研究者詳細 - 北郷　実

論文 - 北郷　実

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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 ） 1258 - 1258 2022年04月

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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Transplantation of bioengineered liver capable of extended function in a preclinical liver failure model

Higashi H., Yagi H., Kuroda K., Tajima K., Kojima H., Nishi K., Morisaku T., Hirukawa K., Fukuda K., Matsubara K., Kitago M., Shinoda M., Obara H., Adachi S., Nishimura K., Natsume T., Tomi M., Soto-Gutierrez A., Kitagawa Y.

American Journal of Transplantation （American Journal of Transplantation） 22 （ 3 ） 731 - 744 2022年03月

ISSN 16006135

Unlimited organ availability would represent a paradigm shift in transplantation. Long-term in vivo engraftment and function of scaled-up bioengineered liver grafts have not been previously reported. In this study, we describe a human-scale transplantable liver graft engineered on a porcine liver-derived scaffold. We repopulated the scaffold parenchyma with primary hepatocytes and the vascular system with endothelial cells. For in vivo functional testing, we performed auxiliary transplantation of the repopulated scaffold in pigs with induced liver failure. It was observed that the auxiliary bioengineered liver graft improved liver function for 28 days and exhibited upregulation of liver-specific genes. This study is the first of its kind to present 28 days of posttransplant evaluation of a bioengineered liver graft using a preclinical large animal model. Furthermore, it provides definitive evidence for the feasibility of engineering human-scale transplantable liver grafts for clinical applications.

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S状結腸憩室穿通に対するハルトマン手術後に発生した鼠径ヘルニア嚢膿瘍の1例

川本潤一郎, 藤田晃司, 三浦弘志, 北郷実

日本腹部救急医学会雑誌（(一社)日本腹部救急医学会） 42 （ 3 ） 469 - 472 2022年03月

ISSN 1340-2242

症例は両側鼠径ヘルニア術後の56歳男性で,左下腹部痛を主訴に当院受診した。身体所見では左下腹部に圧痛を認め,左鼠径部から陰嚢に達する手拳大の再々発ヘルニアを認めた。血液検査では炎症反応の上昇を認め,腹部造影CTでS状結腸を中心に脂肪織濃度の上昇と腸間膜内に微細な遊離ガスを認めた。S状結腸憩室穿通による汎発性腹膜炎と診断し,ハルトマン手術および洗浄ドレナージ術を施行した。左鼠径ヘルニアのヘルニア門は大きく,修復術は行わなかった。術後,発熱と炎症反応が持続し,左陰嚢の腫大・硬結を認めた。術後7日目に再度腹部造影CTを施行したところ,左鼠径ヘルニア嚢内に遺残膿瘍を認めた。局所麻酔下で陰嚢を切開し,ドレナージを施行してフィルム型ドレーンを3本留置した。その後,発熱や炎症反応は著明に改善し,術後29日目に退院となった。(著者抄録)

Endoscopic Diagnosis of Biliary Stricture Combined with Digital Cholangioscope: A Case Series

Fukuhara S., Iwasaki E., Kayashima A., Machida Y., Tamagawa H., Kawasaki S., Horibe M., Hori S., Abe Y., Kitago M., Ogata H., Kanai T.

Healthcare (Switzerland) （Healthcare (Switzerland)） 10 （ 1 ） 2022年01月

ISSN 2227-9032

The endoscopic diagnosis of biliary tract lesions is applied as a non-invasive method; however, its diagnostic accuracy is not yet high. Moreover, digital cholangioscopy is used for directly visualizing the inside of the bile duct, resulting in a more precise biopsy. We present the case series of the outcomes of diagnosis using digital cholangioscopy in patients who underwent cholangioscopy for the evaluation of biliary stenosis in our department between January 2014 and March 2021. The controls were those who underwent a biopsy for biliary stenosis with conventional endoscopic retrograde cholangiopancreatography (ERCP). Background data for each case were collected, and the clinical outcomes by biopsy were evaluated, focusing on the accuracy of the diagnosis. Cholangioscopy was performed in 15 cases, while a conventional biopsy by ERCP was performed in 172 cases. Nine of 15 cases (60.0%) were diagnosed with cholangiocarcinoma. The number of specimens obtained through conventional ERCP and cholangioscopy was 2.5 ± 1.3 and 3.3 ± 1.5, respectively (p = 0.043). The diagnostic accuracy of conventional ERCP and cholangioscopy were 65.7% (113 of 172 cases) and 100%, respectively, which was significantly higher in the group with cholangioscopy. Digital cholangioscopy is useful when the diagnosis of the biliary stricture using the conventional ERCP method is difficult.

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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 2022年

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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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 2022年

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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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年

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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A Case of Mixed Neuroendocrine Non-Neuroendocrine Tumor Diagnosed after Laparoscopic Cholecystectomy and Lymph Node Resection

Kawamoto J., Fujita K., Tokizawa K., Mizota T., Morinaga S., Kitago M.

Japanese Journal of Gastroenterological Surgery 55 （ 10 ） 633 - 641 2022年

ISSN 03869768

An 81-year-old woman presented to our hospital with a chief complaint of hematuria. She was referred to our department of surgery because a 20-mm nodular lesion in the hilar region was noted on abdominal CT. Abdominal US revealed a 6-mm elevated lesion in the gallbladder, a gallbladder stone, and an enlarged lymph node with a diameter of 24 mm adjacent to the neck of the gallbladder. Contrast-enhanced MRI showed ring-enhanced lesions in the same nodule, and diffusion-weighted images gave a faint high signal, suggesting an enlarged lymph node. Laparoscopic cholecystectomy and lymph node (#12c) resection were performed for diagnostic and therapeutic purposes. Histopathological examination enabled the elevated lesion of the gallbladder to be diagnosed as a mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN). The enlarged lymph node was found to be a metastasis of the tumor. Hepatoduodenal mesenteric lymph node dissection was performed on postoperative day 36 as an additional resection, but no metastasis was found in the 12 resected lymph nodes. The final stage was pT2N1M0 pStage IIIb. We report a case of MiNEN with a generally poor prognosis, in which diagnostic surgery and additional regional lymph node dissection were performed.

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Usefulness of selective arterial calcium injection tests for functional pancreatic neuroendocrine tumors

Nakano Y., Kitago M., Shinoda M., Nakatsuka S., Kurihara I., Yagi H., Abe Y., Oshima G., Hori S., Yokose T., Kitagawa Y.

Scientific Reports （Scientific Reports） 11 （ 1 ） 235 2021年12月

ISSN 2045-2322

The selective arterial calcium injection (SACI) test is useful for patients with functional pancreatic neuroendocrine tumors (F-PNETs). This study evaluated which patients with F-PNETs would benefit from the SACI test. We retrospectively analyzed the preoperative findings of patients on computed tomography (CT), magnetic resonance imaging (MRI), CT angiography (CTA), and the SACI test. Fourteen patients who underwent pancreatectomy between January 1997 and September 2016 for F-PNETs were evaluated. We classified these patients into groups A, B, and C; group A, one tumor detected by either CT or MRI; group B, multiple tumors detected; and group C, the tumor location was accordant on CT, MRI, and CTA, but the SACI test revealed another tumor. In group A, the tumor was also detected by CTA and the SACI test was positive on calcium injection. In group B, the focus tumor among the multiple tumors was detected by the SACI test. In group C, another tumor was identified by the SACI test, whose location was different from that detected using CT and MRI. The SACI test is more useful for multiple F-PNETs on CT or MRI. If CT or MRI detects a single tumor, the SACI test or CTA may be unnecessary.

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Laparoscopy-assisted transduodenal papillectomy: how we do it (with video)

Wakabayashi T., Kitago M., Kitagawa Y.

Langenbeck's Archives of Surgery （Langenbeck's Archives of Surgery） 406 （ 8 ） 2887 - 2890 2021年12月

ISSN 14352443

Background: Some authors previously reported that early ampulla of Vater neoplasms have a low potential of lymph node metastasis and favorable prognosis and, therefore, could be indicated for limited resections instead of the standard pancreatoduodenectomy (PD). In limited resections, when compared to endoscopic papillectomy, transduodenal papillectomy is less technically demanding and a sufficient surgical margin can be achieved due to the greater extent of the excisional area. This didactic video article demonstrated our standardized laparoscopy-assisted transduodenal papillectomy (LATDP). Methods: The technique consisted of 3 steps: laparoscopic Kocher mobilization, papillectomy, and reconstruction. This laparoscopy-assisted approach was more favorable than the pure laparoscopic approach as there was no tumor exposure in the abdominal cavity, which might potentially lead to intraabdominal tumor dissemination. Results: Our LATDP served as a total biopsy to decide whether the subsequent PD was inevitable to patients with early ampulla of Vater neoplasms. Conclusion: This procedure provides the benefit of minimal invasiveness and oncological safety. Therefore, it should be considered as an option in the armamentarium of modern pancreatic and biliary tract surgeries.

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Extra-adrenal pheochromocytoma with initial symptom of haemoptysis: a case report and review of literature

Endo Y., Kitago M., Shinoda M., Yagi H., Abe Y., Hori S., Odaira M., Yokose T., Kameyama K., Kitagawa Y.

BMC Surgery （BMC Surgery） 21 （ 1 ） 13 2021年12月

ISSN 1471-2482

Background: Pheochromocytoma is a catecholamine-secreting tumour that leads to various symptoms. Haemoptysis is rarely caused by a pheochromocytoma occurring outside the bronchus or thoracic cavity. Here, we report the case of an extra-adrenal abdominal pheochromocytoma initially manifesting as haemoptysis/dyspnoea during exercise without classic symptoms. Case presentation: A 22-year-old man with a history of severe dyspnoea experienced difficulties in breathing following a marathon owing to haemoptysis that required ventilator management 1 year before presentation. His father had undergone surgery for ectopic pheochromocytoma. Computed tomography (CT) revealed a 30-mm tumour between the inferior vena cava and pancreatic head while urinalysis revealed abnormally high noradrenaline levels. He was clinically diagnosed with an extra-adrenal abdominal ectopic pheochromocytoma. After controlling blood pressure, surgery was performed, and the tumour was successfully removed. Histopathology revealed chromogranin A (+), synaptophysin (+), S100 protein (+), and MIB-1 index of 1%. Therefore, the patient was finally diagnosed with extra-adrenal abdominal ectopic pheochromocytoma. Conclusions: Haemoptysis is a rare manifestation of abdominal ectopic paraganglioma. Prompt consideration of pheochromocytoma/paraganglioma when patients experience haemoptysis without any other possible aetiology may prevent inappropriate diagnosis and treatment and ultimately fatalities.

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Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

Abe K., Ueki A., Urakawa Y., Kitago M., Yoshihama T., Nanki Y., Kitagawa Y., Aoki D., Kosaki K., Hirasawa A.

Hereditary Cancer in Clinical Practice （Hereditary Cancer in Clinical Practice） 19 （ 1 ） 5 2021年12月

ISSN 17312302

Background: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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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年12月

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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Hereditary pancreatic cancer

Abe K., Kitago M., Kitagawa Y., Hirasawa A.

International Journal of Clinical Oncology （International Journal of Clinical Oncology） 26 （ 10 ） 1784 - 1792 2021年10月

ISSN 13419625

Pancreatic cancer is associated with both family and hereditary cancer syndromes. Multigene panel testing for pancreatic cancer detected the germline variants BRCA1/2, PALB2, ATM, TP53, MLH1, STK11/LKB1, APC, CDKN2A, and SPINK1/PRSS1 as high-risk genes. A latest genome-wide association study revealed the common, but low-risk germline variants in pancreatic cancer patients. Active pancreatic surveillance using magnetic resonance imaging and endoscopic ultrasound is recommended for high-risk individuals who have a family history of pancreatic cancer or harbor these germline pathogenic variants to improve the detection rate and prognosis of pancreatic cancer. Since poly-ADP-ribose polymerase (PARP) inhibitor has been shown to be effective in improving the prognosis of BRCA-positive pancreatic cancer as well as hereditary breast and ovarian cancer syndrome, PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring the BRCA1/2 germline variant. This review highlights the importance of surveillance for germline pathogenic variants in pancreatic cancer and is expected to lead to improvements in the diagnosis and prevention of pancreatic cancer as well as facilitate the development of effective therapeutic strategies and precision medicine.

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Reduced beta cell number rather than size is a major contributor to beta cell loss in type 2 diabetes

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

Diabetologia （Diabetologia） 64 （ 8 ） 1816 - 1821 2021年08月

ISSN 0012186X

Aims/hypothesis: Type 2 diabetes is characterised by reduced beta cell mass (BCM). However, it remains uncertain whether the reduction in BCM in type 2 diabetes is due to a decrease in size or number of beta cells. Our aim was to examine the impact of beta cell size and number on islet morphology in humans with and without type 2 diabetes. Methods: Pancreas samples were obtained from 64 Japanese adults with (n = 26) and without (n = 38) type 2 diabetes who underwent pancreatectomy. Using pancreatic tissues stained for insulin, we estimated beta cell size based on beta cell diameter. Beta cell number was estimated from the product of fractional beta cell area and pancreas volume divided by beta cell size. The associations of beta cell size and number with islet morphology and metabolic status were examined. Results: Both beta cell size (548.7 ± 58.5 vs 606.7 ± 65.0 μm3, p < 0.01) and number (5.10 × 108 ± 2.35 × 108 vs 8.16 × 108 ± 4.27 × 108, p < 0.01) were decreased in participants with type 2 diabetes compared with those without diabetes, with the relative reduction in beta cell number (37%) being greater than for beta cell size (10%). Beta cell number but not size was positively correlated with BCM in participants with and without type 2 diabetes (r = 0.97 and r = 0.98, both p < 0.01) and negatively correlated with HbA1c (r = −0.45, p < 0.01). Conclusions/interpretation: Both beta cell size and number were reduced in participants with type 2 diabetes, with the relative reduction in beta cell number being greater. Decrease in beta cell number appears to be a major contributor to reduced BCM in type 2 diabetes. Graphical abstract: [Figure not available: see fulltext.]

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Clinical impact of intraoperative bile leakage during laparoscopic liver resection

Hayashi K., Abe Y., Shinoda M., Kitago M., Yagi H., Oshima G., Hori S., Wakabayashi T., Kitagawa Y.

Surgical Endoscopy （Surgical Endoscopy） 35 （ 8 ） 4134 - 4142 2021年08月

ISSN 09302794

Background: Despite the increasing number of laparoscopic liver resection (LLR) procedures, postoperative bile leakage (POBL) remains a major complication. We occasionally experienced intraoperative bile leakage (IOBL) during LLR and managed it within the restrictions of laparoscopic surgery. However, there have been no reports about IOBL in LLR. We therefore investigated the impact of IOBL on postoperative outcomes and its predictive factors. Methods: We reviewed 137 patients who underwent LLR from April 2016 to March 2019 at our institute and assigned them to IOBL-positive or IOBL-negative groups. We compared clinicopathological characteristics and perioperative outcomes. Patients were further divided into four groups according to IOBL pattern, and the frequency of POBL in each was calculated. Predictors of IOBL were identified using multivariate logistic regression analysis. Results: There were 30 and 107 patients in the IOBL-positive and IOBL-negative groups, respectively. In the IOBL-positive group, operative time and postoperative hospital stays were significantly longer (P < 0.001). The frequency of POBL was significantly higher in the IOBL-positive group (P = 0.006). The IOBL-positive group was divided into two subgroups: IOBL from the transected parenchyma (IOBL-TP, n = 18) and from the main Glissonean pedicle (IOBL-mGP, n = 12). The IOBL-negative group was divided into two subgroups: bile staining in the mGP (BS-mGP, n = 9) and no change (NC, n = 98). POBL occurred in 11% (n = 2/18) of patients with IOBL-TP, 25% (n = 3/12) of those with IOBL-mGP, 11% (n = 1/9) of those with BS-mGP, and 1% (n = 1/98) of those with NC. Age, diabetes mellitus, indocyanine green retention rate, and Glissonean approach were predictors of IOBL (P < 0.05). Conclusions: IOBL was relatively common during LLR and resulted in a higher incidence of POBL. Depending on the predictive factors, IOBL must be promptly identified and appropriately managed.

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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年08月

ISSN 2045-7634

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年08月

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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New strategy for evaluating pancreatic tissue specimens from endoscopic ultrasound-guided fine needle aspiration and surgery

Fukuhara S., Iwasaki E., Iwano T., Machida Y., Tamagawa H., Kawasaki S., Seino T., Yokose T., Endo Y., Yoshimura K., Kashiwagi K., Kitago M., Ogata H., Takeda S., Kanai T.

JGH Open （JGH Open） 5 （ 8 ） 953 - 958 2021年08月

Background and Aim: Preoperative histological evaluation of pancreatic neoplasms is important for guiding the resection strategy and preventing postoperative adverse events. However, conventional endoscopic methods have technical limitations that reduce the accuracy of the histopathological examination. Probe electrospray ionization mass spectrometry (PESI-MS) may be a useful technique for rapidly evaluating small specimens. Methods: This single-center prospective study included patients with pancreatic neoplasms between October 2018 and December 2019. Pancreatic ductal adenocarcinoma (PDAC) specimens were obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and non-neoplastic tissue was obtained via surgery. Specimens were subjected to PESI-MS and the mass spectra were analyzed using partial least squares regression-discriminant analysis. Results: The study included 40 patients with 20 nonneoplastic specimens and 19 PDAC specimens (1 case of neuroendocrine carcinoma was omitted). All nonneoplastic specimens were sufficient for PESI-MS analysis, although only 7 of 19 PDAC specimens were sufficient for PESI-MS analysis because of poor sample quality or insufficient quantity (<1 mg). Among the 27 analyzed cases, the mass spectra clearly differentiated between the PDAC and nonneoplastic specimens. Conclusions: This study revealed that PESI-MS could differentiate between PDAC and nonneoplastic specimens, even in cases where EUS-FNA produced very small specimens.

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Clinical Impact of Portal Vein Distance on Computed Tomography for Postoperative Pancreatic Fistula after Pancreatoduodenectomy

Endo Y., Kitago M., Shinoda M., Yagi H., Abe Y., Oshima G., Hori S., Yokose T., Abe K., Takemura R., Ishi R., Kitagawa Y.

World Journal of Surgery （World Journal of Surgery） 45 （ 7 ） 2200 - 2209 2021年07月

ISSN 03642313

Background: Pancreatic fistulas remain a significant concern after pancreatectomy owing to the associated high risk of mortality and high costs. It is not possible to perform preoperative risk stratification for all patients. This study aimed to evaluate the usefulness of the measurement of portal vein (PV) distance as a predictive indicator of pancreatic fistula development after pancreatoduodenectomy and compare it with the usefulness of other indicators such as body mass index (BMI), and abdominal fat area. Methods: Patient characteristics, preoperative laboratory data, radiographic findings, and their association with pancreatic fistula development after pancreatoduodenectomy were analyzed for 157 patients who underwent resection during 2011–2017. Clinically relevant postoperative pancreatic fistulas (CR-POPF) were defined as Grade B or C fistulas based on the International Study Group of Pancreatic Surgery (ISGPS) 2016 consensus. Results: CR-POPF developed in 38 patients (24.2%). Multivariate logistic regression indicated that PV distance and BMI were potential candidates for predictive models for pancreatic fistula development, and small pancreatic duct diameter, diabetes mellitus development, and pathology of non-pancreatic cancers were independent factors for CR-POPF. When comparing the two risk models (PV distance- and BMI-based models), the PV distance-derived risk model was compatible to the BMI-based stratification models (area under the curve 0.831 vs. 0.830). Conclusions: PV distance was confirmed to be a useful risk predictor for CR-POPF. This research highlighted the efficacy of abdominal thickness measurement, which is simple and easily applicable in the clinical setting.

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