および他の術前腫瘍マーカーと予後との相関性について単変量解析および多変量解析により検討した。さらに、術前補助療法(NAT)の有無別で同様の検討を行った。結果、全症例の術後無再発期間において、ptDNAのKRAS変異とDUPAN-2が独立した予後予測因子であった。NAT有り群ではptDNAのKRAS変異のみが独立した予後予測因子であった。

Preoperative predictive factors for positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas: a retrospective study.

Shimane G, Nakano Y, Kitago M, Yagi H, Abe Y, Hasegawa Y, Soga S, Okuda S, Ishii R, Kitagawa Y

International journal of clinical oncology 29 （ 7 ） 985 - 993 2024年07月

ISSN 1341-9625

Background: The clinical importance of positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas remains controversial. We evaluated the prognosis of these patients and the predictive preoperative risk factors for positive peritoneal cytology results. Methods: We retrospectively reviewed patients who underwent curative-intent surgery at our institution between May 2010 and June 2020. Preoperative risk factors for positive peritoneal cytology results were identified using logistic regression analysis. A scoring model was constructed using the total number of significant independent predictors for positive peritoneal cytology results. Results: Of 233 patients, 18 (7.7%) had positive peritoneal cytology results. The recurrence-free survival and cancer-specific survival were markedly worse in patients with positive peritoneal cytology results than in those with negative peritoneal cytology results (recurrence-free survival: 6.0 months vs. 16.6 months, p = 0.050; cancer-specific survival: 19.4 months vs. 47.5 months, p = 0.034). Tumor location (odds ratio: 3.760, 95% confidence interval: 1.099–11.818, p = 0.023), tumor size > 25 mm (odds ratio: 3.410, 95% confidence interval: 1.031–11.277, p = 0.046), preoperative serosal invasion (odds ratio: 5.193, 95% confidence interval: 1.099–24.531, p = 0.038), and preoperative carcinoembryonic antigen level > 5.6 ng/mL (odds ratio: 3.816, 95% confidence interval: 1.248–10.667, p = 0.019) were identified as significant independent predictive factors. Our predictive model’s optimal cutoff and positive predictive values for positive peritoneal cytology results were 3 and 27.9%, respectively. Conclusions: The indications for curative-intent surgery should be considered carefully in patients with high-risk factors for positive peritoneal cytology results.

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Multiple asynchronous recurrence as a predictive factor for refractoriness against locoregional and surgical therapy in patients with intermediate-stage hepatocellular carcinoma.

Kasuga R, Taniki N, Chu PS, Tamura M, Tabuchi T, Yamaguchi A, Hayatsu S, Koizumi J, Ojiro K, Hoshi H, Kaneko F, Morikawa R, Noguchi F, Yamataka K, Usui S, Ebinuma H, Itano O, Hasegawa Y, Abe Y, Kitago M, Inoue M, Nakatsuka S, Jinzaki M, Kitagawa Y, Kanai T, Nakamoto N

Scientific reports 14 （ 1 ） 10896 2024年05月

Development of subclassification of intermediate-stage hepatocellular carcinoma (HCC) by treatment suitability is in demand. We aimed to identify predictors that define treatment refractoriness against locoregional(transarterial chemoembolization(TACE) or thermal ablation) and surgical therapy. This multicenter retrospective study enrolled 1167 HCC patients between 2015 and 2021. Of those, 209 patients were initially diagnosed with intermediate-stage HCC. Treatment refractoriness was defined as clinical settings that meets the following untreatable progressive conditions by TACE (1) 25% increase of intrahepatic tumor, (2) transient deterioration to Child–Pugh class C, (3) macrovascular invasion or extrahepatic spread, within one year. We then analyzed factors contributing to treatment refractoriness. The Child–Pugh score/class, number of tumors, infiltrative radiological type, and recurrence were significant factors. Focusing on recurrence as a predictor, median time to untreatable progression (TTUP) was 17.2 months in the recurrence subgroup whereas 35.5 months in the initial occurrence subgroup (HR, 2.06; 95% CI, 1.44–2.96; P = 0.001). Median TTUP decreased in cases with more later times of recurrence (3–5 recurrences, 17.3 months; ≥ 6 recurrences, 7.7 months). Recurrence, even more at later times, leads to increased treatment refractoriness. Early introduction of multidisciplinary treatment should be considered against HCC patients after multiple recurrent episodes.

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Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma.

Alaimo L, Endo Y, Catalano G, Ruzzenente A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Kitago M, Pawlik TM

Annals of surgical oncology 31 （ 5 ） 3043 - 3052 2024年05月

ISSN 1068-9265

Introduction: Benchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population. Methods: Patients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group. Results: Among 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0–67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days. Conclusions: Benchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.

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Evidence and Future Perspectives for Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer: A Scoping Review.

Endo Y, Kitago M, Kitagawa Y

Cancers 16 （ 9 ） 2024年04月

ISSN 2072-6694

Pancreatic cancer (PC) is a lethal disease that requires innovative therapeutic approaches to enhance the survival outcomes. Neoadjuvant treatment (NAT) has gained attention for resectable and borderline resectable PC, offering improved resection rates and enabling early intervention and patient selection. Several retrospective studies have validated its efficacy. However, previous studies have lacked intention-to-treat analyses and appropriate resectability classifications. Randomized comparative trials may help to enhance the clinical applicability of evidence. Therefore, after searching the MEDLINE database, this scoping review presents a comprehensive summary of the evidence from published (n = 14) and ongoing (n = 12) randomized Phase II and III trials. Diverse regimens and their outcomes were explored for both resectable and borderline resectable PC. While some trials have supported the efficacy of NAT, others have demonstrated no clear survival benefits for patients with resectable PC. The utility of NAT has been confirmed in patients with borderline resectable PC, but the optimal regimens remain debatable. Ongoing trials are investigating novel regimens, including immunotherapy, thereby highlighting the dynamic landscape of PC treatment. Studies should focus on biomarker identification, which may enable precision in oncology. Future endeavors aim to refine treatment strategies, guided by precision oncology.

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Next‑generation sequencing to identify genetic mutations in pancreatic cancer using intraoperative peritoneal washing fluid.

Nakano Y, Shimane G, Nakamura K, Takamatsu R, Aimono E, Yagi H, Abe Y, Hasegawa Y, Hori S, Tanaka M, Masugi Y, Kitago M, Nishihara H, Kitagawa Y

Oncology letters 27 （ 4 ） 139 2024年04月

ISSN 1792-1074

The efficacy of next‑generation sequencing (NGS) of tumor‑derived DNA from intraoperative peritoneal washing fluid (IPWF) of patients with pancreatic ductal adenocar‑ cinoma (PDAC) who intend to undergo curative resection remains unclear. The aim of the present study was to evaluate whether genomic mutations in tumor‑derived DNA from IPWF samples of patients with PDAC who intend to undergo curative resection could be detected using NGS. A total of 12 such patients were included in this study. Cytology of IPWF (CY) was assessed and NGS of genomic tumor‑derived DNA from the IPWF was performed to determine whether genomic mutations could be detected in these patient samples. A total of 2 patients (16.7%) had a CY(+) status and 1 patient (8.3%) showed intraoperative macro‑peritoneal dissemination; 11 patients underwent radical surgery. Actionable gene altera‑ tions were detected in 8 (80.0%) out of the 10 patients with CY(‑) status based on NGS of IPWF samples, and 3 (37.5%) patients among those with actionable gene mutations identi‑ fied from IPWF samples underwent peritoneal dissemination after surgery within ~12 months. The most common genomic mutation was in KRAS (9 patients, 75.0%), followed by TP53 (3 patients, 25.0%), SMAD4 (1 patient, 8.3%) and CDKN2A (1 patient, 8.3%). These findings indicated that the genomic

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The aMAP score predicts long-term outcomes after resection of hepatocellular carcinoma: a multi-institutional analysis.

Tsilimigras DI, Endo Y, Ratti F, Marques HP, Cauchy F, Lam V, Poultsides GA, Popescu I, Alexandrescu S, Martel G, Kitago M, Guglielmi A, Hugh T, Aldrighetti L, Gleisner A, Shen F, Endo I, Pawlik TM

HPB : the official journal of the International Hepato Pancreato Biliary Association 26 （ 4 ） 541 - 547 2024年04月

ISSN 1365-182X

Background: The aMAP score is a proposed model to predict the development of hepatocellular carcinoma (HCC) among high-risk patients with chronic hepatitis. The role of the aMAP score to predict long-term survival among patients following resection of HCC has not been determined. Methods: Patients undergoing resection for HCC between 2000 and 2020 were identified using a multi-institutional database. The impact of the aMAP score on long-term outcomes following HCC resection was assessed. Results: Among 1377 patients undergoing resection for HCC, a total of 972 (70.6 %) patients had a low aMAP score (≤63), whereas 405 (29.4 %) individuals had a high aMAP score (≥64). aMAP score was associated with 5-year OS in the entire cohort (low vs high aMAP score:66.5 % vs. 54.3 %, p < 0.001). aMAP score predicted 5-year OS following resection among patients with HBV-HCC (low vs. high aMAP:68.8 % vs. 55.6 %, p = 0.01) and NASH/other-HCC (64.7 % vs. 53.7, p = 0.04). aMAP score could sub-stratify 5-year OS among patients undergoing HCC resection within (low vs. high aMAP:81.5 % vs. 67.4 %, p < 0.001) and beyond (55.9 % vs. 38.8 %, p < 0.001) Milan criteria. Discussion: The aMAP score predicted postoperative outcomes following resection of HCC within and beyond Milan criteria. Apart from a surveillance tool, the aMAP score can also be used as a prognostic tool among patients undergoing resection of HCC.

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Textbook outcome in liver surgery: open vs minimally invasive hepatectomy among patients with hepatocellular carcinoma.

Endo Y, Tsilimigras DI, Munir MM, Woldesenbet S, Yang J, Katayama E, Guglielmi A, Ratti F, Marques HP, Cauchy F, Lam V, Poultsides GA, Kitago M, Popescu I, Alexandrescu S, Martel G, Gleisner A, Hugh T, Aldrighetti L, Shen F, Endo I, Pawlik TM

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 28 （ 4 ） 417 - 424 2024年04月

ISSN 1091-255X

Background: We sought to investigate whether minimally invasive hepatectomy (MIH) was superior to open hepatectomy (OH) in terms of achieving textbook outcome in liver surgery (TOLS) after resection of hepatocellular carcinoma (HCC). Methods: Patients who underwent resection of HCC between 2000 and 2020 were identified from an international database. TOLS was defined by the absence of intraoperative grade ≥2 events, R1 resection margin, posthepatectomy liver failure, bile leakage, major complications, in-hospital mortality, and readmission. Results: A total of 1039 patients who underwent HCC resection were included in the analysis. Although most patients underwent OH (n = 724 [69.7%]), 30.3% (n = 315) underwent MIH. Patients who underwent MIH had a lower tumor burden score (3.6 [IQR, 2.6-5.2] for MIH vs 6.1 [IQR, 3.9-10.1] for OH) and were more likely to undergo minor hepatectomy (84.1% [MIH] vs 53.6% [OH]) than patients who had an OH (both P < .001). After propensity score matching to control for baseline differences between the 2 cohorts, the incidence of TOLS was comparable among patients who had undergone MIH (56.6%) versus OH (64.8%) (P = .06). However, MIH was associated with a shorter length of hospital stay (6.0 days [IQR, 4.0-8.0] for MIH vs 9.0 days [IQR, 6.0-12.0] for OH). Among patients who had MIH, the odds ratio of achieving TOLS remained stable up to a tumor burden score of 4; after which the chance of TOLS with MIH markedly decreased. Conclusion: Patients with HCC who underwent resection with MIH versus OH had a comparable likelihood of TOLS, although MIH was associated with a short length of stay.

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