Retrospective National "Real Life" Experience of the SFCE with the Metronomic MEMMAT and MEMMAT-like Protocol.

BACKGROUND: Relapses in pediatric high-risk brain tumors remain unmet medical needs. Over the last 15 years, metronomic chemotherapy has gradually emerged as an alternative therapeutic approach. PATIENTS AND METHODS: This is a national retrospective study of patients with relapsing pediatric brain tumors treated according to the MEMMAT or MEMMAT-like regimen from 2010 to 2022. Treatment consisted of daily oral thalidomide, fenofibrate, and celecoxib, and alternating 21-day cycles of metronomic etoposide and cyclophosphamide associated with bevacizumab and intraventricular chemotherapy. RESULTS: Forty-one patients were included. The most frequent malignancies were medulloblastoma (22) and ATRT (8). Overall, the best responses were CR in eight patients (20%), PR in three patients (7%), and SD in three patients (7%), for a clinical benefit rate of 34%. The median overall survival was 26 months (IC95% = 12.4-42.7), and median EFS was 9.7 months (IC95% = 6.0-18.6). The most frequent grade ¾ toxicities were hematological. Dose had to be adjusted in 27% of the cases. There was no statistical difference in outcome between full or modified MEMMAT. The best setting seems to be when MEMMAT is used as a maintenance and at first relapse. CONCLUSIONS: The metronomic MEMMAT combination can lead to sustained control of relapsed high-risk pediatric brain tumors.

Postsurgical geometrical variations of tumor bed and brainstem during photon and proton therapy for pediatric tumors of the posterior fossa: dosimetric impact and predictive factors.

PURPOSE: Brainstem radionecrosis is an important issue during the irradiation of tumors of the posterior fossa. The aim of the present study is to analyze postsurgical geometrical variations of tumor bed (TB) and brainstem (BS) and their impact on dosimetry. METHODS: Retrospective collection of data from pediatric patients treated at a single institution. Availability of presurgical magnetic resonance imaging (MRI) was verified; availability of at least two postsurgical MRIs was considered a further inclusion criterion. The following metrics were analyzed: total volume, Dice similarity coefficient (DSC), and Haudsdorff distances (HD). RESULTS: Fourteen patients were available for the quantification of major postsurgical geometrical variations of TB. DSC, HD max, and HD average values were 0.47 (range: 0.08;0.76), 11.3 mm (7.7;24.5), and 2.6 mm (0.7;6.7) between the first and the second postoperative MRI, respectively. Postsurgical geometrical variations of the BS were also observed. Coverage to the TB was reduced in one patient (D95: -2.9 Gy), while D2 to the BS was increased for the majority of patients. Overall, predictive factors for significant geometrical changes were presurgical gross tumor volume (GTV) > 33 mL, hydrocephaly at diagnosis, Luschka foramen involvement, and younger age (≤ 8 years). CONCLUSION: Major volume changes were observed in this cohort, with some dosimetric impact. The use of a recent co-registration MRI is advised. The 2-3 mm HD average observed should be considered in the planning target volume/planning organ at risk volume (PTV/PRV) margin and/or robust optimization planning. Results from wider efforts are needed to verify our findings.

Early Toxicities After High Dose Rate Proton Therapy in Cancer Treatments.

BACKGROUND: The conventional dose rate of radiation therapy is 0.01-0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT). MATERIALS AND METHODS: A single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT. RESULTS: There were 127 patients identified, with a median follow up of 14.8 months (3-42.9 months). The median age was 55 years (1.6-89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30-74 Gy), dose per fraction of 2 Gy (1-3 Gy), and CTV size of 47.6 ml (5.6-2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively. CONCLUSION: In this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.

A mathematical model for predicting the adult height of girls with idiopathic central precocious puberty: A European validation.

BACKGROUND: A previous single-center study established a mathematical model for predicting the adult height (AH) in girls with idiopathic central precocious puberty (CPP). OBJECTIVE: To perform internal and external validations by comparing the actual AH to the calculated AH established by this model and to update it. METHODS: The original formula, calculated AH (cm) = 2.21 (height at initial evaluation, SD) + 2.32 (target height, SD) - 1.83 (luteinizing hormone/follicle-stimulating hormone peaks ratio) + 159.68, was established in a sample of 134 girls (group 4) and was applied to additional girls with CPP seen in the same center (group 1, n = 35), in Germany (group 2, n = 43) and in the Netherlands (group 3, n = 72). This formula has been updated based on these extended data, and both versions are available at the following location: http://www.kamick.org/lemaire/med/girls-cpp15.html. RESULTS: Despite the differences among the 4 groups in terms of their characteristics at the initial evaluation and the percentages of patients treated with the gonadotropin-releasing hormone analogue, they have similar calculated and actual AHs. The actual AHs are 162.2±7.0, 163.0±7.6, 162.4±7.7 and 162.1±5.6 cm in groups 1 to 4, respectively. They are highly correlated with the AHs calculated by the formula established in the original group (group 4), with R at 0.84, 0.67 and 0.69 in groups 1 to 3, respectively. When the actual AHs and the AHs predicted by the Bayley and Pinneau method are compared, the R is 0.76, 0.51 and 0.64 in groups 1 to 3, respectively. The absolute differences between actual AHs and the calculated AHs are greater than 1 SD (5.6 cm) in 15%, 35% and 28% of the patients in groups 1 to 3, respectively. CONCLUSION: This study validates and updates the previously established formula for predicting AH in girls with CPP. This updated formula can help clinicians to make treatment decisions.

Paediatric dysgerminoma: Results of three consecutive French germ cell tumours clinical studies (TGM-85/90/95) with late effects study.

METHODS: French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic lymph node irradiation (1985-1998) or a wait-and-see strategy (1998-2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. RESULTS: Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic lymph nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had lymph node irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with lymph node irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. CONCLUSION: Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.

A Dilated Cardiomyopathy Revealing a Neuroblastoma: Which Link?

Acute cardiac dysfunctions associated to neuroblastoma have rarely been reported. Cases already described are mainly related to high blood pressure, and rarely to an "acute catecholamine cardiomyopathy" more frequently found in adults with pheochromocytoma or secreting paraganglioma. We here report a case of an 8-month-old infant with severe acute cardiac failure with dilated cardiomyopathy and moderate ischemic myocardial signs, revealing a favorable histoprognosis neuroblastoma. After specific treatment, evolution was favorable, and cardiac function completely recovered. The association of reversible ischemic signs with high plasmatic level of catecholamines suggests the existence of a catecholamine-induced acute cardiac dysfunction which imitates a Tako-Tsubo syndrome in neuroblastoma.