Details of a Researcher - Hasegawa, Yasushi

Papers - Hasegawa, Yasushi

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Safety and efficacy of pancreaticogastrostomy for hepatopancreatoduodenectomy compared to pancreaticojejunostomy for perihilar cholangiocarcinoma

Nakano Y., Abe Y., Udagawa D., Kitago M., Hasegawa Y., Hori S., Tanaka M., Uemura S., Odaira M., Mihara K., Nishiyama R., Chiba N., Hayatsu S., Kawachi S., Kitagawa Y.

World Journal of Surgical Oncology 23 ( 1 ) 2025.12

Background: Hepatopancreatoduodenectomy (HPD) is one of the most challenging surgeries for perihilar cholangiocarcinoma. Postoperative pancreatic fistula (POPF) is a critical and fatal complication. The safety and efficacy of pancreaticogastrostomy (PG) for HPD compared to pancreaticojejunostomy (PJ) remain unclear. In this study, we aimed to investigate and compare the short-term outcomes of PG and PJ for HPD in terms of the POPF rate. Methods: Two groups of patients (PG group vs. PJ group) were retrospectively compared between January 2013 and January 2024. The reconstruction method was changed from PJ to PG in March 2021. Results: A total of 50 patients were enrolled in this study. The PG and PJ groups comprised 15 (30.0%) and 35 (70.0%) patients, respectively. In the PJ group, three (8.6%) patients died after surgery because of clinically relevant POPF (CR-POPF), intraabdominal bleeding, and post-hepatectomy liver failure. The operative time was longer in the PG group (909 min vs. 706 min, P = 0.020); however, the CR-POPF rate was lower in the PG group than in the PJ group (0 [0%] vs. 19 [54.3%], P < 0.001). Moreover, the number of patients who developed massive postoperative ascites (≥ 1,500 mL/day) was lower in the PG group than in the PJ group (3 [20.0%] vs. 16 [45.7%] patients, P = 0.028). Conclusions: Changing the method of pancreatic reconstruction for HPD from PJ to PG improved the short-term outcomes of patients at our institution. PG reconstruction is safe and effective for HPD as it reduces the incidence of CR-POPF.

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Laparoscopic cholecystectomy with synchronous navigation of ICG fluorescence and Yellow Enhance mode

Sonoda K., Abe Y., Kitago M., Yagi H., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Kojima H., Kitagawa Y.

Asian Journal of Surgery 48 ( 7 ) 4186 - 4187 2025.07

ISSN 10159584

Technique: Laparoscopic cholecystectomy (LC), widely performed for gallbladder (GB) diseases poses risks of severe complications. To minimize these risks, Tokyo Guidelines 2018 advocated for “safe steps in LC for acute cholecystitis (AC)” including “maintaining the plane of dissection on the GB surface throughout LC”. Moreover, the dissection along the inner layer of the subserosa (SS-inner) of GB helps surgeons avoid bile duct or vascular injury. This step occasionally becomes challenging when distinguishing the GB surface from adjacent fat. ICG, injected into biliary tract, illuminates in green under Infra-red (IR) mode and facilitates the identification of biliary tract. Otherwise, Yellow Enhance (YE) mode developed by Olympus Corporation, which highlights yellow-colored tissues by converting orange-yellow tissues to a clearer yellow, improves the contrast between anatomical structures. Results: In a case of AC following percutaneous transhepatic gallbladder drainage (PTGBD), we applied both ICG fluorescence and YE mode. The ICG injected from PTGBD illuminated the GB surface in green, while YE mode highlighted the fatty tissue in a clearer yellow, facilitating the distinction between these two tissues and the accurate dissection along the SS-inner. An additional advantage of injecting ICG from PTGBD, or from the cannulation tube intraoperatively inserted to GB, over intravenous administration is that the GB surface can be illuminated in cases of GB stone incarceration. Conclusion: The combination of ICG fluorescence and YE mode encourages surgeons to identify the boundary between the GB surface and the surrounding fatty tissues, which assists the accurate dissection along the SS-inner.

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Potential Impact of Screening Examinations on Prognosis of De Novo Malignancies in Adult Patients After Liver Transplantation

Uemura S., Hasegawa Y., Obara H., Kitago M., Yagi H., Abe Y., Hori S., Tanaka M., Nakano Y., Kitagawa Y.

Livers 5 ( 2 ) 2025.06

Background: De novo malignancies (DNMs) after liver transplantation (LT) are a major cause of long-term mortality. However, no definitive screening protocol has been established due to their diversity. This study aimed to evaluate DNM diagnosis methods, screening protocols, and prognoses. Methods: This retrospective study included 231 adult LT recipients from April 1997 to March 2021. Disease-specific survival (DSS) was analyzed to assess the impact of screening on prognosis. Most recipients underwent serum tests every three months, annual gastrointestinal endoscopy, and chest-abdominal CT as part of routine surveillance. Results: Twenty-five DNMs were diagnosed in 22 patients, with median age of 61 years (range, 23–72), of whom 13 (59.1%) were female. The duration from transplantation to DNM diagnosis of DNM was 88 months (range, 4–195). DNM was diagnosed as follows: seven patients (31.8%) through screening (screening group) and 15 patients (68.2%) by other means (non-screening group). Curative treatment was achieved in all of the patients diagnosed by screening, whereas it was possible in only 60.0% of patients diagnosed by other means (p = 0.026). DSS in the screening group was significantly longer than that in the non-screening group (p = 0.024). Conclusions: While screening was associated with earlier-stage diagnosis and improved outcomes in some patients, the overall efficacy of the protocol requires further validation in larger studies.

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A case of hepatic epithelioid hemangioendothelioma with features resembling those of acute-onset autoimmune hepatitis that was undiagnosed before liver transplantation

Usui S., Chu P.S., Hirano M., Hasegawa Y., Ueno A., Nomura R., Obara H., Kitagawa Y., Kanai T., Nakamoto N.

Clinical Journal of Gastroenterology 18 ( 3 ) 514 - 519 2025.06

ISSN 18657257

Hepatic epithelioid hemangioendothelioma (HEHE), which is extremely rare, is considered to have a malignant grade between that of hepatic hemangioma and that of hepatic hemangiosarcoma; however, some cases progress so quickly that they present with portal hypertension. We report the case of a woman with findings similar to those of acute-onset autoimmune hepatitis (AIH) that was not diagnosed before liver transplantation. The patient presented with jaundice and ascites. A hematological examination revealed negative tumor markers, high IgG levels, and negative hepatitis virus markers. Computed tomography findings of the liver showed map-like signs characteristic of acute-onset AIH. Despite some response, immunosuppressive drugs such as prednisolone, cyclosporine, and mycophenolate mofetil did not improve liver failure, and she underwent liver transplantation after 200 days of treatment. The explanted liver exhibited white areas that extended in a map-like manner and were occupied by fibrous stroma. Tumors with WWTR1-CAMTA1 gene fusion were recognized and diagnosed as HEHE. Although a histological examination is essential, a percutaneous liver biopsy could not be performed preoperatively because of the presence of ascites. Furthermore, the rarity of the disease, similarity of imaging findings with non-neoplastic patterns, and serological findings made it difficult to differentiate this case from acute-onset autoimmune hepatitis.

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Chronological changes in etiology, pathological and imaging findings in primary liver cancer from 2001 to 2020

Tsuzaki J., Ueno A., Masugi Y., Tamura M., Yamazaki S., Matsuda K., Kurebayashi Y., Sakai H., Yokoyama Y., Abe Y., Hayashi K., Hasegawa Y., Yagi H., Kitago M., Jinzaki M., Sakamoto M.

Japanese Journal of Clinical Oncology 55 ( 4 ) 362 - 371 2025.04

ISSN 03682811

Purpose: To achieve a historical perspective, the chronological changes in primary liver cancer over a 20-year period were investigated at a single institution, focusing on shifts in etiology and the impact on imaging and pathological findings using The Liver Imaging Reporting and Data System. Materials and methods: A retrospective study of surgically resected primary liver cancer in 680 patients from 2001 to 2020 resulted in 434 patients with 482 nodules being analyzed. Dynamic contrast-enhanced computed tomography imaging and the Liver Imaging Reporting and Data System 2018 classification were employed. Two pathologists and two radiologists independently evaluated specimens and images. Results: This study highlighted a significant decline in cases of viral hepatitis and cirrhosis in primary liver cancer patients but an increase in intrahepatic cholangiocarcinoma and scirrhous hepatocellular carcinoma. Notably, there was a rise in non-viral hepatitis cases, potentially pointing toward an increase in steatohepatitic hepatocellular carcinoma cases in the future. Intrahepatic cholangiocarcinoma, scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma tumors exhibited slightly different distributions in the Liver Imaging Reporting and Data System classification compared with ordinary hepatocellular carcinoma, which may reflect the presence of fibrosis and lipid in tumor parenchyma. Conclusions: Consistent with past reports, this study demonstrated the emergence of primary liver cancer against a backdrop of non-viral and non-cirrhotic liver. Liver Imaging Reporting and Data System has been consistently useful in diagnosing primary liver cancer; however, among the histological subtypes of hepatocellular carcinoma, an increase is anticipated in scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma, which may present imaging findings different from those of ordinary hepatocellular carcinoma. This development may necessitate a reevaluation of the current approach for diagnosing and treating hepatocellular carcinoma based solely on imaging.

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Clinical Impact of Neoadjuvant Therapy for Resectable Pancreatic Ductal Adenocarcinoma: A Single-Center Retrospective Study

Shimane G., Kitago M., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Tsuzaki J., Yokoyama Y., Masugi Y., Takemura R., Kitagawa Y.

Annals of Surgical Oncology 32 ( 4 ) 2830 - 2840 2025.04

ISSN 10689265

Background: Neoadjuvant therapy is recommended for treating resectable pancreatic ductal adenocarcinoma (PDAC); however, its appropriate use in patients with resectable PDAC remains debatable. Objective: This study aimed to identify independent poor prognostic factors and evaluate the clinical significance of neoadjuvant therapy in patients with resectable PDAC. Methods: We retrospectively reviewed consecutive patients diagnosed with resectable PDAC at our institute between January 2003 and December 2022. We analyzed poor prognostic factors at the time of diagnosis in patients who underwent upfront surgery using the Cox proportional hazards model for overall survival (OS). The prognostic score was calculated by adding the individual prognostic factor scores. Results: Overall, 359 patients were included in this study, with 308 patients undergoing upfront surgery and the remaining 51 patients receiving neoadjuvant therapy. The R0 resection rate was significantly higher in the neoadjuvant therapy group (70.6%) than in the upfront surgery group (64.0%). Multivariate analysis in the upfront surgery group revealed the following independent poor prognostic factors: tumor size ≥ 35 mm, serum albumin level ≤.5 g/dL, neutrophil-to-lymphocyte ratio ≥ 3.5, carbohydrate antigen 19-9 level ≥ 250 U/mL, and Duke pancreatic monoclonal antigen type 2 level ≥ 750 U/mL. Among patients with prognostic scores of 0–1 (n = 263), the intention-to-treat OS did not significantly differ between the neoadjuvant therapy and upfront surgery groups. Among those patients with a prognostic score of ≥ 2 (n = 96), the neoadjuvant therapy group had significantly longer intention-to-treat OS than the upfront surgery group. Conclusions: Prognostic score-based stratification can help identify patients who could benefit from neoadjuvant therapy.

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New criteria for preoperative liver function assessment with safety margins to avoid postoperative mortality during liver resection for hilar cholangiocarcinoma

Kojima H., Abe Y., Udagawa D., Hayashi K., Chiba N., Imai S., Mihara K., Higashi H., Odaira M., Oshima G., Koizumi W., Kitago M., Yagi H., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Kawachi S., Kitagawa Y.

HPB 27 ( 2 ) 159 - 166 2025.02

ISSN 1365182X

Background: Despite recent medical advancements, surgery for hilar cholangiocarcinoma is associated with high complication and mortality rates. This may be partly attributed to the absence of established preoperative liver evaluation criteria for safe surgery. This study aimed to propose a reliable indicator for safe and well-planned management of major hepatectomy with extrahepatic bile duct resection. Methods: We included 150 patients who underwent major hepatectomy with extrahepatic bile duct resection between 2013 and 2021 in Japan. The risk factors for post-hepatectomy liver failure (PHLF) were retrospectively analyzed. Results: PHLF was observed in 24 (16.0 %) patients who underwent major hepatectomy with extrahepatic bile duct resection. In the multivariate analysis, the identified risk factors for PHLF were the ratio of future remnant liver volume to total liver volume (FRLV/TLV) ≤ 42 % and indocyanine green clearance fraction of the future remnant liver (ICGK-F) ≤ 0.07. Patients with these two factors were significantly associated with PHLF compared with those with either one or none of the risk factors (60.0 % vs 15.1 % and 8.1 %, respectively). Conclusion: The combinational use of ICGK-F and FRLV/TLV is useful for preoperative liver function assessment with a safety margin to avoid PHLF and postoperative mortality in hepatectomy for hilar cholangiocarcinoma.

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Splenic Metastasis of Endometrial Carcinoma Manifesting as a Hemorrhagic Splenic Cyst 17 Years After Surgery

Kitago M., Kamiyama M., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Masugi Y., Ueno A., Sakai K., Yokota M., Yamagami W., Kitagawa Y.

Asian Journal of Endoscopic Surgery 18 ( 1 ) 2025.01

ISSN 17585902

Splenic metastases from solid tumors are rare, particularly when they occur after a long postsurgical interval. We report the case of a 69-year-old woman who developed a splenic metastasis from endometrial carcinoma, presenting as a hemorrhagic splenic cyst, 17 years after her initial surgery. Laparoscopic splenectomy achieving R0 resection was successfully performed; however, the patient subsequently developed multiple liver metastases. This case highlights the importance of periodic evaluation for recurrence, including monitoring for symptoms and elevated tumor markers, in patients with a history of endometrial carcinoma or other solid tumors.

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Laparoscopic Donor Left Lateral Sectionectomy Using the Glissonean Pedicle Approach: Technical Details With Video

Hasegawa Y., Abe Y., Obara H., Yamada Y., Kitago M., Fujino A., Kitagawa Y.

Asian Journal of Endoscopic Surgery 18 ( 1 ) 2025.01

ISSN 17585902

Introduction: Pure laparoscopy for living donor hepatectomy is gaining popularity due to its advantages. However, despite the long-standing application of laparoscopic donor left lateral sectionectomy, the dissection of the Glisson branch, portal vein, and biliary ducts, particularly those of the caudate lobe, remains insufficiently described. Although the Glissonean approach offers easy standardization for hilar dissection, clear landmarks for parenchymal transection, and reduces postoperative bile leakage, it has not been widely adopted in laparoscopic donor hepatectomy. Here, we introduce a modified Glissonean pedicle approach to address the movement restrictions in laparoscopic surgery. Surgical Technique: After liver mobilization, the Glisson of Spiegel lobe (G1L) was divided, followed by encircling the left Glissonean pedicle. A tape for the liver hanging maneuver was placed from the right edge of the left Glissonean pedicle, along the Arantius plate, to the left edge of the left hepatic vein. When the parenchymal transection was completed, the left hepatic vein was automatically taped. The left hepatic artery and left portal vein were exposed, and some branches of P1 were divided to lengthen for anastomosis. The left hepatic duct was taped by removing the left hepatic artery and left hepatic vein from the left Glissonean pedicle. The left hepatic duct was divided under intraoperative cholangiography. Next, the left hepatic artery, left portal vein, and left hepatic vein were sequentially divided, and the graft liver was retrieved. Discussion: Our Glissonean approach can help standardize donor left lateral sectionectomy, minimize the exposure of the left hepatic duct, and clarify B1 branch dissection.

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Spatial Dynamics of T- and B-Cell Responses Predicts Clinical Outcome of Resectable and Unresectable Hepatocellular Carcinoma

Kurebayashi Y., Sugimoto K., Tsujikawa H., Matsuda K., Nomura R., Ueno A., Masugi Y., Yamazaki K., Effendi K., Takeuchi H., Itoi T., Hasegawa Y., Abe Y., Kitago M., Ojima H., Sakamoto M.

Clinical Cancer Research 30 ( 24 ) 5666 - 5680 2024.12

ISSN 10780432

Purpose: Immunotherapies have led to a paradigm shift in the treatment of hepatocellular carcinoma (HCC). Studies have revealed the single-cell catalogs of tumor-infiltrating immune cells and the trajectories of their differentiation. Nevertheless, the spatial distribution of these immune cells with distinct phenotypes in the tumor microenvironment and their clinicopathologic significance in resectable and unresectable HCCs are still largely unclear. Experimental Design: We analyzed the spatial dynamics of intratumoral CD4 and CD8 T cells and their association with B and plasma cells using 283 surgically resected HCC samples, 58 unresectable HCC samples before combined immunotherapy [atezolizumab plus bevacizumab (Atezo + Bev)], and autopsy specimens from 50 cases of advanced-stage HCC through multiplex IHC combined with transcriptomic and driver gene mutation analyses. Classification based on the spatial dynamics of T- and B-cell responses (refined immunosubtype) was developed, and its clinicopathologic significance was analyzed. Results: We found that stem-like CD4 and CD8 T cells were mainly observed in T-cell aggregates and T-cell zone of tertiary lymphoid structure (TLS). The differentiation of T follicular helper cells was associated with the development of TLS, whereas the differentiation of CXCL13-expressing CD4 T<inf>CXCL13</inf> cells with a phenotype resembling T peripheral helper cells was associated with the development of the lymphoplasmacytic microenvironment. The refined immunosubtype could predict clinical outcomes of resectable HCC after surgery and unresectable HCC after Atezo + Bev therapy. The immune microenvironment of metastatic lesions tended to reflect those of primary lesions. Conclusions: We revealed the spatial dynamics of T- and B-cell responses in HCC, which is closely associated with the clinical outcome after surgical resection or Atezo + Bev therapy.

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Vessels encapsulating tumor clusters contribute to the intratumor heterogeneity of HCC on Gd-EOB-DTPA-enhanced MRI

Matsuda K., Ueno A., Tsuzaki J., Kurebayashi Y., Masugi Y., Yamazaki K., Tamura M., Abe Y., Hasegawa Y., Kitago M., Jinzaki M., Sakamoto M.

Hepatology Communications 9 ( 1 ) 2024.12

Background: Vessels encapsulating tumor clusters (VETC) pattern is tumor vasculature of HCC and is a predictor of prognosis and therapeutic efficacy. Recent radiological studies have demonstrated the predictability of VETC from preoperative images, but the mechanisms of image formation are not elucidated. This study aims to determine the relationship between VETC and intratumor heterogeneity in Gd-EOB-DTPA-enhanced magnetic resonance imaging (EOB-MRI) and to provide its pathological evidence. Methods: Radiologists visually classified preoperative arterial- and hepatobiliary-phase EOB-MRI images of 204 surgically resected HCCs into patterns based on heterogeneity and signal intensity; these classifications were validated using texture analysis. Single and multiplex immunohistochemistry for CD34, h-caldesmon, and OATP1B3 were performed to evaluate VETC, arterial vessel density (AVD), and OATP1B3 expression. Recurrence-free survival was assessed using the generalized Wilcoxon test. The contribution of clinicoradiological factors to the prediction of VETC was evaluated by random forest and least absolute shrinkage and selection operator regression. Results: VETC was frequently found in tumors with arterial-phase heterogeneous hyper-enhancement patterns and in tumors with hepatobiliary-phase heterogeneous hyperintense/isointense patterns (HBP-Hetero). AVD and OATP1B3 expression positively correlated with signal intensity in the arterial and hepatobiliary phases, respectively. Intratumor spatial analysis revealed that AVD and OATP1B3 expression were lower in VETC regions than in tumor regions without VETC. Patients with HBP-Hetero tumors had shorter recurrence-free survival. Machine learning models highlighted the importance of serum PIVKA-II, tumor size, and enhancement pattern of arterial and hepatobiliary phase for VETC prediction. Conclusions: VETC is associated with local reductions of both AVD and OATP1B3 expression, likely contributing to heterogeneous enhancement patterns in EOB-MRI. Evaluation of the arterial and hepatobiliary phases of EOB-MRI would enhance the predictability of VETC.

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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 ) 2024.12

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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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 P.S., 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 ) 2024.12

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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Efficacy and safety of neoadjuvant S-1-based chemoradiotherapy in resectable and borderline-resectable pancreatic cancer: a long-term follow-up study

Shimane G., Kitago M., Endo Y., Aiura K., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Fukada J., Masugi Y., Kitagawa Y.

World Journal of Surgical Oncology 22 ( 1 ) 2024.12

Background/objectives: This study aimed to evaluate the safety, efficacy, and long-term outcomes of S-1-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable or borderline-resectable pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study included patients with PDAC who underwent S-1-based NACRT at our institute between 2010 and 2017. Results: Forty patients were included in the study, including 15 (37.5%) with resectable PDAC and 25 (62.5%) with borderline-resectable PDAC. The NACRT completion and resection rates were 85.0% (n = 34) and 67.5% (n = 27), respectively. Several grade 3 adverse events were observed, including leukopenia (25.0%), anorexia (17.5%), neutropenia (10.0%), thrombocytopenia (7.5%), febrile neutropenia (2.5%), elevated aspartate aminotransferase/alanine aminotransferase (2.5%) levels, and hyponatremia (2.5%). The R0 resection rate was 70.4% (n = 19/27) in patients who underwent pancreatectomy. Grades 1, 2, and 3 according to the College of American Pathologists grading system were observed in 1 (3.7%), 12 (44.4%), and 14 (51.9%) patients, respectively. Over a median follow-up period of 32.9 months (interquartile range, 9.1–68.0), the 1-, 3-, and 5-year OS rates were 81.4%, 45.5%, and 30.3%, respectively, in the intention-to-treat analysis. In the curative-intent surgery cohort (n = 27), the 1-, 3-, and 5-year OS rates were 88.9%, 48.2%, and 37.0%, respectively. Conclusions: S-1-based NACRT is safe and yields acceptable long-term outcomes for patients with resectable or borderline-resectable PDAC.

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Prognosis prediction of PDAC via detection of O-glycan altered extracellular vesicles in perioperative sera

Uemura S., Kabe Y., Kitago M., Matsuda S., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Sato Y., Itonaga M., Ono M., Kawakami T., Suematsu M., Kitagawa Y.

Cancer Science 115 ( 11 ) 3718 - 3728 2024.11

ISSN 13479032

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy due to the difficulty in diagnosis and poor prognosis because of the high recurrence rate, necessitating reliable biomarkers to improve the diagnosis and prognosis. However, the existing markers have limitations. We previously identified extracellular vesicles (EVs) recognized by O-glycan-binding lectins (Amaranthus caudatus agglutinin [ACA]) as a novel diagnostic biomarker for PDAC using an EV-counting system (ExoCounter). This retrospective study analyzed changes in ACA-positive EVs in perioperative PDAC serum and its association with prognosis using ExoCounter. Absolute EV levels in the pre- and postoperative sera of 44 patients who underwent curative pancreatectomy for PDAC were quantified using ExoCounter. The carbohydrate antigen 19-9 levels declined in most samples postoperatively, and presented no correlation with poor prognosis. In contrast, ACA-positive EVs increased in serum at 7 days postoperatively in 27 of 44 patients (61.4%). We therefore divided participants with ACA-positive EVs before and after surgery into elevation and decline groups. The overall survival (OS) and recurrence-free survival (RFS) of patients with higher ACA-positive EVs were significantly shorter than those with lower ACA-positive EVs (26.1 months vs. not reached, P = 0.018; 11.9 vs. 38.6 months, P = 0.013). Multivariable analysis revealed that ACA-positive EV elevation in postoperative serum was an independent prognostic factor for poor OS (hazard ratio [HR] = 3.891, P = 0.023) and RFS (HR = 2.650, P = 0.024). The detection of ACA-positive EVs in perioperative serum may be used to predict the prognosis of PDAC in the early postoperative period.

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Improved survival of pediatric deceased donor liver transplantation recipients after introduction of the pediatric prioritization system: Analysis of data from a Japanese national survey

Takemura Y., Shinoda M., Kasahara M., Sakamoto S., Hatano E., Okamoto T., Ogura Y., Sanada Y., Matsuura T., Ueno T., Obara H., Soejima Y., Umeshita K., Eguchi S., Kitagawa Y., Egawa H., Ohdan H., Ogawa E., Ito T., Sakuma Y., Yoshizumi T., Eguchi H., Shimamura T., Mita A., Hibi T., Fukumoto T., Hasegawa K., Marubashi S., Umeda Y., Nobori S., Hasegawa Y., Yamada Y., Kitago M.

Journal of Hepato Biliary Pancreatic Sciences 31 ( 11 ) 782 - 797 2024.11

ISSN 18686974

Background: In Japan, there has never been a national analysis of pediatric deceased donor liver transplantation (pDDLT) based on donor and recipient factors. We constructed a Japanese nationwide database and assessed outcomes of pDDLT focusing on the pediatric prioritization system introduced in 2018. Methods: We collected data on pDDLTs (<18 years) performed between 1999 and 2021 from the Japan Organ Transplant Network and Japanese Liver Transplantation Society, identified risk factors for graft survival and compared the characteristics and graft survival in pDDLTs conducted before and after the introduction of the pediatric prioritization system. Results: Overall, 112 cases of pDDLT were included, with a 1-year graft survival rate of 86.6%. Four poor prognostic factors were identified: recipient intensive care unit stay, model for end-stage liver disease/pediatric end-stage liver disease score, donor cause of death, and donor total bilirubin. After the introduction of the system, allografts from pediatric donors were more reliably allocated to pediatric recipients and the annual number of pDDLTs increased. The 1-year graft survival rate improved significantly as did pDDLT conditions indicated by the risk factors. Conclusions: Under the revised allocation system, opportunities for pDDLT increased, resulting in favorable recipient and donor conditions and improved survival.

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A novel scoring system to predict short-term mortality after living donor liver transplantation for acute liver failure

Shimata K., Yoon Y.I., Hibi T., Morinaga J., Narayanan A.K., Toshima T., Ito T., Akamatsu N., Kotera Y., Hong S.K., Hasegawa Y., Umeda Y., Reddy M.S., Ong A.D.L., Sivaprasadan S., Varghese J., Sugawara Y., Chen C.L., Nakayama N., Mochida S., Tanaka A., Suh K.S., Ikegami T., Lee K.W., Lee S.G., Sudhindran S., Yoshizumi T., Hatano E., Okumura S., Hasegawa K., Egawa H., Obara H., Yasui K., Ogura Y., Jobara K., Nitta H., Katagiri H., Otsuka M., Kuboki S., Eguchi S., Hara T., Eguchi H., Sasaki K., Aoki T., Ohdan H., Ohira M., Takada Y., Ogawa K., Fukumoto T., Kuramitsu K., Saiura A., Ichida H., Hashimoto T., Marubashi S., Sato N., Ushigome H., Harada S., Soejima Y., Masuda Y., Shimada M., Saitou Y., Taketomi A., Goto R., Shimamura T., Mizuno S., Tanemura A., Endo I., Unno M., Miyagi S., Okamura Y., Aramaki O., Hakamada K., Ishido K., Kato Y., Takahara T., Takatsuki M., Ono S.

American Journal of Transplantation 24 ( 10 ) 1857 - 1867 2024.10

ISSN 16006135

Liver transplantation is often the only lifesaving option for acute liver failure (ALF); however, the predictors of short-term mortality (death within one year) after living donor liver transplantation (LDLT) for ALF have yet to be defined. We retrospectively collected patients ≥18 years old who underwent LDLT for ALF between 2010 and 2020 at 35 centers in Asia. Univariate and multivariate logistic regression analyses were conducted to identify the clinical variables related to short-term mortality and establish a novel scoring system. The Kaplan-Meier method was performed to explore the association between the score and overall survival. Of the 339 recipients, 46 (13.6%) died within 1 year after LDLT. Multivariate analyses revealed 4 independent risk factors for death: use of vasopressors or mechanical ventilation, the higher model for end-stage liver disease score, and a lower graft-to-recipient weight ratio. The internally validated c-statistic of the short-term mortality after transplant (SMT) score derived from these 4 variables was 0.80 (95% confidence interval: 0.74-0.87). The SMT score successfully stratified recipients into low-, intermediate-, and high-risk groups with 1-year overall survival rates of 96%, 80%, and 50%, respectively. In conclusion, our novel SMT score based on 4 predictors will guide ALF recipient and living donor selection.

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Japanese living donor liver transplantation criteria for hepatocellular carcinoma: nationwide cohort study

Ohira M., Aoki G., Orihashi Y., Yoshimura K., Toshima T., Hatano E., Eguchi S., Hibi T., Hasegawa K., Umeda Y., Hashimoto T., Hasegawa Y., Nobori S., Ogura Y., Nitta H., Egawa H., Eguchi H., Takada Y., Ueda Y., Kasahara M., Kawachi S., Soejima Y., Tokushige K., Nagano H., Haga H., Fukumoto T., Mochida S., Umeshita K., Ohdan H., Mizuno S., Kuboki S., Otsuka M., Kobayashi T., Wakai T., Ishigame T., Marubashi S., Watanabe M., Taketomi A., Nakamuma S., Yagi S., Wakiya T., Ishido K., Sawada Y., Endo I., Goto Y., Hisaka T., Uryuhara K., Sakuma Y., Ichida H., Saiura A., Haruki K., Ikegami T., Iso Y., Aoki T., Takahara T., Yokoo H., Beck Y., Miyagi S., Tokodai K.

Bjs Open 8 ( 4 ) 2024.08

Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set. Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model. Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors. Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy.

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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 ) 2024.08

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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Excess mortality in COVID-19-affected solid organ transplant recipients across the pandemic

Yamanaga S., Shimata K., Ohfuji S., Yoshikawa M., Natori Y., Hibi T., Yuzawa K., Egawa H., Unagami K., Ishida H., Omoto K., Kasahara M., Uchida H., Sakamoto S., Futamura K., Nishikawa K., Imamura R., Nakazawa S., Hatano E., Ito T., Masano Y., Nishihira M., Hirata Y., Sakuma Y., Onishi Y., Yokoyama N., Yamamoto S., Yamada Y., Ogura Y., Kurata N., Uchida J., Kabei K., Iwamoto H., Ikeda C., Shinoda K., Yoshiike M., Hotta K., Hidaka Y., Iwami D., Ishii Y., Kamiyama M., Yoshizumi T., Kosai-Fujimoto Y., Kobayashi T., Motoyama K., Yamamoto M., Asai T., Tasaki M., Kenmochi T., Ito T., Tokodai K., Fujio A., Tsukamoto Y., Watanabe T., Akamatsu N., Yamashina S., Ishii D., Kitajima K., Yamada Y., Mitsuke A., Sakaguchi T., Nakamura M., Tomita Y., Nakamura Y., Ishimoto T., Ohdan H., Tanimine N., Fujiwara T., Yanagihara M., Hatakeyama S., Takai M., Nose K., Kikuchi T., Mori Y., Araki M., Sekito T., Nishimura S., Tanabe T., Igarashi Y., Hidaka S., Watanabe M., Ariyoshi Y., Hasegawa Y., Kamiyama M., Yoneda T., Shimizu T., Nishikawa K., Fukumoto T., Kuramitsu K., Kato M., Saito M., Shinkai M., Usui H., Sato M., Eguchi H., Imamura H., Kobayashi S., Soejima Y., Mita A., Kobayashi T.

American Journal of Transplantation 24 ( 8 ) 1495 - 1508 2024.08

ISSN 16006135

The excess mortality of coronavirus disease 2019 (COVID-19) solid organ transplant recipients (SOTRs) throughout the pandemic remains unclear. This prospective cohort study based on the Japanese nationwide registry included 1632 SOTRs diagnosed with COVID-19 between February 1, 2020, and July 31, 2022, categorized based on dominant phases of variants of concern (VOCs): Waves 1 to 3 (Beta), 4 (Alpha), 5 (Delta), 6 (Omicron BA.1/BA.2), and 7 (Omicron BA.5). Excess mortality of COVID-19-affected SOTRs was analyzed by calculating standardized mortality ratios (SMRs). Overall, 1632 COVID-19-confirmed SOTRs included 1170 kidney, 408 liver, 25 lung, 20 heart, 1 small intestine, and 8 multiorgan recipients. Although disease severity and all-cause mortality decreased as VOCs transitioned, SMRs of SOTRs were consistently higher than those of the general population throughout the pandemic, showing a U-shaped gap that peaked toward the Omicron BA.5 phase; SMR (95% CI): 6.2 (3.1-12.5), 4.0 (1.5-10.6), 3.0 (1.3-6.7), 8.8 (5.3-14.5), and 21.9 (5.5-87.6) for Waves 1 to 3 (Beta), Wave 4 (Alpha), Wave 5 (Delta), Wave 6 (Omicron BA.1/2), and Wave 7 (Omicron BA.5), respectively. In conclusion, COVID-19 SOTRs had greater SMRs than the general population across the pandemic. Vaccine boosters, immunosuppression optimization, and other protective measures, particularly for older SOTRs, are paramount.

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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 2024.07

ISSN 13419625

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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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 2024.07

ISSN 09411291

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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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., Yuta A.B.E., Hasegawa Y., Hori S., Tanaka M., Masugi Y., Kitago M., Nishihara H., Kitagawa Y.

Oncology Letters 27 ( 4 ) 2024.04

ISSN 17921074

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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Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation

Kanamori H., Yamada Y., Ito Y., Shirosaki K., Yamagishi S., Maeda Y., Kudo Y., Umeyama T., Takahashi N., Kato M., Hasegawa Y., Matsubara K., Shinoda M., Obara H., Irie R., Tsujikawa H., Okita H., Nguyen P.T., Saigo K., Mitsunaga S., Inoue I., Kitagawa Y., Kuroda T.

Hepatology Research 54 ( 3 ) 300 - 314 2024.03

ISSN 13866346

Aim: To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors. Methods: A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms. Results: The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples. Conclusions: Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.

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Comparison Between Plastic and Metallic Biliary Stent Placement for Preoperative Patients with Pancreatic Head Cancer: A Systematic Review and Meta-Analysis

Endo Y., Tanaka M., Kitago M., Yagi H., Abe Y., Hasegawa Y., Hori S., Nakano Y., Iwasaki E., Kitagawa Y.

Annals of Surgical Oncology 31 ( 2 ) 1319 - 1327 2024.02

ISSN 10689265

Background: Optimal preoperative biliary drainage for patients with pancreatic cancer before pancreatoduodenectomy remains unclear. This study aimed to investigate the comparison of efficacy and safety between a metallic stent (MS) and a plastic stent (PS). Methods: Comparative studies on the use of MS and PS for pancreatic cancer before pancreatoduodenectomy were systematically searched using the MEDLINE and Web of Science databases. Pre- and postoperative data also were extracted. Random-effects meta-analyses were performed to compare post-endoscopic retrograde cholangiopancreatography (ERCP) complications as well as intra- and postoperative outcomes between the two arms of the study, and pooled odds ratios (ORs) or mean differences (MDs) were calculated with 95 percent confidence intervals (CIs). Results: The study analyzed 12 studies involving 683 patients. Insertion of MS was associated with a lower incidence of re-intervention (OR, 0.06; 95% CI 0.03–0.15; P < 0.001), increased post-ERCP adverse events (OR, 2.22; 95% CI 1.13–4.36; P = 0.02), and similar operation time (MD, 18.0 min; 95% CI –29.1 to 65.6 min; P = 0.46), amount of blood loss (MD, 43.0 ml; 95% CI –207.1 to 288.2 ml; P = 0.73), and surgical complication rate (OR, 0.78; 95% CI 0.53–1.15; P = 0.21). The cumulative stent patency rate after 3 months was higher in the MS group than in the PS group (70–100 % vs 30.0–45.0 %). Conclusion: For biliary drainage in patients with pancreatic cancer during this era of multidisciplinary treatment, MS use might be the first choice because MS provides a more durable biliary drainage and a similar risk of postoperative outcomes compared with PS.

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A Novel Approach to Orthotopic Hepatocyte Transplantation Engineered With Liver Hydrogel for Fibrotic Livers, Enhancing Cell–Cell Interaction and Angiogenesis

Udagawa D., Nagata S., Yagi H., Nishi K., Morisaku T., Adachi S., Nakano Y., Tanaka M., Hori S., Hasegawa Y., Abe Y., Kitago M., Kitagawa Y.

Cell Transplantation 33 2024.01

ISSN 09636897

Hepatocyte transplantation (HCT) is a potential bridging therapy or an alternative to liver transplantation. Conventionally, single-cell hepatocytes are injected via the portal vein. This strategy, however, has yet to overcome poor cell engraftment and function. Therefore, we developed an orthotopic HCT method using a liver-derived extracellular matrix (L-ECM) gel. PXB cells (flesh mature human hepatocytes) were dispersed into the hydrogel solution in vitro, and the gel solution was immediately gelated in 37°C incubators to investigate the affinity between mature human hepatocyte and the L-ECM gel. During the 3-day cultivation in hepatocyte medium, PXB cells formed cell aggregates via cell–cell interactions. Quantitative analysis revealed human albumin production in culture supernatants. For the in vivo assay, PXB cells were encapsulated in the L-ECM gel and transplanted between the liver lobes of normal rats. Pathologically, the L-ECM gel was localized at the transplant site and retained PXB cells. Cell survival and hepatic function marker expression were verified in another rat model wherein thioacetamide was administered to induce liver fibrosis. Moreover, cell–cell interactions and angiogenesis were enhanced in the L-ECM gel compared with that in the collagen gel. Our results indicate that L-ECM gels can help engraft transplanted hepatocytes and express hepatic function as a scaffold for cell transplantation.

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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 (Langenbeck's Archives of Surgery) 408 ( 1 ) 2023.12

ISSN 14352443

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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Malignant lymphoma after liver transplantation for liver cirrhosis caused by human immunodeficiency virus and hepatitis C virus co-infection

Hasegawa Y., Obara H., Kikuchi T., Uno S., Tsujikawa H., Yamada Y., Hori S., Eguchi S., Kitagawa Y.

Journal of Infection and Chemotherapy 29 ( 12 ) 1160 - 1163 2023.12

ISSN 1341321X

Here, we describe a rare case of malignant lymphoma after liver transplantation for liver cirrhosis caused by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection. A male patient was diagnosed with hemophilia A at 8 months of age. Since then, he had been receiving blood products, which led to HIV and HCV co‐infection. His HIV viral load was suppressed with antiretroviral therapy, and a sustained virologic response was achieved for HCV using direct-acting antivirals. However, his decompensated liver cirrhosis progressed, and deceased donor liver transplantation was performed. A post-transplant lymphoproliferative disorder (PTLD) developed 105 days after liver transplantation, with enlarged para-aortic and hilar lymph nodes, a right renal mass, and masses in the small and large intestines. Histopathological examination confirmed monomorphic PTLD (diffuse large B-cell lymphoma). Against the treatment (reduction of immunosuppression, rituximab, and chemotherapy), the response was poor, and the patient died 94 days after the outbreak of PTLD. Both transplantation and HIV infection are risk factors for lymphoproliferative diseases. To the best of our knowledge, this is one of the very few reports of PTLD in a patient with HIV/HCV co-infection.

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Long-term survival after surgical resection for bone metastasis from pancreatic cancer: A case report

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

Medicine United States 102 ( 46 ) 2023.11

ISSN 00257974

Introduction: Pancreatic cancer (PC) is highly malignant and metastatic; however, bone metastases are rare. Although the effectiveness of conversion surgery for distant metastases of PC has been reported in a few cases, there are no reports on surgical resection for bone metastases. Here, we report a case of long-term survival after resection of bone metastasis from PC. Patient concerns: A 60-year-old woman underwent pancreaticoduodenectomy after neoadjuvant chemoradiotherapy for pancreatic head cancer. At 28 months after surgery, multiple lung metastases from PC were diagnosed, and chemotherapy was administered. After 59 months, chemotherapy was terminated because all target lesions had disappeared on imaging. Diagnosis: At 77 months after the initial surgery, bone metastasis in the left 9<sup>th</sup>rib was detected by positron emission tomography/computed tomography, which was performed due to elevated carbohydrate antigen 19-9 levels. Interventions: Chemotherapy was readministered as the initial treatment. Subsequently, due to the long-term well-controlled status of the recurrence site and the absence of other metastases, thoracoscopic-assisted partial resection of the left 9<sup>th</sup>rib was performed 128 months following pancreaticoduodenectomy. Pathological examination revealed adenocarcinoma metastasis from PC. Outcomes: The patient is currently alive without recurrence 44 months after resection for bone metastasis and 172 months after the initial surgery. Conclusion: Surgical resection may be favorable in patients with bone metastasis of PC that is well-controlled with chemotherapy.

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Risk Assessment of Liver Transplantation After Kasai Portoenterostomy in Children and Adults

Udagawa D., Hasegawa Y., Obara H., Yamada Y., Shinoda M., Kitago M., Abe Y., Kuroda T., Kitagawa Y.

Journal of Surgical Research (Journal of Surgical Research) 290 109 - 115 2023.10

ISSN 00224804

Introduction: Reports of liver transplantation (LT) after Kasai portoenterostomy (KPE) in adult patients with biliary atresia are scarce. The aim of this study was to evaluate the outcomes and investigate the risk factors of LT after KPE in both pediatric and adult patients. Methods: We retrospectively reviewed a prospective database of patients with biliary atresia who underwent LT after KPE. Eighty-nine consecutive patients were included, and risk factors for in-hospital mortality after LT were assessed. Results: The median age of the patients was 2 y (range, 0-45 y). Forty-six patients (51.7%) had a history of upper abdominal surgery after KPE. The in-hospital mortality rate was 5.6% (5 patients). Of these, 80% of patients with mortality were aged ≥17 y, and all patients with mortality had a history of two or more upper abdominal surgeries. In the univariate and receiver operating characteristic curve analyses, age ≥17 y and the number of previous upper abdominal surgeries ≥2 were identified as possible risk factors. Conclusions: Our study suggests that older age and multiple previous upper abdominal surgeries are important risk factors for mortality after LT following KPE. We believe that these findings will serve as indications for safe LT in future patients.

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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 (Annals of Gastroenterological Surgery) 7 ( 3 ) 523 - 532 2023.05

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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Clot waveform analysis for perioperative hemostatic monitoring in a hemophilia A patient on emicizumab undergoing liver transplantation

Awane M., Wakui M., Ozaki Y., Kondo Y., Oka S., Fujimori Y., Yatabe Y., Arai T., Yamada Y., Hori S., Obara H., Hasegawa Y., Matsushita H.

Clinica Chimica Acta (Clinica Chimica Acta) 544 2023.04

ISSN 00098981

How to optimize perioperative factor VIII (FVIII) replacement through hemostatic monitoring is critically important to manage hemophilia A patients. The bispecific antibody emicizumab binds activated FIX (FIXa) and FX to functionally mimic FVIIIa. While being used for hemostatic control in hemophilia A, this therapeutic antibody inconveniently interferes with coagulation tests using human FIXa and FX, such as activated partial thromboplastin time (APTT) and FVIII activity measurement based on one-stage clotting assays. Clot waveform analysis (CWA) extends the interpretation of measurement curves for coagulation time to provide global information. We performed APTT-CWA to monitor perioperative hemostasis in a hemophilia A patient on emicizumab undergoing liver transplantation. Plasma samples were treated with anti-idiotype monoclonal antibodies against emicizumab to enable accurate coagulation assays. Kinetics of maximum coagulation velocity and acceleration mimicked that of FVIII activity. These CWA parameters better correlated with FVIII activity than APTT. The plateaus of them were observed at FVIII activity of 100% or more, supporting the protocol for perioperative FVIII replacement. Thus, CWA may measure coagulation potential in hemophilia A patients undergoing liver transplantation, aiding in optimizing perioperative hemostasis.

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Extrahepatic approach for taping the common trunk of the middle and left hepatic veins or the left hepatic vein alone in laparoscopic hepatectomy (with videos)

Nakano Y., Abe Y., Kitago M., Yagi H., Hasegawa Y., Hori S., Koizumi W., Ojima H., Imanishi N., Kitagawa Y.

Journal of Hepato-Biliary-Pancreatic Sciences (Journal of Hepato-Biliary-Pancreatic Sciences) 30 ( 2 ) 192 - 201 2023.02

ISSN 18686974

Background: Outflow control is difficult, and techniques required for effectively handling intraoperative hemorrhage during laparoscopic hepatectomy have not previously been adequately reported. Methods: Sixteen patients underwent surgery, of which 15 underwent laparoscopic left hepatectomy and one underwent laparoscopic partial hepatectomy of the caudate lobe. Encircling and taping of the common trunk of the middle (MHV) and left hepatic veins (LHV) was performed in 12 patients, and that of the LHV alone in four patients. Surgical techniques based on anatomical landmarks and histological findings are presented with videos. Histological confirmation of the anatomical landmarks for these procedures was performed in fresh cadavers to understand the anatomical structures and layers involved. Results: The median procedure duration was 15 (6-25) minutes. All procedures were performed safely with no major bleeding. Histological findings showed fibrous connective tissue between the tunica adventitia of the inferior vena cava (IVC) and the Laennec’s capsule of the liver. The layer of dissection was along the tunica adventitia of the IVC. Conclusions: The surgical techniques for encircling and taping of the common trunk of the MHV and LHV and the LHV alone based on anatomical landmarks were feasible and could allow for efficient outflow control in laparoscopic hepatectomy.

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Combinational Treatment Involving Decellularized Extracellular Matrix Hydrogels With Mesenchymal Stem Cells Increased the Efficacy of Cell Therapy in Pancreatitis

Kojima H., Kushige H., Yagi H., Nishijima T., Moritoki N., Nagoshi N., Nakano Y., Tanaka M., Hori S., Hasegawa Y., Abe Y., Kitago M., Nakamura M., Kitagawa Y.

Cell Transplantation (Cell Transplantation) 32 2023.01

ISSN 09636897

Cell transplantation using mesenchymal stem cells (MSCs) has emerged as a promising approach to repairing and regenerating injured or impaired organs. However, the survival and retention of MSCs following transplantation remain a challenge. Therefore, we investigated the efficacy of co-transplantation of MSCs and decellularized extracellular matrix (dECM) hydrogels, which have high cytocompatibility and biocompatibility. The dECM solution was prepared by enzymatic digestion of an acellular porcine liver scaffold. It could be gelled and formed into porous fibrillar microstructures at physiological temperatures. MSCs expanded three-dimensionally in the hydrogel without cell death. Compared to the 2-dimensional cell culture, MSCs cultured in the hydrogel showed increased secretion of hepatocyte growth factor (HGF) and tumor necrosis factor-inducible gene 6 protein (TSG-6), both of which are major anti-inflammatory and anti-fibrotic paracrine factors of MSCs, under TNFα stimulation. In vivo experiments showed that the co-transplantation of MSCs with dECM hydrogel improved the survival rate of engrafted cells compared to those administered without the hydrogel. MSCs also demonstrated therapeutic effects in improving inflammation and fibrosis of pancreatic tissue in a dibutyltin dichloride (DBTC)-induced rat pancreatitis model. Combinational use of dECM hydrogel with MSCs is a new strategy to overcome the challenges of cell therapy using MSCs and can be used for treating chronic inflammatory diseases in clinical settings.

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Standardized upfront Glissonean approach and liver hanging maneuver reduces bile leakage from the hepatic hilum in living donors

Hirukawa K., Masuda Y., Abe Y., Yagi H., Ibuki S., Itano O., Shinoda M., Kitago M., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Matsubara K., Obara H., Yamada Y., Kuroda T., Hibi T., Kitagawa Y.

Liver Transplantation (Liver Transplantation) 29 ( 1 ) 48 - 57 2023.01

ISSN 15276465

Biliary complications after hepatectomy in living donors have yet to be eradicated. We hypothesized that a standardized upfront Glissonean approach and liver hanging maneuver (GH) would prevent mechanical and thermal injuries to the hilar plate of the remnant liver by determining the point of bile duct division and the final destination of hepatectomy preceding liver parenchymal transection (safety) and facilitate liver transection deep within the parenchyma and allow maximum length of hilar structures (rationality). GH was implemented in 2016 and its incidence of bile leakage was retrospectively compared against the conventional technique. GH comprises six steps: (1) development of the retrohepatic avascular plane between the right hepatic vein (RHV) and the middle hepatic vein (MHV) and isolation of the hepatic vein(s); (2) isolation of the right or left Glissonean pedicle with the corresponding Glissonean pedicles of the caudate lobe; (3) for right liver grafts and left liver grafts with the caudate lobe, passage of the tape for the liver hanging maneuver along the retrohepatic avascular plane and above the hilar plate, and for left liver grafts without the caudate lobe and for left lateral section grafts, passage of the tape from between the RHV and the MHV, along the Arantius ligament, and to the right of the umbilical portion; (4) liver transection; (5) isolation of hilar structures; and (6) graft procurement. Until 2020, 62 consecutive living donors underwent GH (success rate, 100%). The incidence of bile leakage from the hepatic hilum (0%) was significantly lower than that among 59 donors who underwent the conventional technique in 2011-2015 (9%; p = 0.01). In conclusion, GH is highly effective in reducing bile leakage from the hepatic hilum in living donors.

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Pure laparoscopic left lateral graft procurement with removing segment 3 employing Glissonean approach, indocyanine green fluorescence imaging and in situ splitting for a small infant

Umemura A., Nitta H., Takahara T., Hasegawa Y., Katagiri H., Kanno S., Takeda D., Sasaki A.

Journal of Minimal Access Surgery (Journal of Minimal Access Surgery) 19 ( 1 ) 165 - 167 2023.01

ISSN 09729941

We report on a pure laparoscopic left lateral graft procurement with removing segment 3 that employs the Glissonean approach, indocyanine green (ICG) fluorescence imaging and in situ splitting. We first mobilised the liver and confirmed the root of the left hepatic vein (LHV). We then encircled the left Glissonean pedicle, and the segment 3 Glissonean pedicle (G3) was also individually encircled. We performed parenchymal transection of the left lateral segmentectomy using Pringle's manoeuvre. We clipped G3 and confirmed the demarcation line using ICG fluorescence imaging. The inflow in the S2 area was confirmed via intraoperative sonography, and we split segment 3 (S3) from the left lateral sector graft in situ. The left hepatic artery, left portal vein and left hepatic duct were also encircled and divided. The LHV was transected using a linear stapler, and the S2 monosegment liver graft and removed S3 were procured. Our technique reasonably prevents graft-related complications.

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Impact of sustained viral response for hepatitis C virus on the outcomes of liver transplantation in hemophilic patients with human immunodeficiency virus/hepatitis C virus co-infection: A nationwide survey in Japan

Hidaka M., Eguchi S., Hasegawa K., Shimamura T., Hatano E., Ohdan H., Hibi T., Hasegawa Y., Kaneko J., Goto R., Egawa H., Eguchi H., Tsukada K., Yotsuyanagi H., Soyama A., Hara T., Takatsuki M.

Hepatology Research (Hepatology Research) 53 ( 1 ) 18 - 25 2023.01

ISSN 13866346

Aim: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection from blood products for hemophilia has been a social problem in Japan, and liver transplantation (LT) for these patients has been a challenging procedure. However, with the advent of the direct-acting antiviral agent for HCV and change in the policy for prioritization of deceased donor LT, the results of LT for patients co-infected with HCV/HIV may have improved. Methods: This study was conducted to provide updated results of our nationwide survey of LT for patients co-infected with HCV/HIV, from January 1997 to December 2019. We collected data on 17 patients with HIV/HCV co-infection who underwent either deceased donor LT (n = 5) or living donor LT (n = 12). Results: All the patients were men with hemophilia, and the median age was 41 (range, 23–61) years. The median CD4 count before LT was 258 (range, 63–751). Most patients had poor liver function before surgery with Child–Pugh grade C and a Model for End-stage Liver Disease score of 20 (range, 11–48). The right lobe was used for most grafts for living donor liver transplantation (n = 10). Overall survival was significantly better with a sustained viral response (SVR) than without an SVR, and a univariate analysis indicated that SVR after direct-acting antiviral or interferon/ribavirin showed the highest hazard ratio for patient survival after LT. A multivariate analysis was not possible because of the limited number of cases. Conclusion: SVR for HCV showed the highest impact on the outcome of LT for patients with hemophilia co-infected with HIV/HCV. SVR for HCV should be achieved before or after LT for patients with hemophilia co-infected with HIV/HCV for a better outcome.

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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 (Annals of Gastroenterological Surgery) 7 ( 4 ) 654 - 665 2023

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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Long-term outcomes following ABO-incompatible living donor liver transplantation for acute liver failure: a single-center experience of over 20 years

Hirukawa K., Shinoda M., Hasegawa Y., Obara H., Kitago M., Yagi H., Abe Y., Yamada Y., Tanabe M., Kitagawa Y.

Surgery Today (Surgery Today) 53 ( 10 ) 1160 - 1172 2023

ISSN 09411291

Purpose: Acute liver failure is a life-threatening condition for which ABO-incompatible living donor liver transplantation (ABOi-LDLT) is sometimes the only life-saving treatment option. We reviewed a single-center experience of adult ABOi-LDLT treatment for acute liver failure (ALF). Methods: Preoperative treatment, immune indices (B cell marker, anti-donor blood-type antibody), and postoperative outcomes were compared between ALF and non-ALF groups. Results: There were 5 and 33 patients in the ALF and non-ALF groups, respectively. The ALF group received higher doses of steroids, underwent more rounds of plasma exchange (PE), and underwent transplantation for ALF with a shorter interval following preoperative rituximab (RTx) administration (median: 2 vs 13 days; P < 0.05) than the non-ALF group. Preoperatively, CD19-positive lymphocytes in the peripheral blood were sufficiently depleted in all of the non-ALF group patients, whereas they were poorly depleted in the ALF group. Postoperatively, neither group suffered anti-donor blood-type antibody titer rebound or antibody-mediated rejection. The ALF group had a comparable 5-year survival rate to the non-ALF group (80.0% vs 77.9%). Conclusions: Despite the delayed preoperative administration of RTx, the ALF group showed an uneventful immunological response and acceptable long-term survival rate. Thus, ABOi-LDLT seems a viable treatment option for ALF.

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Reconsideration of operative indications in pancreatic neuroendocrine neoplasms

Abe K., Kitago M., Iwasaki E., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Kitagawa Y.

World Journal of Surgical Oncology (World Journal of Surgical Oncology) 20 ( 1 ) 2022.12

Background: The incidence of pancreatic neuroendocrine neoplasm (PNEN) has been increasing. Resection is typically indicated for PNEN, regardless of its size; however, the indications for its resection are controversial. This study aimed to evaluate the treatment results of surgical resection of PNEN at our institute. Methods: In this single-center, retrospective, case-control study, 87 patients who underwent PNEN resection and 17 patients with PNEN who did not undergo surgical resection between 1993 and 2020 were included in this study. Clinical characteristics and outcomes were reviewed and statistically compared. Survival was also estimated for the patients in each cohort. Results: Seventeen patients who underwent resection (20%) had lymph node metastasis. Tumors measuring ≥ 2.0 cm and multiple lesions were identified as independent predictors for lymph node metastasis (odds ratio [OR] 17.3, 95% confidence interval [CI] 3.0–100.0, p = 0.001 and OR 8.7, 95% CI 1.5–52.0, p = 0.018, respectively). There was a significant difference in the survival curves depending on the presence or absence of lymph node metastasis (5-year overall survival 74.7% vs. 94.3%, p < 0.001; 5-year recurrence-free survival: 66.3% vs. 93.6%, p < 0.001). All 17 PNEN cases under observation with a median 8 mm (range 5–23) tumor size for a median of 34 (range 2.4–114) months showed slight morphological change with a median tumor growth rate of 0.15 mm (range 0–3.33) per year. Conclusion: Patients with tumors measuring ≥ 2.0 cm have a high probability of lymph node metastasis or recurrence, thereby requiring resection. PNEN measuring < 1.0 cm may be acceptable for observation.

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Successful Case of Deceased Donor Liver Transplant for Polycystic Liver Disease

Sugimoto H., Oshima Y., Oba Y., Ikuma D., Sekine A., Mizuno H., Yamanouchi M., Hasegawa E., Suwabe T., Chu P.S., Hasegawa Y., Obara H., Sawa N., Ubara Y.

Transplantation Proceedings (Transplantation Proceedings) 54 ( 10 ) 2779 - 2783 2022.12

ISSN 00411345

A 58-year-old woman was admitted to hospital for deceased donor liver transplant. Her liver volume, measured by computed tomography, had reached 22,764 cm3 and she was bedridden with performance status 3 because of abdominal distention. The Model for End-Stage Liver Disease score was 24 with exception points. The final weight of the removed liver after cystic fluid puncture was 14 kg. The patient recovered well after transplant and was discharged on postoperative day 43 with a weight of 41 kg and performance status of 1.

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Development of a risk score model for 1-year graft loss after adult deceased donor liver transplantation in Japan based on a 20-year nationwide cohort

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

Annals of Gastroenterological Surgery (Annals of Gastroenterological Surgery) 6 ( 5 ) 712 - 725 2022.09

Aim: Using nationwide data collected over the past 20 years, we aimed to investigate deceased donor liver transplantation (DDLT) outcomes to develop a unique risk model that can be used to establish a standard for organ acceptance in Japan. Methods: Data were collected for 449 recipients aged ≥18 years who underwent DDLT between 1999 and 2019. Least absolute shrinkage and selection operator (LASSO) regression analysis was utilized to develop an original risk score model for 1-year graft loss (termed the Japan Risk Index [JRI]). We developed risk indices according to recipient, donor, and surgery components (termed JRI-R, D, and S, respectively). The JRI was validated via a 5-fold cross-validation. We also compared DDLT outcomes and risk indices among Era1 (−2011), Era2 (−2015), and Era3 (−2019). Results: The 1-year graft survival rate was 89.5% and improved significantly, reaching 84.7%, 87.6%, and 93.9% in Era1, Era2, and Era3, respectively. The JRI was calculated as JRI-R (re-transplantation, Model for End-Stage Liver Disease score, medical condition in intensive care unit) × JRI-D (age, catecholamine index, maximum sodium, maximum total bilirubin) × JRI-S (total ischemic time) × 0.84. The risk model achieved a mean C-statistic value of 0.81 in the validation analysis. The risk index was significantly lower in Era3 than in Era2. Conclusion: Changes in the risk index over time indicated that avoiding risks contributed to the improved outcomes in Era3. The JRI is unique to adult DDLT in Japan and may be useful as a reference for organ acceptance in the future.

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Association Between Clinical Backgrounds and Malignant Progression of Suspected Intraductal Papillary Mucinous Neoplasm

Fukushima G., Abe K., Kitago M., Iwasaki E., Hirata A., Takemura R., Ishii R., Yagi H., Abe Y., Hasegawa Y., Fukuhara S., Hori S., Tanaka M., Nakano Y., Yokose T., Shimane G., Kitagawa Y.

Pancreas (Pancreas) 51 ( 6 ) 617 - 623 2022.07

ISSN 08853177

Objectives Some intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can become pancreatic cancer. The mechanism behind the malignant progression of IPMN remains unknown. We aimed to identify the risk factors and interactions between backgrounds for IPMN. Methods We retrospectively enrolled 980 patients of pancreatic cancer or suspected IPMN (sIPMN) who underwent endoscopic ultrasound or retrograde cholangiopancreatography. We classified them into pancreatic cancer, high-risk sIPMN, and low-risk sIPMN, and investigated the risk factors for high-risk sIPMN. Results Smoking habits (odds ratio [OR], 3.74; 95% confidence interval [CI], 2.04-6.85; P < 0.001), serum carbohydrate antigen 19-9 ≥37 U/mL (OR, 6.30; 95% CI, 2.88-13.80; P < 0.001), and family history of cancers (OR, 2.38; 95% CI, 1.30-4.37; P = 0.005) were independent risk factors for high-risk suspected IPMN. Odds ratios of diabetes and neutrophil-to-lymphocyte ratio of 2.45 or greater were significantly higher in patients with a family history of cancer than those without a family history of cancer (OR, 3.28; 95% CI, 0.52-20.80 vs 1.85; 95% CI, 0.78-4.41; OR, 2.44; 95% CI, 0.81-7.34 vs 1.24; 95% CI, 0.67-2.30, respectively). Conclusions Understanding the interactions between background factors can effectively prevent IPMNs' malignant transformation.

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Reappraisal of liver transplantation for erythropoietic protoporphyria: A deadly combination of disease recurrence and biliary complication

Endo Y., Hibi T., Shinoda M., Obara H., Kitago M., Yagi H., Abe Y., Hasegawa Y., Matsubara K., Hori S., Tanaka M., Makiuchi S., Nakano Y., Itano O., Kuroda T., Kitagawa Y.

Pediatric Transplantation (Pediatric Transplantation) 26 ( 4 ) 2022.06

ISSN 13973142

Background: Erythropoietic protoporphyria (EPP) is a rare inherited disorder that causes the accumulation of protoporphyrin in the erythrocytes, skin, and liver. Severe protoporphyric hepatopathy results in liver failure, requiring both liver and bone marrow transplantation as a life-saving procedure and to correct the underlying enzymatic defect, respectively. Case presentation: We report a 20-year-old man who underwent split liver transplantation using a right trisegment and caudate lobe graft for EPP-induced liver failure, but succumbed to a deadly combination of early relapse of EPP and subsequent, intractable, late-onset bile leakage from the cut surface of segment 4. EPP recurrence most likely created a high-risk situation for bile leakage from the non-communicating bile ducts of segment 4; therefore, this case shed light on the potential relationship between EPP recurrence and biliary complications. Conclusion: Physicians should recognize the potentially rapid and life-threatening progression of protoporphyric hepatopathy that leads to liver failure. For young patients with EPP, LT and sequential BMT should thoroughly be considered by a multidisciplinary team as soon as hepatic reserve deterioration becomes evident. Split liver transplantation should preferably be avoided and appropriate post-transplant management is critical before protoporphyrin depositions to the bile duct and hepatocyte causes irreversible damage to the liver graft.

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Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study

Abe K., Kitago M., Kosaki K., Yamada M., Iwasaki E., Kawasaki S., Mizukami K., Momozawa Y., Terao C., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Kitagawa Y.

Cancer Science (Cancer Science) 113 ( 5 ) 1821 - 1829 2022.05

ISSN 13479032

Environmental and genetic factors play a critical role in the pathogenesis of pancreatic cancer, which is likely to follow a multistep process that includes intraductal papillary mucinous neoplasm. The pathogenesis of familial pancreatic cancer has been reported; however, epidemiological characteristics and causative genes remain unclear. This study aimed to determine the relationship between the family history of pancreatic cancer and tumor malignancy and identify novel susceptible germline variants of pancreatic cancer. We performed an epidemiologic study at our institute on a cohort of 668 patients with intraductal papillary mucinous neoplasm and 242 with pancreatic cancer but without associated intraductal papillary mucinous neoplasm stratified by family history of pancreatic cancer. Whole-exome sequencing was conducted for 10 patients from seven families with familial pancreatic cancer and intraductal papillary mucinous neoplasm. We found that patients who had intraductal papillary mucinous neoplasm with positive family history of pancreatic cancer within first-degree relatives were more likely to develop malignancy in a shorter period than those without family history. Duplicate frameshift variants in TET2 c.3180dupG (p.Pro1061fs) and ASXL1 c.1934dupG (p.Gly646fs) in one family and POLN c.1194dupT (p.Glu399fs) in another were identified as pathogenic truncating germline variants which were previously recognised susceptibility genes. Moreover, PDIA2 c.1403C>T (p.Pro468Leu) and DPYSL4 c.926C>A (p.Pro309Gln) were shared in four and two patients, respectively. In particular, PDIA2 was identified as a novel candidate for one of the deleterious variants of familial pancreatic cancer.

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Standardized single-incision plus one-port laparoscopic left lateral sectionectomy: a safe alternative to the conventional procedure

Katagiri H., Nitta H., Takahara T., Hasegawa Y., Kanno S., Umemura A., Takeda D., Makabe K., Kikuchi K., Kimura T., Yanari S., Sasaki A.

Langenbeck's Archives of Surgery (Langenbeck's Archives of Surgery) 407 ( 3 ) 1277 - 1284 2022.05

ISSN 14352443

Purpose: Laparoscopic left lateral sectionectomy (LLLS) is a feasible and safe procedure with a relatively smooth learning curve. However, single-incision LLLS requires extensive surgical experience and advanced techniques. The aim of this study is to report the standardized single-incision plus one-port LLLS (reduced port LLLS, RPLLLS) technique and evaluate its safety, feasibility, and effectiveness for junior surgeons. Methods: Between January 2008 and November 2020, the clinical records of 49 patients who underwent LLLS, divided into the conventional LLLS (n = 37) and the RPLLLS group (n = 12), were retrospectively reviewed. The patient characteristics, pathologic results, and operative outcomes were evaluated. Results: A history of previous abdominal surgery in the RPLLLS group was significantly high (56.8% vs. 91.7%, p = 0.552). Notably, junior surgeons performed 62.2% of the conventional LLLSs and 58.4% of the standardized RPLLLSs. There were no significant differences between the two groups in terms of median operative time (121.0 vs. 113.5, p = 0.387), median blood loss (13.0 vs. 8.5, p = 0.518), median length of hospital stays (7.0 vs. 7.0, p = 0.408), and morbidity rate (2.7% vs. 0%, p = 0.565), respectively. Conclusion: This standardized RPLLLS is a feasible and safe alternative to conventional LLLS and may become the ideal training procedure for both junior surgeons and surgeons aiming to learn more complex procedures.

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Patients with liver cirrhosis due to nonalcoholic steatohepatitis have lesser chances for liver transplantation

Hasegawa Y., Obara H., Chu P.S., Shinoda M., Kitago M., Abe Y., Yagi H., Matsubara K., Nakamoto N., Kitagawa Y.

Journal of Hepato-Biliary-Pancreatic Sciences (Journal of Hepato-Biliary-Pancreatic Sciences) 29 ( 5 ) 562 - 569 2022.05

ISSN 18686974

Background: The main causes of liver cirrhosis have changed over the past decade. In Japan, the number of deceased donors is increasing but is still insufficient relative to the number of patients awaiting a liver transplant. In the present study we aimed to assess the outcomes of candidates for liver transplantation. Methods: This was a retrospective study of adult patients who visited our department for consultation regarding liver transplantation from January 2009 to December 2020. Of a total of 601 patients, 336 were followed-up. The following data were collected and analyzed: patient's characteristics, liver etiology, Child-Pugh and MELD scores, and the eventual outcome, that is, whether liver transplantation was performed. Results: Only 153 of 336 (45.5%) patients underwent liver transplantation, of which 42 (27.5%) received deceased donor liver transplantation, and 129 (38.4%) died without transplantation. The proportion of patients who underwent liver transplantation was low among patients with nonalcoholic steatohepatitis (NASH) (10.7%) (P <.001). The rate of qualified living donors was the lowest for patients with NASH (28.6%) and that for the other etiologies ranged from 55.6% to 67.4% (P =.050). Conclusion: Patients with liver cirrhosis due to NASH may have a lesser chance of undergoing liver transplantation from both living and deceased donors.

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Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments

Kurebayashi Y., Matsuda K., Ueno A., Tsujikawa H., Yamazaki K., Masugi Y., Kwa W.T., Effendi K., Hasegawa Y., Yagi H., Abe Y., Kitago M., Ojima H., Sakamoto M.

Hepatology (Hepatology) 75 ( 5 ) 1139 - 1153 2022.05

ISSN 02709139

Background and Aims: Immune cells and tumor vessels constitute important elements in tumor tissue; however, their detailed relationship in human tumors, including HCC, is still largely unknown. Consequently, we expanded our previous study on the immune microenvironment of HCC and analyzed the relationship among the immune microenvironment, inflammatory/angiostatic factor expression, angiogenic factor expression, and tumor vessel findings, including vessels encapsulating tumor clusters (VETC) and macrotrabecular-massive (MTM) patterns. Approach and Results: We classified HCC into four distinct immunovascular subtypes (immune-high/angiostatic [IH/AS], immune-mid/angio-mid [IM/AM], immune-low/angiogenic [IL/AG], and immune-low/angio-low [IL/AL]). IH/AS, IM/AM, and IL/AG subtypes were associated with decreasing lymphocytic infiltration and increasing angiogenic factor expression and VETC/MTM positivity, reflecting their reciprocal interaction in the tumor microenvironment of HCC. IL/AG subtype was further characterized by CTNNB1 mutation and activation of Wnt/β-catenin pathway. IL/AL subtype was not associated with increased lymphocyte infiltration or angiogenic factor expression. Prognostically, IH/AS subtype and VETC/MTM positivity were independently significant in two independent cohorts. Increased angiogenic factor expression was not necessarily associated with VETC/MTM positivity and poor prognosis, especially when inflammatory/angiostatic milieu coexisted around tumor vessels. These results may provide insights on the therapeutic effects of immunotherapy, antiangiogenic therapies, and their combinations. The potential of evaluating the immunovascular microenvironment in predicting the clinical effect of these therapies in nonresectable HCC needs to be analyzed in the future study. Conclusions: HCC can be classified into four distinct immunovascular subtypes (IH/AS, IM/AM, IL/AG, and IL/AL) that reflect the reciprocal interaction between the antitumor immune microenvironment and tumor angiogenesis. In addition to its clinicopathological significance, immunovascular classification may also provide pathological insights on the therapeutic effect of immunotherapy, antiangiogenic therapy, and their combination.

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Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes

Kojima H., Yagi H., Kushige H., Toda Y., Takayama K., Masuda S., Morisaku T., Tsuchida T., Kuroda K., Hirukawa K., Inui J., Nishi K., Nakano Y., Tanaka M., Hori S., Hasegawa Y., Abe Y., Kitago M., Adachi S., Tomi M., Matsuura K., Mizuguchi H., Kitagawa Y.

Cells (Cells) 11 ( 8 ) 2022.04

Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research.

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National survey of hepatobiliary and pancreatic surgery in hemophilia patients in Japan

Yoshimoto-Haramura T., Hidaka M., Hasegawa K., Suzumura K., Takemura N., Hama N., Mizuno T., Nomi T., Kobayashi T., Sano K., Yokomizo H., Nitta H., Kurata M., Hasegawa Y., Nagayama M., Tani M., Fukumoto T., Ohta M., Hayashi H., Taniguchi H., Ishino S., Aihara T., Murase T., Tsuchida A., Shimamura T., Marubashi S., Kaneko J., Hara T., Matsushima H., Soyama A., Endo T., Eguchi S.

Journal of Hepato-Biliary-Pancreatic Sciences (Journal of Hepato-Biliary-Pancreatic Sciences) 29 ( 3 ) 385 - 393 2022.03

ISSN 18686974

Background: Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan. Methods: The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications. Results: The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients. Conclusions: As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS.

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Dynamic contrast-enhanced CT at the early stage confirms two cases of acute liver failure due to acute-onset autoimmune hepatitis with extensive liver necrosis

Watanabe T., Chu P.S., Ehira T., Hasegawa Y., Hattori N., Shinoda M., Ikeda H., Tsujikawa H., Obara H., Hara M., Suzuki T., Matsunaga K., Okuse C., Itoh F.

Acta Hepatologica Japonica (Acta Hepatologica Japonica) 63 ( 3 ) 158 - 169 2022

ISSN 04514203

[Case 1] A 54-year-old female presented with severe liver damage. During diagnosis, contrast-enhanced CT enhanced the area of hypoattenuation on unenhanced CT in the arterial phase, after which the enhanced effect was prolonged to the equilibrium phase. Then, we started immunosuppressive therapy based on the results, including corticosteroid administration, and her hepatitis subsided. [Case 2] A 57-year-old female also presented with severe hepatitis. Contrast-enhanced CT findings were similar to those of Case 1. Since hepatic encephalo-pathy developed and worsened to degree IV, a brain-dead liver transplant was conducted on the 21st day. Nev-ertheless, histological diagnosis was challenging in both cases. Therefore, when unenhanced CT shows hetero-geneous hypoattenuation in the liver and contrast-enhanced CT shows a characteristic blood flow disorder, acute-onset autoimmune hepatitis and corticosteroid treatment should be considered, including in complex se-rological or histological case diagnoses.

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Intravenous administration of dehydroxymethylepoxyquinomicin with polymer enhances the inhibition of pancreatic carcinoma growth in mice

Fujisaki H., Nakano Y., Matsuda S., Suzuki K., Itano O., Tanaka M., Hori S., Hasegawa Y., Abe Y., Yagi H., Kitago M., Konno T., Ishihara K., Ohno K., Kishino S., Umezawa K., Kitagawa Y.

Anticancer Research (Anticancer Research) 41 ( 12 ) 6003 - 6012 2021.12

ISSN 02507005

Background/Aim: Pancreatic cancer, which exhibits resistance to cytotoxic and molecular targeted drugs, has an extremely poor prognosis. Nuclear factor-ĸB (NF-ĸB) is constitutively activated in many pancreatic cancer cases. Although the NF-ĸB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has exhibited anti-cancer effects in pancreatic cancer models, its poor solubility limits its use to intraperitoneal administration. Materials and Methods: Poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB) forms stable polymer aggregates with DHMEQ. The stability of DHMEQ aggregated with PMB in the human blood was measured by high-performance liquid chromatography–mass spectrometry (HPLC-MS) ex vivo. Anti-pancreatic cancer effects in AsPC-1 and MIA PaCa-2 pancreatic cancer cells were evaluated by cell growth inhibition assay in vitro and tumor growth inhibition assay in vivo. Results: DHMEQ aggregated with PMB (PMBDHMEQ) remained detectable after 60 min of incubation in the human blood, whereas DHMEQ aggregated with carboxymethyl cellulose (CMC-DHMEQ) was barely detectable. PMB-DHMEQ significantly inhibited AsPC-1 and MIA PaCa-2 cell growth in vitro compared to CMC-DHMEQ. Intravenous administration of PMB-DHMEQ reduced the tumor volume and liver metastasis compared to untreated or CMC-DHMEQ-treated mice. Conclusion: Aggregation with PMB improved the solubility of DHMEQ, and effectively inhibited pancreatic cancer cell growth both in vitro and in vivo.

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Pure Laparoscopic Donor Hepatectomy: Right Posterior Section Graft

Hasegawa Y., Nitta H., Takahara T., Katagiri H., Kanno S., Umemura A., Sasaki A.

Journal of Gastrointestinal Surgery (Journal of Gastrointestinal Surgery) 25 ( 10 ) 2718 - 2719 2021.10

ISSN 1091255X

Background: The use of laparoscopic liver resection (LLR) is widespread owing to its several advantages, especially smaller incision (Kaneko et al., Ann Gastroenterol Surg 1:33–43, 1; Ciria et al., Surg Endosc 34:349–360, 2). However, both posterior sectionectomy and donor hepatectomy are extremely difficult procedures to perform in LLR (Hasegawa et al., Ann Gastroenterol Surg 2:376–382, 3; Soubrane and Kwon, J Hepatobiliary Pancreat Sci 24:E1–E5, 4; Takahara et al., Transplantation 101:1628–1636, 5; Lee et al., Clin Transplant 33:e13683, 6; Hong et al., Surg Endosc 33:3741–3748, 7; Rhu et al., J Hepatobiliary Pancreat Sci 27:16–25, 8). Moreover, the right posterior section graft procurement is also difficult even in open laparotomy procedure (Sugawara et al., Transplantation 73:111–114, 9; Hwang et al., Liver Transpl 10:1150–1155, 10; Hori, Kirino, and Uemoto, Hepatol Res 45:1076–1082, 11; Kusakabe et al., Liver Transpl 26:299–303, 12). The pure laparoscopic donor posterior sectionectomy has not been reported yet. Therefore, we aimed to introduce a novel procedure through a video clip. Methods: The donor was placed in the semi-left lateral decubitus position with the reverse Trendelenburg position using a bean bag device. The right liver was mobilized, and the right hepatic vein was exposed. To adopt the liver hanging maneuver, a tape was inserted between the middle and right hepatic veins along the inferior vena cava. The posterior Glissonean pedicle was encircled and controlled, and the liver parenchyma was completely transected using the liver hanging maneuver. The vessels to the posterior section were respectively isolated. The posterior branches of the hepatic duct, hepatic artery, and portal vein were cut. The right hepatic vein was divided, and the graft liver was retrieved via a suprapubic incision. This study was approved by institutional ethics board (No. MH2019-119), and informed consent was taken from the patient. Results: The overall surgical time was 503 min, and the blood loss was 400 mL. No complications were observed, and the donor was discharged from the hospital on postoperative day 11. Conclusion: This is the first report of pure laparoscopic donor hepatectomy of the posterior section graft. This procedure is more difficult than other laparoscopic donor hepatectomies because it involves parenchymal transection in the right intersectional plane and dissection of the posterior branches of hilar vessels.

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Gamma-synuclein is a novel prognostic marker that promotes tumor cell migration in biliary tract carcinoma

Takemura Y., Ojima H., Oshima G., Shinoda M., Hasegawa Y., Kitago M., Yagi H., Abe Y., Hori S., Fujii-Nishimura Y., Kubota N., Masuda Y., Hibi T., Sakamoto M., Kitagawa Y.

Cancer Medicine (Cancer Medicine) 10 ( 16 ) 5599 - 5613 2021.08

Gamma-synuclein (SNCG) promotes invasive behavior and is reportedly a prognostic factor in a range of cancers. However, its role in biliary tract carcinoma (BTC) remains unknown. Consequently, we investigated the clinicopathological significance and function of SNCG in BTC. Using resected BTC specimens from 147 patients with adenocarcinoma (extrahepatic cholangiocarcinoma [ECC, n = 96]; intrahepatic cholangiocarcinoma [ICC, n = 51]), we immunohistochemically evaluated SNCG expression and investigated its correlation with clinicopathological factors and outcomes. Furthermore, cell lines with high SNCG expression were selected from 16 BTC cell lines and these underwent cell proliferation and migration assays by siRNAs. In the results, SNCG expression was present in 22 of 96 (22.9%) ECC patients and in 10 of 51 (19.6%) ICC patients. SNCG expression was significantly correlated with poorly differentiated tumor in both ECC and ICC (p = 0.01 and 0.03, respectively) and with perineural invasion and lymph node metastases in ECC (p = 0.04 and 0.003, respectively). Multivariate analyses revealed that SNCG expression was an independent poor prognostic factor in both OS and RFS in both ECC and ICC. In vitro analyses showed high SNCG expression in three BTC cell lines (NCC-BD1, NCC-BD3, and NCC-CC6-1). Functional analysis revealed that SNCG silencing could suppress cell migration in NCC-BD1 and NCC-CC6-1 and downregulate cell proliferation in NCC-CC6-1 significantly. In conclusion, SNCG may promote tumor cell activity and is potentially a novel prognostic marker in BTC.

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Invasive pulmonary aspergillosis after liver transplantation: lessons from successfully treated cases and review of the literature

Abe K., Shinoda M., Uno S., Obara H., Kitago M., Abe Y., Hishida T., Yagi H., Hasegawa Y., Kitagawa Y.

Surgery Today (Surgery Today) 51 ( 8 ) 1361 - 1370 2021.08

ISSN 09411291

Purpose: Invasive pulmonary aspergillosis (IPA) after liver transplantation (LT) is most often fatal. We analyzed the outcomes of IPA in a single center. Methods: We reviewed, retrospectively, the medical records of recipients of living donor LT (LDLT) or deceased donor LT (DDLT) performed between 1995 and 2019 at our institute. We analyzed the incidence of IPA and assessed the treatment courses of patients treated successfully and those not treatment successfully. Results: Among 326 recipients, IPA was diagnosed in 6 (1.8%). The incidence of IPA was significantly higher in patients with acute liver failure (ALF, 9.8%) than in those without ALF (0.4%), after DDLT (8.8%) than after LDLT (1.0%), and in recipients who received preoperative steroid pulse therapy (16.0%) than in those who did not (0.7%). Complete cure of IPA was achieved in the most recent three patients, by administering voriconazole immediately after the diagnosis of IPA and performing lung resection, while the IPA lesion was single and localized. Conclusions: Patients with risk factors for IPA must be monitored closely. Our three successfully treated cases demonstrate that initiating immediate voriconazole treatment and making a calculated decision about lung resection can contribute to a favorable outcome.

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Indication for resection and possibility of observation for intraductal papillary mucinous neoplasm with high-risk stigmata

Abe K., Kitago M., Masugi Y., Iwasaki E., Yagi H., Abe Y., Hasegawa Y., Fukuhara S., Hori S., Tanaka M., Nakano Y., Yokose T., Shimane G., Sakamoto M., Kitagawa Y.

Pancreatology (Pancreatology) 21 ( 4 ) 755 - 762 2021.06

ISSN 14243903

Background/Objectives: According to the revised international intraductal papillary mucinous neoplasm (IPMN) guidelines (2017), the indication for surgery is based on risk classification. However, some IPMNs with high-risk stigmata (HRS) can be observed for long periods without resection. Hence, we need to reconsider the risk stratification, and this study aimed to propose a novel risk stratification for HRS-IPMNs. Methods: We enrolled 328 patients diagnosed with IPMN using endoscopic ultrasound between 2012 and 2019. We compared clinicopathological features between HRS and worrisome features (WF) and evaluated outcomes of HRS-IPMN. Results: Fifty-three patients (HRS 38, WF 15) underwent resection at initial diagnosis and 275 patients were observed. Following observation for 30 months, 22 patients (17 HRS, 5 WF) underwent resection. Analysis of resected IPMNs (n = 75) revealed that HRS had dominantly pancreatobiliary mucin subtype. Pancreatobiliary-type IPMN had larger nodule sizes and lymphatic invasion and high recurrence with poor prognosis. Seventy-four patients were diagnosed with HRS, 55 underwent resection, and 19 continue to be observed. The resected group had larger nodule sizes (median 8 mm vs. 5 mm; P = 0.060), whereas the observed group had more main pancreatic duct (MPD) dilation (median 10 mm vs. 5 mm; P = 0.005). In the resected HRS group, only patients with MPD dilation ≥10 mm (n = 10) had no recurrence but had a favorable prognosis compared with those nodule size ≥5 mm (n = 45). Conclusions: Large nodule size may be associated with pancreatobiliary subtype and poor prognosis; however, patients with MPD dilation ≥10 mm with nodule size <5 mm did not require resection.

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Pure laparoscopic living donor left lateral sectionectomy using glissonean approach and original bridging technique

Umemura A., Nitta H., Takahara T., Hasegawa Y., Katagiri H., Kanno S., Takeda D., Makabe K., Kobayashi M., Sasaki A.

Surgical Laparoscopy, Endoscopy and Percutaneous Techniques (Surgical Laparoscopy, Endoscopy and Percutaneous Techniques) 31 ( 3 ) 389 - 392 2021.06

ISSN 15304515

Background: Living donor liver transplantation (LDLT) is the final treatment for children with end-stage liver disease. Congenital biliary atresia (CBA) is the most common disease requiring LDLT in Japan, and a left lateral sector graft is preferably procured owing to its anatomic predictivity and identical graft volume for preschool recipients. Laparoscopic left lateral sectionectomy (L-LLS) for LDLT has been recently established; however, there is no report about the innovative technique in L-LLS. The aim of this study was to introduce our L-LLS using the Glissonean approach and bridging technique for pediatric LDLT. Materials and Methods: From September 2017 to September 2020, 5 cases of L-LLS for pediatric LDLT because of CBA were performed and we performed L-LLS using the original technique on their donors. In this novel procedure, the left Glissonean pedicle was encircled at the parenchymal side of the Laennec capsule after mobilization of the lateral sector and visualization of the left hepatic vein. Then, we passed 2 tapes through the encircled Glissonean pedicle at the hepatic side and the duodenal side, as the caudate lobe branch is enclosed like a bridge. By virtue of this bridging technique, we encircled the caudate lobe branch alone by switching the tape, and we clipped and divided it; this technique secured an adequately long hepatic duct on the graft side to perform a hepaticojejunostomy. The left hepatic duct was divided after indocyanine green fluorescence cholangiography, and the left hepatic artery and portal vein were divided as well. Finally, the left hepatic vein was transected and procured from an extended intraumbilical incision. Results: We achieved L-LLS by using the Glissonean approach and the bridging technique in the 5 donors. The median operating time and blood loss were 282 (268 to 332) minutes and 34 (25 to 75) mL, respectively. There was no conversion to hybrid or open LLS and no postoperative complications. Regarding recipient outcomes, hepatic artery thrombosis occurred on postoperative day 4 in a 5-year-old female. All grafts function well and all recipients are alive after discharge (range of observation period, 3 to 26 mo). Conclusions: We herein present standardized L-LLS using the Glissonean approach and bridging technique for pediatric LDLT. Our technique can secure a longer margin of the left hepatic duct for recipients' hepaticojejunotomy. Our results have demonstrated the advantage in pediatric LDLT, especially in patients with CBA after the Kasai procedure.

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Central hepatic bisectionectomy with hepatic artery and biliary tracts reconstruction for the patient with nodular type intrahepatic hilar cholangiocarcinoma: A case report

Umemura A., Nitta H., Takahara T., Hasegawa Y., Sugai T., Sasaki A.

International Journal of Surgery Case Reports (International Journal of Surgery Case Reports) 82 2021.05

ISSN 22102612

Introduction and importance: A central hepatic bisectionectomy (CHBS) for a hilar cholangiocarcinoma (CCA) is technically challenging because bilateral biliary reconstruction is required after resection. On the other hand, hepatic artery resection and reconstruction in a major liver resection are also technical procedures. In this report, we describe our radical CHBS with hepatic artery and biliary tracts reconstruction for a patient with nodular type intrahepatic hilar CCA. Case presentation: A 76-year-old man was referred for further investigation of an incidental hepatic tumor. The hepatic tumor was located from medial sector to anterior sector with encasement of the anterior branch of the right hepatic artery. Based on these findings, we performed a CHBS with right hepatic artery and biliary tracts reconstruction. The histopathological findings revealed that the tumor consisted of moderately differentiated tubular adenocarcinoma with tumor necrosis without a fibrous capsule. In this area, tumors cells had invaded branches of the hepatic vein; however, there was no destructive invasion to the hepatic artery. Consequently, he was diagnosed with a nodular type intrahepatic hilar CCA with pT2aN0M0. Clinical discussion: A CHBS is usually performed with the intent of anatomically preserving a patient's liver as much as possible. Concomitant resection and reconstruction of the hilar vessels and biliary tracts with CHBS is one of the most technically challenging procedures in liver resections. Conclusion: A CHBS with hepatic artery and biliary reconstruction may be a promising alternative if expert surgeons perform it on strictly selected patients.

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Peritoneal dissemination of pancreatic cancer caused by endoscopic ultrasound-guided fine needle aspiration: A case report and literature review

Kojima H., Kitago M., Iwasaki E., Masugi Y., Matsusaka Y., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Takemura Y., Fukuhara S., Ohara Y., Sakamoto M., Okuda S., Kitagawa Y.

World Journal of Gastroenterology (World Journal of Gastroenterology) 27 ( 3 ) 294 - 304 2021.01

ISSN 10079327

BACKGROUND Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a biopsy technique widely used to diagnose pancreatic tumors because of its high sensitivity and specificity. Although needle-tract seeding caused by EUS-FNA has been recently reported, dissemination of pancreatic cancer cells is generally considered to be a rare complication that does not affect patient prognosis. However, the frequency of dissemination and needle-tract seeding appears to have been underestimated. We present a case of peritoneal dissemination of pancreatic cancer due to preoperative EUS-FNA. CASE SUMMARY An 81-year-old man was referred to the Department of Surgery of our hospital in Japan owing to the detection of a pancreatic mass on computed tomography during medical screening. Trans-gastric EUS-FNA revealed that the mass was an adenocarcinoma; hence laparoscopic distal pancreatectomy with lymphadenectomy was performed. No intraoperative peritoneal dissemination and liver metastasis were visually detected, and pelvic lavage cytology was negative for carcinoma cells. The postoperative surgical specimen was negative for carcinoma cells at the dissected margin and the cut end margin; however, pathological findings revealed adenocarcinoma cells on the peritoneal surface proximal to the needle puncture site, and the cells were suspected to be disseminated via EUS-FNA. Hence, the patient received adjuvant therapy with S-1 (tegafur, gimeracil, and oteracil potassium); however, computed tomography performed 5 mo after surgery revealed liver metastasis and cancerous peritonitis. The patient received palliative therapy and died 8 mo after the operation. CONCLUSION The indications of EUS-FNA should be carefully considered to avoid iatrogenic dissemination, especially for cancers in the pancreatic body or tail.

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Efficacy of enhanced prehabilitation for patients with esophageal cancer undergoing esophagectomy

Akiyama Y., Sasaki A., Fujii Y., Fujisawa R., Sasaki N., Nikai H., Endo F., Baba S., Hasegawa Y., Kimura T., Takahara T., Nitta H., Otsuka K., Koeda K., Nishimura Y., Iwaya T.

Esophagus (Esophagus) 18 ( 1 ) 56 - 64 2021.01

ISSN 16129059

Background: Several studies have demonstrated that prehabilitation helps reduce the incidence of postoperative complications. In this study, we investigated the safety and efficacy of enhanced prehabilitation (EP) in the hospital for patients with esophageal cancer. Methods: We retrospectively reviewed the data of 48 consecutive patients who underwent radical esophagectomy with gastric tube reconstruction between September 2015 and June 2019. EP program had been introduced in August 2017. In the EP group, patients received the EP program during hospitalization 7 days before surgery in addition to conventional perioperative rehabilitation. The EP program consisted of aerobic exercise and muscle strength training in the morning and afternoon. Operative outcomes were compared between patients who received EP (EP group; 23 patients) and patients who did not receive EP (control group; 25 patients). Results: The preoperative (EP group vs. control group, 492.9 ± 79.7 vs. 418.9 ± 71.8 m, p < 0.001) and postoperative (EP group vs. control group, 431.5 ± 80 vs. 378 ± 68.7 m, p < 0.001) 6-min walk distance was significantly higher in the EP group than in the control group. The respiratory complications rate was significantly lower in the EP group (4.3%) than in the control group (36%) (p = 0.007). The incidence of atelectasis was particularly significantly lower in the EP group (0%) than in the control group (24%) (p = 0.012). Conclusions: EP was performed safely for patients before esophagectomy. EP improved the exercise tolerance of the patients before esophagectomy and might be useful in preventing respiratory complications.

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Indocyanine green fluorescence imaging via endoscopic nasal biliary drainage during laparoscopic deroofing of liver cysts

Umemura A., Nitta H., Suto T., Fujiwara H., Takahara T., Hasegawa Y., Katagiri H., Kanno S., Ando T., Sasaki A.

Journal of Minimal Access Surgery (Journal of Minimal Access Surgery) 17 ( 1 ) 131 - 134 2021.01

ISSN 09729941

Laparoscopic deroofing of liver cysts is widely accepted as the treatment of symptomatic huge liver cysts. As bile leakage is a common complication of this procedure, indocyanine green (ICG) imaging has played an active role in detecting intrahepatic biliary tract. However, infusion ICG imaging needs time rag after injection due to moving from bloodstream to bile, and also, additional injection is needed when the fluorescent imaging is not clear. To cover this weakness of ICG imaging, we first applied ICG imaging via 5-Fr endoscopic nasal biliary drainage (ENBD) during laparoscopic deroofing of liver cysts. This technique promptly gives us ICG imaging after ICG injection from ENBD; in addition, direct ICG imaging sometimes reveals minor leakage from sealing line and staple lines; therefore, we believe that direct ICG imaging via ENBD helps us to prevent post-operative bile leakage.

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Aggressive laparoscopic cholecystectomy in accordance with the Tokyo guideline 2018

Takahashi N., Umemura A., Suto T., Fujiwara H., Ariyoshi Y., Nitta H., Takahara T., Hasegawa Y., Sasaki A.

Journal of the Society of Laparoendoscopic Surgeons (Journal of the Society of Laparoendoscopic Surgeons) 25 ( 1 ) 2021

ISSN 10868089

Objectives: The Tokyo Guidelines 2018 have been widely adopted since their publication. However, the few reports on clinical outcomes following laparoscopic cho-lecystectomy have not taken into account the severity of the acute cholecystitis and the patient's general condition, as estimated by the Charlson comorbidity index. This study aimed to assess the relationships between severity, Charlson comorbidity index, and clinical outcomes subsequent to laparoscopic cholecystectomy. Methods: We extracted the retrospective data for 370 Japanese patients who underwent emergency or scheduled early laparoscopic cholecystectomy within 72 hours from onset between February 2015 and August 2018. We compared postoperative factors in relationship to severity (grade I versus grade II/III). Then, we made a similar comparison between those with low (< 4) and high Charlson comorbidity index (> 4). Results: According to the Tokyo guideline 2018 levels of severity, there were 282 (76.2%), 61 (16.5%), and 27 (7.3%) patients in grades I, II, and III, respectively. With regards to surgical outcomes, the mean operating time was 62.3 minutes and the mean blood loss was 24.4 mL. The mean hospital stay was 3.6 days, with no mortalities. Blood loss was the only factor affected by severity (20.9 mL versus 60.1 mL, P = 0.0164), and operating time was the only factor affected by high Charlson comorbidity index (53.4 versus 67.8 minutes, P = 0.0153). Conclusion: Our aggressive strategy is acceptable, and severity and Charlson comorbidity index are not critical factors suggesting the disqualification of early laparoscopic cholecystectomy in patients with any grade acute cholecystitis.

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Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report

Fujimura T., Yamada Y., Umeyama T., Kudo Y., Kanamori H., Mori T., Shimizu T., Kato M., Shimojima N., Hoshino K., Kuroda T., Kawaida M., Hosoe N., Hasegawa Y., Matsubara K., Shinoda M., Obara H., Kitagawa Y., Shinoda M., Naganuma M.

World Journal of Clinical Cases (World Journal of Clinical Cases) 9 ( 19 ) 5270 - 5279 2021

BACKGROUND Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE SUMMARY The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab. CONCLUSION Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.

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Laparoscopic left hepatectomy with middle hepatic vein resection for hepatocellular carcinoma with extrahepatic portal vein obstruction

Umemura A., Nitta H., Takahara T., Hasegawa Y., Katagiri H., Kanno S., Kobayashi M., Ando T., Sato A., Uesugi N., Sugai T., Sasaki A.

American Journal of Case Reports (American Journal of Case Reports) 22 ( 1 ) 1 - 6 2021

Patient: Female, 70-year-old Final Diagnosis: Hepatocellular carcinoma with extrahepatic portal vein obstruction Symptoms: — Medication: — Clinical Procedure: Preoperative simulation and intraoperative navigation technique Specialty: Surgery Objective: Background: Case Report: Conclusions: Unusual setting of medical care Extrahepatic portal vein obstruction (EHPVO) is one of the most important diseases that causes pre-hepatic portal hypertension, and EHPVO sometimes develops cavernous transformation to maintain hepatopetal flow. In this report, we describe the first case of hepatocellular carcinoma (HCC) with EHPVO having underwent pure laparoscopic left hepatectomy with middle hepatic vein (MHV) resection. A 70-year-old woman with a diagnosis of mixed-type HCC or cholangiocarcinoma located in segment 4b was referred to our hospital, and computed tomography revealed EHPVO with cavernous transformation. We suc-cessfully performed pure laparoscopic left hepatectomy with MHV resection by using the individual hilar ap-proach, frequent intraoperative sonography, and indocyanine green imaging. In this case, the routine Glissonian approach was impossible due to cavernous transformation growth and the absence of a portal vein. Therefore, frequent confirmation of intrahepatic flow was crucial to avoid intraoperative complications. The patient was discharged with no complications on postoperative day 7. A histopathological examination revealed that the moderately differentiated HCC formed a pseudoglandular pattern and cord-like structures, thereby defined as type II according to Edmondson’s classification. Currently, difficulty scoring systems for laparoscopic liver resection (LLR) usually contain the procedure and location of the hepatic tumor, but they do not contain the variety of anatomical abnormality due to its rarity. However, the false recognition of hilar vessels and biliary ducts in patients with an anatomical abnormality, in-cluding EHPVO, leads to severe injury; therefore, anatomical variety and abnormality are also important fac-tors increasing the difficulty of LLR.

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