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Although right-sided colon cancer is increasingly recognized as having a worse prognosis than left-sided colorectal cancer for colorectal liver metastases, little is known about the differences between the left-sided colon and rectum.This study evaluated the prognostic value of primary tumor location in patients with colorectal liver metastases by examining the left-sided colon and rectum separately.This was a retrospective study from 2003 to 2017.The study was conducted in a National Cancer Center Hospital.The study cohort included 489 patients with colorectal liver metastases from right-sided colon cancer (n=119, 24%), left-sided colon cancer (n=251, 51%), or rectal cancer (n=119, 24%) who underwent hepatic resection.Primary outcomes were relapse-free survival and overall survival.Five-year relapse-free survival rates for patients with right-sided colon cancer, left-sided colon cancer, and rectal cancer were 28.6%, 34.1%, and 26.4%, respectively, and 5-year overall survival rates were 53.9%, 70.3%, and 60.8%, respectively. Multivariable analysis revealed significant differences in relapse-free survival and overall survival between left-sided colon cancer and rectal cancer (relapse-free survival: HR=1.37, p=0.03; overall survival: HR=1.49, p=0.03) and between left-sided colon cancer and right-sided colon cancer (relapse-free survival: HR=1.39, p=0.02; overall survival: HR=1.60, p=0.01), but not between right-sided colon cancer and rectal cancer. In patients with recurrence (n=325), left-sided colon cancer had the lowest multiple-site recurrence rate and the highest surgical resection rate for recurrence (left-sided colon cancer, 20%/46%; right-sided colon cancer, 32%/30%; rectal cancer, 26%/39%).This study was retrospective in design.Rectal cancer was associated with worse relapse-free survival and overall survival compared with left-sided colon cancer in patients with colorectal liver metastases who underwent hepatic resection. Our findings suggest that the left-sided colon and rectum should be considered distinct entities in colorectal liver metastases. See Video Abstract at http://links.lww.com/DCR/B882 .

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers.

Splenic artery (SpA) involvement heralds poor prognosis in pancreatic ductal adenocarcinoma (PDAC) of the body and tail but is not included in the resectability criteria. This study evaluated the prognostic impact of radiological SpA involvement in PDAC of the body and tail.Preoperative computed tomography images of patients who underwent distal pancreatectomy for resectable PDAC of the body and tail (n = 242) at our hospital between 2004 and 2018 were graded according to splenic vessel involvement status as clear, abutment, or encasement. Clinicopathological prognostic factors and overall survival (OS) and recurrence-free survival (RFS) rates were compared between the three groups. The prognostic value of radiological involvement status was assessed using Harrell's concordance statistic (C-index) and time-dependent receiver-operating characteristic curve analysis and compared with pathological findings.The diagnostic concordance rate was 0.87 (weighted κ statistic). Prognosis worsened with progression from clear, abutment, to encasement status. SpA encasement (hazard ratio [HR] 1.97, p = 0.04) predicted poor OS in multivariate Cox hazard regression analysis. SpA abutment (HR 1.77, p = 0.017) and encasement (HR 1.86, p = 0.034) independently predicted poor RFS. Splenic vein abutment and encasement were not significant predictors of poor OS or RFS. SpA encasement without adjuvant chemotherapy had the poorest prognosis because of early distant metastasis. The prognostic value was higher for radiological SpA involvement than for pathological SpA invasion.Radiological SpA involvement status is a meaningful and reproducible prognostic indicator that can be used preoperatively for determining the treatment strategy in PDAC of the body and tail.

Hepatoid carcinoma or related entities (HPC/RTs) are extremely rare, especially in the extrahepatic bile duct (EHBD). Only a few case reports have been published. We analyzed the clinicopathological features of HPCs/RTs in EHBD. HPC/RT of extrahepatic cholangiocarcinoma (eCCA) cases were selected based on the histological characteristics and immunohistochemical detection of spalt-like transcription factor 4 (SALL4) and/or alpha-fetoprotein (AFP). Four HPC/RT cases arose in the distal but not in the perihilar EHBD. The four patients with HPC/RT included one female and three males with a median age of 77 years. There are various macroscopic types of HPC/RT. The predominant histological features were two solid-type carcinomas that mimicked hepatocellular carcinoma and two well-differentiated tubular adenocarcinomas. Immunohistochemically, SALL4 and glypican-3 were expressed in all cases, and AFP was expressed in one case. Cancer cell phenotypes included intestinal, pancreatobiliary, and mixed pancreatobiliary and intestinal types. Focal neuroendocrine differentiation and severe perineural and lymphovascular invasions were also observed. HPC/RT recurred in two patients within 2 years, and one patient died 13 months postoperatively. It is suggested that the HPC/RT of EHBD shares common characteristics with HPC/RT arising in various organs, and has some unique characteristics. HPC/RT of EHBD might be more aggressive than conventional eCCA.

BACKGROUND: The treatment of pancreatic cancer (PDAC) remains clinically challenging, and neoadjuvant therapy (NAT) offers down staging and improved surgical resectability. Abundant fibrous stroma is involved in malignant characteristic of PDAC. We aimed to investigate tissue remodelling, particularly the alteration of the collagen architecture of the PDAC microenvironment by NAT. METHODS: We analysed the alteration of collagen and gene expression profiles in PDAC tissues after NAT. Additionally, we examined the biological role of Ephrin-A5 using primary cultured cancer-associated fibroblasts (CAFs). RESULTS: The expression of type I, III, IV, and V collagen was reduced in PDAC tissues after effective NAT. The bioinformatics approach provided comprehensive insights into NAT-induced matrix remodelling, which showed Ephrin-A signalling as a likely pathway and Ephrin-A5 (encoded by EFNA5) as a crucial ligand. Effective NAT reduced the number of Ephrin-A5(+) cells, which were mainly CAFs; this inversely correlated with the clinical tumour shrinkage rate. Experimental exposure to radiation and chemotherapeutic agents suppressed proliferation, EFNA5 expression, and collagen synthesis in CAFs. Forced EFNA5 expression altered CAF collagen gene profiles similar to those found in PDAC tissues after NAT. CONCLUSION: These results suggest that effective NAT changes the extracellular matrix with collagen profiles through CAFs and their Ephrin-A5 expression.

Recent studies highlighted the clinicopathological heterogeneity of non-ampullary duodenal adenomas and adenocarcinomas, but the detailed process of the malignant transformation remains unclear. We analyzed 144 adenomas and 54 adenocarcinomas of the non-ampullary duodenum for immunohistochemical phenotypes, genetic alterations, and mismatch repair (MMR) status to probe their histogenetic relationship. The median ages of patients with adenoma and adenocarcinoma were the same (66 years). Adenomas were histologically classified as intestinal-type adenoma (n = 124), pyloric gland adenoma (PGA, n = 10), gastric-type adenoma, not otherwise specified (n = 9), and foveolar-type adenoma (n = 1). Protein-truncating APC mutations were highly frequent in adenomas (85%), with the highest prevalence in intestinal-type adenomas (89%), but rare in adenocarcinomas (9%; P = 2.1 × 10–23). Close associations between phenotypic marker expression and genetic alterations were observed in adenomas, but not in adenocarcinomas, excluding the common association between GNAS mutations and MUC5AC expression. MMR deficiency was more frequent in adenocarcinomas (20%) than in adenomas (1%; P = 2.6 × 10–6). One MMR-deficient adenoma and three MMR-deficient adenocarcinomas occurred in patients with Lynch syndrome. Additionally, three other patients with an MMR-deficient adenocarcinoma fulfilled the revised Bethesda criteria. The discrepant APC mutation frequency between adenomas and adenocarcinomas suggests that APC-mutated adenomas, which constitute the large majority of non-ampullary duodenal adenomas, are less prone to malignant transformation. Non-ampullary duodenal adenocarcinomas frequently exhibit MMR deficiency and should be subject to MMR testing to determine appropriate clinical management, including the identification of patients with Lynch syndrome.

Progress of non-surgical treatments in the last decade has improved the prognosis of pancreatic neuroendocrine neoplasms (PanNEN). However, the improvement of surgery for advanced PanNEN remains unknown. This study aimed to investigate the chronological changes of the clinical impact of pancreatectomy for PanNEN.Patients undergoing curative-intent pancreatectomy for PanNEN between 1991 and 2010 were categorized into the earlier period group, and those between 2011 and 2021 were into the later period group. Advanced PanNEN was defined as showing resectable synchronous liver metastases or invasion to portal venous systems or adjacent organs. The recurrence-free survival (RFS) and overall survival (OS) were analyzed among patients with non-advanced and advanced PanNENs. The independent prognostic risk factors were identified using a Cox proportional hazard model.A total of 189 patients (n = 54 in the earlier period and n = 135 in the later period) were included. The proportion of advanced PanNEN increased from 15% to 30% (P = 0.027). The RFS and OS of non-advanced PanNEN were similar between the periods. Whereas, among patients with advanced PanNEN, the later period group showed improved prognosis; The 5-year RFS of the earlier period vs. the later period was 0% vs. 27%, and the 5-year OS was 38% vs. 82% (p = 0.013).A radical surgical treatment for advanced PanNEN has shown prognostic improvement in this decade. However, more careful perioperative examinations and possibly, additional treatments are required for PanNEN with portal vein invasion.

Objective Preventing postoperative delirium with agitation is vital in the older population. We examined the preventive effect of yokukansan on postoperative delirium with agitation in older adult patients undergoing highly invasive cancer resection. Methods We performed a secondary per-protocol analysis of 149 patients’ data from a previous clinical trial. Patients underwent scheduled yokukansan or placebo intervention 4–8 days presurgery and delirium assessment postoperatively. Delirium with agitation in patients aged ≥75 years was assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and the Japanese version of the Delirium Rating Scale-Revised-98. We assessed odds ratios for yokukansan (TJ-54) compared with placebo for the manifestation of postoperative delirium with agitation across patients of all ages (n = 149) and those aged ≥65 years (n = 82) and ≥ 75 years (n = 21) using logistic regression. Results Delirium with agitation manifested in 3/14 and 5/7 patients in the TJ-54 and placebo groups, respectively, among those aged ≥75 years. The odds ratio for yokukansan vs. placebo was 0.11 (95% confidence interval: 0.01–0.87). An age and TJ-54 interaction effect was detected in patients with delirium with agitation. No intergroup differences were observed in patients aged ≥65 years or across all ages for delirium with agitation. Conclusions This is the first study investigating the preventive effect of yokukansan on postoperative delirium with agitation in older adults. Yokukansan may alleviate workforce burdens in older adults caused by postoperative delirium with agitation following highly invasive cancer resection.

Purpose: This study evaluated the prognostic impact of conversion hepatectomy in patients with initially unresectable colorectal liver metastasis (CRLM) and to identify prognostic factors after conversion hepatectomy.Methods: Correlations of conversion hepatectomy with relapse-free survival (RFS) and overall survival (OS) were retrospectively investigated in 554 consecutive patients who underwent hepatectomy for CRLM in 2000–2017. Prognostic factors after conversion hepatectomy were examined in multivariable analysis.Results: Five hundred and nine patients (92%) had initially resectable CRLM at the time of diagnosis and underwent hepatectomy (primary resection group) and 45 (8%) underwent conversion hepatectomy following chemotherapy (conversion group). The 5-year RFS was 30.0% in the primary resection group and 19.8% in the conversion group (p=0.042); the respective 5-year OS rates were 62.0% and 52.4% (p=0.253). Multivariable analysis did not identify conversion hepatectomy as a significant prognostic factor for RFS (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.65–1.38, p=0.787) or OS (HR 1.12, 95% CI 0.69–1.83, p=0.643). In the conversion group, multivariable analysis identified timing of liver metastases (synchronous: HR 3.14, 95% CI 1.20–8.24, p=0.020) and the preoperative CEA level to be independent prognostic factors for RFS (>5 ng/ml: HR 3.10, 95% CI 1.45–6.61, p=0.003) and OS (>5 ng/ml: HR 3.29, 95% CI 1.18–9.17, p=0.023).Conclusions: RFS and OS rates after conversion hepatectomy were not inferior to those after primary resection in patients with CRLM. Patients with a normal CEA level before hepatectomy can be expected to have a good long-term prognosis after conversion hepatectomy.

Introduction: Although the safety of biliary tract cancer resection has improved over the years, the recurrence rate is still high, and the postoperative prognosis remains low after biliary tract cancer resection. Therefore, the development of effective adjuvant therapy is essential to improve treatment outcomes. Because biliary tract cancer is rare compared with other gastrointestinal cancers, there have been only a small number of clinical trials of adjuvant therapy. However, in recent years, the results of several large-scale randomized controlled trials have been published, and clinical trials investigating the efficacy of new regimens are currently ongoing.Areas covered: This review presents the results of previously published important phase II and III clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and discusses their interpretation. The future direction of new research on resectable biliary tract cancer treatment is also discussed.Expert opinion: The foundations of large-scale clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer are underway, and new trials will establish evidence of their effectiveness. Additionally, breakthroughs in treatment through genetic and molecular research are expected.

Background: In hepatocellular carcinoma (HCC), several standard regimens with angiogenesis inhibitors and immune checkpoint inhibitors have been established; however, novel therapeutic strategies to target key molecules associated with HCC are further required to improve treatment options. ErbB3 (HER3), a member of the HER receptor tyrosine kinase family, has recently emerged as a promising therapeutic target in various cancers. In this study, HER3 expression status after current targeted therapies in HCC was evaluated in order to explore an opportunity for developing anti-HER3 therapy for HCC. Methods: We collected clinical data and tumor tissue from HCC patients (pts) who received systemic therapy between January 2010 and June 2020 and the tissue samples at post systemic therapy were also obtained. Immunohistochemical staining for HER3 was conducted using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: Seventeen pts were eligible. Eight pts (47%) were HER3 2+/3+, (2+: 7, 3+: 1,), while nine pts (53%) were 0/1+ (0: 4, 1+: 5). For HER3 2+/3+ and HER3 0/1+ groups, median age (range) was 63(43-71)/69(47-78), median alpha-fetoprotein levels were 6071(4-23620)/19.1(1.2-1138) [ng/ml], and median des-gamma-carboxy prothrombin levels were 1351(135-92650)/302(10-10916) [mAU/ml], respectively. The proportions of patients with HER3 2+/3+ were 67% in HCV+ pts, 25% in HBV+ pts, and 43% in other etiologies. Median overall survival of HER3 2+/3+ and 0/1+ pts after start of first line systemic therapy was 32.3 (95% CI: 8.7-51.4) and 12.9 (95% CI: 6.1-20.7) months, respectively (HR: 0.28, 95% CI: 0.09-0.92, p=0.036).Paired pre- and post-treatment samples were available for eight pts. The median number of regimens administered between the pre- and post-treatment samples was 2(1-5). Treatment regimens were sorafenib: 7; lenvatinib: 2; ramucirumab: 1; others: 10, including duplicates. At post-treatment, HER3 was upregulated in 4 pts (1 pt: 0 to 1+, 3 pts: 1+ to 2+) and downregulated in 3 pts (all pts: 1+ to 0). Pts with HER3 upregulation had developed resistance after at least one prior tyrosine kinase inhibitor (TKI) with stable disease or partial response as best response. Conclusion: In this study, 47% of pts were HER3 2+/3+ at post-treatment. In paired analysis, half of pts upregulated HER3 expression after systemic therapy including TKIs, suggesting HER3 might be one of the factors associated with resistance to systemic therapy. Citation Format: Mao Okada, Chigusa Morizane, Tomoyuki Satake, Mariko Nishioka, Nobuyoshi Hiraoka, Satoshi Nara, Tomoya Kakegawa, Maki Kobayashi, Kumiko Koyama, Minoru Esaki, Takuji Okusaka. HER3 expression after systemic therapy and clinical characteristics in patients with hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4484.

To validate the newly developed artificial intelligence (AI)-assisted simulation by evaluating the speed of three-dimensional (3D) reconstruction and accuracy of segmental volumetry among patients with liver tumors.AI with a deep learning algorithm based on healthy liver computer tomography images has been developed to assist three-dimensional liver reconstruction in virtual hepatectomy.3D reconstruction using hepatic computed tomography scans of 144 patients with liver tumors was performed using two different versions of Synapse 3D (Fujifilm, Tokyo, Japan): the manual method based on the tracking algorithm and the AI-assisted method. Processing time to 3D reconstruction and volumetry of whole liver, tumor-containing and tumor-free segments were compared.The median total liver volume and the volume ratio of a tumor-containing and a tumor-free segment were calculated as 1035 mL, 9.4%, and 9.8% by the AI-assisted reconstruction, whereas 1120 mL, 9.9%, and 9.3% by the manual reconstruction method. The mean absolute deviations were 16.7 mL and 1.0% in the tumor-containing segment and 15.5 mL and 1.0% in the tumor-free segment. The processing time was shorter in the AI-assisted (2.1 vs. 35.0 min; p 0.001).The virtual hepatectomy, including functional liver volumetric analysis, using the 3D liver models reconstructed by the AI-assisted methods, was reliable for the practical planning of liver tumor resections.

Applicability of the albumin-bilirubin (ALBI) grade in preoperative decision-making criteria based on the indocyanine green retention (ICG) test remains unclear. This study aimed to predict abnormal ICG values using standard blood tests and evaluate the impact on postoperative outcomes among patients undergoing hepatectomy for hepatocellular carcinoma (HCC).Data on 949 consecutive HCC patients undergoing curative-intent hepatectomy between 1996 and 2014 were retrospectively assessed. A nomogram using preoperative standard blood tests was created to predict abnormal ICGR15 (15%).Three-hundred nine patients had abnormal ICGR15. Predictors of abnormal ICGR15 included in the nomogram were: ALBI grade1 (hazard ratio [HR]: 2.16, 95% confidence interval [CI]: 1.59-2.94), platelet count130 000/mmThe PLT-ALBI score is applicable in distinguishing HCC patients with abnormal ICGR15. Patients with higher PLT-ALBI score require more careful postoperative care, despite following the ICG criteria.

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has improved clinical outcomes in patients with HER2-positive breast and gastric cancers, although ineffective or recurrent cases are present. One reason for this is the heterogeneity of HER2 expression in cancer cells. The aim of this study was to investigate the clinicopathological characteristics and HER2 status of patients with biliary tract cancers (BTCs). We examined HER2 protein expression by immunohistochemistry, HER2 gene amplification by fluorescence in situ hybridization, and both HER2 protein and gene levels simultaneously by gene-protein assay. Samples were collected from 454 patients who underwent surgical resection for BTCs (110 intrahepatic cholangiocarcinomas [ICC], 67 perihilar extrahepatic cholangiocarcinomas [ECC-Bp], 119 distal extrahepatic cholangiocarcinomas [ECC-Bd], 80 gallbladder carcinomas [GBC], and 79 ampullary carcinomas [AVC]). HER2 status was assessed according to the guidelines for HER2 testing in gastroesophageal adenocarcinoma. HER2-positive status was detected in 14.5% of BTCs (3.7% of ICC, 3.0% of ECC-Bp, 18.5% of ECC-Bd, 31.3% of GBC, and 16.4% of AVC). Furthermore, HER2-positivity tended to correlate with low histological grade, tumor histology, and macroscopic features in certain tumors. HER2 heterogeneity was common and highly frequent (83%) in BTC cases. Reduced HER2 protein expression in the deeper invasive areas with simultaneous dedifferentiation was frequently observed in HER2-positive cancer cells. The findings of this study suggest that a large subgroup of HER2-positive BTC cases can be considered for HER2-targeted therapy. Moreover, the HER2 status in BTCs should be determined carefully using a sensitive approach toward larger cancer tissues.

The expression of classical human leukocyte antigen class I antigens (HLA‐I) on the surfaces of cancer cells allows cytotoxic T cells to recognize and eliminate these cells. Reduction or loss of HLA‐I is a mechanism of escape from antitumor immunity. The present study aimed to investigate the clinicopathological impacts of HLA‐I and non–classical HLA‐I antigens expressed on pancreatic ductal adenocarcinoma (PDAC) cells. We performed immunohistochemistry to detect expression of HLA‐I antigens in PDAC using 243 PDAC cases and examined their clinicopathological influences. We also investigated the expression of immune‐related genes to characterize PDAC tumor microenvironments. Lower expression of HLA‐I, found in 33% of PDAC cases, was significantly associated with longer overall survival. Higher expression of both HLA‐E and HLA‐G was significantly associated with shorter survival. Multivariate analyses revealed that higher expression of these three HLA‐I antigens was significantly correlated with shorter survival. Higher HLA‐I expression on PDAC cells was significantly correlated with higher expression of IFNG, which also correlated with PD1, PD‐L1 and PD‐L2 expression. In vitro assay revealed that interferon gamma (IFNγ) stimulation increased surface expression of HLA‐I in three PDAC cell lines. It also upregulated surface expression of HLA‐E, HLA‐G and immune checkpoint molecules, including PD‐L1 and PD‐L2. These results suggest that the higher expression of HLA‐I, HLA‐E and HLA‐G on PDAC cells is an unfavorable prognosticator. It is possible that IFNγ promotes a tolerant microenvironment by inducing immune checkpoint molecules in PDAC tissues with higher HLA‐I expression on PDAC cells., human leukocyte antigen class I antigens (HLA‐I) are needed for T cells to recognize target cells. Here, we showed that higher HLA‐I expression on pancreatic cancer cells is associated with poor prognosis, where formation of the tolerant microenvironment may be involved in IFNγ.

Background and aim A risk-stratification score may be useful for colorectal cancer (CRC) screening, alongside screening colonoscopy (CS) and fecal immunochemical test (FIT). This study aimed to evaluate the effectiveness and cost-effectiveness of population-based CRC screening strategies using CS, FIT, and the Japanese CRC screening score. Methods The effectiveness in quality-adjusted life years (QALYs), cost-effectiveness, and required number of CS procedures were evaluated for screening strategies with primary screening CS (strategy 1), FIT (strategy 2), and the risk score (strategy 3), using a simulation model analysis with two scenarios. In scenario 1, uptake rates for all tests were 60%. In scenario 2, uptake rates for FIT and a risk score were 40%, and those for screening CS and CS following a positive FIT or high risk score were 20% and 70%, respectively. Results In scenario 1, strategy 1 gained the highest QALYs and required the highest cost. The incremental cost-effectiveness ratios per QALY gained for strategy 1 against the others were lower than 5 000 000 JPY. Strategy 1 required more than twice as many CS procedures as the other strategies. In scenario 2, strategy 3 had the highest QALYs and lowest cost, and strategy 1 had the lowest QALYs and highest cost. Conclusions Screening CS has the potential to be the most effective and cost-effective form of CRC screening, although it requires a large number of CS procedures. However, if non-invasive tests are preferred by recipients, other screening strategies, particularly those using the risk score, can be more effective and cost-effective.

BACKGROUND A right-sided round ligament (RSRL) is a rare, congenital anomaly of the intrahepatic portal vein, with a reported frequency of 0.2%-1.2%. For patients with perihilar cholangiocarcinoma associated with an RSRL, an accurate understanding of the vascular and biliary anatomy is indispensable. CASE SUMMARY We report a 70-year-old male with perihilar cholangiocarcinoma associated with an RSRL. After percutaneous transhepatic embolization of the left and anterior portal branches, we conducted a left trisectionectomy of the liver with extrahepatic bile duct resection and hepaticojejunostomy. The postoperative course was uneventful, and R0 resection was achieved. When the liver volume of each section was compared between 7 patients with an RSRL and 20 patients with normal portal vein anatomy, the posterior section in RSRL patients was significantly larger than that in patients with normal portal vein anatomy (median: 457 mL vs 306 mL, P = 0.031). In patients with perihilar cholangiocarcinoma associated with an RSRL, left trisectionectomy has several surgical advantages: (1) The posterior branch of the portal vein often ramifies independently, and the division of the portal vein is easily conducted; (2) A relatively large amount of remnant liver can be retained; and (3) The anatomy of the posterior branch of the Glissonian pedicle is similar to that in patients with normal anatomy. CONCLUSION In patients with an RSRL and perihilar cholangiocarcinoma that does not involve the posterior section, left trisectionectomy may be a favorable choice.

TPS621 Background: Biliary tract cancer (BTC) is a highly lethal disease. The prognosis remains poor even after macroscopically curative resection due to the high recurrence rate. Therefore, developing effective adjuvant therapy is essential to improve treatment outcomes. In 2021, a phase III trial (JCOG1202: ASCOT) showed the superiority of adjuvant S-1 chemotherapy to surgery alone in the overall survival (OS) in BTC patients with curative resection (hazard ratio [HR] 0.694, 95% confidence interval [CI]: 0.514–0.935; p=0.008). Consequently, adjuvant S-1 chemotherapy has become the standard of care for resected BTC. In contrast, only a few studies have been conducted to assess the effectiveness of neoadjuvant therapy for BTC until now. Recently, a phase III trial (KHBO1401-MITSUBA) demonstrated the superiority of gemcitabine + cisplatin + S-1 (GCS) therapy to gemcitabine + cisplatin in patients with advanced unresectable BTC in terms of OS (HR 0.79, 90% CI: 0.628–0.996; p=0.046). The GCS arm showed a high response rate (41.5%), with promise in a neoadjuvant setting. This phase III trial aims to confirm the superiority of neoadjuvant GCS to surgery first in patients with resectable BTC. Methods: The main eligibility criteria are: (1) histologically diagnosed with adenocarcinoma or adenosquamous carcinoma; (2) diagnosed as resectable BTC with clinical stage II–IVA for perihilar bile duct cancer, stage IB–III for distal bile duct cancer, stage IIIA–IVA for gallbladder cancer, stage IIA–III for ampullary cancer, or stage III–IVA/stage IVB (T4N1M0) for intrahepatic bile duct cancer by diagnostic imaging; (3) Eastern Cooperative Oncology Group Performance Status 0 or 1; and (4) age ≥20 years. Enrolled patients are randomized 1:1 to neoadjuvant GCS + surgery + adjuvant S-1 or surgery + adjuvant S-1 regarding the center and primary site (perihilar/distal/gall bladder/ampulla of Vater/intrahepatic) by the minimization method. The GCS regimen comprises gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on day 1 and S-1 (80-120 mg/day) on days 1–7, every 2 weeks for 3 courses. After surgery, S-1 (80-120 mg/day) for 4 weeks-on, 2 weeks-off, for a total of 4 cycles, is administered in both arms. The primary endpoint is OS, and secondary endpoints are progression-free survival (PFS), OS and PFS in patients who underwent R0/R1 resection, incidence of non-resection, %R0 resection, %R0/R1 resection, %lymph node metastasis, postoperative complications of Clavien–Dindo Grade IIIa or severer, serious adverse events, and objective response rate in the GCS arm. We calculated a sample size of 330 patients to obtain 70% power at a one-sided alpha error of 5%, a hazard ratio of 0.698 (3-year OS 67% vs 75.6%), an accrual period of 5 years, and a follow-up period of 3 years. The patient accrual was started in March 2021, and 126 patients have been enrolled as of September 2022. Clinical trial information: jRCTs031200388 .

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths worldwide. The high mortality rate in HCC is largely due to the difficulty of early detection. In this study, to improve patient outcomes, serum samples from 345 patients with HCC, 46 patients with chronic hepatitis (CH), 93 patients with liver cirrhosis (LC), and 1,033 healthy individuals were analyzed with microRNA (miRNA) microarrays. We investigated the diagnostic potential of circulating miRNAs in serum and developed a detection model of HCC, including early stage. A diagnostic model was constructed based on the expression levels of a combination of miRNAs in a discovery set. We selected 52 miRNAs that had altered expressions according to disease progression status, established the diagnostic model with a combination of eight miRNAs in the discovery set, and tested the model in a validation set. The diagnostic values for discriminating cancer from HCC at-risk control samples were as follows: area under the curve, 0.99; sensitivity, 97.7%; specificity, 94.7%. With this model, 98% of stage I HCC cases were detected; these results were much better than those observed from conventional methods. Conclusion: Circulating miRNAs could serve as biomarkers for the accurate detection of HCC. Because the diagnostic accuracy was maintained even in stage I, this may represent an accurate detection method even for early stage HCC.

BACKGROUND/PURPOSE Endoscopic transpapillary re-intervention (ETP-RI) after multiple self-expandable metallic stent (SEMS) placement for unresectable malignant hilar biliary obstruction (MHBO) is challenging, but endoscopic ultrasound-guided biliary drainage (EUS-BD) could be an alternative following failed ETP-RI. We investigated appropriate re-intervention (RI) methods in MHBO after multiple SEMS placement and evaluated RI with EUS-BD (EUS-RI) benefits following ETP-RI failure. METHODS Patients requiring RI after multiple SEMS placement for MHBO between October 2017 and April 2021 were enrolled. Patients' characteristics, metallic-stent type, stent-placement configuration, overall survival, stent patency, re-intervention results, and re-intervention technical and clinical success rates were reviewed. RESULTS Forty-nine patients underwent ETP-RI for MHBO. ETP-RI's technical success rate was 69.4%. Of 15 failed ETP-RI cases, all underwent EUS-RI, achieving technical and clinical success rates of 86.7% and 100%, respectively. Time to recurrent biliary obstruction (TRBO) after RI was significantly different between EUS-RI and ETP-RI (212 vs 84 days; P = .01). On multivariate analysis, EUS-RI was the only factor associated with TRBO (odds ratio: 4.48; 95% confidence interval: 1.01-19.91; P = .04). Acute pancreatitis and bile peritonitis were present in 6.1% of ETP-RI and 13.3% of EUS-RI cases, respectively; both improved conservatively. CONCLUSIONS EUS-RI was effective and safe in difficult ETP-RI cases after multiple SEMS placement for MHBO.

Gadoxetic acid-enhanced MRI (Gd-EOB-MRI) shows higher sensitivity for colorectal liver metastases (CRLM) than contrast-enhanced computed tomography (CECT). However, the details of false-positive lesions for each imaging modality are unknown.Cases undergoing hepatectomy for CRLM following a preoperative evaluation with both CECT and Gd-EOB-MRI between July 2008 and December 2016 were reviewed. The false-positive and false-negative rates were assessed for each modality, and the characteristics of false-positive lesions were evaluated.We evaluated 275 partial hepatectomies in 242 patients without preoperative chemotherapy. Among the 275 hepatectomies, 546 lesions were recognized by CECT and/or Gd-EOB-MRI. The false-positive rates for CECT and Gd-EOB-MRI were 4% (18/422) and 7% (37/536), respectively. The size of false-positive lesions was significantly smaller than that of correctly diagnosed lesions (median: 28 mm [3-120 mm] vs 7.6 mm [320 mm], P 0.001). Compared with the 233 correctly diagnosed lesions ≤ 20 mm in diameter, false-positive lesions were more frequently located near the liver surface or vasculobiliary structures than true lesions (33/37 [89%] vs 149/233 [64%], respectively; P = 0.0021).Gd-EOB-MRI had a 7% false-positive rate. A small size and tumor location near the surface or near vasculobiliary structures were associated with false positivity.

Tissue amino acid profiles depend on the cell types and extracellular components that constitute the tissue, and their functions and activities. We aimed to characterize the tissue amino acid profiles in several types of pancreatic tumors and lesions. We examined tissue amino acid profiles in 311 patients with pancreatic tumors or lesions. We used newly developed LC-MS/MS methods to obtain the profiles, which were compared with clinicopathological data. Each tumor or lesion presented a characteristic tissue amino acid profile. Certain amino acids were markedly altered during the multistep pancreatic carcinogenesis and pancreatic ductal adenocarcinoma (PDAC) progression. A tissue amino acid index (TAAI) was developed based on the amino acids that were notably changed during both carcinogenesis and cancer progression. Univariate and multivariate survival analyses revealed that PDAC patients with a high TAAI exhibited a significantly shorter survival rate, and these findings were validated using a second cohort. We suggest that tissue amino acid profiles are characteristic for normal tissue type, tumor histological type, and pathological lesion, and are representative of the cancer grade or progression stage in multistep carcinogenesis and of malignant characteristics. The TAAI could serve as an independent prognosticator for patients with PDAC.

Bacillus cereus is associated with foodborne illnesses characterized by vomiting and diarrhea. Although some B. cereus strains that cause severe extraintestinal infections and nosocomial infections are recognized as serious public health threats in healthcare settings, the genetic backgrounds of B. cereus strains causing such infections remain unknown. By conducting pulsed-field gel electrophoresis and multilocus sequence typing, we found that a novel sequence type (ST), newly registered as ST1420, was the dominant ST isolated from the cases of nosocomial infections that occurred in 3 locations in Japan in 2006, 2013, and 2016. Phylogenetic analysis showed that ST1420 strains belonged to the Cereus III lineage, which is much closer to the Anthracis lineage than to other Cereus lineages. Our results suggest that ST1420 is a prevalent ST in B. cereus strains that have caused recent nosocomial infections in Japan.

According to the revised staging of the American Joint Committee on Cancer, 8th edition (AJCC8), the N category in pancreatic ductal adenocarcinoma is classified as N0 (0), N1 (1–3), and N2 (≥ 4) based on the number of metastatic lymph nodes (LNs). This study aimed to validate this classification and analyze cutoff values of metastatic LN numbers. Patients with pancreatic head ductal adenocarcinoma who underwent pancreaticoduodenectomy at our institution between 2005 and 2016 without preoperative therapy were retrospectively analyzed. The patients were staged by AJCC8, and prognostic analyses were performed. The best cutoff value for the metastatic LN number was determined by the minimum P value approach. In 228 of 309 patients, LN metastases were found (median number of examined LNs, 41). The median survival time (MST) was 56 months in the N0 group, 34 months in the N1 group, and 20 months in the N2 group (N0 vs N1: P = 0.023; N1 vs N2: P

Neural invasion is one of the malignant features contributing to locally advanced and/or metastatic disease progression in patients with pancreatic ductal adenocarcinoma (PDAC). Few studies exist on the distribution and state of nerve fibers in PDAC tissue and their clinicopathological impacts. The aim of the present study was to investigate the clinicopathological characteristics and prognostic value of intrapancreatic neural alterations in patients with PDAC. We retrospectively analyzed 256 patients with PDAC who underwent macroscopic curative surgery. Nerve fibers, immunolabeled with a specific neural marker GAP‐43, were digitally counted and compared among PDAC, chronic pancreatitis (CP) and normal pancreatic tissues. Interlobular nerve fibers were apparently hypertrophic in both CP and PDAC, although intrapancreatic neural density and nerve number decreased characteristically in PDAC. They tended to decrease toward the center of the tumor. Kaplan‐Meier survival analyses revealed a statistically significant correlation between low neural density and shorter overall survival (OS) (P = 0.014), and between high neural invasion and shorter OS (P = 0.017). Neural density (P = 0.04; HR = 1.496; 95% CI 1.018‐2.199) and neural invasion ratio (P = 0.064; HR = 1.439; 95% CI .980‐2.114) were prognostic factors of shorter OS in the multivariate analysis. These findings suggest low intrapancreatic neural density in patients with PDAC as an independent prognosticator, which may represent aggressive tumor behavior. Furthermore, we propose a simple, practical and reproducible method (to measure neural density and the neural invasion ratio during conventional histopathological diagnosis of PDAC), which has been validated using another cohort (n = 81).

The outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors. This retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital. The 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226–10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594–10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0–1 risk factors and those with 2–3 risk factors, respectively (P

Background Whether the portal/superior mesenteric vein (PV) should be resected during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) based on preoperative CT or intraoperative findings is controversial. Methods This was a retrospective study with data of patients who had undergone pancreatoduodenectomy for PDAC between 2002 and 2016 in a tertiary referral centre. Based on the extent of contact between the PV and tumour on CT, patients were categorized into: group 1, no contact; group 2, contact 180° or less; group 3, contact greater than 180°. Extent of pathological PV invasion (pPV) (no invasion, pv0; invasion to tunica adventitia, pv1; invasion to media, pv2; invasion to intima, pv3) was compared with patient survival. To assess the feasibility of performing PV resection (PVR) based on intraoperative findings, the prognosis of patients in groups 1 and 2 with pv0 and no PVR (PVR(-)pv0) was compared with that of patients who had PVR (PVR(+)pv0), selected using propensity score matching. Results Groups 1, 2 and 3 comprised 230, 232 and 38 patients respectively, and PVR was performed in 10·9, 73·3 and 95 per cent of them (P

Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P