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Abstract: Aim: This study was aimed to determine p73 status in thyroid tumours. Methods: Differential expression of the TAp73, ΔTAp73 transcripts was measured in a panel of 60 thyroid malignancies by quantitative RT-PCR. Results: By comparison to normal thyroid tissue surrounding the tumours, we observed significant downregulation of TP73 transcripts in adenomas and in differentiated carcinomas. Correlations were found in normal tissue specimens between the expression of TAp73 and ΔNp73 transcripts and that of p53, p14ARF p16INK4a, but these correlations were lost in carcinomas (PTC or FTC). Conclusions: We have found significant variations of TAp73, ΔNp73, p53, p14ARF p16INK4a, expressions and correlations between the expressions of those different genes in thyroid cancer. [Copyright &y& Elsevier]

• Phase 1 trial of concomitant ralimetinib with radiotherapy (and TMZ) in glioblastoma patients. • First worldwide phase 1 trial to evaluate the combination of a p38-MAPK inhibitor (ralimetinib) with radiotherapy. • The recommended dose of ralimetinib was 100 mg/12 h with chemoradiotherapy. • At recommended dose, potentially ralimetinib-related toxicity included grade 3 hepatic cytolysis (13%) and rash (7%). This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150–200 mg/m2 on days 1–5 every 28 days). The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (−54%) was observed in peripheral blood mononuclear cells. This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash. [ABSTRACT FROM AUTHOR]

Background A microsatellite instability (MSI) phenotype is found in about 12% of colorectal cancers (CRCs) and is associated with a low recurrence rate after curative surgery. Several studies have identified clinical and pathological factors predictive of recurrence in resected CRC, but not in the MSI subgroup. Patients and methods This multicentre retrospective study included patients with stage I, II or III MSI CRCs. Disease-free survival (DFS) was calculated with the Kaplan–Meier method. Factors associated with DFS were identified in univariate and multivariate Cox analyses. Results We studied 521 patients with MSI CRC. Respectively 11%, 51% and 38% of patients were at stage I, II and III. Mean age was 68.7 years and 36% of the patients received adjuvant chemotherapy. Median follow-up was 32.8 months. The disease recurrence rates were 6% and 21% in stage II and III patients, respectively. The 3-year DFS rate was 77%. In univariate analysis, age, bowel obstruction, lymph node invasion, stage T4, vascular emboli, lymphatic invasion and perinervous invasion were associated with poorer DFS ( P < 0.05). Three relevant independent predictors of poor DFS were identified in multivariate analysis, namely bowel obstruction (HR = 2.46; 95%CI 1.31–4.62, P = 0.005), vascular emboli (HR = 2.79; 95%CI 1.74–4.47, P < 0.001) and stage T4 (HR = 2.16; 95%CI 1.31–3.56, P = 0.002). Conclusions Bowel obstruction, vascular emboli and stage T4 are independently associated with MSI CRC recurrence, suggesting that screening for vascular emboli in routine clinical practice may assist with adjuvant chemotherapy decision-making. [ABSTRACT FROM AUTHOR]

Background Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. Patients and methods Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). Results A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). Conclusions These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study. [ABSTRACT FROM AUTHOR]

Background Epigenetic inactivation of MGMT by methylation of its promoter is a prognostic factor and is predictive of Temozolomid (TMZ) response in glioblastoma (GBM). MGMT is located on chromosome 10q26 and the loss of chromosome 10q is observed in 70% of GBM. In this study, we assessed the hypothesis that the dual inactivation of MGMT, by hypermethylation of MGMT promoter and by loss of chromosome 10q, may confer greater sensitivity to TMZ. Methods A total of 149 patients diagnosed with GBM, based on the WHO 2016 classification, and initially treated according to the Stupp's protocol between November 2016 and December 2018, were included in this multicentre retrospective study. Methylation status of MGMT promoter was evaluated by pyrosequencing and status of chromosome 10q was assessed by array comparative genomic hybridization. Overall survival (OS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method. Results The present study showed that GBM patients with chromosome 10q loss associated with hypermethylation of MGMT promoter had significantly longer OS (p = 0.0024) and PFS (p = 0.031). Indeed, median OS of patients with dual inactivation of MGMT was 21.5 months compared to 12 months, 8.2 months and 9.5 months for groups with single MGMT inactivation (hypermethylation or 10q loss) or none. Moreover, all long-term survivors with persistent response to TMZ treatment (OS > 30 months) displayed dual inactivation of MGMT. Conclusions To our knowledge, our study is the first to demonstrate the prognostic relevance of combining chromosome 10q loss factor and methylation of MGMT promoter factor in patients with GBM. Our data suggest that the molecular subgroup characterized by the dual inactivation of MGMT receives greater benefit from TMZ treatment. The results of our study may be of immediate clinical interest since chromosome 10q status and methylation of MGMT promoter are commonly determined in routine practice. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]