論文 - 北郷　実

Post-operative mortality and recurrence patterns in pancreatic cancer according to KRAS mutation and CDKN2A, p53, and SMAD4 expression.

Masugi Y, Takamatsu M, Tanaka M, Hara K, Inoue Y, Hamada T, Suzuki T, Arita J, Hirose Y, Kawaguchi Y, Nakai Y, Oba A, Sasahira N, Shimane G, Takeda T, Tateishi K, Uemura S, Fujishiro M, Hasegawa K, Kitago M, Takahashi Y, Ushiku T, Takeuchi K, Sakamoto M, GTK Pancreatic Cancer Study Group in Japan

The journal of pathology. Clinical research 9 （ 5 ） 339 - 353 2023年09月

　概要を見る

Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post-operative survival outcomes. To test this hypothesis, we utilised a multi-institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (ptrend < 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time (ptrend = 0.003) and to develop liver metastasis (ptrend = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post-operative survival among patients with pancreatic cancer.

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Phase I study of neoadjuvant S-1 plus cisplatin with concurrent radiation for biliary tract cancer (Tokyo Study Group for Biliary Cancer: TOSBIC02).

Abe Y, Itano O, Takemura Y, Minagawa T, Ojima H, Shinoda M, Kitago M, Obara H, Shigematsu N, Kitagawa Y

Annals of gastroenterological surgery 7 （ 5 ） 808 - 818 2023年09月

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Aim: Neoadjuvant chemoradiotherapy may improve survival in patients with advanced cholangiocarcinoma. This Phase I study aimed to determine the recommended dose of neoadjuvant chemoradiotherapy and decide whether to move to a Phase II study. Methods: Patients diagnosed with resectable stage II–IVa cholangiocarcinoma were administered cisplatin (40 [level 0], 50 [level 1 as starting dose], or 60 [level 2] mg/m2), 80 mg/m2 of S-1, and 50.4 Gy of external beam radiation. The recommended dose was defined as a dose one-step lower than the maximum-tolerated dose, which was defined when dose-limiting toxicity was observed in three or more of the six patients. Results: Twelve patients were eligible from November 2012 to May 2016. Ten patients had perihilar cholangiocarcinoma and two patients had distal cholangiocarcinoma. Dose-limiting toxicity was observed in one of the first six patients at level 1 and two of the next six patients at level 2; thus, the maximum-tolerated dose was not determined even at level 2 and the recommended dose was determined as level 2. Four patients had partial response, four patients had stable disease, and two patients had progression of disease because of liver metastases. Finally, nine patients underwent radical surgery and seven cases achieved R0 resection. However, five cases suffered biliary leakage and one suffered intrahospital death due to rupture of the hepatic artery. Conclusion: We determined the recommended dose of neoadjuvant chemoradiotherapy for resectable cholangiocarcinoma. However, we terminated the trial due to a high incidence of morbidity and unexpected mortality.

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Features of T1 pancreatic cancer and validation of the eighth edition AJCC staging system definition using a Korean-Japanese joint cohort and the SEER database.

Kwon W, Heo JS, Han IW, Kang CM, Hwang HK, Kim SC, Park SJ, Yoon YS, Kim YH, Lim CS, Lee SY, Park T, Takami H, Watanabe N, Shimizu Y, Okuno M, Yamaue H, Kawai M, Seiko H, Nagakawa Y, Osakabe H, Sugiura T, Toyama H, Ohtsuka M, Unno M, Endo I, Kitago M, Jang JY

Journal of hepato-biliary-pancreatic sciences 30 （ 9 ） 1129 - 1140 2023年09月

ISSN  1868-6974

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Background/Purpose: Little is known about the features of T1 pancreatic ductal adenocarcinoma (PDAC) and its definition in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system needs validation. The aims were to analyze the clinicopathologic features of T1 PDAC and investigate the validity of its definition. Method: Data from 1506 patients with confirmed T1 PDAC between 2000 and 2019 were collected and analyzed. The results were validated using 3092 T1 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Results: The median survival duration of patients was 50 months, and the 5-year survival rate was 45.1%. R0 resection was unachievable in 10.0% of patients, the nodal metastasis rate was 40.0%, and recurrence occurred in 55.2%. The current T1 subcategorization was not feasible for PDAC, tumors with extrapancreatic extension (72.8%) had worse outcomes than those without extrapancreatic extension (median survival 107 vs. 39 months, p <.001). Extrapancreatic extension was an independent prognostic factor whereas the current T1 subcategorization was not. The results of this study were reproducible with data from the SEER database. Conclusion: Despite its small size, T1 PDAC displayed aggressive behavior warranting active local and systemic treatment. The subcategorization by the eighth edition of the AJCC staging system was not adequate for PDAC, and better subcategorization methods need to be explored. In addition, the role of extrapancreatic extension in the staging system should be reconsidered.

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Effect of aqueous olanexidine versus alcohol-based chlorhexidine for surgical skin antisepsis on incidence of surgical site infections in gastrointestinal surgery: multicentre randomised controlled clinical trial (OEDO trial) protocol.

Takeuchi M, Obara H, Furube T, Kawakubo H, Kitago M, Okabayashi K, Aoyama J, Amemiya R, Fujisaki H, Sano J, Goto R, Sato Y, Kitagawa Y

BMJ open 13 （ 8 ） e074169 2023年08月

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Introduction Surgical site infections (SSIs) are among the most common nosocomial infections in surgery patients. Two types of preparations, povidone-iodine and chlorhexidine-alcohol, are commonly used in preoperative antiseptic procedures worldwide. However, there are inconsistencies among international guideline recommendations concerning skin antiseptics. This trial aimed to evaluate the superiority of olanexidine, which reduced SSI rates more than povidone-iodine in our previous randomised trial, over chlorhexidine-alcohol in clean-contaminated surgery. Methods and analysis This multicentre randomised controlled clinical trial will compare two antiseptics (1.5% olanexidine and 1.0% chlorhexidine-alcohol) to prevent SSI in clean-contaminated gastrointestinal surgeries with surgical wounds. On providing consent, patients aged <18 years will be included. The primary outcome will be the postoperative 30-day overall SSI rate, while the secondary outcomes will be the postoperative 30-day superficial incisional SSI rate, deep incisional SSI rate, organ/space SSI rate, positive bacterial wound culture rate, cultured bacterial strains, rates of intervention-related toxicity and allergic events (eg, erythema, pruritus, dermatitis and other symptoms of allergy around the region disinfected by the antiseptic during surgery), rate of reoperations due to SSI, medical economic effect indicators (based on health insurance claims) and hospital duration. The Mantel-Haenszel method will be used to estimate the adjusted risk ratio and its 95% CI for the primary analysis, which will compare the treatment effects. Ethics and dissemination The protocol was approved by the Institutional Review Board of Keio University School of Medicine and subsequently by the board of each participating site. Participant recruitment began in January 2023. The final results will be published in medical journals after international peer review. Trial registration number UMIN000049712.

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The Impact of a Liver Transplant Program on the Outcomes of Hepatocellular Carcinoma.

Endo Y, Sasaki K, Moazzam Z, Woldesenbet S, Yang J, Araujo Lima H, Alaimo L, Munir MM, Shaikh CF, Schenk A, Kitago M, Pawlik TM

Annals of surgery 278 （ 2 ） 230 - 238 2023年08月

ISSN  0003-4932

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Objective: We sought to evaluate the impact of liver transplantation (LT) programs on the prognosis of hepatocellular carcinoma (HCC) patients who underwent liver resection (LR) and noncurative intent treatment. Background: LT programs have an array of resources and services that would positively affect the prognosis of patients with HCC. Methods: Patients who underwent LT, LR, radiotherapy (RT), or chemotherapy (CTx) for HCC between 2004 and 2018 were included in the National Cancer Database. Institutions with LT programs were defined as those that performed 1 or more LT for at least 5 years. Centers were stratified by hospital volume. The impact of LT programs was assessed after propensity score matching to achieve covariate balance. Results: A total of 71,735 patients were identified, of which 7997 received LT (11.1%), 12,683 LR (17.7%), 15,675 RT (21.9%), and 35,380 CTx (49.3%). Among a total of 1267 distinct institutions, 94 (7.4%) were categorized as LT programs. Designation as an LT program was also associated with a high volume of LR and noncurative intent treatment (both P<0.001). After propensity score matching, LT programs were associated with better survival among LR and noncurative intent treatment patients. Although hospital volume was also associated with improved prognosis, LT programs were associated with additional survival benefits in noncurative intent treatment. On the other hand, no such benefit was noted in patients who underwent LR. Conclusions: The presence of an LT program was associated with a higher volume of LR and noncurative intent treatment. Furthermore, designation as an LT program had a "halo effect" on the prognosis of patients undergoing RT/CTx that went beyond the procedure-volume effect.

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Short- and long-term outcomes of laparoscopic radical gallbladder resection for gallbladder carcinoma: A multi-institutional retrospective study in Japan.

Minagawa T, Itano O, Hasegawa S, Wada H, Abe Y, Kitago M, Katsura Y, Takeda Y, Adachi T, Eguchi S, Oshima G, Aiko S, Ome Y, Kobayashi T, Hashida K, Nara S, Esaki M, Watanabe J, Ohtani H, Endo Y, Shirobe T, Tokumitsu Y, Nagano H

Journal of hepato-biliary-pancreatic sciences 30 （ 8 ） 1046 - 1054 2023年08月

ISSN  1868-6974

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Background/Purpose: Laparoscopic resection of gallbladder carcinomas remains controversial. This study aimed to evaluate the surgical and oncological outcomes of laparoscopic procedures for suspected gallbladder carcinoma (GBC). Methods: In this retrospective study, data regarding suspected GBC treated with laparoscopic radical cholecystectomy before 2020 in Japan, was included. Patient characteristics, surgical procedure details, surgical outcomes, and long-term outcomes were analyzed. Results: Data of 129 patients with suspected GBC who underwent laparoscopic radical cholecystectomy were retrospectively collected from 11 institutions in Japan. Among them, 82 patients with pathological GBC were included in the study. Laparoscopic gallbladder bed resection was performed in 114 patients and laparoscopic resection of segments IVb and V was performed in 15 patients. The median operation time was 269 min (range: 83–725 min), and the median intraoperative blood loss was 30 mL (range: 0–950 mL). The conversion and postoperative complication rates were 8% and 2%, respectively. During the follow-up period, the 5-year overall survival rate was 79% and the 5-year disease-free survival rate was 87%. Recurrence was detected in the liver, lymph nodes, and other local tissues. Conclusion: Laparoscopic radical cholecystectomy is a treatment option with potential favorable outcomes in selected patients with suspected GBC.

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Japanese national survey on declined liver allografts from brain-dead donors: High decline rate but promising outcomes in allografts with moderate steatosis.

Takemura Y, Shinoda M, Hasegawa Y, Yamada Y, Obara H, Kitago M, Kasahara M, Umeshita K, Eguchi S, Kitagawa Y, Ohdan H, Egawa H

Annals of gastroenterological surgery 7 （ 4 ） 654 - 665 2023年07月

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Aim: Liver allografts from brain-dead donors, which were declined and were eventually not transplanted due to accompanying marginal factors, have never been surveyed in Japan. We surveyed the declined allografts and discussed the graft potential focusing on various marginal factors. Methods: We collected data on brain-dead donors between 1999 and 2019 from the Japan Organ Transplant Network. We divided their liver allografts into declined (nontransplanted) and transplanted ones, and then characterized declined ones focusing on their timepoints of decline and accompanying marginal factors. For each marginal factor, we calculated the decline rate from the number of declined and transplanted allografts, and assessed the 1-year graft survival rate from transplanted allografts. Results: A total of 571 liver allografts were divided into 84 (14.7%) declined and 487 (85.3%) transplanted ones. In the declined allografts, a majority was declined after laparotomy (n = 55, 65.5%), most of which had steatosis and/or fibrosis (n = 52). Out of the moderate steatotic (without F ≥ 2 fibrosis) allografts (n = 33), 21 were declined and 12 were transplanted, leading to a 63.6% decline rate. The latter 12 achieved a 92.9% 1-year graft survival rate after transplantation. Comparison of donor background showed no significant difference between the declined and transplanted allografts. Conclusion: Pathological abnormalities of steatosis/fibrosis seem to be the most common donor factor leading to graft decline in Japan. Allografts with moderate steatosis were highly declined; however, transplanted ones achieved promising outcomes. This national survey highlights the potential utility of liver allografts with moderate steatosis.

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胃癌術後22年目に十二指腸狭窄と胆管狭窄で発症した胃癌晩期再発の1切除例

小泉 亘, 北郷 実, 関戸 康友, 壁島 康郎

日本消化器外科学会雑誌 （(一社)日本消化器外科学会）  56 （ 7 ） 377 - 383 2023年07月

ISSN  0386-9768

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症例は71歳の男性で,胃癌に対して幽門側胃切除術後22年目に十二指腸狭窄および胆管狭窄を認めた.十二指腸癌または遠位胆管癌の疑いで,膵頭十二指腸切除術を施行した.術中所見では胃十二指腸吻合部周囲に高度の癒着を認めた.膵切離断端の術中迅速病理診断で,膵実質周囲に低分化腺癌の所見を認めた.切除検体の胆管内腔には腫瘍性病変を認めず,壁外からの浸潤による胆管狭窄が認められた.病理組織学的検査では,前回の胃癌と同じ低分化腺癌と診断された.術中迅速病理検査でCY0と診断された腹腔洗浄細胞診は,アルシアンブルー-PAS染色を追加した結果,癌細胞を認めCY1と診断され,術中にサンプリングした小腸間膜結節も低分化腺癌と診断された(P1).以上より,胃癌術後の局所再発,腹膜播種と診断した.今回,最終病理組織学的検査で22年後の胃癌晩期再発と診断された1切除例を経験したため報告する.(著者抄録)

The Application of Artificial Intelligence to Investigate Long-Term Outcomes and Assess Optimal Margin Width in Hepatectomy for Intrahepatic Cholangiocarcinoma.

Alaimo L, Moazzam Z, Endo Y, Lima HA, Butey SP, Ruzzenente A, Guglielmi 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, Kim A, Ejaz A, Beane J, Cloyd J, Pawlik TM

Annals of surgical oncology 30 （ 7 ） 4292 - 4301 2023年07月

ISSN  1068-9265

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Background: Intrahepatic cholangiocarcinoma (ICC) is associated with poor long-term outcomes, and limited evidence exists on optimal resection margin width. This study used artificial intelligence to investigate long-term outcomes and optimal margin width in hepatectomy for ICC. Methods: The study enrolled patients who underwent curative-intent resection for ICC between 1990 and 2020. The optimal survival tree (OST) was used to investigate overall (OS) and recurrence-free survival (RFS). An optimal policy tree (OPT) assigned treatment recommendations based on random forest (RF) counterfactual survival probabilities associated with each possible margin width between 0 and 20 mm. Results: Among 600 patients, the median resection margin was 4 mm (interquartile range [IQR], 2–10). Overall, 379 (63.2 %) patients experienced recurrence with a 5-year RFS of 28.3 % and a 5-year OS of 38.7 %. The OST identified five subgroups of patients with different OS rates based on tumor size, a carbohydrate antigen 19-9 [CA19-9] level higher than 200 U/mL, nodal status, margin width, and age (area under the curve [AUC]: training, 0.81; testing, 0.69). The patients with tumors smaller than 4.8 cm and a margin width of 2.5 mm or greater had a relative increase in 5-year OS of 37 % compared with the entire cohort. The OST for RFS estimated a 46 % improvement in the 5-year RFS for the patients younger than 60 years who had small (<4.8 cm) well- or moderately differentiated tumors without microvascular invasion. The OPT suggested five optimal margin widths to maximize the 5-year OS for the subgroups of patients based on age, tumor size, extent of hepatectomy, and CA19-9 levels. Conclusions: Artificial intelligence OST identified subgroups within ICC relative to long-term outcomes. Although tumor biology dictated prognosis, the OPT suggested that different margin widths based on patient and disease characteristics may optimize ICC long-term survival.

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Predictors and Prognostic Significance of Postoperative Complications for Patients with Intrahepatic Cholangiocarcinoma.

Endo Y, Moazzam Z, Woldesenbet S, Araujo Lima H, Alaimo L, Munir MM, Shaikh CF, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Kitago M, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM

World journal of surgery 47 （ 7 ） 1792 - 1800 2023年07月

ISSN  0364-2313

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Background: The prognostic impact of major postoperative complications (POCs) for intrahepatic cholangiocarcinoma (ICC) remains ill-defined. We sought to analyze the relationship between POCs and outcomes relative to lymph node metastases (LNM) and tumor burden score (TBS). Methods: Patients who underwent resection of ICC between 1990–2020 were included from an international database. POCs were defined according to Clavien-Dindo classification ≥ 3. The prognostic impact of POCs was estimated relative to TBS categories (i.e., high and low) and lymph node status (i.e., N0 or N1). Results: Among 553 patients who underwent curative-intent resection for ICC, 128 (23.1%) individuals experienced POCs. Low TBS/N0 patients who experienced POCs presented with a higher risk of recurrence and death (3-year cumulative recurrence rate; POCs: 74.8% vs. no POCs: 43.5%, p = 0.006; 5-year overall survival [OS], POCs 37.8% vs. no POCs 65.8%, p = 0.003), while POCs were not associated with worse outcomes among high TBS and/or N1 patients. The Cox regression analysis confirmed that POCs were significant predictors of poor outcomes in low TBS/N0 patients (OS, hazard ratio [HR] 2.91, 95%CI 1.45–5.82, p = 0.003; recurrence free survival [RFS], HR 2.42, 95%CI 1.28–4.56, p = 0.007). Among low TBS/N0 patients, POCs were associated with early recurrence (within 2 years) (Odds ratio [OR] 2.79 95%CI 1.13–6.93, p = 0.03) and extrahepatic recurrence (OR 3.13, 95%CI 1.14–8.54, p = 0.03), in contrast to patients with high TBS and/or nodal disease. Conclusions: POCs were independent, negative prognostic determinants for both OS and RFS among low TBS/N0 patients. Perioperative strategies that minimize the risk of POCs are critical to improving prognosis, especially among patients harboring favorable clinicopathologic features.

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TBS-Based Preoperative Score to Predict Non-transplantable Recurrence and Identify Candidates for Upfront Resection Versus Transplantation for Hepatocellular Carcinoma.

Lima HA, Moazzam Z, Endo Y, Alaimo L, Shaikh C, Munir MM, Resende V, Guglielmi A, Marques HP, Cauchy F, Lam V, Poultsides GA, Popescu I, Alexandrescu S, Martel G, Hugh T, Endo I, Kitago M, Shen F, Pawlik TM

Annals of surgical oncology 30 （ 6 ） 3363 - 3373 2023年06月

ISSN  1068-9265

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Background: Recurrence following liver resection (LR) for hepatocellular carcinoma (HCC) can be as high as 50–70%. While salvage liver transplantation may be feasible, patients may develop a non-transplantable recurrence (NTR) (recurrence beyond Milan criteria). We sought to identify preoperative risk factors to predict NTR after resection. Patients and Methods: Patients who underwent curative-intent LR for HCC were identified from a multi-institutional database. Preoperative factors associated with NTR were identified and a risk score model (NTR score) was developed and validated. Results: Among 1620 patients, 842 (52.0%) developed recurrence; among patients with recurrence, NTR occurred in 341 (40.5%) with a median recurrence-free survival (RFS) of 30 months (24.7–35.3 months). On multivariable analysis, factors associated with NTR included alpha fetoprotein (AFP) > 400 ng/mL [hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.33–2.19], albumin–bilirubin grade (ALBI) (referent low, medium ALBI: HR 1.41, 95% CI 1.10–1.81, high ALBI: HR 2.47, 95% CI 0.91–6.68), and tumor burden score (TBS) (referent low, high TBS: HR 2.55, 95% CI, 1.99–3.28). A simplified TBS-based NTR score was developed using the β-coefficients of each factor (C-index 0.68, 95% CI 0.65–0.71). Higher NTR score was associated with incrementally worse 5-year RFS (low 44.8%, medium 37.5%, high 24.5%) [area under the curve (AUC) 0.59] and increased incidence of NTR (low 13.7%, medium 25.4%, high 38.2%) (AUC 0.65) (both p < 0.001). Moreover, higher NTR score was associated with higher risk of extrahepatic recurrence (low 11.3%, medium 28.8%, high 37.5%) (p < 0.001). Conclusion: NTR following curative-intent resection of HCC occurred in one in five patients. A simple TBS-based NTR score accurately predicted the risk of NTR and may help identify candidates for upfront resection versus transplantation.

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The impact of tumor location on the value of lymphadenectomy for intrahepatic cholangiocarcinoma.

Endo Y, Moazzam Z, Lima HA, Alaimo L, Munir MM, Shaikh CF, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Kitago M, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM

HPB : the official journal of the International Hepato Pancreato Biliary Association 25 （ 6 ） 650 - 658 2023年06月

ISSN  1365-182X

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Background: The therapeutic role of lymphadenectomy (LND) for intrahepatic cholangiocarcinoma (ICC) patients remains ill-defined. We sought to analyze the therapeutic value of LND relative to tumor location and preoperative lymph node metastasis (LNM) risk. Methods: Patients who underwent curative-intent hepatic resection of ICC between 1990 and 2020 were included from a multi-institutional database. Therapeutic LND (tLND) was defined as LND that harvested ≥3 lymph nodes. Results: Among 662 patients, 178 (26.9%) individuals received tLND. Patients were categorized into central type ICC (n = 156, 23.6%) and peripheral type ICC (n = 506, 76.4%). Central type harbored multiple adverse clinicopathologic factors and worse overall survival (OS) compared with peripheral type (5-year OS, central: 27.0% vs. peripheral: 47.2%, p < 0.001). After consideration of preoperative LNM risk, patients with central type and high-risk LNM who underwent tLND survived longer than individuals who did not (5-year OS, tLND: 27.9% vs. non-tLND: 9.0%, p = 0.001), whereas tLND was not associated with better survival among patients with peripheral type ICC or low-risk LNM. The therapeutic index of hepatoduodenal ligament (HDL) and other regions was higher in central type than in peripheral type, which was more pronounced among high-risk LNM patients. Conclusions: Central type ICC with high-risk LNM should undergo LND involving regions beyond the HDL.

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Clinical characteristics and predictive factors of postoperative intra-abdominal abscess after distal pancreatectomy.

Nakano Y, Endo Y, Kitago M, Nishiyama R, Yagi H, Abe Y, Hasegawa Y, Hori S, Tanaka M, Shimane G, Soga S, Egawa T, Okuda S, Kitagawa Y

Langenbeck's archives of surgery 408 （ 1 ） 170 2023年05月

ISSN  1435-2443

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Purpose: The postoperative mortality rate of distal pancreatectomy is lower than that of pancreaticoduodenectomy, although persistent complications may occur after distal pancreatectomy. Fluid collection (FC) is frequently observed after distal pancreatectomy; however, FC may occasionally progress to postoperative intra-abdominal abscess (PIAA), which requires conservative or progressive interventional treatment. This study aimed to compare the status between patients with or without PIAA, identify predictive factors for PIAA and clinically relevant postoperative pancreatic fistula, and investigate the clinical characteristics of patients with PIAA with interventional drainage. Methods: We retrospectively reviewed data of patients who underwent distal pancreatectomy between January 2012 and December 2019 at two high-volume centers, where hepatobiliary-pancreatic surgeries were performed by expert specialist surgeons. Logistic regression analysis was performed to determine the predictive factors for PIAA. Results: Overall, 242 patients were analyzed, among whom 49 (20.2%) had PIAA. The median postoperative period of PIAA formation was 9 (range: 3–49) days. Among the 49 patients with PIAA, 25 (51.0%) underwent percutaneous ultrasound, computed tomography, or endoscopic ultrasound-guided interventions for PIAA. In the univariate analysis, preoperative indices representing abdominal fat mass (i.e., body mass index, subcutaneous fat area, and visceral fat area) were identified as predictive factors for PIAA; in the multivariate analysis, C-reactive protein (CRP) level (continuous variable) on postoperative day (POD) 3 (odds ratio: 1.189, 95.0% confidence interval: 1.111 − 1.274; P < 0.001) was the only independent and significant predictive factor for PIAA. Conclusions: CRP level on POD 3 was an independent and significant predictive factor for PIAA after distal pancreatectomy.

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Hospital Volume and Textbook Outcomes in Minimally Invasive Hepatectomy for Hepatocellular Carcinoma.

Endo Y, Moazzam Z, Woldesenbet S, Lima HA, Alaimo L, Munir MM, Shaikh CF, Yang J, Azap L, Katayama E, Kitago M, Pawlik TM

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 27 （ 5 ） 956 - 964 2023年05月

ISSN  1091-255X

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Background: Hospital volume affects outcomes of patients who underwent resection for hepatocellular carcinoma (HCC). We sought to assess the impact of minimally invasive hepatectomy (MIH) volume on short- and long-term outcomes among patients with HCC. Methods: Patients who underwent MIH for HCC from 2010 to 2018 were identified from the National Cancer Database. Multivariable modeling with restricted cubic splines (RCS) was utilized to identify the MIH hospital volume threshold. Textbook outcome (TO) was defined as no conversion to open resection, negative margins after resection (R0), no extended length-of-stay, no readmission, and no 90-day mortality. Results: Among 3268 patients who underwent MIH for HCC, median age was 65.0 (IQR 59.0–72.0) and the majority was male (n = 2308, 70.6%). MIH hospital volume ranged from 1 to 87 cases, with a median of 13 (IQR 7–23). Overall, 2151 (60.9%) patients achieved TO after resection. While particularly high rates of achievement were found for no 90-day mortality (n = 3106, 95.0%), no readmission (n = 3153, 96.5%), and R0 resection (n = 3,017, 92.3%), other TO components including no conversion to open (n = 2778, 85.0%) and no prolonged LOS (n = 2584, 79.1%) were achieved less frequently. Patients treated at high-volume centers (≥50 MIH cases) were more likely to experience TO (high volume centers, n = 334, 68.7% vs. low volume centers, n = 1656, 59.5%, p < 0.001) and better long-term survival (5-year OS; high volume centers, 64.7% vs. low volume centers, 54.6%, p < 0.001). Conclusions: MIH hospital volume was associated with a higher likelihood of achieving TO and improved long-term survival among patients undergoing resection of HCC.

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Prognostic impact of preoperative skeletal muscle change from diagnosis to surgery in patients with perihilar cholangiocarcinoma.

Hayashi K, Abe Y, Kitago M, Yagi H, Hasegawa Y, Hori S, Tanaka M, Nakano Y, Kitagawa Y

Annals of gastroenterological surgery 7 （ 3 ） 523 - 532 2023年05月

　概要を見る

Background: Loss of skeletal muscle mass is a prognostic factor after surgery for gastrointestinal cancers. The treatment for perihilar cholangiocarcinoma (PHC) is a highly invasive surgery. Biliary drainage and portal vein embolization, which can prolong the preoperative waiting time (PWT), are often required before surgery. Assuming that the skeletal muscle mass can change during PWT, we investigated the clinical effect of skeletal muscle change on surgical outcomes of PHC. Methods: We retrospectively reviewed the medical records of 89 patients who underwent curative surgery for PHC from January 2013 to December 2019. We defined the psoas muscle area (PMA) at the third lumbar vertebra as the skeletal muscle mass. The PMA just before surgery was divided by that at the time of diagnosis, and we defined it as the rate of change of PMA (CPMA). Patients were divided into two groups according to CPMA: wasting (n = 44, below the median CPMA) and no-change (n = 45, above the median CPMA). Results: The median PWT was 63 d, and CPMA was 96.1%. The median recurrence-free survival and overall survival were significantly shorter in the wasting group than in the no-change group (8.0 vs 33.2 mo, P = 0.001 and 14.2 vs 48.7 mo, P < 0.001, respectively). Multivariate analysis revealed that histological differentiation, R1 resection, lymph node metastasis, and preoperative skeletal muscle wasting were independent prognostic factors of PHC. Conclusion: This study suggests that preoperative skeletal muscle wasting in patients with PHC has a negative effect on survival outcomes.

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Surgical and Oncological Outcomes of Salvage Hepatectomy for Locally Recurrent Hepatocellular Carcinoma after Locoregional Therapy: A Single-Institution Experience.

Minagawa T, Itano O, Kitago M, Abe Y, Yagi H, Hibi T, Shinoda M, Ojima H, Sakamoto M, Kitagawa Y

Cancers 15 （ 8 ）  2023年04月

ISSN  2072-6694

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Surgical and oncological outcomes of hepatectomy for recurrent hepatocellular carcinoma (HCC) after locoregional therapy, including locally recurrent HCC (LR-HCC), were examined. Among 273 consecutive patients who underwent hepatectomy for HCC, 102 with recurrent HCC were included and retrospectively reviewed. There were 35 patients with recurrent HCC after primary hepatectomy and 67 with recurrent HCC after locoregional therapies. Pathologic review revealed 30 patients with LR-HCC. Background liver function was significantly worse in patients with recurrent HCC after locoregional therapy (p = 0.002). AFP (p = 0.031) and AFP-L3 (p = 0.033) serum levels were significantly higher in patients with LR-HCC. Perioperative morbidities were significantly more frequently observed with recurrent HCC after locoregional therapies (p = 0.048). Long-term outcomes of recurrent HCC after locoregional therapies were worse than those after hepatectomy, though there was no prognostic difference according to the recurrence patterns after locoregional therapies. Multivariate analyses showed that prognostic factors for resected recurrent HCC were previous locoregional therapy (hazard ratio [HR] 2.0; p = 0.005), multiple HCCs (HR 2.8; p < 0.001), and portal venous invasion (HR 2.3; p = 0.001). LR-HCC was not a prognostic factor. In conclusion, salvage hepatectomy for LR-HCC showed worse surgical outcomes but a favorable prognosis.

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Higher Tumor Burden Status Dictates the Impact of Surgical Margin Status on Overall Survival in Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma.

Endo Y, Sasaki K, Moazzam Z, Lima HA, Alaimo L, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Poultsides GA, Kitago M, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM

Annals of surgical oncology 30 （ 4 ） 2023 - 2032 2023年04月

ISSN  1068-9265

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Background: The present study aimed to examine the prognostic significance of margin status following hepatectomy of intrahepatic cholangiocarcinoma (ICC) relative to overall tumor burden and nodal status. Method: Patients who underwent curative-intent surgery for ICC between 1990 and 2017 were included from a multi-institutional database. The impact of margin status and width on overall survival (OS) was examined relative to TBS and preoperative nodal status. Results: Among 1105 patients with ICC who underwent resection, median tumor burden score (TBS) was 6.1 (IQR 4.2–8.8) and 218 (19.7%) patients had N1 disease. More than one in eight patients had an R1 surgical margin (n = 154, 13.9%). Among patients with low or medium TBS, an increasing margin width was associated with an incrementally improved 5-year OS (R1 31.9% vs. 1–3 mm 38.5% vs. 3–10 mm 48.0% vs. ≥ 10 mm 52.3%). In contrast, among patients with a high TBS, margin width was not associated with better survival (R1 28.9% vs. 1–3 mm 22.8% vs. 3–10 mm 29.6% vs. ≥ 10 mm 13.7%). In addition, surgical margin status did not impact survival with cutoffs of TBS 7 or greater. Furthermore, patients with low or medium TBS and preoperative negative lymph nodes derived a survival benefit from an R0 resection (R1 resection, HR 2.15, 95% CI 1.35–3.44, p = 0.001). In contrast, margin status was not associated with prognosis among patients with a high TBS and preoperative positive/suspicious lymph nodes (R1 resection, HR 1.34, 95% CI 0.58–3.11, p = 0.50). Conclusion: R0 resection and wider margin resection resulted in improved outcomes in patients with low tumor burden; however, the survival benefit of negative margin status disappeared in patients with underlying poor tumor biology.

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Immunovascular microenvironment in relation to prognostic heterogeneity of WNT/β-catenin-activated hepatocellular carcinoma.

Matsuda K, Kurebayashi Y, Masugi Y, Yamazaki K, Ueno A, Tsujikawa H, Ojima H, Kitago M, Itano O, Shinoda M, Abe Y, Sakamoto M

Hepatology research : the official journal of the Japan Society of Hepatology 53 （ 4 ） 344 - 356 2023年04月

ISSN  1386-6346

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Aim: WNT/β-catenin-activated hepatocellular carcinoma (W/B subclass HCC) is considered a molecularly homogeneous entity and has been linked to resistance to immunotherapy. However, recent studies have indicated possible heterogeneity in the immunovascular microenvironment in this subclass. We set out to test the hypothesis that specific immunovascular features might stratify W/B subclass HCCs into tumors having distinct aggressive natures. Methods: In this study, we analyzed 352 resected HCCs including 78 immunohistochemically defined W/B subclass HCCs. The density of tumor-infiltrating CD3+ T cells and the area ratio of vessels encapsulating tumor clusters (VETC) were calculated on tissue specimens. The gene expressions of angiogenic factors were measured by quantitative reverse transcription–polymerase chain reaction. Disease-free survival (DFS) was assessed using multivariable Cox regression analyses. Results: The T-cell density of W/B subclass HCCs was regionally heterogenous within tumor tissues, and focally reduced T-cell density was observed in areas with VETC. VETC-positivity (defined as VETC area ratio greater than 1%) was inversely associated with T-cell infiltration in both W/B subclass and non-W/B subclass HCCs. Fibroblast growth factor 2 (FGF2) gene expression was higher in W/B subclass than in non-W/B subclass HCCs. The VETC-positivity and low T-cell density correlated with increased expression of FGF2 in W/B subclass HCCs. Additionally, VETC-positive HCCs showed significantly shorter DFS in W/B subclass HCCs. Conclusions: In conclusion, the immune and vascular microenvironments are interrelated and are also correlated with clinicopathological heterogeneity in W/B subclass HCC. These results could inform clinical practice and translational research on the development of therapeutic stratification of HCCs.

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Albumin-Bilirubin Grade and Tumor Burden Score Predict Outcomes Among Patients with Intrahepatic Cholangiocarcinoma After Hepatic Resection: a Multi-Institutional Analysis.

Munir MM, Endo Y, Lima HA, Alaimo L, Moazzam Z, Shaikh C, Poultsides GA, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, Kitago M, Maithel SK, Marques HP, Martel G, Pulitano C, Shen F, Cauchy F, Koerkamp BG, Endo I, Pawlik TM

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 27 （ 3 ） 544 - 554 2023年03月

ISSN  1091-255X

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Background: The prognostic role of tumor burden score (TBS) relative to albumin-bilirubin (ALBI) grade among patients undergoing curative-intent resection of ICC has not been examined. Methods: We identified patients who underwent curative-intent resection for ICC between 1990 and 2017 from a multi-institutional database. Multivariable analysis was performed to assess the effect of TBS relative to ALBI grade on both short- and long-term outcomes. Results: Among 724 patients, 360 (49.7%) patients had low TBS and low ALBI grade, 142 (19.6%) patients had low TBS and high ALBI grade, 138 (19.1%) patients had high TBS and low ALBI grade, and 84 patients (11.6%) had high TBS and high ALBI grade. Decreased tumor burden was associated with better long-term outcomes among patients with both low (5-year OS; low TBS vs. high TBS: 52.4% vs 21.4%; p < 0.001) and high ALBI grade (5-year OS; low TBS vs. high TBS: 40.7% vs 12.0%; p < 0.001). On multivariable analysis, higher ALBI grade was associated with greater odds of an extended hospital LOS (> 10 days) (OR 2.80, 95%CI 1.62–4.82; p < 0.001), perioperative transfusion (OR 2.04, 95%CI 1.25–3.36; p = 0.005), 90-day mortality (OR 2.56, 95%CI 1.12–5.81; p = 0.025), as well as a major complication (OR 1.99, 95%CI 1.13–3.49; p = 0.016) among patients with similar tumor burden. Of note, patients with high TBS and high ALBI grade had markedly worse overall survival compared with patients who had low TBS and low ALBI grade disease (HR 2.27; 95%CI 1.44–3.59; p < 0.001). Importantly, high TBS and high ALBI grade were strongly associated with both early recurrence (88.1%%) and 5-year risk of death (96.4%). Conclusion: Both TBS (i.e., tumor morphology) and ALBI grade (i.e., hepatic function reserve) were strong predictors of outcomes among patients undergoing ICC resection. There was an interplay between TBS and ALBI grade relative to patient prognosis after hepatic resection of ICC with high ALBI grade predicting worse outcomes among ICC patients with different TBS.

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TAC score better predicts survival than the BCLC following resection of hepatocellular carcinoma.

Lima HA, Endo Y, Moazzam Z, Alaimo L, Shaikh C, Munir MM, Resende V, Guglielmi A, Marques HP, Cauchy F, Lam V, Poultsides GA, Popescu I, Alexandrescu S, Martel G, Endo I, Kitago M, Shen F, Pawlik TM

Journal of surgical oncology 127 （ 3 ） 374 - 384 2023年03月

ISSN  0022-4790

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Background: Heterogeneity in hepatocellular carcinoma (HCC) still exists within the Barcelona clinic liver cancer (BCLC) subcategories. We developed a simple model to better discriminate and predict prognosis following resection. Methods: Patients who underwent curative-intent resection for HCC were identified from a multi-institutional database. Predictive factors of survival were identified to develop TAC (tumor burden score [TBS], alpha-fetoprotein [AFP], Child−Pugh CP]) score. Results: Among 1435 patients, median TBS was 5.1 (interquartile range [IQR]: 3.2−8.1), median AFP was 18.3 ng/ml (IQR 4.0−362.5), and 1391 (96.9%) patients were classified as CP-A. Factors associated with overall survival (OS) included TBS (low: referent; medium: HR 2.26, 95% CI: 1.73−2.96; high: HR = 3.35, 95% CI: 2.22−5.07), AFP (<400 ng/ml: referent; >400 ng/ml: HR = 1.56, 95% CI: 1.27−1.92), and CP (A: referent; B: HR = 1.81, 95% CI: 1.12−2.92) (all p < 0.05). A simplified risk score demonstrated superior concordance index, Akaike information criteria, homogeneity, and area under the curve versus BCLC (0.620 vs. 0.541; 5484.655 vs. 5536.454; 60.099 vs. 16.194; 0.62 vs. 0.55, respectively), and further stratified patients within BCLC groups relative to OS (BCLC 0, very low: 86.8%, low: 47.8%) (BCLC A, very low: 79.7%, low: 68.1%, medium: 52.5%, high: 35.6%) (BCLC B, low: 59.8%, medium: 43.7%, high: N/A). Conclusion: TAC is a simple, holistic score that consistently outperformed BCLC relative to discrimination power and prognostication following resection of HCC.

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