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Metastatic Medulloblastoma in Childhood: Chang's Classification Revisited  [PDF]
Christelle Dufour,Annick Beaugrand,Barry Pizer,Julie Micheli,Marie-Stephanie Aubelle,Aurelie Fourcade,Dominique Couanet,Agnes Laplanche,Chantal Kalifa,Jacques Grill
International Journal of Surgical Oncology , 2012, DOI: 10.1155/2012/245385
Abstract: Purpose. To correlate the radiological aspects of metastases, the response to chemotherapy, and patient outcome in disseminated childhood medulloblastoma. Patients and Methods. This population-based study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF), nodular or laminar), and their extension (positive cerebrospinal fluid, local, extensive). All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response ( ). Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival. 1. Introduction Medulloblastoma (MB) is the most common malignant brain tumor of childhood. It has a propensity for leptomeningeal spread via the cerebrospinal fluid (CSF) circulation, and approximately 30–35% of the patients present with evidence of metastatic disease [1]. Currently, patients with disseminated medulloblastoma are classified according to Chang’s operative staging system [2], where the extent of metastasis is subdivided into M0 (no metastasis), M1 (presence of tumor cells in the CSF), M2 (nodular seeding in the cerebellar or cerebral subarachnoid space or in the third or lateral ventricle), M3 (metastasis in spinal subarachnoid space), and M4 (metastases outside the cerebrospinal axis). This sensitive operative system was initially determined from operative records and autopsy specimens and has been later adapted to modern imaging techniques such as MRI. Neither the extent nor the various aspects of the metastases are taken into account, and only the location is considered. The relevance of intracranial (M2) and spinal (M3) leptomeningeal spread for classification as high-risk disease is unequivocal and the outcome for M2 patients is not significantly different from M3 patients [1, 3]. Since the original classification in 1969 that did not separate the outcome of patients with M0 and M1 disease, there is still some uncertainty about the prognostic impact of M1 stage [3–8]. In addition, the assessment of
Postoperative craniospinal radiotherapy of medulloblastoma in children and young adults  [PDF]
Golubi?i? Ivana V.,Bokun Jelena,Nikitovi? Marina R.,Mladenovi? Jasmina
Srpski Arhiv za Celokupno Lekarstvo , 2003, DOI: 10.2298/sarh0306226g
Abstract: PURPOSE The aim of this study was: 1. to evaluate treatment results of combined therapy (surgery, postoperative craniospinal radiotherapy with or without chemotherapy) and 2. to assess factors affecting prognosis (extend of tumor removal, involvement of the brain stem, extent of disease postoperative meningitis, shunt placement, age, sex and time interval from surgery to start of postoperative radiotherapy). PATIENTS AND METHODS During the period 1986-1996, 78 patients with medulloblastoma, aged 1-22 years (median 8.6 years), were treated with combined modality therapy and 72 of them were evaluable for the study end-points. Entry criteria were histologically proven diagnosis, age under 22 years, and no history of previous malignant disease. The main characteristics of the group are shown in Table 1. Twenty-nine patients (37.2%) have total, 8 (10.3%) near total and 41 (52.5%) partial removal. Seventy-two of 78 patients were treated with curative intent and received postoperative craniospinal irradiation. Radiotherapy started 13-285 days after surgery (median 36 days). Only 13 patients started radiotherapy after 60 days following surgery. Adjuvant chemotherapy was applied in 63 (80.7%) patients. The majority of them (46 73%) received chemotherapy with CCNU and Vincristine. The survival rates were calculated with the Kaplan-Meier method and the differences in survival were analyzed using the Wilcoxon test and log-rank test. RESULTS The follow-up period ranged from 1-12 years (median 3 years). Five-year overall survival (OS) was 51% and disease-free survival (DFS) 47% (Graph 1). During follow-up 32 relapses occurred. Patients having no brain stem infiltration had significantly better survival (p=0.0023) (Graph 2). Patients with positive myelographic findings had significantly poorer survival compared to dose with negative myelographic findings (p=0.0116). Significantly poorer survival was found in patients with meningitis developing in the postoperative period, with no patient living longer than two years (p=0.0134) (Graph 3). By analysis of OS and DFS in relation to presence of the malignant cells in liquor, statistically significant difference, i. e. positive CSF cytology was not obtained, which was of statistical importance for survival (p=0.8207). Neither shunt placement nor shunt type showed any impact on survival (p=0.5307 and 0.7119, respectively). Children younger than three years had significantly poorer survival compared to those older than 16 years (p=0.0473). Although there was a better survival rate in females than in males this was not statist
Medulloblastoma in China: Clinicopathologic Analyses of SHH, WNT, and Non-SHH/WNT Molecular Subgroups Reveal Different Therapeutic Responses to Adjuvant Chemotherapy  [PDF]
Zhen-Yu Zhang, Jian Xu, Yong Ren, Yu Yao, Kay Ka-Wai Li, Ho-Keung Ng, Ying Mao, Liang-Fu Zhou, Ping Zhong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099490
Abstract: Medulloblastoma (MB) is one of the most common primary central nervous system tumors in children. Data is lacking of a large cohort of medulloblastoma patients in China. Also, our knowledge on the sensitivity of different molecular subgroups of MB to adjuvant radiation therapy (RT) or chemotherapy (CHT) is still limited. The authors performed a retrospective study of 173 medulloblastoma patients treated at two institutions from 2002 to 2011. Formalin-fixed paraffin embedded (FFPE) tissues were available in all the cases and sections were stained to classify histological and molecular subgroups. Univariate and multivariate analyses were used to investigate prognostic factors. Of 173 patients, there were 118 children and 55 adults, 112 males and 61 females. Estimated 5-year overall survival (OS) rates for all patients, children and adults were 52%, 48% and 63%, respectively. After multivariate analysis, postoperative primary radiation therapy (RT) and chemotherapy (CHT) were revealed as favorable prognostic factors influencing OS and EFS. Postoperative primary chemotherapy (CHT) was found significantly improving the survival of children (p<0.001) while it was not a significant prognostic factor for adult patients. Moreover, patients in WNT subtype had better OS (p = 0.028) than others (SHH and Non-SHH/WNT subtypes) given postoperative adjuvant therapies. Postoperative primary RT was found to be a strong prognostic factor influencing the survival in all histological and molecular subgroups (p<0.001). Postoperative primary CHT was found significantly to influence the survival of classic medulloblastoma (CMB) (OS p<0.001, EFS p<0.001), SHH subgroup (OS p = 0.020, EFS p = 0.049) and WNT subgroup (OS p = 0.003, EFS p = 0.016) but not in desmoplastic/nodular medulloblastoma (DMB) (OS p = 0.361, EFS p = 0.834) and Non-SHH/WNT subgroup (OS p = 0.127, EFS p = 0.055). Our study showed postoperative primary CHT significantly influence the survival of CMB, SHH subgroup and WNT subgroup but not in DMB and Non-SHH/WNT subgroup of MB.
c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
André O von Bueren, Christoph Oehler, Tarek Shalaby, Katja von Hoff, Martin Pruschy, Burkhardt Seifert, Nicolas U Gerber, Monika Warmuth-Metz, Duncan Stearns, Charles G Eberhart, Rolf D Kortmann, Stefan Rutkowski, Michael A Grotzer
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-74
Abstract: We used DAOY and UW228 human MB cells engineered to stably express different levels of c-MYC, and tested whether c-MYC expression has an effect on radio- and chemosensitivity using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay, clonogenic survival, apoptosis assays, cell cycle analysis, and western blot assessment. In an effort to validate our results, we analyzed c-MYC mRNA expression in formalin-fixed paraffin-embedded tumor samples from well-documented patients with postoperative residual tumor and compared c-MYC mRNA expression with response to radio- and chemotherapy as examined by neuroradiological imaging.In DAOY - and to a lesser extent in UW228 - cells expressing high levels of c-MYC, the cytotoxicity of cisplatin, and etoposide was significantly higher when compared with DAOY/UW228 cells expressing low levels of c-MYC. Irradiation- and chemotherapy-induced apoptotic cell death was enhanced in DAOY cells expressing high levels of c-MYC. The response of 62 of 66 residual tumors was evaluable and response to postoperative radio- (14 responders (CR, PR) vs. 5 non-responders (SD, PD)) or chemotherapy (23 CR/PR vs. 20 SD/PD) was assessed. c-MYC mRNA expression was similar in primary MB samples of responders and non-responders (Mann-Whitney U test, p = 0.50, ratio 0.49, 95% CI 0.008-30.0 and p = 0.67, ratio 1.8, 95% CI 0.14-23.5, respectively).c-MYC sensitizes MB cells to some anti-cancer treatments in vitro. As we failed to show evidence for such an effect on postoperative residual tumors when analyzed by imaging, additional investigations in xenografts and larger MB cohorts may help to define the exact function of c-MYC in modulating response to treatment.Medulloblastomas (MB) are the most common malignant brain tumors of childhood and constitute 20% of all pediatric brain tumors [1]. Progress in the treatment of MB has been achieved in multiple areas including neurosurgical tech
Combined radiotherapy and chemotherapy for pediatric medulloblastoma: a clinical study of 33 cases  [cached]
Wei ZHENG,Qing NIE,Jing-bo KANG,Ping YANG
Medical Journal of Chinese People's Liberation Army , 2011,
Abstract: Objective To retrospectively review the clinical characteristics of medulloblastoma,discuss the optimized treatment regimen,and analyze the prognostic influential factors.Methods Thirty-three children with pathologically certified medulloblastoma(aged 3-14 years with average of 6.5 years),admitted from Aug.2004 to Dec.2007,received radiotherapy within 3 weeks post surgery.Ratiotherapy consisted of 28~36Gy whole craniospinal radiation and a supplementary radiation aimed at tumors by three-dimensional conformal radiotherapy(3D-CRT) for a total dose of 50~54Gy(conventional fraction dose of 1.8-2.0Gy).A part of patients received hyperfractionation radiotherapy(1.0Gy/f,2f/d) for alleviating the tardive adverse events.Meanwhile,a synchronized chemotherapy,consisting of lomustine + vincristine + cisplatin,or isophosphamide + carboplatin + etoposide,was administered after the completion of whole craniospinal radiation,and 3-5 courses of sequential chemotherapy were given after the overall radiotherapy was finished.According to the metastasis,and the residual tumor and its size,the 33 patients were divided into 2 groups as follows: low-risk group(n=24): no metastases,total or sub-total excision of tumors(residual tumors ≤1.5cm3);high-risk group(n=9): either metastases or residual tumor > 1.5cm3.The 3-year survival rates of two groups were then compared.Results The combined radiotherapy and chemotherapy was effective to 10 of the 11 patients(90.9%) with residual tumors.Out of the 33 patients,31 obtained complete remission(93.9%),and 2 patients showed partial remission or stable status(3.0%,respectively).The median survival time of 33 patients was 51 months,3-year disease free survival(DFS) was 75.8%,and 3-year overall survival(OS) was 78.8%,including 33.3% in high-risk group and 95.8% in low-risk group(P < 0.01).The major side effects occurred in haematological system and digestive system,such as an incidence of 21.2%(7/33) with grade Ⅲ-Ⅳ bone marrow suppression,87.9%(29/33) with nausea,and 66.7%(22/33) with nausea and vomiting.Conclusions It is not difficult to make a definite diagnosis of pediatric medulloblastoma.Combined radiotherapy and chemotherapy following surgery,which is primarily recommended therapy,will give favorable effects with a low risk of complicating severe adverse events.The eradication of the tumor plays a pivotal role in influencing the prognosis of patients.
Early traits of metabolic syndrome in pediatric post-cancer survivors: outcomes in adolescents and young adults treated for childhood medulloblastoma
Siviero-Miachon, Adriana Aparecida;Monteiro, Carlos Manoel de Castro;Pires, Liliane Viana;Rozalem, Ana Carolina;Silva, Nasjla Saba da;Petrilli, Antonio Sergio;Spinola-Castro, Angela Maria;
Arquivos Brasileiros de Endocrinologia & Metabologia , 2011, DOI: 10.1590/S0004-27302011000800022
Abstract: objective: to analyze traits of metabolic syndrome (mets) in medulloblastoma survivors. subjects and methods: sixteen childhood medulloblastoma survivors aged 18.0 (4.4) years, with history of craniospinal radiation therapy (rt) were compared with nine control subjects matched by age, gender, and body mass index, according to fat distribution, metabolic and cardiovascular variables. results: medulloblastoma patients showed increases in waist circum-ference and its relationships (all p < 0.05), and homa1-ir (p = 0.006), which were modified by growth hormone (gh) secretion status. however, these increases were within normal range. conclusions: adolescent and young adult survivors of medulloblastoma showed centripetal fat deposition and decreased insulin sensitivity, associated with gh status. pediatric brain tumor survivors following rt should be monitored for the diagnosis of mets traits predisposing to cardiovascular disease.
Application of Postoperative Chemotherapy on Thymomas and Its Prognostic Effect  [PDF]
Ke MA, Zhitao GU, Yongtao HAN, Jianhua FU, Yi SHEN, Yucheng WEI, Lijie TAN, Peng ZHANG, Chun CHEN, Renquan ZHANG, Yin LI, Ke-Neng CHEN, Hezhong CHEN, Yongyu LIU, Youbing CUI, Yun WANG, Liewen PANG, Zhentao YU, Xinming ZHOU, Yangchun LIU, Yuan LIU, Wentao FANG, Members of the Chinese Alliance for Research in Thymomas
- , 2016, DOI: : 10.3779/j.issn.1009-3419.2016.07.10
Abstract: Background and objective To study the role of postoperative chemotherapy and its prognostic effect in Masaoka-Koga stage III and IV thymic tumors. Methods Between 1994 and 2012, 1,700 patients with thymic tumors who underwent surgery without neoajuvant therapy were enrolled for the study. Among them, 665 patients in Masaoka-Koga stage III and IV were further analyzed to evaluate the clinical value of postoperative chemotherapy. The Kaplan-Meier method was used to obtain the survival curve of the patients divided into different subgroups, and the Cox regression analysis was used to make multivariate analysis on the factors affecting prognosis. A Propensity-Matched Study was used to evaluate the clinical value of chemotherapy. Results Two-hundred-twenty-one patients were treated with postoperative chemotherapy, while the rest 444 cases were not. The two groups showed significant differences (P<0.05) regarding the incidence of myasthenia gravis, World Health Organization (WHO) histological subtypes, pathological staging, resection status and the use of postoperative radiotherapy. WHO type C tumors, incomplete resection, and postoperative radiotherapy were significantly related to increased recurrence and worse survival (P<0.05). Five-year and 10-year disease free survivals (DFS) and recurrence rates in patients who underwent surgery followed by postoperative chemotherapy were 51% and 30%, 46% and 68%, comparing with 73% and 58%, 26% and 40% in patients who had no adjuvant chemotherapy after surgery (P=0.001, P=0.001, respectively). In propensity-matched study, 158 pairs of patients with or without postoperative chemotherapy (316 patients in total) were selected and compared accordingly. Similar 5-year survival rates were detected between the two groups (P=0.332). Conclusion Pathologically higher grade histology, incomplete resection, and postoperative radiotherapy were found to be associated with worse outcomes in advanced stage thymic tumors. At present, there is no evidence to show that postoperative chemotherapy may help improve prognosis in patients with Masaoka-Koga-Koga stage III and IV thymic tumors.
Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine  [cached]
Hutzen Brian,Pierson Christopher R,Russell Stephen J,Galanis Evanthia
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-508
Abstract: Background Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. Methods We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later. Results MV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. Conclusions These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma.
Management of Posterior Fossa Medulloblastoma in Adults
W Fouad, I Zidan
Alexandria Journal of Medicine , 2010,
Abstract: Background: Medulloblastoma is a malignant tumor of the cerebellum that occurs predominantly in children. It is rare in adults and accounts for less than 1 % of all adult primary brain tumors. Objective: This study was done to study clinical picture, radiological findings, to evaluate the surgical outcome and to assess the effects of postoperative adjuvant therapy in 12 adult patients who had posterior fossa medulloblastoma Methods: This prospective study was carried out on consecutive 12 adult patients who had posterior fossa medulloblastoma. This study was done in Alexandria hospitals over a period of 3 years starting from March 2006 to March 2009. The male to female ratio was 2 to 1(8 males and 4 females) and their ages ranged from 19 to 51 years with mean age of 33, 8 years. Headache was the most frequent symptom (93,5% of patients). As regards the clinical presentation, manifestations of increased intracranial pressure was found in 10 patients (83,3%), cerebellar dysfunction in 8 patients (66,6%), cranial nerve deficits in half of the cases. The tumour was hemispheric in 10 cases (6 lateral and 4 paramedian) and vermian in 2 cases. All patients had preoperative craniospinal MRI examination. No distant or spinal metastases were detected in our patients at the time of diagnosis. All cases underwent surgery in the form of resection of the tumour followed by postoperative craniospinal irradiation. Also two patients with recurrence and metastases received ad-juvant craniospinal radiotherapy and systemic chemotherapy. Mean postoperative follow up period was 24 months, including both clinical and MRI examination. Results: There were no operative mortality, and surgery did not provoke any permanent neurological aggravation. Postoperative MRI studies showed complete tumour resection was achieved in 9 patients (75%). After initial treatment only two patients relapsed in the posterior fossa after one and half year. Recurrence was probably related to incomplete tumor resection and long delay in initiating radiotherapy (3 months after operation). Two of the patients that received adjuvant treatment died: one from distant metastasis and one from recurrent disease. Ten patients remained alive and disease-free with Karnofsky performance status ranging from 80 to100. Conclusion: Adult medulloblastoma was predominant in males and the majority of patients had hemispheric cerebellar tumors. Adults are more likely to have heterogeneous cerebellar tumours on MRI, and this is thought to be related to the greater prevalence of desmoplastic variant in adulthood. Long-term survival was not uncommon. The outcome depends on the site of the tumour with better results obtained in cases with lateral hemispherical tumour that facilitate its complete surgical resection and good irradiation planning.
Postoperative Chemoradiotherapy Combined with Epirubicin-Based Triplet Chemotherapy for Locally Advanced Adenocarcinoma of the Stomach or Gastroesophageal Junction  [PDF]
Guichao Li, Zhen Zhang, Xuejun Ma, Ji Zhu, Gang Cai
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054233
Abstract: Background Due to low tolerance to chemotherapy, the maximum number of cycles of postoperative adjuvant chemotherapy is 4 in adjuvant gastric clinical trials. The aim of this study is to retrospectively evaluate the safety and efficacy of adjuvant epirubicin-based triplet chemotherapy and radiotherapy in the treatment of resected locally advanced stomach or gastroesophageal junction adenocarcinoma. Methodology/Principal Findings From January 2004 to July 2008, ninety-seven consecutive gastric or gastroesophageal junction adenocarcinoma patients in stages T3–4/N+ were treated with postoperative radiotherapy and chemotherapy. The recommended treatment plan was radical resection followed by 1–2 cycles of adjuvant chemotherapy (ACT), postoperative chemoradiotherapy (CRT), and, finally, 4–5 cycles of ACT. The patients were classified into two groups depending on the number of cycles of ACT: group 1 received 4–6 cycles (n = 59), and group 2 received 0–3 cycles (n = 38). The detailed grouping is as follows: RT alone, 2; RT and CT, 18; concurrent RTCT and CT, 41; and CRT, 36. Of the 97 patients, 77 patients received concurrent therapy (CRT, (5-fluorouracil or capecitabine), and 20 received radiotherapy alone because of patient refusal (n = 15) or treatment toxicity (n = 5). After a median follow-up of 44 months, the 3-year disease free survival(DFS) and overall survival (OS) were 66.5% and 69.5% for group 1 and 45.5% and 50% for group 2, respectively (p = 0.005 and p = 0.024). Multivariate analysis revealed that 4–6 cycles of ACT, lymphovascular invasion, or peritoneal metastasis were independent prognostic factors for disease-free survival or overall survival (p<0.05). Conclusions/Significance This study demonstrates that concurrent chemoradiation with adjuvant epirubicin-based triplet chemotherapy is feasible and tolerable for gastric or gastroesophageal junction carcinoma patients. Patients can benefit from more cycles of ACT.
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