研究者詳細 - 北郷　実

論文 - 北郷　実

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Predictive risk-score model to select patients with intrahepatic cholangiocarcinoma for adjuvant chemotherapy.

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

HPB : the official journal of the International Hepato Pancreato Biliary Association 25 （ 2 ） 229 - 238 2023年02月

ISSN 1365-182X

Background: The aim of this study was to develop a predictive model to identify individuals most likely to derive overall survival (OS) benefit from adjuvant chemotherapy (AC) after hepatic resection of intrahepatic cholangiocarcinoma (ICC). Methods: Patients who underwent hepatic resection of ICC between 1990 and 2020 were identified from a multi-institutional database. Factors associated with worse OS were identified and incorporated into an online predictive model to identify patients most likely to benefit from AC. Results: Among 726 patients, 189 (26.0%) individuals received AC. Factors associated with OS on multivariable analysis included CA19-9 (Hazard Ratio [HR]1.17, 95%CI 1.04–1.31), tumor burden score (HR1.09, 95%CI 1.04–1.15), T-category (T2/3/4, HR1.73, 95%CI 1.73–2.64), nodal disease (N1, HR3.80, 95%CI 2.02–7.15), tumor grade (HR1.88, 95%CI 1.00–3.55), and morphological subtype (HR2.19, 95%CI 1.08–4.46). A weighted predictive score was devised and made available online (https://yutaka-endo.shinyapps.io/ICCrisk_model_for_AC/). Receipt of AC was associated with a survival benefit among patients at high/medium-risk (high: no AC, 0% vs. AC, 20.6%; medium: no AC, 36.4% vs. 40.8%; both p < 0.05) but not low-risk (low: no AC, 65.1% vs. AC, 65.1%; p = 0.73) tumors. Conclusion: An online predictive model based on tumor characteristics may help identify which patients may benefit the most from AC following resection of ICC.

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Adverse effects of long-term drain placement and the importance of direct aspiration: a retrospective cohort study.

Okui J, Obara H, Uno S, Sato Y, Shimane G, Takeuchi M, Kawakubo H, Kitago M, Okabayashi K, Kitagawa Y

The Journal of hospital infection 131 156 - 163 2023年01月

ISSN 0195-6701

Background: Long-term placement of prophylactic drains may result in retrograde infections. Aim: To investigate the association between the timing of drain removal and clinical outcomes. Methods: This retrospective, single-centre cohort study evaluated 110 patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery and developed subsequent organ/space surgical site infection (SSI) between 2016 and 2020. The difference between the culture-positive species of prophylactic drains and direct aspiration was evaluated; whether the prophylactic drains functioned effectively at the time of SSI diagnosis; and whether the empirical antibiotics administered before drainage were effective against all the detected bacteria. Finally, clinical outcomes were compared between early (i.e. cases wherein the prophylactic drain had already been removed or replaced at the time of SSI diagnosis) and late (removal after diagnosis) drain removal. Findings: The prophylactic drains functioned effectively in only 27 (25%) patients at the time of SSI diagnosis. Due to the results of direct aspiration cultures, 43% of patients required antibiotic escalation. The median time to drain removal or first replacement was seven postoperative days. The early removal group included 43 patients (39%). Compared with early removal, late removal resulted in a higher frequency of vancomycin use (7.0% vs 22.4%; P = 0.037). Conclusion: Prolonged prophylactic drain placement is associated with complicated infections requiring vancomycin; therefore, the drains should be removed as soon as possible. Additionally, obtaining the cultures of direct aspiration should be actively considered, as escalation of antimicrobial therapy is often performed based on culture results.

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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 32 9636897231170437 2023年01月

ISSN 0963-6897

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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Resection of Late Recurrence of Gastric Cancer with Duodenal and Bile Duct Strictures 22 Years after Surgery for Gastric Cancer

Koizumi W., Kitago M., Sekido Y., Kabeshima Y.

Japanese Journal of Gastroenterological Surgery 56 （ 7 ） 377 - 383 2023年

ISSN 03869768

A 71-year-old man was referred to our hospital due to duodenal and bile duct strictures. He had a history of distal gastrectomy for gastric cancer 22 years ago. Pancreatoduodenectomy was planned for diagnosis of duodenal cancer or cholangiocarcinoma. Severe adhesion was observed around the gastroduodenal anastomosis. Poorly differentiated adenocarcinoma was detected around the pancreatic parenchyma in intraoperative rapid pathological diagnosis of the resected pancreatic stump. Macroscopic findings of the specimen revealed tumor invasion from outside the bile duct wall. The adenocarcinoma was similar to gastric cancer resected 22 years ago. Due to addition of Alcian blue-PAS staining, peritoneal washing cytology, which had previously indicated cancer cells to be negative in rapid intraoperative examination, revealed positive cancer cells (CY1). Small mesenteric nodules of the small intestine sampled intraoperatively were also diagnosed as poorly differentiated adenocarcinoma (P1). The final diagnosis was local recurrence and peritoneal dissemination of gastric cancer. We report this case as an example of histological diagnosis of late recurrence of gastric cancer 22 years after initial treatment.

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The Association between Electroencephalography with Auditory Steady-State Response and Postoperative Delirium.

Arai N, Miyazaki T, Nakajima S, Okamoto S, Moriyama S, Niinomi K, Takayama K, Kato J, Nakamura I, Hirano Y, Kitago M, Kitagawa Y, Takahashi T, Shimizu H, Mimura M, Noda Y

Journal of personalized medicine 13 （ 1 ） 2022年12月

ISSN 2075-4426

Delirium is a disorder of consciousness and a risk factor for cognitive dysfunction and poor prognosis. We hypothesized that preoperative gamma activities would be linked to postoperative delirium. We enrolled 71 subjects for elective surgery and recorded auditory steady-state response (ASSR) by electroencephalography (EEG) before the surgery and examined postoperative delirium with DSM-5. The EEG data were analyzed for baseline power, and ASSR evoked power (EP) and phase-locking factor (PLF) within the gamma range. Postoperative delirium was found in 18 patients (delirium group) but not in 53 patients (non-delirium group). There were no significant differences in the 40-Hz EP or PLF between the two groups. The baseline gamma activity negatively correlated with the 40-Hz PLF in the non-delirium group (ρ = −0.444, p < 0.01). The correlation between baseline gamma activity and 40-Hz EP was not significant in either the delirium or non-delirium group. In all patients, both preoperative PLF and EP had no significant correlations with the Delirium Rating Scale Revised-98 and the Memorial Delirium Assessment Measure at the post-operation, respectively. The disruption of the neurophysiological relationship between baseline gamma activity before sound stimuli and the PLF of the 40-Hz ASSR may be one of the potential neurophysiological indicators associated with postoperative delirium.

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Epstein-Barr virus-associated inflammatory pseudotumor variant of follicular dendritic cell sarcoma of the liver: a case report and review of the literature.

Abe K, Kitago M, Matsuda S, Shinoda M, Yagi H, Abe Y, Oshima G, Hori S, Endo Y, Yokose T, Miura E, Kubota N, Ueno A, Masugi Y, Ojima H, Sakamoto M, Kitagawa Y

Surgical case reports 8 （ 1 ） 220 2022年12月

ISSN 2198-7793

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An organ-derived extracellular matrix triggers in situ kidney regeneration in a preclinical model

Tajima K., Yagi H., Morisaku T., Nishi K., Kushige H., Kojima H., Higashi H., Kuroda K., Kitago M., Adachi S., Natsume T., Nishimura K., Oya M., Kitagawa Y.

npj Regenerative Medicine （npj Regenerative Medicine） 7 （ 1 ） 18 2022年12月

It has not been considered that nephrons regenerate in adult mammals. We present that an organ-derived extracellular matrix in situ induces nephron regeneration in a preclinical model. A porcine kidney-derived extracellular matrix was sutured onto the surface of partial nephrectomy (PN)-treated kidney. Twenty-eight days after implantation, glomeruli, vessels, and renal tubules, characteristic of nephrons, were histologically observed within the matrix. No fibrillogenesis was observed in the matrix nor the matrix-sutured kidney, although this occurred in a PN kidney without the matrix, indicating the structures were newly induced by the matrix. The expression of renal progenitor markers, including Sall1, Six2, and WT-1, within the matrix supported the induction of nephron regeneration by the matrix. Furthermore, active blood flow was observed inside the matrix using computed tomography. The matrix provides structural and functional foundations for the development of cell-free scaffolds with a remarkably low risk of immune rejection and cancerization.

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Incisional wound closure by sequential partial split-thickness skin grafting following failure of primary abdominal fascia closure after open abdomen management: A case report.

Suzuki S, Yamamoto R, Hori S, Kitago M, Kitagawa Y, Sasaki J

International journal of surgery case reports 101 107802 2022年12月

ISSN 2210-2612

Introduction: Open abdomen (OA) is a widely used technique for managing abdominal organ injury, abdominal compartment syndrome, and abdominal sepsis. While various methods have contributed to successful primary closure of the abdominal fascia after OA, some patients still develop enteroatmospheric fistulas that impede abdominal fascia closure. We report a case of successful epithelialization of the incision by sequential partial split-thickness skin grafting (STSG) in a patient who had failure in primary abdominal fascia closure due to enteroatmospheric fistulas after OA for incisional dehiscence and anastomotic leakage. Presentation of case: A 73-year-old male patient underwent pancreaticoduodenectomy for duodenal adenocarcinoma. The abdominal incision was then necrosed and dehisced due to anastomotic leakage on postoperative day (POD) 6, and multiple intra-abdominal lavages with OA were performed. On POD 15, the patient developed enteroatmospheric fistulas; thus, primary fascia closure was considered impossible. On PODs 72 and 106, STSG was conducted on the granulation tissue at the incisional wound, and complete epithelialization was achieved on POD 111. Discussion: Sequential partial STSG only needed basic surgical skills and standard devices for surgery. Conclusion: We reported the case with successful epithelialization of the incision by sequential partial STSG, in which primary abdominal fascia closure was failed due to enteroatmospheric fistulas after OA for incisional dehiscence and anastomotic leakage.

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Tumor Burden Score and Serum Alpha-fetoprotein Subclassify Intermediate-Stage Hepatocellular Carcinoma.

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

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 26 （ 12 ） 2512 - 2521 2022年12月

ISSN 1091-255X

Background: Resection of Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) remains controversial. While not recommended by the BCLC algorithm, some patients may indeed benefit from hepatectomy. We sought to identify that subset of patients who might derive long-term survival benefit from resection. Methods: Intermediate-stage HCC patients who underwent curative-intent resection were identified from an international multi-institutional database. Factors associated with long-term prognosis were identified using multivariate analysis and a risk score was developed and assessed. Results: Among 194 patients, most individuals had two tumors (n = 123, 63.4%) with a median size of 6.0 cm (IQR, 4.0–8.4) for a median tumor burden score (TBS) of 6.5 (IQR, 5.0–9.1); median alpha-fetoprotein (AFP) was 23.9 ng/mL (IQR, 5.0–503.2), and median overall survival (OS) was 69 months (IAR, 60.7–77.3). Factors associated with OS included AFP (referent ≤ 20 ng/mL, > 20 ng/mL: HR 1.78 95%CI, 1.09–2.89) and TBS (referent TBS ≤ 8.0, TBS > 8.0: HR 1.72 95%CI, 1.07–2.75). While 71 (36.6%) patients had neither risk factor, 79 (40.7%) and 44 (22.7%) had 1 or 2, respectively. A simplified score stratified patients relative to recurrence-free survival (RFS) (0: 33.6% vs. 1: 18.0% vs. 2: 14.7%) (AUC 0.60) and recurrence time (i.e., < 6 months after surgery) (0: 21.3% vs. 1: 43.1% vs. 2: 68.6%) (AUC 0.69) (both p < 0.001). Of note, a higher score was also associated with incrementally worse 5-year OS (0: 68.1% vs. 1: 61.0% vs. 2: 29.9%) (AUC 0.62) (p < 0.001). Conclusion: Long-term OS and RFS outcomes varied considerably. Using a simple risk score, patients with low AFP and low TBS were identified as the subset of individuals most likely to benefit from resection.

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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 20 （ 1 ） 366 2022年11月

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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腹腔鏡下胆嚢摘出術とリンパ節切除を施行し混合性神経内分泌非神経内分泌腫瘍と診断された1例

川本潤一郎, 藤田晃司, 鴇沢一徳, 溝田高聖, 森永正二郎, 北郷実

日本消化器外科学会雑誌（(一社)日本消化器外科学会） 55 （ 10 ） 633 - 641 2022年10月

ISSN 0386-9768

症例は81歳の女性で,血尿を主訴に当院泌尿器科を受診した.腹部CTにて肝門部に20mmの結節性病変を指摘され,当科紹介となった.腹部超音波検査では,胆嚢結石と胆嚢内に6mm大の隆起性病変を認め,胆嚢頸部に接して径24mmのリンパ節腫大を認めた.造影MRIでは同結節にring-enhanced lesionを認め,拡散強調像では淡い高信号を示し,リンパ節腫大が疑われた.診断的治療目的に腹腔鏡下胆嚢摘出術とリンパ節(#12c)切除術を施行した.病理組織学的検査で,胆嚢隆起性病変は混合性神経内分泌非神経内分泌腫瘍(mixed neuroendocrine-non- neuroendocrine neoplasm;以下,MiNENと略記)と診断され,腫大したリンパ節は腫瘍の転移であった.追加切除として術後36日目に肝十二指腸間膜リンパ節郭清を施行したが,切除した12個のリンパ節に転移は認めなかった.最終病期はpT2N1M0 pStage IIIbであった.一般的に予後不良といわれるMiNENに対して,診断的治療目的の手術および追加の領域リンパ節郭清手術を経験したため報告する.(著者抄録)

A Novel Online Calculator to Predict Risk of Microvascular Invasion in the Preoperative Setting for Hepatocellular Carcinoma Patients Undergoing Curative-Intent Surgery.

Endo Y, Alaimo L, Lima HA, Moazzam Z, Ratti F, Marques HP, Soubrane O, Lam V, Kitago M, Poultsides GA, Popescu I, Alexandrescu S, Martel G, Workneh A, Guglielmi A, Hugh T, Aldrighetti L, Endo I, Pawlik TM

Annals of surgical oncology 30 （ 2 ） 725 - 733 2022年09月

ISSN 1068-9265

Background: The presence of microvascular invasion (MVI) has been highlighted as an important determinant of hepatocellular carcinoma (HCC) prognosis. We sought to build and validate a novel model to predict MVI in the preoperative setting. Methods: Patients who underwent curative-intent surgery for HCC between 2000 and 2020 were identified using a multi-institutional database. Preoperative predictive models for MVI were built, validated, and used to develop a web-based calculator. Results: Among 689 patients, MVI was observed in 323 patients (46.9%). On multivariate analysis in the test cohort, preoperative parameters associated with MVI included α-fetoprotein (AFP; odds ratio [OR] 1.50, 95% confidence interval [CI] 1.23–1.83), imaging tumor burden score (TBS; hazard ratio [HR] 1.11, 95% CI 1.04–1.18), and neutrophil-to-lymphocyte ratio (NLR; OR 1.18, 95% CI 1.03–1.35). An online calculator to predict MVI was developed based on the weighted β-coefficients of these three variables (https://yutaka-endo.shinyapps.io/MVIrisk/). The c-index of the test and validation cohorts was 0.71 and 0.72, respectively. Patients with a high risk of MVI had worse disease-free survival (DFS) and overall survival (OS) compared with low-risk MVI patients (3-year DFS: 33.0% vs. 51.9%, p < 0.001; 5-year OS: 44.2% vs. 64.8%, p < 0.001). DFS was worse among patients who underwent an R1 versus R0 resection among those patients at high risk of MVI (R0 vs. R1 resection: 3-year DFS, 36.3% vs. 16.1%, p = 0.002). In contrast, DFS was comparable among patients at low risk of MVI regardless of margin status (R0 vs. R1 resection: 3-year DFS, 52.9% vs. 47.3%, p = 0.16). Conclusion: Preoperative assessment of MVI using the online tool demonstrated very good accuracy to predict MVI.

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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 51 （ 6 ） 617 - 623 2022年09月

ISSN 0885-3177

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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ASO Visual Abstract: A Novel Online Calculator to Predict Risk of Microvascular Invasion in the Preoperative Setting for HCC Patients Undergoing Curative-Intent Surgery.

Endo Y, Alaimo L, Lima HA, Moazzam Z, Ratti F, Marques HP, Soubrane O, Lam V, Kitago M, Poultsides GA, Popescu I, Alexandrescu S, Martel G, Workneh A, Gulielmi A, Hugh T, Aldrighetti L, Endo I, Pawlik TM

Annals of surgical oncology 2022年09月

ISSN 1068-9265

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KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer.

Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka M, Takamatsu M, Arita J, Kato T, Kawaguchi Y, Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N, Takeda T, Tateishi K, Uemura S, Koike K, Ushiku T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago M, Takahashi Y, Fujishiro M, GTK Pancreatic Cancer Study Group in Japan.

Cancer science 113 （ 9 ） 3097 - 3109 2022年09月

ISSN 1347-9032

KRAS mutation is a major driver of pancreatic carcinogenesis and will likely be a therapeutic target. Due to lack of sensitive assays for clinical samples of pancreatic cancer with low cellularity, KRAS mutations and their prognostic association have not been fully examined in large populations. In a multi-institutional cohort of 1162 pancreatic cancer patients with formalin-fixed paraffin-embedded tumor samples, we undertook droplet digital PCR (ddPCR) for KRAS codons 12/13/61. We examined detection rates of KRAS mutations by clinicopathological parameters and survival associations of KRAS mutation status. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed using the Cox regression model with adjustment for potential confounders. KRAS mutations were detected in 1139 (98%) patients. The detection rate did not differ by age of tissue blocks, tumor cellularity, or receipt of neoadjuvant chemotherapy. KRAS mutations were not associated with DFS or OS (multivariable HR comparing KRAS-mutant to KRAS-wild-type tumors, 1.04 [95% CI, 0.62–1.75] and 1.05 [95% CI, 0.60–1.84], respectively). Among KRAS-mutant tumors, KRAS variant allele frequency (VAF) was inversely associated with DFS and OS with HRs per 20% VAF increase of 1.27 (95% CI, 1.13–1.42; ptrend <0.001) and 1.31 (95% CI, 1.16–1.48; ptrend <0.001), respectively. In summary, ddPCR detected KRAS mutations in clinical specimens of pancreatic cancer with high sensitivity irrespective of parameters potentially affecting mutation detections. KRAS VAF, but not mutation positivity, was associated with survival of pancreatic cancer patients.

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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 ） e14261 2022年06月

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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Severity of early diagnosed organ/space surgical site infection in elective gastrointestinal and hepatopancreatobiliary surgery

Okui J., Obara H., Shimane G., Sato Y., Kawakubo H., Kitago M., Okabayashi K., Kitagawa Y.

Annals of Gastroenterological Surgery （Annals of Gastroenterological Surgery） 6 （ 3 ） 445 - 453 2022年05月

Background: Organ/space surgical site infection (SSI) is a significant clinical problem. The postdiagnosis course of organ/space SSIs and the impact of its early diagnosis on clinical outcomes are yet to be clarified. Thus, we aimed to investigate the association between the timing of diagnosis and the clinical outcome of organ/space SSI. Methods: This retrospective, single-center cohort study evaluated patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery between 2016 and 2020. Clinical outcomes were compared between the early group (ie, SSI diagnosed until postoperative day [POD] 4) and normal-late group (ie, SSI diagnosed after POD 5). The primary outcome was the final C-reactive protein (CRP) level within 14 d after organ/space SSI diagnosis. Results: In total, 110 patients were evaluated. The median time of diagnosis was 7 d postoperatively (interquartile range, 5–9 d postoperatively). Compared with the normal-late group, the early group included a higher proportion of patients with Clavien–Dindo grade ≥IIIb (8/21 vs 11/89, P =.01), higher final CRP value within 14 d after SSI diagnosis (mean, 4.49 mg/dL vs 2.27 mg/dL, P =.01), longer postoperative length of hospitalization (median, 45.0 d vs 33.0 d; P =.028), and worse 1-y overall survival rate (74.8% vs 89.3%, P =.08). Conclusion: Early diagnosed organ/space SSI are originally severe and may therefore be detected earlier. Importantly, early diagnosed organ/space SSI is likely to be severe and refractory.

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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年05月

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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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年05月

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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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年05月

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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