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The identification and development of therapeutic targets in cancer stem cells that lead to tumor development, recurrence, metastasis, and drug resistance is an important goal in cancer research. The hepatocellular carcinoma cell line Li-7 contains functionally different types of cells. Cells with tumorforming activity are enriched in cancer stem cell-like CD13+CD166- cells and this cell population gradually decreases during culture in conventional culture medium (RPMI1640 containing 10% fetal bovine serum). When Li-7 cells are cultured in mTeSR1, a medium developed for human pluripotent stem cells, CD13+CD166- cells and their tumorigenicity are maintained. Here, we sought to identify the mechanisms of tumorigenicity in this sub-population. We compared gene expression profiles of CD13+CD166- cells with other cell sub-populations and identified nine overexpressed genes (ENPP2, SCGN, FGFR4, MCOLN3, KCNJ16, SMIM22, SMIM24, SERPINH1, and TMPRSS2) in CD13+CD166- cells. After transfer from mTeSR1 to RPMI1640 containing 10% fetal bovine serum, the expression of these nine genes decreased in Li-7 cells and they lost tumorigenicity. In contrast, when these genes of Li-7 cells were forcibly expressed in cultures using RPMI1640 containing 10% fetal bovine serum, Li-7 cells maintained tumorigenicity. A metabolome analysis using capillary electrophoresis-mass spectrometry showed that two metabolic pathways, “Alanine, aspartate and glutamate metabolism” and “Arginine biosynthesis”, were activated in cancer stem cell-like cells. Our analyses here showed potential therapeutic target genes and metabolites for treatment of cancer stem cells in hepatocellular carcinoma.

Background We hypothesized that thermal damage accumulation during endoscopic submucosal dissection (ESD) causes the pathogenesis of post-ESD electrocoagulation syndrome (PECS). Aim To determine the association between Joule heat and the onset of PECS. Methods We performed a retrospective cohort study in patients who underwent colorectal ESD from May 2013 to March 2021 in Japan. We developed a novel device that measures swift coagulation time with a sensor adjacent to the electrosurgical coagulation unit foot switch, which enabled us to calculate total Joule heat. PECS was defined as localized abdominal pain (visual analogue scale ≥ 30 mm during hospitalization or increased by ≥ 20 mm from the baseline) and fever (temperature ≥ 37.5 degrees or white blood cell count ≥ 10000 µ/L). Patients exposed to more or less than the median Joule heat value were assigned to the high and low Joule heat groups, respectively. Statistical analyses included Mann-Whitney U and chi-square tests and logistic regression and receiver operating characteristic curve (ROC) analyses. Results We evaluated 151 patients. The PECS incidence was 10.6% (16/151 cases), and all patients were followed conservatively and discharged without severe complications. In multivariate analysis, high Joule heat was an independent PECS risk factor. The area under the ROC curve showing the correlation between PECS and total Joule heat was high [0.788 (95% confidence interval: 0.666-0.909)]. Conclusion Joule heat accumulation in the gastrointestinal wall is involved in the onset of PECS. ESD-related thermal damage to the peeled mucosal surface is probably a major component of the mechanism underlying PECS.

The standard chemotherapies for neuroendocrine tumors (NETs) are somatostatin analog (SSA) and targeted-agents for NET G1/G2 and platinum-based chemotherapy for neuroendocrine carcinoma (NEC), classified according to the WHO criteria of 2010. We report a case of NET, in which tumors were successfully treated with platinum-containing chemotherapy after remarkable progression with SSA. A 46-year-old man with multiple lymph nodes and liver metastases of unknown primary origin was diagnosed with NET G2 based on the examination of a biopsy specimen. His tumors were stable with SSA for a year, but rapidly became enlarged. A second biopsy revealed NEC. He received cisplatin plus etoposide, and his tumors showed a marked reduction in size.

Advanced liver cancers and biliary cancers represent diseases with dismal prognosis because of frequent local invasion and metastasis. Effective therapeutic agents for these cancers have not been established. Oncolytic viruses (OVs) constitute a novel class of promising, selective anticancer agents and recent studies have elucidated their unique features. Moreover, clinical trials are demonstrating promising results. Numerous OVs are being tested in preclinical models of hepatocellular carcinoma (HCC). The lead agent Pexa-Vec (pexastimogene devacirepvec, JX-594), a recombinant Wyeth strain vaccinia virus, has demonstrated preliminary evidence of safety and efficacy for HCC in clinical trials. Few other OVs have entered clinical testing. Relatively few preclinical studies and clinical trials exist for biliary cancers. In this review, we introduce various approaches using OVs to treat the intractable hepatobiliary cancers.

Combination chemotherapy of mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) plus panitumumab, a fully human monoclonal antibody against epidermal growth factor receptor (EGFR), is one of the standard treatments for metastatic colorectal cancer (mCRC) without KRAS mutation. A few reports suggested no need of dose adjustment of cetuximab, a similar chimeric anti-EGFR antibody, in patients with renal impairment. However, panitumumab combined with cytotoxic drugs for hemodialysis patients has not been reported. We herein report a case of a hemodialysis mCRC patient successfully treated with mFOLFOX6 and panitumumab combination therapy.

Background Pulmonary metastases from colorectal cancer are resected due to the favourable 5-year overall survival rates of 30–60% reported in many studies. However, the efficacy of subsequent adjuvant chemotherapy remains unclear. Patient and methods We retrospectively collected clinical data of 1237 patients who underwent surgical resection of pulmonary metastasis from colorectal cancer at 46 Japanese institutions between 2004 and 2008. Patients with non-curative resection, pre-operative chemotherapy, extra-thoracic metastasis, complications after surgery, and inadequate data were excluded. Then, a 1:1 propensity score nearest-neighbour matching between patients with and without adjuvant chemotherapy was performed, considering relevant co-variables, and survival of patients between groups was compared. Results Data of 524 patients (surgery alone, 269 patients; surgery with adjuvant chemotherapy, 255 patients) were used for matching. From each group, 192 patients with similar background characteristics between groups were selected. Adjuvant chemotherapies included fluoropyrimidine alone (71%), an oxaliplatin-containing regimen (23%), or an irinotecan-containing regimen (6%). In the surgery alone and adjuvant chemotherapy groups, 5-year overall survival rates were 68% and 69%, and 5-year disease-free survival rates were 40% and 34%, respectively. There were no significant differences between the two groups in terms of overall survival (hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.69–1.45, P = 1.00) and disease-free survival (HR: 1.07, 95% CI: 0.82–1.39, P = 0.62). Conclusions Adjuvant chemotherapy after curative resection of lung-limited metastasis from colorectal cancer did not show a survival benefit in the propensity score–matched analysis and should not be recommended without further clinical trials.

Background To develop a triplet regimen containinggemcitabine,cisplatin,andS-1(GPS),weassessedtherecom-mendeddoseforpatientswithuntreatedadvancedbiliarytractcancer in this phase I study.Methods Dose-limitingtoxicities(DLTs)wereevaluatedforthe following two dose levels: gemcitabine (1000mg/m 2 forlevel 1 and 1200mg/m 2 for level 2 on day 1), cisplatin(30mg/m 2 fixeddoseonday1),andS-1(40–60mg/dayfixeddose twice a day for 7days), every 2weeks until progression.DLTs for each level were evaluated in six or more patientsduring the first twocycles.Results A total of 18 patients were enrolled and 16 patientswere evaluated. DLTs at level 1 were observed in two of10 patients. At level 2, a DLT was observed in one of sixpatients. The main grade 3 or 4 treatment-related adverseevents were neutropenia and leukopenia, and a few non-hematological toxicities were observed. Among 14 patientswith measurable lesions, the best response rate was 50%.Conclusions GPS with a relative dose intensity correspond-ingto90%ofthestandardgemcitabinepluscisplatinregimencould be administered safely, and showed preliminary antitu-mor activity. Survival benefits will be studied subsequently.Keywords Biliary tract cancer · Cholangiocarcinoma ·Cisplatin · Gallbladder carcinoma · Gemcitabine · S-1IntroductionGemcitabine and fluoropyrimidine (FU) are used widely inpatients with advanced biliary tract cancer (ABTC). Re-cently, gemcitabine plus cisplatin (GP) combination che-motherapy has been recognized as a standard first-linechemotherapy based on the results of a phase III study(ABC-02), which compared GP to gemcitabine alone inpatients with ABTC [1]. Since then, FU-containingregimens have been used as second-line chemotherapyfor ABTC. S-1, which contains tegafur, gimeracil, andoteracil, has been approved for the treatment of varioussolid tumors including ABTC in Japan, and S-1 incombination with cisplatin has been approved for gastriccancer therapy in Europe [2]. It showed promisingactivity against ABTC in several studies [3–10] and ismainly used in gemcitabine-refractory patients in Japan.However, all patients do not receive second-line chemo-therapy. The proportion of patients who receivedsecond-line chemotherapy after the failure of first-linechemotherapy was reportedly 20 to 70% [1, 11, 12]. It was60% in our previous study, where we explored prognosticfactors for ABTC [13].This study aimed to develop a triplet regimen, GP plusS-1, using valid drugs in the upfront treatment of patientswith ABTC.

788 Background: A number of retrospective studies reported that 5-year survival rate was 30-60% in patients who underwent curative resection of pulmonary metastases (PM) from colorectal cancer (CRC), and PM-CRC resection was recommended in clinical practice. Efficacy of adjuvant chemotherapy after resection of PM remains unclear. Therefore, using a large-scale data obtained from patients who underwent R0 resection of PM in Japan, we investigated it with a propensity score-matching analysis. Methods: We retrospectively collected clinical data of 1237 patients who underwent metastasectomy of PM-CRC at 46 Japanese institutions from 2004 to 2008. Excluding non-curative resection, preoperative chemotherapies, extra-thoratic metastases, complications after surgery, and inadequate data, 530 patients’ data (surgery alone 269 and surgery with adjuvant chemotherapy 261) were used for the matching. Patient backgrounds affecting doctor’s recommendation of adjuvant chemotherapy and including commonly reported prognostic factors were adjusted, using a propensity score-matching method. Primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively. Results: After the matching with propensity-score, 167 patients for each group were selected. Patient backgrounds were balanced between both groups. Adjuvant chemotherapies were fluorouracil alone (67%), oxaliplatine-containing regimen (24%), irinotecan-containing regimen (7%) and others (2%). There were no significant differences between both groups in OS (HR 0.97, 95%CI 0.64-1.46, p = 0.88) and DFS (HR 0.99, 95%CI 0.75-1.32, p = 0.96). Conclusions: A propensity score-matching analysis did not show a survival benefit of adjuvant chemotherapy after resection of PM in patients with CRC. A large prospective observational study with high quality or randomized clinical trial is needed.

We performed a retrospective study on the use of cetuximab or panitumumab alone in patients with KRAS wild-type metastatic colorectal cancer between November 2008 and February 2012. Twenty-two patients were analyzed and classified as PS 0/1 (good PS group)and PS 2/3/4 (poor PS group)with 11 patients in each group. The response rate, disease control rate, median progression-free survival, and median overall survival were 9%, 73%, 5.1 months (95%confidence interval[CI]: 1.5-8.7), and 16 months (95% CI: 8.8-24), respectively, in the good PS group, and the corresponding values in the poor PS group were 0%, 18%, 0.7 months (95% CI: 0.3-1.0), and 1.5 months (95% CI: 0.7-2.4). Grade 3 or 4 adverse events were skin toxicities (2 patients with grade 3 toxicities), panitumumab-related interstitial lung disease (1 patient with grade 4 toxicity), and cetuximab infusion-related reaction (1 patient with grade 4 toxicity). No treatment-related deaths were observed. In conclusion, the efficacy and safety of cetuximab or panitumumab monotherapy in patients with a good PS in our study were similar to those reported in previous clinical trials, whereas patients with a poor PS showed poorer outcomes.

A 45-year-old man presented with severe abdominal distention with massive ascites due to a diffusely disseminated peritoneal tumor. A core needle biopsy specimen was obtained from the peritoneal lesion. Histological diagnosis was epithelioid type mesothelioma. He did not choose to receive chemotherapy. For 2.5 years, he went without medical intervention, and his disease gradually progressed, leading to a worsening of his symptoms. The patient then chose to be treated with combination chemotherapy of cisplatin and pemetrexed, followed by pemetrexed alone. There was remarkable tumor shrinkage and his symptoms improved. These effects have been sustained for two years after the initial chemotherapy. Chemotherapy appears to have contributed to survival prolongation for this patient. This case exemplifies the fact that malignant peritoneal mesothelioma may progress slowly when fits with some good prognostic factors, and it is important to consider the prognostic factors.

Aim: GEM plus CDDP has been established as standard first-line chemotherapy based on the results of the phase III study (ABC-02) in ABTC. An oral FU derivative, S-1 showed a similar activity to GEM in a phase II study and is mainly used in GEM-refractory pts in Japan. To develop a triplet regimen, GEM + CDDP + S-1 (GPS), we assessed its safety in this phase I study. Methods: The main eligibility criteria were; histologically or cytologically confirmed ABTC, ECOG Performance Status (PS) 0-2, no prior chemotherapy, and written informed consent. Dose limiting toxicities (DLT) were evaluated in following 2 dose levels; GEM (1000 mg/m2 at level 1 and 1200 mg/m2 at level 2 on day 1) + CDDP (fixed dose of 30 mg/m2 on day 1) + S-1 (fixed dose of 40—60 mg/day bid for 7 days), repeated every 2 weeks until progression. The relative dose intensity of GEM and CDDP at level 2 corresponded to 90% of standard GEM plus CDDP regimen. In each level, 6-10 pts were enrolled and assessed. DLTs were evaluated during the first 2 cycles. Results: Between Oct 2011 and Oct 2013, 18 pts were enrolled and 16 pts were evaluated (median age: 71 years, ECOG PS 0/1: 10/6, intrahepatic/extrahepatic/gallbladder: 7/3/6). DLTs (grade 3 nausea to stop S-1 in cycle 1 and treatment delay due to grade 3 neutropenia in cycle 2) at level 1 were observed in 2 of the first 6 pts. Additional 4 pts enrolled at this dose level experienced no DLTs. A DLT (G3 anorexia) at level 2 was observed in 1 of 6 pts. Grade 3 or 4 treatment-related adverse events within the first 2 cycles were leukocytopenia (38%), neutropenia (50%), thrombocytopenia (0.6%), nausea (0.6%), and anorexia (0.6%). Of 14 pts with measurable lesions, 7 (50%) pts had partial response and 6 (43%) patients had stable disease. Median progression free survival was 9.2 months (95%CI 6.8-11.6, event in 63%) and overall survival did not reach the median value (event in 38%). Conclusions: GPS of dose level 2 (GEM 1200 mg/m2 and 30 mg/m2 on day 1 plus S-1 for 1-7 days, given bi-weekly) was well tolerated, and showed preliminary anti-tumor activity. Further study is warranted. Clinical trial information: UMIN000006123. Disclosure: T. Moriwaki: Research funding for other study and honoraria from Taiho Pharmaceutical; I. Hyodo: Research funding for other study from Taiho Pharmaceutical and Lilly. Honoraria from Taiho Pharmaceutical. All other authors have declared no conflicts of interest.