Kentaro Sudo’s research while affiliated with Chiba Cancer Center and other places

Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens obtained from a single ACC patient, such as bile, biopsy, and resected tumor. Despite initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of pure exocrine lineage, designated as HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. Summarily, we document a novel ACC cell line, which could be useful for ACC studies in the future.

In the era of genomic medicine, there is a growing need to obtain tissue samples suitable for tumor genotyping. Recent studies have focused on the development of optimal devices and techniques in endoscopic ultrasound-guided tissue acquisition (EUS-TA) for pancreatic cancer. In addition to sufficient tissue acquisition, it is also necessary to optimize preanalytical steps (e.g. sample processing, formalin fixation, and specimen preparation for analysis) to improve the success rate of gene panel testing. Close cooperation with pathologists and technicians is essential for successful analysis. However, in some cases, it is still challenging to obtain sufficient tissue samples. In such cases, we should consider other methods of genomic testing such as plasma cell-free DNA genotyping, microsatellite instability testing, and germline BRCA1/2 testing depending on the patient's condition. In this review, we discuss the role of EUS-TA in the clinical practice of gene panel testing for pancreatic cancer.

Overall survival in a phase III study for metastatic pancreatic cancer has significantly improved with gemcitabine (GEM) plus nab-paclitaxel. However, to date, there is limited data on the efficacy and safety of its use for patients with locally advanced (LA) or borderline resectable pancreatic cancer (BRPC). Here, we investigated the efficacy and safety of first-line GEM plus nab-paclitaxel for LA or BRPC. We retrospectively analysed consecutive patients with pathologically confirmed, untreated LA or BRPC who started receiving first-line GEM plus nab-paclitaxel. A total of 30 patients (LA, n = 22; BRPC, n = 8) were analysed. Twelve patients (40%) without distant metastasis received additional chemoradiotherapy using S-1. Laparotomy was performed on 8 patients and 6 (20%; LA, n = 3; BR, n = 3) achieved R0 resection. Objective response rate was 44.8%. For all patients, median progression-free survival and overall survival were 14.8 and 29.9 months, respectively. Median overall survival for LA was 24.1 months with a 2-year survival rate of 50.8%. The most frequently observed grade 3 or 4 toxicities were neutropenia (73%) and biliary infection (13%). First-line GEM plus nab-paclitaxel was well-tolerated and feasible with an encouraging survival for LA or BRPC.

260 Background: Advances in technology of genomic sequencing have revealed the mutational landscape of pancreatic cancer. However, little is known with regard to molecular mechanisms underlying clinical diversity in “unresectable” advanced pancreatic cancer. Methods: We performed whole-exome sequencing using frozen cancer tissues prospectively obtained by EUS-FNA from primary tumors before chemotherapy in patients with metastatic or locally advanced pancreatic cancer (n = 35). All patients had pathological confirmation (adenocarcinoma, n = 34; carcinoma, n = 1). Somatic alterations in the cancer genome were compared with clinical outcomes. Results: Seventeen patients had metastatic disease and 18 had locally advanced disease. Thirty-four patients received chemotherapy with or without radiotherapy and one patient was treated with supportive care alone because of rapidly progressive disease. With a median follow-up time of 60.6 months (range 41.9–94.0) for censored cases, the median survival for all patients was 10.8 months. Nine patients survived more than 2 years ( > 6 years, n = 2; > 3 years, n = 3; > 2 years, n = 4), while 11 patients died within 4 months. We show mutational landscape of unresectable advanced pancreatic cancer and identified somatic mutations in known cancer related genes including KRAS (89%), TP53 (71%), SMAD4 (20%), CDKN2A (17%) and ARID1A (14%). We found that ARID1A mutation was mutually exclusive with TP53 mutation except for one tumor and had a significant correlation with survival outcomes. Among 9 patients who survived more than 2 years, 5 patients (56%) had ARID1A somatic mutation, whereas none (0%) had mutations in the remaining 26 patients who died within 2 years ( P = 0.0004). The median overall survival was 47.7 months for 5 patients with ARID1A-mutated tumors and 8.9 months for 30 patients with ARID1A wild-type tumors ( P = 0.0101). Conclusions: This is the first study to perform whole-exome sequencing in unresectable pancreatic cancer patients including very long-term survivors. We found that ARID1A mutations were associated with longer survival.

Advances in next-generation sequencing (NGS) technology have revealed the landscape of genomic alterations in patients with pancreatic cancer. NGS-based genomic profiling forms the basis of precision cancer medicine through the identification of potentially actionable mutations. However, few studies have addressed genomic analysis in patients with unresectable pancreatic cancer partly because of the difficulty in acquiring a biopsy sample suitable for genomic analysis due to abundant fibrosis in cancer tissue. In this article, we provide an overview of genomic alterations in patients with pancreatic cancer and discuss the current status and future issues regarding genomic analysis using EUS-FNA samples.

Purpose: S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed. Methods: The treatment consisted of four cycles of induction GS (S-1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m(2) on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1-14 and 22-35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1-4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival. Results: A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild. Conclusions: This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies. Clinical trials information: UMIN000006332.