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Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N 6 ,2’-O-dimethyladenosine (m 6 A m ) demethylase activity. While m 6 A m is strategically located next to the m 7 G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m 6 A m level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m 6 A m methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m 6 A m modification in stem-like properties acquisition. FTO-mediated regulation of m 6 A m marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m 6 A m modification and its potential adverse consequences for colorectal cancer management. The demethylase FTO was shown to remove on N6-methyladenosine (m6A) and N6, 2’-O-dimethyladenosine (m6A m ) modifications on RNAs. Here the authors show that FTO impedes cancer stem cell-like abilities in colorectal cancer cells through its m6A m demethylase activity, not through internal m6A demethylase activity.

Survival rates in the European population with gastric and gastroesophageal junction (G/GEJ) adenocarcinoma remain low. Epidemiologic research is warranted to understand the population size, unmet need, and current treatment patterns of G/GEJ adenocarcinoma. The objective of this research was to develop an algorithm to link patients across the FRench EsoGAstric Tumours (FREGAT) and Système National des Données de Santé (SNDS) databases to develop a real-world dataset for G/GEJ adenocarcinoma. A step-by-step, indirect, deterministic record linkage algorithm was developed to match patient records from the FREGAT and SNDS databases. Corresponding variables in each data source were matched at an individual level. Each step in the linkage process used a given scoring criterion; the linkage process proceeded until a unique pair of patient records had equal observations across the databases, at which time patient data were considered linked. Due to the large number of potential matches, the linkage process was performed in two parts: first, matching on the stratified population using individual corresponding variables, and second, by linking without any stratification. Descriptive and inferential statistics were used to assess validity of the linkage process. This study was approved by the National Expertise Committee (Ethical and Scientific Committee for Research, Studies and Evaluations in the Field of Health; 5758940) and the French Personal Data Protection Agency (CNIL; 92 1441/DR 2022 088). Of 1617 patients included in the FREGAT database, 1385 (85.7%) were successfully linked to the SNDS database. A majority of the linked patients (1159 [83.7%] of 1385) were matched in the first part of the linkage process. We established an algorithm that enabled linkage of the FREGAT and SNDS databases that may be applied to capture additional data related to G/GEJ adenocarcinoma in France.

Background Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. Methods Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy. Discussion Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA. Trial registration NCT03519295 .

In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) emerged as a new option in patients with metastatic pancreatic cancer and a good performance status. However, at that time, some doubts were raised regarding safety issues. Similarly, no data on FOLFIRINOX were published in patients with unresectable/locally advanced or borderline resectable pancreatic cancer. This article presents the available experience with FOLFIRINOX outside clinical trials in metastatic and locally advanced pancreatic cancer patients. The safety of the regimen in patients with biliary stents and in previously treated patients is also described. FOLFIRINOX usage in clinical practice, including modification of the regimen (omission of bolus 5-fluorouracil; FOLFOXIRI regimen), is also presented. These data suggest that a phase III randomized study is warranted to further explore the role of FOLFIRINOX in locally advanced pancreatic cancer.

ObjectiveThe BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system.DesignA partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values.Outcome measuresThe effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted.ResultsThe ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively.ConclusionsThis analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.

BackgroundThe AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas.ObjectiveThe objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options.Patients and MethodsMET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib.ResultsMET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5–70), the best overall response rate was 55.6% (95% CI 21.2–86.3), with median progression-free survival of 3.2 months (95% CI 1.0–5.4), and overall survival of 8.1 months (95% CI 1.7–24.6). Safety was consistent with that previously reported for crizotinib.ConclusionsLarge-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation.Trial Registration NumberNCT02034981.Date of Registration14 January 2014.

Aims: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies. Patients & methods: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen. Results: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6–16.1] [11.0 months (9.3–16.0) in -HPV02, and 15.6 months (11.2–34.5) in -HPV01, (p = 0.06)]. The median overall survival was 39.2 months (26.0–109.1) [36.3 in -HPV02 (25.2–NR), and 61.1 months (21.4–120.0) in -HPV01 (p = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF (n = 54) and mDCF (n = 58) in terms of OS (p = 0.57) and PFS (p = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed. Conclusion: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.

Globally, doublet or triplet chemotherapy regimens with a platinum-fluoropyrimidine backbone are the preferred first-line treatment for fit patients with HER2-negative gastric cancer.3,4 Regarding the use of fluoropyrimidines, capecitabine or S-1 can be used as an alternative to infusional fluorouracil in doublet regimens.3 In addition, cisplatin or oxaliplatin are viewed as platinum agents with similar effectiveness when incorporated in doublet or triplet regimens,3 although this aspect remains a matter of debate.5 S-1 plus cisplatin has been widely used in eastern Asia, whereas infusional fluorouracil (plus leucovorin) or capecitabine, combined with oxaliplatin or cisplatin, are standard practices in Europe and North America. [...]the reported data would qualify this treatment for a European Society for Medical Oncology Magnitude of Clinical Benefit Scale score of 1, which is the lowest available score in this tool used to assess the clinical benefit of new cancer therapies.8 In addition, due to the lack of a companion quality-of-life study and the absence of a more favourable safety profile of the experimental treatment, this score of 1 cannot be upgraded to a more favourable grade. [...]TAS-118 plus oxaliplatin deserves to also be tested in non-Asian patients, although it is known that S-1 is not equally tolerated in non-Asian patients and Asian patients.10 Finally, ongoing phase 3 trials will elucidate the role of many promising compounds such as trifluridine–tipiracil, anti-CLDN18.2 monoclonal antibodies (zolbetuximab), or checkpoint inhibitors, in other clinically relevant subsets of patients with advanced HER2-negative gastric cancer, including frail or fit patients, with diffuse-type histology, and CLDN18.2-positive or microsatellite-unstable tumours.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38–0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39–0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324–0.521; p < 0.0001) and 0.406 (95% CI, 0.261–0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376–0.576; p < 0.0001) and 0.438 (95% CI, 0.298–0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

Background Docetaxel–cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC. Methods Data were collected at six  French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m 2 ), oxaliplatin (85 mg/m 2 ), and leucovorin (40 mg/m 2 ) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m 2 ) every 2 weeks. Results Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3–4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %). Conclusion TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.