研究者詳細 - 北郷　実

論文 - 北郷　実

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Urgent distal pancreatectomy for intraperitoneal hemorrhage due to the spontaneous rupture of a pancreatic metastatic tumor from synovial sarcoma: a case report

Yokose T., Kitago M., Oshima G., Abe K., Masugi Y., Miura E., Shinoda M., Yagi H., Abe Y., Hori S., Matsusaka Y., Endo Y., Toyama K., Okuda S., Kitagawa Y.

BMC Surgery （BMC Surgery） 20 （ 1 ） 175 2020年08月

ISSN 1471-2482

Background: Synovial sarcoma is a soft tissue malignancy that frequently affects the extremities, adjacent to the large joints. Synovial sarcoma has a high rate of distant metastasis; however, pancreatic metastasis is extremely rare, and to our knowledge, there has been no report of bleeding due to spontaneous tumor rupture. This study reports the case of a patient with synovial sarcoma pancreatic metastasis causing tumor rupture and bleeding, which was successfully managed with emergent distal pancreatectomy. Case presentation: A 27-year-old woman underwent extensive resection of the primary tumor and partial lung resection after chemotherapy for left femoral synovial sarcoma and multiple lung metastases 4 years prior. During the follow-up, a 35-mm tumor was noted in the pancreatic tail on abdominal computed tomography (CT), and no other distant metastases were detected via positron emission tomography CT. Laparoscopic distal pancreatectomy was scheduled for pancreatic metastasis of synovial sarcoma. However, before the scheduled pancreatectomy could be conducted, the patient visited the emergency department because of abdominal pain that occurred after consuming a small amount of alcohol, and CT showed ascites with high CT values and leakage of contrast media. She was diagnosed with intra-abdominal hemorrhage due to a ruptured metastatic pancreatic tumor, and an emergency operation was performed. In total, 1500 mL of blood was evacuated from the abdomen, and the bleeding pancreatic tail tumor was resected. Histopathological findings revealed synovial sarcoma metastasis and a ruptured tumor capsule, and tumor cells were observed in the hematoma. After discharge on postoperative day 18, the patient was carefully monitored and confirmed to be in relapse-free survival, without chemotherapy, at 6 months post-surgery. Conclusions: While the rate of tumor growth varies depending on the grade of the tumor, the possibility of rupture should be considered even in metastatic pancreatic tumors. In the case of pancreatic tumor rupture with stable circulation, radiological evaluation for oncology is necessary, and primary resection may be compatible with resectable cases.

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A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01)

Itano O., Takemura Y., Kishida N., Tamagawa E., Shinozaki H., Ikeda K., Urakami H., Ei S., Hayatsu S., Suzuki K., Sakuragawa T., Ishii M., Shito M., Aiura K., Fujisaki H., Takano K., Matsui J., Minagawa T., Shinoda M., Kitago M., Abe Y., Yagi H., Oshima G., Hori S., Kitagawa Y.

BMC Cancer （BMC Cancer） 20 （ 1 ） 688 2020年07月

ISSN 1471-2407

Background: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. Methods: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). Results: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. Conclusions: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. Trial registration: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347

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Successful minimally invasive two-stage operation for rare synchronous cancers of the esophagus and the pancreatic head: A case report

Ozawa H., Kawakubo H., Kitago M., Mayanagi S., Fukuda K., Nakamura R., Suda K., Wada N., Kitagawa Y.

Asian journal of endoscopic surgery （Asian journal of endoscopic surgery） 13 （ 3 ） 410 - 414 2020年07月

ISSN 1758-5902

We report the case of a 70-year-old woman with synchronous advanced esophageal cancer and pancreatic head cancer. To reduce the surgical invasiveness, we performed a two-stage operation that included percutaneous endoscopic gastrostomy and minimally invasive esophagectomy. In the first stage, we performed a percutaneous endoscopic gastrostomy, a thoracoscopic esophagectomy with cervical and mediastinal lymph node dissection, and an esophagostomy without a laparotomy. The second stage, which was performed 28 days after the first operation, consisted of a total gastrectomy, pancreaticoduodenectomy, colonic reconstruction, and jejunostomy. Fifty days after the second operation, the patient was discharged from the hospital. A two-stage operation that includes minimally invasive esophagectomy seems to be useful for avoiding serious postoperative complications, even in patients with rare, synchronous advanced cancers of the esophagus and the pancreatic head.

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A case of pancreatic hamartoma with characteristic radiological findings: radiological-pathological correlation

Toyama K., Matsusaka Y., Okuda S., Miura E., Kubota N., Masugi Y., Kitago M., Hori S., Yokose T., Shinoda M., Sakamoto M., Jinzaki M.

Abdominal Radiology （Abdominal Radiology） 45 （ 7 ） 2244 - 2248 2020年07月

ISSN 2366004X

Pancreatic hamartoma is a rare benign tumor. Its preoperative diagnosis is challenging. We present a case of pancreatic hamartoma whose radiological-pathological correlation was evaluated in detail. A 53-year-old man was referred to our institution for diagnosis and treatment. Contrast-enhanced computed tomography (CT) and magnetic resonance image revealed a 3.5 cm long tumor arising from the head of the pancreas with cystic and solid components, the latter of which was gradually and inhomogeneously enhanced in the delayed phase. Fluorodeoxyglucose (FDG) positron emission tomography/CT revealed slight FDG uptake in the solid component. Histologically, a number of pancreatic lobule-like structures, which were mainly composed of aggregates of small ducts embedded in concentric fibrous stroma with no apparent islets or peripheral nerves, were observed in the solid component, whereas multiple dilated ducts were seen in the cystic region. The solid component also contained a narrow area of edematous fibrous stroma with low vessel density, which corresponded with the unenhanced part in the inhomogeneously enhanced solid component. There was no remarkable cytological atypia throughout the mass. A pathological diagnosis of pancreatic hamartoma was made. The radiological findings agree well with the pathological findings. When a pancreatic tumor is of the solid type, preoperatively diagnosing it as pancreatic hamartoma is not possible. However, when a pancreatic tumor with cystic and solid components is inhomogeneously enhanced in contrast-enhanced studies, a diagnosis of pancreatic hamartoma can be considered.

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Perforated duodenal diverticulum successfully treated with a combination of surgical drainage and endoscopic nasobiliary and nasopancreatic drainage: a case report.

Shimada A, Fujita K, Kitago M, Ichisaka S, Ishikawa K, Kikunaga H, Kumai K, Miura H

Surgical case reports 6 （ 1 ） 129 2020年06月

ISSN 2198-7793

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Usefulness of <sup>18</sup>F-fluorodeoxyglucose positron emission tomography/computed tomography for predicting the prognosis and treatment response of neoadjuvant therapy for pancreatic ductal adenocarcinoma

Yokose T., Kitago M., Matsusaka Y., Masugi Y., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Endo Y., Toyama K., Iwabuchi Y., Takemura R., Ishii R., Nakahara T., Okuda S., Jinzaki M., Kitagawa Y.

Cancer Medicine （Cancer Medicine） 9 （ 12 ） 4059 - 4068 2020年06月

ISSN 2045-7634

Background: The Response Evaluation Criteria in Solid Tumors (RECIST) for computed tomography (CT) is preoperatively used to evaluate therapeutic effects. However, it does not reflect the pathological treatment response (PTR) of pancreatic ductal adenocarcinoma (PDAC). The Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for positron emission tomography (PET)/CT is effective in other cancers. This study aimed to confirm the usefulness of PERCIST and the prognostic utility of PET/CT for PDAC. Methods: Forty-two consecutive patients with PDAC who underwent neoadjuvant therapy (NAT) and pancreatectomy at our institution between 2014 and 2018 were retrospectively analyzed. We evaluated the treatment response and prognostic significance of PET/CT parameters and other clinicopathological factors. Results: Twenty-two patients who underwent PET/CT both before and after NAT with the same protocol were included. RECIST revealed stable disease and partial response in 20 and 2 cases, respectively. PERCIST revealed stable metabolic disease, partial metabolic response, and complete metabolic response in 8, 9, and 5 cases, respectively. The PTR was G3, G2, and G1 in 8, 12, and 2 cases, respectively. For comparing the concordance rates between PTR and each parameter, PERCIST (72.7% [16/22]) was significantly superior to RECIST (36.4% [8/22]) (P =.017). The area under the curve survival values of PET/CT parameters were 0.777 for metabolic tumor volume (MTV), 0.500 for maximum standardized uptake value, 0.554 for peak standardized uptake value corrected for lean body mass, and 0.634 for total lesion glycolysis. A 50% cut-off value for the MTV reduction rate yielded the largest difference in survival between responders and nonresponders. On multivariate analysis, MTV reduction rates < 50% were independent predictors for relapse-free survival (hazard ratio [HR], 3.92; P =.044) and overall survival (HR, 14.08; P =.023). Conclusions: PERCIST was more accurate in determining NAT’s therapeutic effects for PDAC than RECIST. MTV reduction rates were independent prognostic factors for PDAC.

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Combination of KRAS and SMAD4 mutations in formalin-fixed paraffin-embedded tissues as a biomarker for pancreatic cancer

Yokose T., Kitago M., Matsuda S., Sasaki Y., Masugi Y., Nakamura Y., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Yusuke F., Nakano Y., Endo Y., Abe K., Tokino T., Kitagawa Y.

Cancer Science （Cancer Science） 111 （ 6 ） 2174 - 2182 2020年06月

ISSN 13479032

Formalin-fixed paraffin-embedded (FFPE) tissues used for routine pathological diagnosis are valuable for cancer genomic analysis; however, the association between mutation status derived from these specimens and prognosis in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We analyzed 50 cancer-related gene mutations including driver genes in PDAC, using next-generation sequencing (NGS) to clarify the association between gene mutations and prognosis. DNA was extracted from FFPE tissues obtained from 74 patients with untreated resectable PDAC who underwent surgery at our institution between 2013 and 2018. Fifty of the 74 patients with DNA extracts from FFPE samples suitable for NGS were analyzed. The prevalence of driver gene mutations was as follows: 84% for KRAS, 62% for TP53, 32% for SMAD4, and 18% for CDKN2A. There were no cases of single SMAD4 mutations; its rate of coincidence with KRAS or TP53 mutations was 30% and 2%, respectively. The combination of KRAS and SMAD4 mutations resulted in significantly shorter relapse-free survival (RFS; median survival time [MST], 12.3 vs. 28.9 months, P =.014) and overall survival (OS; MST, 22.3 months vs. not reached, P =.048). On multivariate analysis, the combination of KRAS and SMAD4 mutations was an independent prognostic factor for RFS (hazard ratio [HR] 4.218; 95% confidence interval [CI], 1.77-10.08; P =.001) and OS (HR 6.730; 95% CI, 1.93-23.43; P =.003). The combination of KRAS and SMAD4 mutations in DNA obtained from FFPE tissues is an independent poor prognostic factor in PDAC.

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Associations of birthweight and history of childhood obesity with beta cell mass in Japanese adults

Sasaki H., Saisho Y., Inaishi J., Watanabe Y., Tsuchiya T., Makio M., Sato M., Kitago M., Yamada T., Itoh H.

Diabetologia （Diabetologia） 63 （ 6 ） 1199 - 1210 2020年06月

ISSN 0012186X

Aims/hypothesis: Low birthweight is associated with a high risk of diabetes, but there are no reports discussing birthweight and pancreatic tissues in humans. The purpose of this study was to examine the correlation between birthweight and beta and alpha cell mass in humans. Methods: Sixty-four Japanese adults with and without diabetes who underwent pancreatectomy and were able to recall their weight history including birthweight were included. Pancreatic tissues were stained for insulin and glucagon, and fractional beta cell area (BCA) and alpha cell area (ACA) were quantified. Islet size and density and beta cell replication were also quantified and their associations with birthweight were evaluated. Results: In participants without diabetes, there was a weak positive correlation between birthweight and BCA (R = 0.34, p = 0.03). The group with a history of childhood obesity, but not the group with a history of obesity in adulthood only, showed higher BCA compared with those without a history of obesity (1.78 ± 0.74% vs 0.99 ± 0.53%, p = 0.01), and the correlation coefficient between birthweight and BCA increased after excluding those with a history of childhood obesity (R = 0.51, p < 0.01). In those with diabetes, there was no correlation between birthweight and BCA. No correlation was found between birthweight and ACA in either those with or without diabetes. Conclusions/interpretation: Birthweight and beta, but not alpha, cell mass are positively correlated in non-diabetic adults, and a history of childhood obesity may affect beta cell mass. [Figure not available: see fulltext.].

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Predictive factors for liver volume and function recovery after resection using three-dimensional analysis

Nakano Y., Itano O., Shinoda M., Kitago M., Yagi H., Abe Y., Takeuchi A., Takemura Y., Kitagawa Y.

HPB （HPB） 22 （ 6 ） 845 - 854 2020年06月

ISSN 1365182X

Background: Clinical and biological factors that predict liver volume recovery rate (LVRR) after liver resection of different resected volume (RV) have not been studied extensively. Moreover, it remains uncertain whether remnant liver volume influences the liver function recovery rate (LFRR). This study examined the predictive factors for LVRR after liver resections of different RV and investigated LFRR by focusing on LVRR improvements after hepatectomy. Methods: Patients who underwent hepatectomy between January 2013 and August 2015 were reviewed retrospectively. LVRR and LFRR were assessed at postoperative months (POMs) 3, 6, and 12. LVRR was evaluated on the basis of RV (0%–15%, 15%–30%, 30%–45%, and >45%). LFRR was evaluated using total bilirubin, prothrombin time, and platelet count. Results: LVRR was lower with more extensive liver resections. Significant independent predictors of LVRR were type IV collagen 7s domain levels and resection magnitude. Platelet count correlated positively with LVRR at all POMs. Conclusions: Resected livers regenerated after surgery but did not reach preoperative volumes. Preserving the liver as much as possible during resection can result in greater LFRR after hepatectomy. Therefore, decisions regarding liver resection volume should be made very carefully, particularly in patients with higher type IV collagen 7s domain levels.

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早期遠位胆管癌術後3年目にPTBD刺入部再発と4年6ヵ月後に孤立性右腋窩リンパ節転移を来した1切除例

横瀬崇寛, 北郷実, 秋山芳伸, 星野大樹, 瀧川穣, 松原健太郎, 猪股研太, 緒方謙太郎, 北川雄光

日本消化器外科学会雑誌（(一社)日本消化器外科学会） 53 （ 5 ） 418 - 424 2020年05月

ISSN 0386-9768

症例は72歳の女性で,閉塞性黄疸にて当院紹介となった.右第7肋間より経皮経肝胆道ドレナージ(percutaneous transhepatic biliary drainage;以下,PTBDと略記)を挿入した後,遠位胆管癌の診断で幽門輪温存膵頭十二指腸切除術を施行した.病理組織学的に中分化型管状腺癌Stage IAと診断された.術後3年目にPTBD刺入部痕に発赤疹を認め皮膚生検にて転移性腺癌と診断された.他臓器には明らかな病変を認めず皮膚腫瘤摘出術を施行し,胆管癌のPTBD刺入部再発(ly+,v+)と診断された.初回手術後4年6ヵ月の体幹部CTで右腋窩に孤立性腫瘤を指摘され他臓器に異常所見を認めず,切除診断目的に腫瘤摘出術を施行し胆管癌の腋窩リンパ節転移と診断された.その後化学療法を開始したが4ヵ月後に多発肺転移が出現し,初回手術から6年後に原病死した.今回,遠位胆管癌術後の異時性PTBD刺入部再発がその後のリンパ行性および血行性転移の起点となったと考えられる症例を経験した.(著者抄録)

Clinicopathological features of hepatocellular carcinoma with fatty change: Tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin

Kubota N., Ojima H., Hatano M., Yamazaki K., Masugi Y., Tsujikawa H., Fujii-Nishimura Y., Ueno A., Kurebayashi Y., Shinoda M., Kitago M., Abe Y., Kitagawa Y., Sakamoto M.

Pathology International （Pathology International） 70 （ 4 ） 199 - 209 2020年04月

ISSN 13205463

The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.

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Activation of extracellular signal-regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes

Minagawa T., Yamazaki K., Masugi Y., Tsujikawa H., Ojima H., Hibi T., Abe Y., Yagi H., Kitago M., Shinoda M., Itano O., Kitagawa Y., Sakamoto M.

Hepatology Research （Hepatology Research） 50 （ 3 ） 353 - 364 2020年03月

ISSN 13866346

Aim: Sorafenib inhibits multiple kinase signaling pathways, including the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and is a promising therapy for hepatocellular carcinoma (HCC). However, the role of ERK activation in HCC remains unclear. This study was designed to investigate the potential link between ERK activation and aggressive HCC phenotypes. Methods: We evaluated nuclear ERK expression by immunohistochemistry in 154 resected HCC nodules from 136 patients. We then investigated the associations of ERK expression with the clinicopathological characteristics of HCC, c-MET expression, and the molecular subclass biomarkers Ki-67, keratin 19 (KRT19, CK19, or K19), and sal-like protein 4. Multivariate Cox regression analysis was carried out to determine independent prognostic factors for overall survival and recurrence-free survival. The effects of ERK activation by hepatocyte growth factor (HGF) on eight HCC cell lines were further examined. Results: High-level nuclear expression of ERK was observed in 20 (13%) of 154 nodules and was significantly associated with higher serum alpha-fetoprotein levels (P = 0.034), poorer differentiation (P = 0.003), a higher Ki-67 index (P < 0.001), high-level expression of c-MET (P = 0.008), KRT19 (P = 0.002), or sal-like protein 4 (P < 0.001), and shorter overall survival (multivariate hazard ratio 3.448; P = 0.028) and recurrence-free survival (multivariate hazard ratio 2.755; P = 0.004). HCC cells treated with hepatocyte growth factor showed enhanced cell proliferation together with ERK activation and upregulated KRT19 expression, both of which were inhibited by sorafenib. Conclusions: High-level ERK activation is associated with a KRT19-positive highly proliferative subtype of HCC with a dismal prognosis. These findings support the key role of the hepatocyte growth factor/c-MET/ERK axis in HCC progression.

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Pre-hepatectomy type IV collagen 7S predicts post-hepatectomy liver failure and recovery

Ishii M., Itano O., Shinoda M., Kitago M., Abe Y., Hibi T., Yagi H., Takeuchi A., Tsujikawa H., Abe T., Kitagawa Y.

World Journal of Gastroenterology （World Journal of Gastroenterology） 26 （ 8 ） 725 - 739 2020年02月

ISSN 10079327

BACKGROUND Liver resection is an effective treatment for benign and malignant liver tumors. However, a method for preoperative evaluation of hepatic reserve has not yet been established. Previously reported assessments of preoperative hepatic reserve focused only on liver failure in the early postoperative period and did not consider the long-term recovery of hepatic reserve. When determining eligibility for hepatectomy, the underlying pathophysiology needs to be considered to determine if the functional hepatic reserve can withstand both surgery and any postoperative therapy. AIM To identify pre-hepatectomy factors associated with both early postoperative liver failure and long-term postoperative liver function recovery. METHODS This study was a retrospective cohort study. We retrospectively investigated 215 patients who underwent hepatectomy at our hospital between May 2013 and December 2016. Early post-hepatectomy liver failure (PHLF) was defined using the International Study Group of Liver Surgery’s definition of PHLF. Long-term postoperative recovery of liver function was defined as the time taken for serum total bilirubin and albumin levels to return to levels of < 2 mg/dL and > 2.8 g/dL, respectively, and the time taken for Child-Pugh score to return to Child-Pugh class A. RESULTS Preoperative type IV collagen 7S was identified as a significant independent factor associated with both PHLF and postoperative long-term recovery of liver function. Further analysis revealed that the time taken for the recovery of Child-Pugh scores and serum total bilirubin and albumin levels was significantly shorter in patients with type IV collagen 7S ≤ 6 ng/mL than in those with type IV collagen 7S > 6 ng/mL. In additional analyses, similar results were observed in patients without chronic viral hepatitis associated with fibrosis. CONCLUSION Preoperative type IV collagen 7S is a preoperative predictor of PHLF and long-term postoperative liver function recovery. It can also be used in patients without chronic hepatitis virus.

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Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Fujita Y., Matsuda S., Sasaki Y., Masugi Y., Kitago M., Yagi H., Abe Y., Shinoda M., Tokino T., Sakamoto M., Kitagawa Y.

Cancer Science （Cancer Science） 111 （ 2 ） 739 - 748 2020年02月

ISSN 13479032

There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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Impact of electrical pulse cut mode during endoscopic papillectomy: Pilot randomized clinical trial

Iwasaki E., Minami K., Itoi T., Yamamoto K., Tsuji S., Sofuni A., Tsuchiya T., Tanaka R., Tonozuka R., Machida Y., Takimoto Y., Tamagawa H., Katayama T., Kawasaki S., Seino T., Horibe M., Fukuhara S., Kitago M., Ogata H., Kanai T.

Digestive Endoscopy （Digestive Endoscopy） 32 （ 1 ） 127 - 135 2020年01月

ISSN 09155635

Objective: Endoscopic papillectomy is increasingly being used for ampullary adenoma treatment. However, it remains challenging despite increased safety with treatment advances. The ideal power output and electrosurgical current mode for mucosal resection are not established. We aimed to identify the ideal electrical pulse for use during resection. Methods: This pilot randomized, single-blind, prospective, multicenter trial, recruited patients with ampullary adenomas and conventional anatomy who were scheduled to undergo endoscopic papillectomy. Endoscopic treatment was performed using a standardized algorithm and patients were randomized for endoscopic papillectomy with Endocut or Autocut. The primary outcome was the incidence of delayed bleeding. Incidence of procedure-related pancreatitis, successful complete resection, pathological findings, and other adverse events were secondary endpoints. Results: Sixty patients were enrolled over a 2-year period. The incidences of delayed bleeding (13.3% vs. 16.7%, P = 1.00) and pancreatitis (27% vs. 30%, P = 0.77) were similar between both groups. The rate of crush artifacts was higher in the Endocut than in the Autocut group (27% vs. 3.3%, P = 0.03). Immediate bleeding when resecting tumors greater than 14 mm in diameter was more common in the Autocut than in the Endocut group (88% vs. 46%, P = 0.04). Conclusions: The Autocut and Endocut modes have similar efficacy and safety for endoscopic papillectomy. The Endocut mode may prevent immediate bleeding in cases with large tumor sizes, although it causes more frequent crush artifacts. Registry and the registration number: The Japanese UMIN Clinical Trials Registry (UMIN-CTR: 000021382).

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Laparoscopic repeat liver resection after open liver resection: A comparative study from a single-centre

Wakabayashi T., Abe Y., Itano O., Shinoda M., Kitago M., Yagi H., Hibi T., Oshima G., Minagawa T., Kitagawa Y.

Journal of Minimal Access Surgery （Journal of Minimal Access Surgery） 16 （ 1 ） 59 - 65 2020年01月

ISSN 09729941

Background: Technological innovations have made it possible to use laparoscopic liver resection in cases with pre-existing adhesions or cicatricial changes. However, laparoscopic repeat liver resection (LRLR) still represents a challenge for surgeons, especially in case of previous open liver surgery. This study evaluated the outcomes of LRLR after open liver resection (OLR) in cases of recurrent liver cancer. Materials and Methods: A total of 62 patients who underwent laparoscopic minor liver resection at our institution between September 2012 and September 2016 were retrospectively divided into an LRLR group (n = 13) and a laparoscopic primary liver resection group (LPLR; n = 49). The two groups were compared in terms of patient demographics, surgical procedures and short-term outcomes. Recurrence-free survival (RFS) and overall survival (OS) were compared for patients with hepatocellular carcinoma (HCC) or colorectal liver metastases (CRLMs). Results: There was a significant intergroup difference in the hepatitis virus background, although the two groups' primary histology and pre-operative liver function were comparable. The two groups had statistically similar values for extent of resection, operative time, estimated blood loss, transfusion requirement, conversion to laparotomy, post-operative complications, surgical margins, time to oral intake and hospital stay. No significant differences were detected when we stratified the cases according to low and intermediate difficulty. Furthermore, there were no intergroup differences in RFS or OS in the two groups for patients with HCC and CRLM. Conclusions: The findings suggest that minor LRLR after OLR is safe and comparable with minor LPLR in the present study.

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Recurrence of distal bile duct carcinoma on percutaneous transhepatic biliary drainage fistula and lymph node of the right axilla

Yokose T., Kitago M., Akiyama Y., Hoshino H., Takigawa Y., Matsubara K., Inomata K., Ogata K., Kitagawa Y.

Japanese Journal of Gastroenterological Surgery （Japanese Journal of Gastroenterological Surgery） 53 （ 5 ） 418 - 424 2020年

ISSN 03869768

One potential risk of percutaneous transhepatic biliary drainage (PTBD) is tumor seeding along the catheter tract. A 72-year-old woman was referred to our hospital because of obstructive jaundice. Five weeks after inserting PTBD from the 7th right intercostal space, a pylorus-preserving pancreaticoduodenectomy was performed for the diagnosis of distal bile duct carcinoma. The patient was given a pathological diagnosis of stage I (T1 N0 M0) distal bile duct carcinoma. A tumor with rash on PTBD fistula was found and was removed 3 years after the first operation. Histological findings were compatible with bile duct carcinoma metastasis. An isolated lymph nodal mass of the right axilla was found by CT 4 years and 6 months after the first operation, and an excision biopsy was performed. Histological findings were compatible with bile duct carcinoma metastasis again. The patient underwent chemotherapy, but multiple lung metastases appeared 4 months later and she died 6 years after the first operation. We report on a case of PTBD fistula recurrence and right axillary lymph node recurrence after radical surgery for early distal bile duct carcinoma.

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Elucidation of the Effects of a Current X-SCID Therapy on Intestinal Lymphoid Organogenesis Using an In Vivo Animal Model

Nochi T., Suzuki S., Ito S., Morita S., Furukawa M., Fuchimoto D., Sasahara Y., Usami K., Niimi K., Itano O., Kitago M., Matsuda S., Matsuo A., Suyama Y., Sakai Y., Wu G., Bazer F.W., Watanabe K., Onishi A., Aso H.

Cellular and Molecular Gastroenterology and Hepatology （Cellular and Molecular Gastroenterology and Hepatology） 10 （ 1 ） 83 - 100 2020年

ISSN 2352-345X

Background & Aims: Organ-level research using an animal model lacking Il2rg, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable and would be a powerful tool to gain deeper insights into the symptoms of patients with X-SCID. Methods: We used an X-SCID animal model, which was first established in our group by the deletion of Il2rg gene in pigs, to understand the clinical signs from multiple perspectives based on pathology, immunology, microbiology, and nutrition. We also treated the X-SCID pigs with bone marrow transplantation (BMT) for mimicking a current therapeutic treatment for patients with X-SCID and investigated the effect at the organ-level. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID. Results: We demonstrated that X-SCID pigs completely lacked Peyer's patches (PPs) and IgA production in the small intestine, but possessed some dysfunctional intestinal T and B cells. Another novel discovery was that X-SCID pigs developed a heterogeneous intestinal microflora and possessed abnormal plasma metabolites, indicating that X-SCID could be an immune disorder that affects various in vivo functions. Importantly, the organogenesis of PPs in X-SCID pigs was not promoted by BMT. Although a few isolated lymphoid follicles developed in the small intestine of BMT-treated X-SCID pigs, there was no evidence that they contributed to IgA production and microflora formation. Consistently, most patients with X-SCID who received BMT possessed abnormal intestinal immune and microbial environments regardless of the presence of sufficient serum IgG. Conclusions: These results indicate that the current BMT therapies for patients with X-SCID may be insufficient to induce the organogenesis of intestinal lymphoid tissues that are associated with numerous functions in vivo.

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Methicillin-resistant Staphylococcus aureus carriers are vulnerable to bloodstream infection after living donor liver transplantation

Takemura Y., Hibi T., Shinoda M., Obara H., Minagawa T., Kitago M., Yagi H., Abe Y., Matsubara K., Oshima G., Hori S., Hoshino K., Yamada Y., Itano O., Takano Y., Kuroda T., Hasegawa N., Kitagawa Y.

Clinical Transplantation （Clinical Transplantation） 33 （ 12 ） e13753 2019年12月

ISSN 09020063

Background: Bloodstream infection (BSI) is a life-threatening complication after living donor liver transplantation (LDLT). We aimed to explore the incidence and predisposing factors of BSI at our institution. Methods: We conducted a retrospective cohort analysis on all consecutive adults with BSI within 6 months after LDLT performed between 2005 and 2016. For antimicrobial prophylaxis, ampicillin/sulbactam, cefotaxime, and micafungin were administered. From 2011, methicillin-resistant Staphylococcus aureus (MRSA) carriers were decolonized using mupirocin ointment and chlorhexidine gluconate soap. Risk factors for BSI were identified by uni- and multivariate logistic regression. Results: Of a total of 106 LDLTs, 42 recipients (40%) suffered BSI. The BSI group demonstrated significantly higher in-hospital mortality rates compared with the non-BSI group (24% vs. 7%, P =.01). We identified MRSA carrier (odds ratio [OR], 19.1; P <.001), ABO incompatibility (OR, 2.9; P =.03), and estimated glomerular filtration rate <30 mL/min/1.73m2 (OR, 15.8; P =.02) as independent risk factors for BSI. Decolonization treatment for MRSA carriers did not reduce the incidence of all-cause BSI but reduced the frequency of BSI caused by MRSA. Conclusion: To our knowledge, for the first time, MRSA carriers were revealed to be highly vulnerable to BSI after LDLT.

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Decellularized liver scaffolds promote liver regeneration after partial hepatectomy

Shimoda H., Yagi H., Higashi H., Tajima K., Kuroda K., Abe Y., Kitago M., Shinoda M., Kitagawa Y.

Scientific Reports （Scientific Reports） 9 （ 1 ） 12543 2019年12月

ISSN 2045-2322

The resectable liver volume is strictly limited and this reduces the number of patients who may be treated. Recently, “tissue/organ decellularization”, a new approach in bioengineering, has been investigated for its ability to produce a native organ scaffold by removing all the viable cells. Such a scaffold may support the repair of damaged or injured tissue. The purpose of this study was to evaluate the potential contribution of liver scaffolds to hepatic regeneration after hepatectomy. We sutured the partial liver scaffolds onto the surfaces of partially hepatectomized porcine livers and assessed their therapeutic potential by immune histological analysis at various time points. Animals were sacrificed after surgery and the implanted scaffolds were evaluated for the infiltration of various types of cells. Immune histochemical study showed that blood vessel-like structures, covered with CD31 positive endothelial cells and ALB positive cells, were present in all parts of the scaffolds at days 10 and 28. Blood inflow was observed in some of these ductal structures. More interestingly, CK19 and EpCAM positive cells appeared at day 10. These results suggest that the implantation of a decellularized organ scaffold could promote structural reorganization after liver resection.

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