Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer. METHODS: This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688). FINDINGS: Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]). INTERPRETATION: Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. FUNDING: The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.

Correlation of Vein-Rich Tumor Microenvironment of Intrahepatic Cholangiocarcinoma With Tertiary Lymphoid Structures and Patient Outcome.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer composed of large-duct and small-duct types. Understanding the tumor immune microenvironment and its related vascular system is important for developing novel and efficient therapies. We focused on tertiary lymphoid structure (TLS) as a hallmark of antitumor immunity and investigated the clinicopathologic significance of TLSs and the influence of vascular microenvironment on TLS formation in iCCAs. We examined 261 iCCA cases clinicopathologically and analyzed the vascular system using immunohistochemistry. Single-cell (102,685 cells) and bulk RNA (33 iCCA cases) sequencing analyses were performed using data sets downloaded from public databases, and endothelial cell characteristics in iCCA tissues and functional networks related to the tumor microenvironment were bioinformatically examined. High densities of both intratumoral and peritumoral TLSs were significantly associated with prolonged survival only in large-duct-type iCCA. Multivariate analyses showed that peritumoral TLS was a prognostic factor for the large-duct type. TLS-rich iCCA had a significantly higher vein density and tumor-infiltrating T-cell count than TLS-poor iCCA. Both the presence of TLSs and high vein endothelial cells in iCCA tissues were significantly associated with molecular networks representing active immune responses in transcriptomic analysis. Vein density was a prognostic factor in patients with large-duct and small-duct types. This suggests that TLS formation is involved in a microenvironment with high vein density, which represents an antitumor-directed immune microenvironment.

Impact of Surgical Margin Status on Survival and Recurrence After Pancreaticoduodenectomy for Distal Cholangiocarcinoma: Is Microscopic Residual Tumor (R1) Associated with Higher Rates of Local Recurrence?

BACKGROUND: Patients undergoing macroscopically curative resection for distal cholangiocarcinoma (DCC) have high recurrence rates and poor prognoses. This study aimed to investigate the impact of surgical margin status on survival and recurrence after resection of DCC, specifically focusing on microscopic residual tumor (R1) and its relationship to local recurrence. PATIENTS AND METHODS: This was a retrospective analysis of patients who had undergone pancreaticoduodenectomy (PD) for DCC between 2005 and 2021. Surgical margin was classified as R0, R1cis (positive bile duct margin with carcinoma in situ), and R1inv (positive bile duct margin with an invasive subepithelial component and/or positive radial margin). RESULTS: In total, 29 of 133 patients (21.8%) had R1cis and 23 (17.3%) R1inv. The 5-year overall survival (OS) for R0 (55.7%) did not differ significantly from that for R1cis/R1inv (47.4%/33.6%, respectively). The 5-year recurrence-free survival (RFS) for R0 was significantly longer than that for R1inv (50.1% vs. 17.4%, p = 0.003), whereas RFS did not differ significantly between those with R0 and R1cis. R1cis/R1inv status was not an independent predictor of OS and RFS in multivariate analysis. Cumulative incidence of isolated distant recurrence was significantly higher for R1cis/R1inv than for R0 (p = 0.0343/p = 0.0226, respectively), whereas surgical margin status was not significantly associated with rates of local or local plus distant recurrence. CONCLUSIONS: Surgical margin status does not significantly impact OS and RFS in patients undergoing PD for DCC following precise preoperative imaging evaluation. Additionally, R1 status is significantly linked to higher isolated distant recurrence rather than local recurrence, highlighting the importance of multidisciplinary therapy.

Prognostic Role for Primary Tumor Location in Patients With Colorectal Liver Metastases: A Comparison of Right-Sided Colon, Left-Sided Colon, and Rectum.

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: This was a retrospective study from 2003 to 2017. SETTINGS: The study was conducted in a National Cancer Center Hospital. PATIENTS: 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. MAIN OUTCOME MEASURES: Primary outcomes were relapse-free survival and overall survival. RESULTS: 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%, and 5-year overall survival rates were 53.9%, 70.3%, and 60.8%. 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%). LIMITATIONS: This study was retrospective in design. CONCLUSIONS: 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 . PAPEL PRONSTICO DE LA UBICACIN DEL TUMOR PRIMARIO EN PACIENTES CON METSTASIS HEPTICAS COLORRECTALES UNA COMPARACIN ENTRE COLON DERECHO, COLON IZQUIERDO Y RECTO: ANTECEDENTES:Aunque se reconoce cada vez más que el cáncer de colon del lado derecho tiene un peor pronóstico que el cáncer colorrectal del lado izquierdo para las metástasis hepáticas colorrectales, se sabe poco acerca de las diferencias entre el recto y el colon del lado izquierdo.OBJETIVO:Este estudio evaluó el valor pronóstico de la ubicación del tumor primario en pacientes con metástasis hepáticas colorrectales examinando el recto y el colon del lado izquierdo por separado.DISEÑO:Este fue un estudio retrospectivo de 2003 a 2017.ENTORNO CLÍNICO:El estudio se llevó a cabo en un Hospital del Centro Nacional de Cáncer.PACIENTES:La cohorte del estudio incluyó a 489 pacientes con metástasis hepáticas colorrectales de cáncer de colon del lado derecho (n = 119, 24%), cáncer de colon del lado izquierdo (n = 251, 51%) o cáncer de recto (n = 119, 24%). %) que fueron sometidos a resección hepática.PRINCIPALES MEDIDAS DE VALORACIÓN:Los resultados primarios fueron la supervivencia sin recaídas y la supervivencia general.RESULTADOS:Las tasas de supervivencia sin recaída a cinco años para los pacientes con cáncer de colon derecho, cáncer de colon izquierdo y cáncer de recto fueron del 28,6%, 34,1%, y 26,4%, respectivamente, y las tasas de supervivencia general a los 5 años fueron del 53,9%, 70,3%, y 60,8%, respectivamente. El análisis multivariable reveló diferencias significativas en la supervivencia sin recaída y la supervivencia general entre el cáncer de colon izquierdo y el cáncer de recto (supervivencia sin recaída: HR = 1,37, p = 0,03; supervivencia general: HR = 1,49, p = 0,03) y entre el cáncer de colon izquierdo y el cáncer de colon del lado derecho (supervivencia libre de recaídas: HR = 1,39, p = 0,02; supervivencia global: HR = 1,60, p = 0,01), pero no entre el cáncer de colon del lado derecho y el cáncer de recto. En pacientes con recurrencia (n = 325), el cáncer de colon izquierdo tuvo la tasa de recurrencia en sitios múltiples más baja y la tasa de resección quirúrgica más alta por recurrencia (cáncer de colon izquierdo, 20%/46%; cáncer de colon derecho, 32%/30%; cáncer de recto, 26%/39%).LIMITACIONES:Este estudio fue de diseño retrospectivo.CONCLUSIONES:El cáncer de recto se asoció con una peor supervivencia sin recaída y una supervivencia general peor en comparación con el cáncer de colon izquierdo en pacientes con metástasis hepáticas colorrectales que se sometieron a resección hepática. Nuestros hallazgos sugieren que el colon y el recto del lado izquierdo deben considerarse entidades distintas en las metástasis hepáticas colorrectales. Consulte Video Resumen en http://links.lww.com/DCR/B882 . (Tradducción-Dr. Ingrid Melo ).

A new era of the Asian clinical research network: a report from the ATLAS international symposium.

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia.

A multi-centre, double-blind, randomized, placebo-controlled trial to evaluate the effectiveness and safety of ramelteon for the prevention of postoperative delirium in elderly cancer patients: a study protocol for JORTC-PON2/J-SUPPORT2103/NCCH2103.

Postoperative delirium is an important issue in cancer patients, affecting surgical outcomes and the quality of life. Ramelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors. Clinical trials and observational studies in Japan, including in surgical cancer patients, have shown efficacy of ramelteon in delirium prevention, with no serious safety concerns. However, clinical trials from the USA have reported conflicting results. A Japanese phase II study investigated the efficacy and safety of ramelteon for delirium prevention following gastrectomy in patients aged ≥75 years, with findings suggesting the feasibility of a phase III trial. The aim of this multi-centre, double-blind, randomized placebo-controlled phase III trial is to evaluate the effectiveness and safety of oral ramelteon for postoperative delirium prevention in cancer patients aged ≥65 years as advanced medical care. The trial protocol is described here.

Objective Definition and Optimized Strategy for "Biologically Borderline Resectable" Colorectal Liver Metastases.

BACKGROUND: The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. METHODS: A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu's nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensity score matching analysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. RESULTS: Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS (n = 139) and bBR-NAC (n = 101). Ten (10%) in the bBR-NAC group (n = 101) experienced biological status change from unfavorable to favorable after NAC (Biological Conversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37-23.1; P = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups (n = 67 for each) was found in long-term outcomes. CONCLUSIONS: NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the Biological Conversion.

Enhanced Recognition Confidence of Millimeter-Sized Intrahepatic Targets by Real-Time Virtual Sonography.

OBJECTIVES: Real-time virtual sonography (RVS) is an artificial-intelligence-assisted ultrasonographic navigation system that displays synchronized preoperative computed tomography (CT) images corresponding to real-time intraoperative ultrasonograms (IOUS). This study aimed to investigate whether RVS can enhance IOUS identification of small intrahepatic targets found in preoperative CT. METHODS: Patients with small intrahepatic targets detected by preoperative thin-slice dynamic CT before liver resection were included. The targets included millimeter-sized liver tumors or a third-order or more distal portal branch and were marked on CT images using 3D simulation software. After laparotomy, the targets were searched using fundamental IOUS, and participating liver surgeons subjectively scored the target identifying confidence on a scale of 1-5 (5 points for detection with the highest confidence and one point for undetectable). Then, the search procedure was repeated using the RVS, and the scores were compared. RESULTS: Totally, 55 patients with 117 small targets were investigated. The median target size was 6.0 mm, and the median registration time was 3.6 seconds. The target identification confidence score significantly increased from 2.78 to 4.52 points after using RVS. Seventeen targets (14.5%) were undetectable in fundamental IOUS, and 14 of them were identified by RVS. The detectability of small liver tumors (2-5 points of identification confidence) by IOUS was 81.1 and 96.7% by RVS. CONCLUSION: RVS enhanced surgeons' confidence in identifying millimeter-sized intrahepatic targets found in preoperative CT.

Neoadjuvant therapy alters the collagen architecture of pancreatic cancer tissue via Ephrin-A5.

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.

Prognostic Impact of Radiological Splenic Artery Involvement in Pancreatic Ductal Adenocarcinoma of the Body and Tail.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Chronological improvement of pancreatectomy for resectable but advanced pancreatic neuroendocrine neoplasms.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Application of albumin-bilirubin grade and platelet count to indocyanine green-based criteria for hepatectomy: Predicting impaired liver function and postoperative outcomes of hepatocellular carcinoma.

BACKGROUND: 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). METHODS: 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%). RESULTS: Three-hundred nine patients had abnormal ICGR15. Predictors of abnormal ICGR15 included in the nomogram were: ALBI grade >1 (hazard ratio [HR]: 2.16, 95% confidence interval [CI]: 1.59-2.94), platelet count <130 000/mm3 (HR: 2.27, 95% CI: 1.68-3.08), aspartate aminotransferase >50 (IU/L) (HR: 1.90, 95% CI: 1.29-2.81), and viral hepatitis infection (HR: 1.46, 95% CI: 1.03-2.07). The nomogram named the PLT-ALBI score was discriminative [C-statistics: 0.719 (0.684-0.754)], and reliable (Hosmer-Lemeshow Chi-Square: 9.05, p = 0.338). The higher PLT-ALBI score was associated with a more frequent incidence of clinically relevant posthepatectomy liver failure and poor overall survival. CONCLUSIONS: The 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.

A novel endoscopic technique using fully covered self-expandable metallic stents for benign strictures after hepaticojejunostomy: the saddle-cross technique (with video).

BACKGROUND: In recent years, the number of patients with hepaticojejunostomy anastomotic strictures has increased. Balloon dilation and placement of multiple plastic stents have proven effective for hepaticojejunostomy anastomotic strictures. However, for refractory strictures, there is often a need for repeated endoscopic procedures within a short period. This study aimed to assess the efficacy and safety of the new saddle-cross technique, which uses two fully covered self-expandable metallic stents. METHODS: This was a retrospective analysis of 20 patients with benign hepaticojejunostomy anastomotic strictures who underwent placement of two fully covered self-expandable metallic stents at the National Cancer Center, Japan, from November 2017 to June 2021. RESULTS: The technical and clinical success rates were 100% (20/20). The median time of the procedure was 61 (range 25-122) min. The scheduled stent removal rate was 70% (14/20). Spontaneous dislodgement of the stent was observed on computed tomography in five patients (25.0%). The non-restenosis rate 12 months after the saddle-cross technique was 88.2% (15/17). Procedure-related early adverse events included mild ascending cholangitis in three patients (15.0%) and sepsis in one patient (5.0%). Procedure-related late adverse events included mild ascending cholangitis in three patients (15.0%) and bile duct hyperplasia in one patient (5.0%). CONCLUSIONS: The saddle-cross technique performed using two fully covered self-expandable metallic stents resulted in promising long-term stricture resolution with a high technical success rate. Based on these findings, the saddle-cross method can be considered an option for the standard procedure for benign hepaticojejunostomy anastomotic strictures.

Hepatoid carcinoma and related entities of the extrahepatic bile duct: A clinicopathological study of four cases.

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.

Prognostic impact of conversion hepatectomy for initially unresectable colorectal liver metastasis.

PURPOSE: This study aimed to evaluate 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 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] 0.64-1.37, p = 0.796) or OS (HR 1.12, 95% CI 0.67-1.79, p = 0.667). In the conversion group, multivariable analysis identified the following independent prognostic factors: timing of liver metastases for RFS (synchronous: HR 3.14, 95% CI 1.20-8.24, p = 0.020) and preoperative CEA level 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 good long-term prognosis after conversion hepatectomy.

Characteristics of false-positive lesions in evaluating colorectal liver metastases on gadoxetic acid-enhanced magnetic resonance imaging.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Characterization of the large-scale Japanese patient-derived xenograft (J-PDX) library.

The use of patient-derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J-PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross-cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1-year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J-PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report.

Drain Placement After Uncomplicated Hepatic Resection Increases Severe Postoperative Complication Rate: A Japanese Multi-institutional Randomized Controlled Trial (ND-trial).

OBJECTIVE: To assess the clinical impact of a no-drain policy after hepatic resection. SUMMARY OF BACKGROUND DATA: Previous randomized controlled trials addressing no-drain policy after hepatic resection seem inconclusive because they did not adopt appropriate study design to validate its true clinical impact. METHODS: This unblinded, randomized controlled trial was done at 7 Japanese institutions. Patients undergoing hepatic resection without biliary reconstruction were randomized to either D group or ND group. When the risk of postoperative bile leakage or hemorrhage were considered high, the patients were excluded during the operation. Primary endpoint was the postoperative complication of C-D grade 3 or higher within 90 postoperative days. A noninferiority of ND group to D group was assessed, and if it was confirmed, a superiority was assessed. RESULTS: Between May 2015 and July 2017, a total of 400 patients were finally included in the per-protocol set analysis: 199 patients in D group and 201 patients in ND group. Intraoperatively, 37 patients were excluded from the final enrollment because of high risk of bile leakage or hemorrhage. Postoperative complication rate of C-D grade 3 or higher was 8.0% (16/199) in the D group and 2.5% (5/201) in the ND group. The risk difference was -5.5% (95% confidence interval: -9.9% to -1.2%) and fulfilled the prescribed noninferiority margin of 4%. No postoperative mortality was experienced in both groups. Bile leakage was diagnosed in 8.0% (16/199) of the D group and none in the ND group (P < 0.001). In none of the subgroups classified based on 8 potentially relevant factors, drain placement was favored in terms of C-D grade 3 or higher complication. CONCLUSIONS: Drains should not be placed after uncomplicated hepatic resections.

Expression of classical human leukocyte antigen class I antigens, HLA-E and HLA-G, is adversely prognostic in pancreatic cancer patients.

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.

Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.