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Objective: To describe treatments and outcomes of French children treated for relapsed/refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL)., Methods: We conducted the analysis of a series of 75 French children treated for a first relapsed/refractory ALK+ ALCL between 1999 and 2017., Results: The median time to first relapse was 8.1 months from initial diagnosis (2.9 after end of treatment), with 12 relapses during frontline treatment or within 1 month of the end of treatment. Treatment of the first relapse varied according to the period of time and risk factors: 48 received multiagent chemotherapy, including 21 and 19 consolidated with allogeneic stem cell transplantation (SCT) and autologous-SCT, respectively. Twenty-one patients received weekly vinblastine, and six received ALK inhibitors (ALKi). Overall, 64/75 patients reached a second complete remission (CR2). Eight out of 11 patients who did not reach CR2 died and the other three were rescued with ALKi, vinblastine, and nivolumab. With a median follow-up of 8.2 years, 60 patients are alive, 43 in CR2, 15 in CR3, two in CR4; and 15 patients died, six from toxicity and nine from disease progression. The 5-year event-free survival and overall survival after first relapse were 51.7% (95% confidence interval [CI]: 39.6%-62.6%) and 80.7% (95% CI: 69.6%-88.1%), respectively. Time to relapse greater than 12 months from initial diagnosis was proven to be a prognostic factor in relapsed/refractory ALK+ ALCL., Conclusion: In relapsed ALK+ ALCL, high survival rate can be reached with various therapeutic strategies. The main challenge remains to prevent subsequent relapses, and to lower long-term morbidity., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

: Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46; p < 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib ( n = 71, 53%) or placebo ( n = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers' values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 ( n = 24, 18%), and TP53 ( n = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers., Competing Interests: N.P., T.B., and J.Y.B. received research funding from Bayer HealthCare SA. T.B. reports personal fees from Roche, Amgen, Bayer, Novartis, PharmaMar, and Eisai outside the submitted work. A.L.C. declares personal fees from Novatis, PharmaMar, Pfizer, Lilly and Ariad, outside the submitted work. O.M. reports personal fees from Roche, Pfizer, Novartis, Bayer, Amgen, Astra-Zeneca, and BMS, outside the submitted work. All other authors declare that they have no conflicts of interest.