Explore the vast range of titles available.

SummaryThis open-label first-in-human study evaluated JPH203, which is a novel selective L-type amino acid transporter 1 inhibitor. We also evaluated the association between the N-acetyltransferase 2 phenotype and outcomes. Japanese patients with advanced solid tumors received daily intravenous JPH203 treatment for 7 days, followed by a 21-day rest period, at escalating doses of 12–85 mg/m2. Dose-limiting toxicities were evaluated during the first cycle using a 3 + 3 design. The study enrolled 17 patients, although grade 3 liver dysfunction was detected in one of six patients receiving 60 mg/m2 and in the first patient to receive 85 mg/m2. Further enrollment was terminated and the maximum tolerated dose was defined as 60 mg/m2. The AUC∞ increased between 12 mg/m2 and 25 mg/m2, although no differences were observed at 25–40 mg/m2. Partial response was observed for one patient with biliary tract cancer (BTC) at the 12 mg/m2 dose, and disease control was achieved by 3 of 6 patients at the 12 mg/m2 and 25 mg/m2 dose levels. Based on these results, we recommend a phase II dose of 25 mg/m2. The disease control rate for BTC was 60%. Two patients with grade 3 liver dysfunction had the rapid N-acetyltransferase 2 phenotype, and disease control was more common for the non-rapid phenotype (50% vs. 12.5%). It appears that JPH203 was well-tolerated and provided promising activity against BTC. The N-acetyltransferase 2 phenotype might help predict the safety and efficacy of JPH203. Clinical trial registration: UMIN000016546.

Although comprehensive genomic profiling has become standard in oncology for advanced solid tumors, the full potential of circulating tumor DNA (ctDNA)-based profiling in capturing tumor heterogeneity and guiding therapy selection remains underexploited, marked by a scarcity of evidence on its clinical impact and the assessment of intratumoral heterogeneity. The GOZILA study, a nationwide, prospective observational ctDNA profiling study, previously demonstrated higher clinical trial enrollment rates using liquid biopsy compared with tissue screening. This updated analysis of 4,037 patients further delineates the clinical utility of ctDNA profiling in advanced solid tumors, showcasing a significant enhancement in patient outcomes with a 24% match rate for targeted therapy. Patients treated with matched targeted therapy based on ctDNA profiling demonstrated significantly improved overall survival compared with those receiving unmatched therapy (hazard ratio, 0.54). Notably, biomarker clonality and adjusted plasma copy number were identified as predictors of therapeutic efficacy, reinforcing the value of ctDNA in reflecting tumor heterogeneity for precise treatment decisions. These new insights into the relationship between ctDNA characteristics and treatment outcomes advance our understanding beyond the initial enrollment benefits. Our findings advocate for the broader adoption of ctDNA-guided treatment, signifying an advancement in precision oncology and improving survival outcomes in advanced solid tumors. In the observational SCRUM-Japan GOZILA study, after a median follow-up of 11 months, patients with metastatic gastrointestinal tumors who received biomarker-matched therapies based on circulating tumor DNA profiling showed a greater clinical benefit than those receiving unmatched therapy.

Studies have indicated an association between UDP‐glucuronosyltransferase‐1A1 (UGT1A1) genetic polymorphisms and irinotecan‐induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 200 mg/m2, bolus 5‐fluorouracil [5‐FU] 400 mg/m2, and continuous 5‐FU 2400 mg/m2) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 200 mg/m2, and continuous 5‐FU 2400 mg/m2) as first‐line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 −/*6 than among those with UGT1A1 −/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 −/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1. The present study is the first report investigating the association between UGT1A1 genetic polymorphisms, specifically UGT1A1*6 and UGT1A1*28 heterozygosity, and toxicity among Japanese patients with pancreatic cancer treated with FOLFIRINOX.

Background We previously demonstrated that interleukin-33 (IL33) plays a key role in treatment resistance through tumor polyploidization and the consequent immune dysfunction by recruiting and expanding various immunosuppressive cells that express its receptor ST2, and that anti-IL33 blockade therapy induces potent anti-tumor effect in mouse tumor models resistant to anti-PD1 therapy. These suggest that IL33 and ST2 are potentially promising targets that could contribute to anti-PD1/PDL1 therapy. Recently, an increasing number of clinical studies have shown a significant correlation between IL33 expression in tumor tissues and poor prognosis in patients with gastric cancer (GC). However, the clinical significance of targeting the IL33-ST2 axis in anti-PD1/PDL1 therapy for GC remains unclear. Methods Tumor tissues and peripheral blood were collected from patients with advanced GC before and after nivolumab monotherapy in the WJOG10417GTR study. Gene expression of il33 in tumor tissues, IL33 in plasma, and ST2 + cell subsets in four cell populations (IL17RB + GATA3 + ILC2s, CD117 + FceRIa + mast cells, CD11b + HLA-DR − PDL1 + MDSCs, and CD3 + CD4 + FOXP3 + Tregs) in peripheral blood cells were analyzed by RNA-sequencing, IHC, ELISA, or flow cytometry, and the relationship between their levels and patient prognosis was statistically analyzed. Results The levels of tumor il33 gene expression and peripheral IL33 and ST2 + cells were higher in patients who showed progressive disease (PD) than in non-PD patients. High levels of tumor il33 gene expression at post-treatment, and high levels of peripheral ST2 + cells at both pre- and post-treatment were significantly associated with shorter progression-free survival and overall survival. Patients with low post-treatment levels of both tumor il33 and peripheral ST2 + cells, especially the mast cell subset, had long-term survival without PD, indicating durable responders. Conclusions These data suggest high IL33/ST2 levels are significant poor prognostic factors for nivolumab therapy for advanced GC. The IL33/ST2 axis may be useful as a biomarker for predicting and pre-selecting possible responders/nonresponders to anti-PD1/PDL1 therapy for GC, and hopefully as a druggable target for developing new drugs for treating GC. The IL33/ST2-targeting strategy will contribute to improving clinical outcomes in the treatment of GC.

The phase III randomized trial, JCOG1113 has demonstrated the non-inferiority of gemcitabine and S-1 (GS) therapy to gemcitabine and cisplatin (GC) therapy for advanced biliary tract cancer (BTC). However, biomarkers for favorable therapy or to predict patient prognosis remain lacking. In this study, we evaluated five candidate biomarkers potentially involved in the efficacy of cisplatin or S-1 by immunostaining tumor specimens obtained from JCOG1113 participants. The participants were randomly divided into training or test sets and classified into high- or low-expression groups based on the cutoff value calculated from the immunostaining results for each biomarker in the training set. Associations between the expression of each biomarker and the outcomes in JCOG1113 were analyzed. Among the 148 eligible participants, no interaction was observed between the treatment arms of GC or GS for any factor or biomarker. However, high excision repair cross-complementing gene 1 (ERCC1) was associated with poor overall survival (HR, 2.226; 95% CI, 1.160–4.272) and progression-free survival (HR, 1.793; 95% CI, 0.945–3.402) compared with low ERCC1 in the training set. Similar trends were observed for the test set. Our results indicate that in advanced BTC, high ERCC1 expression is a poor prognostic factor.

Although sequence-based studies show that basal-like features lead to worse prognosis and chemotherapy-resistance compared to the classical subtype in advanced pancreatic ductal adenocarcinoma (PDAC), a surrogate biomarker distinguishing between these subtypes in routine diagnostic practice remains to be identified. We aimed to evaluate the utility of immunohistochemistry (IHC) expression subtypes generated by unsupervised hierarchical clustering based on staining scores of four markers (CK5/6, p63, GATA6, HNF4a) applied to endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) materials. EUS-FNAB materials taken from 190 treatment-naïve advanced PDAC patients were analyzed, and t hree IHC patterns were established (Classical, Transitional, and Basal-like pattern). Basal-like pattern (high co-expression of CK5/6 and p63 with low expression of GATA6 and HNF4a) was significantly associated with squamous differentiation histology ( p  < 0.001) and demonstrated the worst overall survival among our cohort ( p  = 0.004). IHC expression subtype (Transitional, Basal vs Classical) was an independent poor prognosticator in multivariate analysis [HR 1.58 (95% CI 1.01–2.38), p  = 0.047]. Furthermore, CK5/6 expression was an independent poor prognostic factor in histological glandular type PDAC [HR 2.82 (95% CI 1.31–6.08), p  = 0.008]. Our results suggest that IHC expression patterns successfully predict molecular features indicative of the Basal-like subgroup in advanced PDAC. These results provide the basis for appropriate stratification for therapeutic selection and prognostic estimation of advanced PDAC in a simplified manner.

FOLFIRINOX (FFX) is a standard treatment for patients with advanced pancreatic cancer. However, it often causes serious hematological adverse events. This study aimed to identify the risk factors for febrile neutropenia (FN) and grade 4 (G4) neutropenia during treatment with FFX in the real world. We analyzed data obtained from a nationwide multicenter observational study (JASPAC 06) that included 399 patients with unresectable or recurrent pancreatic cancer who received FFX at 27 institutions in Japan. Nadir neutrophil counts occurred from day 8 to day 22 of cycle 1, and granulocyte colony-stimulating factor was administered to over a quarter of the patients in the first cycle. Of 399 patients, FN and G4 neutropenia occurred in 51 (13%) and 108 (27%) patients, respectively. Most FN (83%) and G4 neutropenia (75%) occurred in the first or second cycles. Multivariate logistic regression analyses showed that total bilirubin (TB) > the upper limit of normal range (ULN) and no dose modification from the original regimen were significantly associated with FN, and that TB > ULN, no dose modification from the original regimen, low platelet count (<15×10 /μl), and recurrent disease after pancreatectomy were independent risk factors for G4 neutropenia. No dose modification from the original regimen and TB > ULN were risk factors for FN and G4 neutropenia.

Background Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. Material and Methods In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. Results The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. Conclusion As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time. This article evaluates the association between early tumor shrinkage and depth of response with clinical outcomes in patients with advanced biliary tract cancer using data from JCOG1113.

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno’s concordance index was 0.661 (95% confidence interval [CI] 0.629–0.696) in the training set and 0.640 (95% CI 0.566–0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians’ prognosis-based decision-making.