Ophthalmologic adverse events in childhood head and neck rhabdomyosarcoma survivors treated according to four different local treatment strategies

Introduction: Ophthalmological adverse events (OAEs) are known to frequently occur following local treatment for pediatric head and neck rhabdomyosarcoma (HNRMS). The exact nature of these OAEs and the burden they put on survivors is less well described. Moreover, it is suspected there might be differences in the prevalence and nature of OAEs depending on local treatment strategy applied: external beam radiation therapy with photons, external beam radiation therapy with protons, macroscopically radical surgery combined with brachytherapy, or microscopically radical surgery combined with external beam radiation therapy. Methods: We cross-sectionally assessed 98 HNRMS survivors with long (median 9 years) follow-up time, according to a predefined list of OAEs based on the Common Terminology Criteria for Adverse Events system. We added information from chart reviews on the nature and management of all OAEs scored grade ≥1. We describe the prevalence of OAEs for the different tumor sites and treatment strategies separately. Results: OAEs occurred following treatment of all HNRMS sites. The most frequently observed OAEs are eyelid abnormalities, dry eyes, and cataracts. Sixty-two percent of survivors had several different OAEs simultaneously. In 27 % of survivors additional (surgical) treatment of OAEs was required during follow-up. The patterns observed suggest a possible relationship between OAE type and treatment strategy. Conclusion: OAEs in HNRMS survivors confer a high burden of chronic toxicity. The simultaneous occurrence of multiple OAEs in individual survivors present a particularly challenging clinical scenario and demand specific expertise. We propose a standardized screening scheme to detect possible OAEs in asymptomatic survivors based on primary tumor localization

Regards sur la séparation aujourd’hui

Points de vue Jean-Pierre Balduyck Deux thèmes : Un cheminement personnel et mon expérience d’élu et de maire de Tourcoing. Le Maire de Tourcoing n’est pas un athée. Il est croyant. Il a été éduqué dans une famille chrétienne flamande traduisant sa foi dans la vie. Je n’ai jamais entendu dans les propos de mes parents le moindre racisme, le moindre sentiment d’exclusion. Mes parents votaient à droite mais jamais à l’extrême droite. La découverte de la JOC a été pour moi un moment important. C..

Patient-reported outcomes in childhood head and neck rhabdomyosarcoma survivors and their relation to physician-graded adverse events—A multicenter study using the FACE-Q Craniofacial module

Introduction: Adverse events (AE) of treatment are prevalent and diverse in head and neck rhabdomyosarcoma (HNRMS) survivors. These AEs are often reported by physicians; however, patients' perceptions of specific AE are not well known. In this study, we explored patient-reported outcomes measuring appearance, health-related quality of life (HRQOL), and facial function in HNRMS survivors. Second, we assess the relationship between physician grading of AE and patient reporting. Materials and Methods: Survivors of pediatric HNRMS, diagnosed between 1993 and 2017, who were at least 2 years after completing treatment were invited to an outpatient clinic as part of a multicenter cross-sectional cohort study. At the outpatient clinics, survivors aged ≥8 years filled out the FACE-Q Craniofacial module; a patient-reported outcome instrument measuring issues specific to patients with facial differences. AE were systematically assessed by a multidisciplinary team based on the Common Terminology Criteria of Adverse Events system. Results: Seventy-seven survivors with a median age of 16 years (range 8–43) and median follow-up of 10 years (range 2–42) completed the questionnaire and were screened for AEs. Patient-reported outcomes varied widely between survivors. Many survivors reported negative consequences: 82% on appearance items, 81% on HRQOL items, and 38% on facial function items. There was a weak correlation between physician-scored AEs and the majority of patient-reported outcomes specific for those AEs. Conclusions: Physician-graded AEs are not sufficient to provide tailored care for HNMRS survivors. Findings from this study highlight the importance of incorporating patient-reported outcome measures in survivorship follow-up

Ophthalmologic adverse events in childhood head and neck rhabdomyosarcoma survivors treated according to four different local treatment strategies

Introduction: Ophthalmological adverse events (OAEs) are known to frequently occur following local treatment for pediatric head and neck rhabdomyosarcoma (HNRMS). The exact nature of these OAEs and the burden they put on survivors is less well described. Moreover, it is suspected there might be differences in the prevalence and nature of OAEs depending on local treatment strategy applied: external beam radiation therapy with photons, external beam radiation therapy with protons, macroscopically radical surgery combined with brachytherapy, or microscopically radical surgery combined with external beam radiation therapy. Methods: We cross-sectionally assessed 98 HNRMS survivors with long (median 9 years) follow-up time, according to a predefined list of OAEs based on the Common Terminology Criteria for Adverse Events system. We added information from chart reviews on the nature and management of all OAEs scored grade ≥1. We describe the prevalence of OAEs for the different tumor sites and treatment strategies separately. Results: OAEs occurred following treatment of all HNRMS sites. The most frequently observed OAEs are eyelid abnormalities, dry eyes, and cataracts. Sixty-two percent of survivors had several different OAEs simultaneously. In 27 % of survivors additional (surgical) treatment of OAEs was required during follow-up. The patterns observed suggest a possible relationship between OAE type and treatment strategy. Conclusion: OAEs in HNRMS survivors confer a high burden of chronic toxicity. The simultaneous occurrence of multiple OAEs in individual survivors present a particularly challenging clinical scenario and demand specific expertise. We propose a standardized screening scheme to detect possible OAEs in asymptomatic survivors based on primary tumor localization

De Georges Clemenceau à Jacques Chirac : l'état et la pratique de la Loi de Séparation

La loi du 9 décembre 1905 sur la Séparation des Églises et de l'État est consacrée aujourd'hui comme une pièce essentielle du socle républicain. Ce n'était pas le cas à la veille de son adoption. Dès lors, c'est dans la pratique de la loi par les pouvoirs publics qu'il faut rechercher les origines de l'adhésion progressive de la société française aux principes affirmés par le texte. En publiant les communications de chercheurs et les interventions d'acteurs politiques et de responsables des grandes institutions religieuses que le colloque tenu les 9 et 10 décembre 2005, cet ouvrage permet de mesurer l'ampleur et la diversité d'une évolution séculaire de la société française tout en identifiant les étapes et l'originalité de la laïcisation française et en évaluant les limites

De Georges Clemenceau à Jacques Chirac : l'état et la pratique de la Loi de Séparation

La loi du 9 décembre 1905 sur la Séparation des Églises et de l'État est consacrée aujourd'hui comme une pièce essentielle du socle républicain. Ce n'était pas le cas à la veille de son adoption. Dès lors, c'est dans la pratique de la loi par les pouvoirs publics qu'il faut rechercher les origines de l'adhésion progressive de la société française aux principes affirmés par le texte. En publiant les communications de chercheurs et les interventions d'acteurs politiques et de responsables des grandes institutions religieuses que le colloque tenu les 9 et 10 décembre 2005, cet ouvrage permet de mesurer l'ampleur et la diversité d'une évolution séculaire de la société française tout en identifiant les étapes et l'originalité de la laïcisation française et en évaluant les limites

Quasi-free (p,2p) reactions in inverse kinematics for studying the fission yield dependence on temperature

Despite the recent experimental and theoretical progress in the investigation of the nuclear fission process, a complete description still represents a challenge in nuclear physics because it is a very complex dynamical process, whose description involves the coupling between intrinsic and collective degrees of freedom, as well as different quantum-mechanical phenomena. To improve on the existing data on nuclear fission, we produce fission reactions of heavy nuclei in inverse kinematics by using quasi-free (p,2p) scattering, which induce fission through particle-hole excitations that can range from few to ten's of MeV. The measurement of the four-momenta of the two outgoing protons allows to reconstruct the excitation energy of the fissioning compound nucleus and therefore to study the evolution of the fission yields with temperature. The realization of this kind of experiment requires a complex experimental setup, providing full isotopic identification of both fission fragments and an accurate measurement of the momenta of the two outgoing protons. This was realized recently at the GSI/FAIR facility and here some preliminary results are presented

MEDULLOBLASTOMA

BACKGROUND: LMD in children with recurrent medulloblastoma and other PNETs carries a poor prognosis and novel therapies are urgently needed to improve disease control. Somatostatin receptor-2 (SSR-2)is overexpressed in medulloblastoma and other central PNETs and can serve as a target for radionuclide tagged somatostatin analogues like 177Lu-DOTA-TATE that has shown considerable efficacy in adults with SSR-2 positive neuro-endocrine tumors. As a preliminary step prior to testing this agent in children with LMD, we performed an efficacy study of i.t. 177Lu-DOTA-TATE in athymic rats bearing LMD from MBL. METHODS: The subarachnoid space was accessed through the animal's cervical spine and a catheter was threaded along the dorsal aspect of spinal cord to the lumbar region and injected with 1 x 107 D341 human MBL cells and treatment initiated 3 days later. Groups of 10 animals received a single i.t. dose of 2, 3, or 5 mCi of 177Lu- DOTA-TATE or saline control. Animals were followed 300 days for survival. RESULTS: Treatment with 2 mCi resulted in an increase in median survival of 58.3% compared with saline control (p < 0.001). Treatment with 5.0 mCi of 177Lu-DOTA-TATE increased median survival by 75.0% compared with the saline control group while a single dose of 3.0 mCi 177Lu-DOTA-TATE increased median survival compared with saline controls by 519.4%. Long-term survivors were seen in 0 of 10 animals treated with saline, 4 of 11 treated with 3 mCi, and 3 of 12 treated with 5.0 mCi. CONCLUSION: Intrathecal 177Lu- DOTA TATE is efficacious in controlling LMD from medulloblastoma in athymic rats. A phase I trial of this agent is being planned in children with LMD from recurrent MBL and other CNS PNETs. INTRODUCTION: Medulloblastoma/PNET is the most common malignant brain tumor in children. For children older than 3 years, the treatment of high risk group includes surgery, craniospinal (CSI) radiation therapy (30-36 Gy) plus local boost radiotherapy (54-56 Gy) and adjuvant chemotherapy, such as cisplatinum, carboplatin, lomustine, cyclophosphamide, and vincristine. The results have demonstrated 5-year overall survival (OS) of 40-60%. This study aimed to evaluate the outcomes of high risk medulloblastoma/PNET patients who were treated with radiation and adjuvant chemotherapy. METHODS: Patients were diagnosed with high risk medulloblastoma/PNET according to the histopathology, medulloblastoma risk classification by an evidence of metastasis or the residual tumor more than 1.5 cm2 and evidence of residual tumor after surgery in PNET. Treatment protocol was CSI RT 36 Gy with local boost at tumor 54-56 Gy. Two to four weeks after RT, patients received 8 courses of chemotherapy consisting of cyclophosphamide 800 mg/m2, day 1-3 and vincristine 2 mg/m2, week 1-3, alternated with carboplatin 200 mg/m2, day 1-3 and etoposide 150 mg/m2, day 1-3. RESULTS: Total of 25 patients, male: female of 2.6:1 and mean ± SD for age of 9.7± 3.0 years, were enrolled. The 5-year progression free survival and OS were 41.6± 11.7% and 61.5± 12.9%,respectively. The age and sex did not determine the difference in outcomes. The hematotoxic side effect, according to the National Cancer Institute's Common Terminology Criteria, were grade 4 leucopenia 60%, grade 4 neutropenia 60%, grade 4 anemia 20%, grade 4 thrombocytopenia 16%, grade 3 leucopenia 20%, grade 3 neutropenia 20%, grade 3 anemia 40%, and grade 3 thrombocytopenia 36%. Febrile neutropenia was found in 11 patients (44%). CONCLUSION: The present study demonstrated the similar outcomes of high risk medulloblastoma/PNET with the previous studies. Although, the grade 3 and 4 hematologic toxicity was high, no treatment related death was found. OBJECTIVE: Recent investigations revealed an association between transcriptional subtypes and morphological features in medulloblastoma. Since both characteristics are of prognostic significance, a precise correlation between them should be well established. Therefore we re-examined paediatric nodular medulloblastoma tumours for correlation with molecular subtypes of disease. METHODS: Paediatric patients with previously diagnosed desmoplastic/nodular (D/N) or medulloblastoma with extensive nodularity (MBEN) histopathology were re-analysed by two neuropathologists. In addition to H&E-stained slides, reticulin preparations were simultaneously analysed from the same FFPE blocks. For identification of transcriptional subtypes of tumours immunohistopathological analyses were performed using a panel of representative antibodies. MYCC amplification was detected by FISH. RESULTS: Altogether 28 tumours with original MBEN or D/N diagnosis where molecular subtypes could be determined were identified. All tumours with MBEN histology belonged to SHH group and displayed distinctive reticulin-positive internodular reaction. However, only ∼60% of tumours with original D/N diagnosis were reticulin-positive. They belonged to SHH type, were mainly infantile and patients are still alive. Among reticulin-negative tumours only two were of the SHH type and were subsequently reclassified as classic and anaplastic tumours with pseudonodules. Importantly, all remaining reticulin-negative tumours with a presence of nodules in H&E staining belonged to the non-WNT,SHH type. Therefore the original diagnosis was again reclassified as classic or anaplastic tumours with pseudonodules. Patients from this group were only males, with median age 14 years old, one had MYCC amplification and two of them died because of disease. Therefore, non-WNT,SHH tumours did not display typical desmoplastic/nodular histology accompanied by reticulin positive reaction as opposite to truly D/N tumours being typical for SHH molecular group (p < 0.001). CONCLUSION: Reticulin staining is necessary to distinguish two different biologically and clinically group of nodular tumours which appear morphologically similar under H&E staining alone. BACKGROUND: In the PNET4 European randomised controlled trial, children with standard risk medulloblastoma were allocated to HFRT or to STRT. All received maintenance chemotherapy. Event-free survival was similar between the two treatment arms. HFRT was associated with worse growth and better questionnaire-based executive function 6.1 years post-diagnosis, especially in children aged <8 years at diagnosis (Kennedy et al., IJROBP, 2014). Therefore the aim of this study was to compare cognitive outcomes between treatment arms. METHODS: Neuropsychological data was collected prospectively in 137 patients from Germany, France, Italy and Sweden. Using results of the Wechsler Intelligence Scales, Kaufman Assessment Battery for Children, and Raven's progressive matrices, we generated: Full scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), working memory index (WMI) and speed of processing index (PSI). RESULTS: Among the 137 participants, [n = 71 HFRT, n = 66 STRT, 63.5% males; mean (SD, range) age at diagnosis 9.3 years (3.2, 4 to 17.6), 40.9% aged <8 years at diagnosis; age at assessment 15.6 years (3.7, 8.3 to 25). Mean (SD, range) FSIQ in all participants was 88 (19, 40-137); mean intergroup difference [95% CIs] (3.88, [-2.66 to 10.41], p = .24). No difference was found in children aged > 8 years at diagnosis. In children aged <8 at diagnosis, VIQ was significantly higher in children receiving HFRT compared to STRT; a similar trend was found for PSI but not for PIQ,WMI and FSIQ (mean inter-group differences [95% CIs]): VIQ 12.02 [2.37 to 21.67], p = 0.02; PIQ (2.73 [-7.89 to 13.35], p > .10); WMI (5.20 [-2.07 to 12.47], p > .10), PSI (10.91 [-1.54 to 23.36], p = .08; FSIQ (5.28 [-4.23 to 14.79], p > .10). CONCLUSION: HFRT was associated with higher verbal IQ in children aged <8 years at diagnosis, consistent with the previous report using questionnaire-based data. Effect sizes were small, albeit with 10 point inter-group differences within their 95% CIs. Preoperative chemotherapy is often used in pediatric oncology to treat metastatic disease and facilitate the surgery of the primary tumor, but not for brain tumors. A first pilot study showed in 2004 the feasibility and effectiveness of preoperative chemotherapy in treating high-risk medulloblastomas. Seventy-one patients were treated for a metastatic medulloblastoma between 2002 and 2010 at Gustave Roussy. Two strategies were compared in intention to treat. Forty-two children were operated at the time of the diagnosis (group A) and the 29 others children were treated with 2 courses of carboplatin and etoposide (group B) after histological diagnosis (biopsy) and before a delayed surgery. Children of group A received the two courses of carboplatin and etoposide afterwards. The rest of the protocol (high-dose chemotherapy and cranio-spinal irradiation) was similar in the both groups. Complete neuropsychological testing, including intelligence quotient measurements, was scheduled before surgery, before radiotherapy and every year thereafter. MRI performed after neo-adjuvant chemotherapy showed an objective response in 24 patients (83%) and a stable disease in 4 patients (14%). Complete excision rate was significantly higher in group B (100% versus 64%, p = 0.00248) without any difference in postoperative complication rate. Medulloblastoma cells could still be evidenced despite preoperative chemotherapy. The median Total Intelligence Quotient (TIQ) was 81 and 90 in group A and B respectively (p = 0.02543). This difference was even more significant in young children (77 vs 91 points for groupe A and B, respectively). Hydrocephalus and brain radiotherapy dose were not associated with TIQ. Neo-adjuvant chemotherapy had no negative impact on local disease control (79 versus 83%). Event-free survival and overall survival at 3 years were 54 versus 62% and 58 versus 68% respectively (p = NS). Neo-adjuvant chemotherapy in metastatic medulloblastoma is safe and could have a positive impact on neuropsychological outcome and completeness of surgery. BACKGROUND: We prospectively evaluated histopathological findings and molecular variables, which have shown to impact prognosis of medulloblastoma patients, for outcome prediction in homogenously treated metastatic medulloblastoma patients. METHODS: One hundred twenty-three patients aged 4-21 years, diagnosed from 2001 to 2007, received systemic induction chemotherapy and intraventricular methotrexate, followed by hyperfractionated radiotherapy, and maintenance chemotherapy. From 86 patients paraffin material was available for immunohistochemical analysis to determine the activation status of the wingless (WNT) pathway, by immunostaining for β-catenin and sequencing of CTNNB1. In 81 of those 86 patients, material was available for gene amplification assessment of MYCC and MYCN by multiplex ligation-dependent probe amplification. RESULTS: Tumors with nuclear β-catenin immunopositivity showed excellent outcome (n = 4, all classic histology, 3 / 4 with CTNNB1 mutation; 5-year event-free (EFS) and overall survival (OS): 100%) compared to patients with tumors lacking nuclear β-catenin staining (n = 82; 5-year rates: 63% and 72%, respectively; p = 0.134 for EFS, p = 0.213 for OS). Patients with tumors characterized by MYC amplification (n = 5; MYCC, n = 2; MYCN, n = 3; all classic histology despite one case with MYCC amplification showing large cell histology) had poor outcome (20% for EFS and OS, respectively) when compared to patients with non-MYCC/MYCN amplified tumors (n = 76; 5-year EFS and OS: 65% and 75%, respectively; p = 0.011 for EFS, p < 0.001 for OS). Based on histopathological and molecular findings, we identified three risk groups: Favorable- (β-catenin nucleopositive and/or desmoplastic histology (n = 7; one death of disease), n = 11; 5-year EFS and OS 89 ± 11%), poor- (MYCC/MYCN amplification and/or anaplastic or large cell histology, n = 6; 5-year EFS and OS 33 ± 19%), and intermediate-risk group (n = 64; 5-year EFS and OS 61 ± 7%, and 72 ± 6%, respectively; p = 0.020 for EFS, and p = 0.002 for OS). CONCLUSION: Histopathological subtyping together with molecular features (WNT pathway and MYCC/MYCN amplification status) differentiate three risk groups in homogenously treated metastatic medulloblastoma patients. Supported by Deutsche Kinderkrebsstiftung. BACKGROUND: A number of different second neoplasms have been reported in patients with neuroblastoma including brain tumors. None of these second cancers have occurred with sufficient frequency to indicate a specific relationship between neuroblastoma and any other neoplasm except in rare cancer syndromes. OBJECTIVE: We report a case of medulloblastoma in a child 5 months after successful treatment of metastatic neuroblastoma. DESIGN AND METHOD: A MEDLINE search was conducted for queries including “Children”, “medulloblastoma” and ‘neuroblastoma”. Relevant papers were selected for literature review. RESULT: A 10 months old female presented with 2-month history of right eye proptosis. CT scan of the abdomen showed a right adrenal mass with liver metastasis. Brain MRI revealed disease at the right orbital fossa extends to middle cranial fossa with no intracranial disease. Pathology of the right adrenal mass confirmed neuroblastoma with non amplified N myc. The patient was classified as intermediate risk disease and started on chemotherapy consisted of vincristine, cyclophosphamide, cisplatin, dacarbazine, ifosphamide and Adriamycin followed by 5 cycles of Accutane. Surveillance MIBG revealed no evidence of residual disease. Five months later, she had a new onset of trouble walking. CT and MRI of the brain showed a mass in the right cerebellar hemisphere with hydrocephalus. Complete Surgical resection of the mass was done and pathology revealed anaplastic medullobastoma. The patient initiated chemoradiation treatment for medulloblastoma. Her treatment was stopped because of disseminated fungal infection. She is currently receiving metronomic therapy with cyclophosphamide and topotecan and has been clinically stable. Molecular genetic tests are pending for familial cancer syndromes. CONCLUSION: We report a case of metachronous medullobastoma after treatment of metastatic neuroblastoma in a two year-old child. The occurrence of metachronous neoplasms is rare and challenging to treat. Cancer familial syndromes like neurofibromatosis type 1 and Simpson-Golabi-Behmel syndrome need to be excluded. Group 3 medulloblastoma with elevated c-MYC has the worst prognoses of the four molecular subgroups. To generate a genetically defined model of this disease, we transformed human fetal cerebellar stem cells with MYC along with hTERT, dominant negative p53 and constitutively active AKT. The resulting xenografts showed morphological similarities to large cell/anaplastic medulloblastoma, leptomeningeal and spinal dissemination, and had a gene expression profile closely aligned with Group 3 primary tumors. Because MYC over-expression leads to increased glutamine metabolism and glutamine addiction in other cancers, we hypothesized that MYC-driven MB would exhibit increased glutamine metabolism and be sensitive inhibitors of glutamine metabolism. In both our human stem cell derived and established medulloblastoma cell lines, MYC expression positively correlates with increased expression of glutaminolytic enzymes. Inhibition of glutamine metabolism was achieved using two glutamine analogs, acivicin and 6-diazo-5-L-norleucine (DON). In our human stem cell models, MYC-transformed cells experienced a significant decrease in proliferation and an increase in apoptosis after acivicin treatment (p < 0.005), while SV40-transformed cells were unaffected. Both compounds also significantly decreased growth and increased apoptosis of the high-MYC MB cell lines D425Med and D283Med. In xenograft experiments using D283Med, fewer mice receiving acivicin developed flank tumors, and the resulting tumors were significantly smaller (80.9 mm3 treated vs 273.8 mm3 untreated). Glutaminase knockdown using short hairpins also significantly decreased growth of D425Med and D283Med. In summary, we present a novel human cerebellar stem cell based model of Group 3 medulloblastoma, and data suggesting that glutamine metabolism may be a therapeutic target in MYC-driven MB