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Abstract: Aim: To identify predictors for infiltrating carcinoma and lymph node involvement, before immediate breast reconstructive surgery, in patients with an initial diagnosis of extensive pure ductal carcinoma in situ of the breast (DCIS). Patients and methods: Between January 2000 and December 2009, 241 patients with pure extensive DCIS in preoperative biopsy had underwent mastectomy. Axillary staging (sentinel node and/or axillary dissection) was performed in 92% (n = 221) of patients. Patients with micro-invasive lesions at initial diagnosis, recurrence or contralateral breast cancer were excluded. Results: Respectively 14% and 21% of patients had a final diagnosis of micro-invasive carcinoma (MIC) and invasive ductal carcinoma (IDC). Univariate analysis showed that the following variables at diagnosis were significantly correlated with the presence of either MIC or IDC in the mastectomy specimen: palpable tumor (p = 0.002), high grade DCIS (p = 0.002) and detection of an opacity by mammography (p = 0.019). Axillary lymph node (ALN) involvement was reported in 9% of patients. Univariate analysis suggested that a body mass index higher than 25 (p = 0.007), a palpable tumor (p = 0.012) and the detection of an opacity by mammography (p = 0.044) were associated with an increased rate of ALN involvement. Conclusion: Skin-sparing mastectomy and immediate breast reconstruction (IBRS) has become increasingly popular, especially for patients with extended DCIS of the breast. This study confirmed that extended DCIS is associated with a substantial risk of finding MIC or IDC on the surgical specimen but also ALN involvement. Adjuvant systemic treatment and/or radiotherapy could be indicated for some of these patients after the surgery. Patients should be informed of the rate of 1) complications associated to IBRS that will potentially delay the introduction of systemic or local therapy 2) complications associated to radiotherapy after IBRS. [Copyright &y& Elsevier]

Abstract: Aim: Improvement of EFS of children older than 3 years with high risk medulloblastoma. Methods: Between 1993 and 1999, 115 patients (3–18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy (‘8in1’ and etoposide/carboplatin) before and after craniospinal radiotherapy. Results: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9–119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. Conclusion: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment. [Copyright &y& Elsevier]

Purpose Due to the extensive initial distant tumour spread in metastatic rhabdomyosarcoma, the importance of local treatment is sometimes underestimated. A retrospective study was conducted to identify the prognostic value of aggressive local treatment in paediatric metastatic rhabdomyosarcoma. Patients Patients with metastatic rhabdomyosarcoma aged 1–21 years treated in France from 1998 to 2011 according to European protocols MMT-4-89, 4-91, 98 and recent national guidelines were selected. Survival comparison were performed between patients with ‘aggressive local treatment’ (surgery and radiotherapy) and exclusive surgery or radiotherapy, after exclusion of patients with early progression. End-points were event-free and overall survival (OS). Results A total of 101 children, median age 9 years, with majority of primaries in unfavourable sites (73 patients, pts), T2 tumours (66 pts), alveolar subtypes (65 pts) and large tumours (>5 cm, 83 pts) received various chemotherapy regimens. On univariate and multivariate analyses, OS was better after ‘aggressive local treatment’ (49 pts; 44.3 ± 8%), than after exclusive surgery (10 pts; 18.8% ± 15.5%) or exclusive radiotherapy (29 pts; 16.1 ± 7.2%, P < 0.006). Moreover, OS was better in the case of surgery with complete resection (41.1 ± 10.2%) or microscopic residue (56.4 ± 14.9%) than macroscopic residue (20.0 ± 12.6%; P < 0.03). Conclusions In this large retrospective analysis, OS appeared to be better for patients receiving ‘aggressive local treatment’ even after adjustment for the initial patient and tumour characteristics. Isolated debulking surgery is associated with a very poor outcome and should be avoided. Aggressive local treatment in patients with rhabdomyosarcoma, even with metastasis, should be seriously considered. [ABSTRACT FROM AUTHOR]

Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells are sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy in TNBC patients may consequently enhance the biological effectiveness of the irradiation ultimately leading to improved locoregional control. We aimed to establish the appropriate dosing and safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed treatment-related toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 68% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. Olaparib used as a radiosensitizer in combination with breast radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered. [ABSTRACT FROM AUTHOR]

Introduction Le traitement des rhabdomyosarcomes orbitaires (RMSO) comporte de la chimiothérapie associée au traitement local, basé sur la chirurgie ou principalement la radiothérapie. Ces derniers peuvent induire des effets tardifs notables peu décrits. Cette analyse rétrospective monocentrique a pour but de décrire les séquelles pour guider les décisions de décroissance thérapeutique pour cette tumeur de bon pronostic. Population 95 patients atteints de RMSO localisés, paraméningés (26%) ou non, ont été traités à l’Institut Curie entre 1975 et 2010, et 82 ont survécu avec suivi médian de 8,5 ans [0,6–24 ans]. Résultats L’âge médian au diagnostic était de 6 ans [0,7–19 ans]. Le taux de conservation oculaire à 5 ans est de 90% avec une atteinte ophtalmologique séquellaire chez 79%, principalement, cataracte (42%) et lésions cornéennes (40%). L’acuité visuelle résiduelle médiane est 4/10 [< 2/10–10/10]. Des séquelles orbito-faciales sont présentent chez 40% à type d’asymétrie (36%) et d’hypoplasie osseuse (35%) post radiques ou à la chirurgie mutilante (énucléation/exentération, 19%). Conclusions Ces données suggèrent que les séquelles locales tardives sont fréquentes et nécessitent un suivi ophtalmologique prolongé. L’irradiation engendre une morbidité iatrogène notable. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Preclinical studies have found that triple-negative breast cancer (TNBC) cells were sensitive to PARP1 inhibitors. The phase I dose-escalation RADIOPARP trial evaluated in TNBC patients the combination of breast radiotherapy and Olaparib, which was escalated to the target dose of 200 mg twice a day without dose-limiting toxicities. We report the one-year toxicity of this trial.Materials/methods: RADIOPARP is a monocentric prospective open-label phase I dose escalation trial evaluating the combination of breast radiotherapy and Olaparib in TNBC patients with inflammatory, locoregionally advanced or metastatic disease, or with residual disease after neoadjuvant chemotherapy. Olaparib was orally given at increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day); radiotherapy consisted of 50 Gy to the breast or chest wall with or without lymph node irradiation. One-year treatment-related toxicity was graded according to the CTCAE (version 4.03).Results: Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without dose-limiting toxicities. At one-year follow-up, no treatment-related grade ≥3 toxicity was observed (Table 1). Three patients had persistent grade 2 adverse events (breast pain, fibrosis and deformity); there were no cardiac, pulmonary or digestive toxicity.Conclusion: The one-year follow-up of the RADIOPARP phase I trial, evaluating breast radiotherapy with Olaparib in TNBC patients, demonstrated an acceptable toxicity profile of this combination with few low-grade adverse events. [ABSTRACT FROM AUTHOR]

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival. [Copyright &y& Elsevier]

Objectifs: Le neuroblastome (NB) est un cancer pédiatrique avec une grande hétérogénéité clinique. Des nombreuses altérations génétiques récurrentes ont été décrites : une amplification de MYCN associée à un pronostic pauvre, ainsi que des variations de la ploïdie ou des altérations chromosomiques segmentaires (délétions du chromosome 1p, 3p, 4p, 11q ; gain du chromosome 2p, 17q) dont l’importance pronostique reste à être déterminée. Afin d’étudier l’association de ces altérations génétiques entre elles et leur impact pronostique, nous avons entrepris une analyse en CGH-array d’une grande série de NB. Méthodes: 389 échantillons de NB ont été analysés en hybridation génomique comparative (CGH), sur une puce d’ADN à BAC/PAC avec une résolution moyenne de 1Mb. Résultats: L’analyse du profil génomique permet de distinguer 2 différents types d’instabilité génétique : une instabilité numérique et une instabilité segmentaire. L’instabilité numérique est caractérisée par une variation en nombre de chromosomes entiers sans altérations segmentaires (n = 162). Elle est associée à une survie sans progression et une survie globale excellente. L’instabilité segmentaire se caractérise par des translocations chromosomiques déséquilibrées. Elle a été observée dans des tumeurs sans (n = 45) ou avec (n = 97) variations numériques, ou en association avec une amplification de MYCN (n = 67). Ce type génomique est associé à un risque élevé de rechute (p < 0.0001, log-rank test), quel que soit le type de l’altération segmentaire. En analyse multivariée, après prise en compte du type génomique, des altérations génétiques individuelles et des caractéristiques cliniques, un profil génomique de type segmentaire est le marqueur pronostique le plus fort (p < 0.0002). Les autres marqueurs retenus sont l’age (p = 0.022) et le stade (p = 0.06). Conclusion: Dans le NB, un profil génomique de type segmentaire est le marqueur pronostique le plus fort. Ceci souligne l’importance du mécanisme à l’origine des translocations déséquilibrées dans l’oncogenèse du NB. Le typage génomique devra donc être pris en compte pour l’attribution à un groupe de risque et la stratification thérapeutique. Le NB est le premier modèle de l’utilité d’une classification génomique pour une meilleure prise en charge thérapeutique. [Copyright &y& Elsevier]

Abstract: Introduction: Malignant sacrococcygeal (SC) germ cell tumours (GCT) may be diagnosed as primary pelvic tumour or malignant recurrence of foetal SC teratoma (FSCT) operated during the neonatal period. In order to evaluate the difference between these two populations, the authors report their experience with SC-GCT registered in the French TGM 95 protocol. Population and methods: The protocol comprised risk-adapted-chemotherapy (CT) followed by surgery. Standard risk (SR: localized tumour completely resected) had no adjuvant therapy. Intermediate-Risk (IR: localized tumour, incomplete or no initial surgery with αFP<15,000 ng/ml) received Vinblastine–Bleomycin–Cisplatin regimen; while High-Risk (HR: αFP > 15,000 ng/ml and/or metastases) received Etoposide–Ifosfamide–Cisplatin. Results: Fifty-seven patients with SC-GCT, aged 0–80 months (median 16), were registered between 1995 and 2005. Nineteen patients had secondary SC-GCT after FSCT. All patients received CT: 17 IR and 1 SR after reevolution; 39 HR (25 with metastases). 51 patients underwent delayed surgery, which was incomplete in 8 patients. Evolution: Seventy-two percent of the secondary SC-GCT had systematic biological follow-up. αFP increasing was the first presenting sign in 80% of the cases. Patients with secondary SC-GCT had a lower median αFP level at diagnosis, were less frequently classified as HR and received less CT. The two groups with secondary vs. primary SC-GCT had a statistically similar favourable outcome (Overall Survival: 93.8% vs. 86.2%; Event-Free Survival: 89.2 vs. 78.2%; p > 0.34 and >0.32), respectively, but with less burden of therapy. Conclusions: SC-GCT has a good overall prognosis provided complete surgery is achieved and CT is administered to IR and HR patients. SC-GCT in patients followed by αFP after treatment for FSCT had less tumour extension than newly-diagnosed patients, probably because of earlier detection of the disease. [Copyright &y& Elsevier]