WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

Implementing long-term follow-up after pediatric cancer: ethical tensions and survivors' perspective

International audienceHow the cancer episode is perceived has an impact on how the follow-up is approached. People for whom cancer is an episode of the past may be less concerned with follow-up than those for whom cancer is experienced as a chronic condition. However, this perception does not always correspond to the medically assessed state of health: the perception of cancer episode depends on the pathology/the perceived health status/the late effects of treatments/the existing medical follow-up, evolves in the same person according to the occurrence of symptoms related to lateeffects/knowledge about the risk of lateeffect/intensification or termination of followup, etc., fluctuates according to time of life and constraints or expectations associated with them. II. Different Expectations at Different Times of Life: Needs and expectations regarding LTFU vary significantly according to age, periods of life, and related constraints, or to the acceptance of the medical history that sometimes evolves

Implementing long-term follow-up after pediatric cancer: ethical tensions and survivors' perspective

International audienceHow the cancer episode is perceived has an impact on how the follow-up is approached. People for whom cancer is an episode of the past may be less concerned with follow-up than those for whom cancer is experienced as a chronic condition. However, this perception does not always correspond to the medically assessed state of health: the perception of cancer episode depends on the pathology/the perceived health status/the late effects of treatments/the existing medical follow-up, evolves in the same person according to the occurrence of symptoms related to lateeffects/knowledge about the risk of lateeffect/intensification or termination of followup, etc., fluctuates according to time of life and constraints or expectations associated with them. II. Different Expectations at Different Times of Life: Needs and expectations regarding LTFU vary significantly according to age, periods of life, and related constraints, or to the acceptance of the medical history that sometimes evolves

Implementing long-term follow-up after pediatric cancer: ethical tensions and survivors' perspective

International audienceHow the cancer episode is perceived has an impact on how the follow-up is approached. People for whom cancer is an episode of the past may be less concerned with follow-up than those for whom cancer is experienced as a chronic condition. However, this perception does not always correspond to the medically assessed state of health: the perception of cancer episode depends on the pathology/the perceived health status/the late effects of treatments/the existing medical follow-up, evolves in the same person according to the occurrence of symptoms related to lateeffects/knowledge about the risk of lateeffect/intensification or termination of followup, etc., fluctuates according to time of life and constraints or expectations associated with them. II. Different Expectations at Different Times of Life: Needs and expectations regarding LTFU vary significantly according to age, periods of life, and related constraints, or to the acceptance of the medical history that sometimes evolves

Relapsing intracranial germ cell tumours warrant retreatment

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Central nervous system germ cell tumor, an archetypal AYA tumor and a model for pediatric and neuro-oncology collaboration, review from the EURACAN domain 10 group.

Peer reviewed: TrueSimple Summary: Adolescents and young adults (AYA) with cancer often fall through gaps between children's and adults' cancer services. They are consequently under-represented in clinical trials, and their survival is often inferior to that of children or adults with the same tumor type; in this paper, we use the example of central nervous system germ cell tumors (CNS-GCT), as a model of AYA tumor to illustrate this challenge. We describe how we have built bridges between pediatric and adult oncology, how this can apply to other types of brain tumors, and discuss ways to promote cancer care in the AYA population. Adolescents and young adults (AYA) with cancer are under-represented in clinical trials and have thus not benefited from the same improvement in outcomes as either younger or older patients. Central nervous system germ cell tumors (CNS-GCT) represent an ideal model of AYA tumor as their incidence peaks during adolescence and young adulthood. Since the early 90's, SIOP (International Society of Pediatric Oncology) has launched two successive European trials: SIOP CNS-GCT96 (January 1996 to December 2005) and SIOP CNS-GCTII protocols (October 2011 to July 2018), for CNS-GCTs. With the removal of the upper age limit in the SIOP CNS-GCTII trial, and closer collaboration between pediatric and adult oncologists within AYA multidisciplinary tumor boards, the proportion of adults enrolled in France has dramatically increased over time. The current article will use the example of CNS-GCT to illustrate how to build a bridge between pediatric and adult oncology, how this can apply to other types of brain tumors, and how to promote cancer care in the AYA population

Two Tumors in 1: What Should be the Therapeutic Target? Pediatric Germ Cell Tumor With Somatic Malignant Transformation

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La neuro-oncologie des adolescents et adultes jeunes (AJAS) : place d’une RCP nationale. Au nom de l’ANOCEF, GO-AJA et de la SFCE

International audienceThe skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro-oncologists are warranted to share expertise. Since 2008, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma.ResultsAttendance during the year 2015 was as follows: 42 meetings were held; the median number of cases discussed at each meeting was 4 (1 to 8); the mean number of attendants was 7 (2 to 12). One hundred and sixty-eight cases concerning 121 patients were discussed. Mean age was 30 years old (7 to 67). Forty-eight percent were discussed at diagnosis. The patients had mostly medulloblastomas (40%), germ cell tumors (11%), ependymomas (11%), pineal tumors (7%) and embryonal tumors (8%). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols.ConclusionMultidisciplinary Web conference for AYAs is feasible and increases the inclusion rate in protocols. It should be developed further.Les compétences en neuro-oncologie pédiatrique et adulte sont différentes mais complémentaires car les histologies, les protocoles thérapeutiques, la tolérance à court et moyen termes et les séquelles tardives attendues sont spécifiques à chaque tranche d’âge. Depuis 2008, ont été mises en place des réunions virtuelles nationales de concertation pluridisciplinaires hebdomadaires initialement dédiées aux adolescents et jeunes adultes (AJA) (15–25 ans) suspects ou porteurs d’une tumeur du système nerveux central dont l’incidence et l’expertise sont plus importantes en milieu pédiatrique. L’expertise a par la suite aussi bénéficié aux adultes plus âgés porteurs de ces affections. En 2015, 168 cas concernant 121 patients ont été discutés lors de 46 réunions. Le nombre moyen de dossiers discutés était de 4 (1 à 8). L’âge moyen de patients présentés était de 30 ans (7 à 67). Dans 48 % des cas, la discussion portait sur la prise en charge initiale. Le nombre moyen de thérapeutes présents était de 7 (2 à 12). Les histologies concernaient principalement des médulloblastomes 40 %, tumeurs germinales malignes 11 %, épendymomes 11 %, tumeurs pinétumeurs embryonnaires 8 %. La RCP AJA a donc prouvé la faisabilité et l’intérêt d’un échange centré sur cette sous-population, entre spécialistes de la neuro-oncologie d’origine diverses. Elle a permis d’optimiser la prise en charge de ces maladies orphelines, et l’inclusion dans des protocoles nationaux et internationaux, en particulier pour les tumeurs germinales malignes intracrâniennes ouverts à tous âges, et les protocoles s’adressant aux médulloblastomes en première ligne (RSMA) ou en rechute (MEVITEM)

Pattern of treatment failures in patients with central nervous system non-germinomatous germ cell tumors (CNS-NGGCT): A pooled analysis of clinical trials.

BACKGROUND: Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, patients with treatment failures remain a poorly characterized group with unfavorable outcomes. In this study, we sought to characterize patients with treatment failures in a large, prospectively treated cohort. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT-96, SFOP-TGM-TC 90/92, COG-ACNS0122, and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy, and additional 11 patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients' metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; P = .026). In our analysis, focal or whole-ventricular radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses are associated with elevated tumor markers and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients

Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors

International audiencePurpose: Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment. Methods: We included children treated for vaginal MGCT according to the French TGM-95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha-fetoprotein (AFP)  10,000 ng/mL) and were treated, respectively, with three to five VBP (vinblastine–bleomycin–cisplatin) or four to six VIP (etoposide–ifosfamide–cisplatin), followed by conservative surgery and/or brachytherapy in case of post-chemotherapy residuum. Results: Fourteen patients were included (median age = 12 months), of which six (43%) were classified as HiR. AFP levels were normalized after first-line chemotherapy in all cases but one. A vaginal post-chemotherapy residuum (median size = 8 mm, range: 1–24 mm) was observed in 13/14 patients, treated by complete resection in seven of 13 (viable cells in three of seven), incomplete resection in four of 13 (viable cells in two of four), with adjuvant brachytherapy in two of 13, and exclusive brachytherapy in two of 13 (viable cells in one of six). Among the six patients with viable disease, four patients received adjuvant chemotherapy. One patient (SR) experienced immediate postoperative relapse despite presenting no viable residual cells and was treated with four VIP cycles and brachytherapy. At last follow-up (median = 4.6 years, range: 0.5–16), all patients were alive in complete remission. Five patients suffered from vaginal sequelae with synechiae and/or stenosis (of whom four had undergone brachytherapy). Conclusion: Childhood vaginal MGCTs show a highly favorable prognosis with risk-adapted chemotherapy and local treatment of post-chemotherapy residuum (preferably by conservative surgery with partial vaginectomy). Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection with residual viable cells