Συμπληρωματικά περί Μακεδόνων κλεφτών και αρματολών

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Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas: Long-Term Results From the International Society of Pediatric Oncology MMT95 Study

Purpose MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. Patients and Methods From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. Results Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. Conclusion Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicit

[Localised rhabdomyosarcoma of the extremities in children and adolescents: results of the French experience]

PATIENTS AND METHODS: Forty-six patients with localised RMS of the limbs entered the MMT 89 and 95 study in France. We studied potential risk factors that were predictive of relapse and survival to propose a therapeutic approach of surgery and radiotherapy appropriate to the risk of relapse. RESULTS: Median age at diagnosis was 6.5 years [9 months to 15.5 years]. At time of diagnosis, 43% had marginal surgery and only 13% radical intervention. Primary re-excision was performed in 12% of the patients. All patients received chemotherapy, 43% had second look surgery and 37% received radiotherapy. Fifty-four percent of all tumors relapsed: local relapse 36%, nodes l8%, metastatic 40%, local and metastatic 16%. Estimated overall 5-year event-free survival (EFS) and overall survival (OS) were 40 and 57%, respectively. CONCLUSIONS: Prognosis of RMS of the limbs is bad but only 37% of the patients had radiotherapy. We could define patients with very high risk among those with limbs RMS as nodal involvement (5 years overall survival OS 22%), alveolar histology (OS 38%) and site of hand and foot (4 survivors out of 10 patients). In further studies, these patients should be treated even more aggressive with early surgery followed by re-excision if necessary, chemotherapy including alkylating agents and systematic radiotherapy

Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial

BACKGROUND Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma. METHODS We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m$^{2}$ given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m$^{2}$ weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m$^{2}$ on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m$^{2}$ given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up. FINDINGS Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6-78·9). The 3-year event-free survival was 67·5% (95% CI 61·2-73·1) in the IVA plus doxorubicin group and 63·3% (56·8-69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65-1·16; p=0·33). Grade 3-4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3-5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group. INTERPRETATIONS The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe. FUNDING Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France

Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study

Early response to induction chemotherapy is used in current European guidelines to evaluate the efficacy of chemotherapy and subsequently to adapt treatment in pediatric patients with rhabdomyosarcoma (RMS). However, existing literature on the prognostic value of early radiologic response on survival is contradictory; here the prognostic value is analyzed with data from the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor 95 (MMT-95) study. This study examined 432 Intergroup Rhabdomyosarcoma Study Grouping III (macroscopic residue) patients enrolled in the SIOP MMT-95 study with a response assessment after 3 courses of chemotherapy (a 2-dimensional assessment). Patients with progressive disease (PD) after 3 courses of chemotherapy were excluded (n = 7). Failure-free survival (FFS) and overall survival (OS), calculated with the Kaplan-Meier method, were compared for 3 groups (complete response [CR]/partial response [PR], objective response [OR], and no response [NR]). The prognostic impact of early response was assessed through the calculation of Cox proportional hazards. After 3 courses of chemotherapy, 85.2% of the patients had CR/PR, 8.6% had OR, and 6.3% had NR. For all patients, the 5-year FFS and OS rates were 60% (95% confidence interval [CI], 56%-65%) and 74% (95% CI, 70%-78%), respectively. However, a Cox proportional hazards regression analysis revealed no significant difference in FFS or OS between the response groups. The adjusted hazard ratios for an OR and NR were 1.09 (95% CI, 0.63-1.88) and 0.81 (95% CI, 0.39-1.67), respectively, for FFS and 0.91 (95% CI, 0.47-1.76) and 1.27 (95% CI, 0.61-2.64), respectively, for OS. No evidence was found for the idea that early radiologic response to chemotherapy is prognostic for survival for patients with RMS. Treatment adaptation based on early response (except for patients with PD) should, therefore, no longer be incorporated into future studies. Cancer 2018;124:1016-24. © 2017 American Cancer Societ

Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor

Abstract Purpose: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT. Experimental Design: hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification. Results: Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P &amp;lt; 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years' overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients. Conclusions: Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence. Clin Cancer Res; 17(1); 31–8. ©2011 AACR.</jats:p

Adaptation aux changements climatiques et à l’augmentation du niveau de la mer en zones côtières

La collection d'articles présentée dans ce hors-série est en grande partie issue du colloque « Adaptation aux changements climatiques et à l’augmentation du niveau de la mer en zones côtières : une perspective mondiale » tenu dans le cadre du 82e Congrès de l’Acfas à l'Université Concordia. L'intention du colloque était d'explorer la manière dont les communautés côtières à travers le monde s'adaptent aux problèmes causés par les changements climatiques et l'augmentation du niveau de la mer. Comment est-ce que la vulnérabilité, la résilience et la capacité d'adaptation se déclinent selon les différents contextes ? Comment est-ce que les processus sociaux se comparent d'une étude de cas à l'autre ? Comment est que les différents acteurs, dont les scientifiques, sont capables de relever les défis qui se posent aux communautés et quels sont les freins à une adaptation efficace ? Ce hors-série amène ainsi la lectrice et le lecteur dans un voyage à travers le monde, incluant Madagascar, le Vietnam, la France et l'Europe de l'Ouest, le Québec, le Nouveau-Brunswick et le monde virtuel du web

Liver disease in germline mutations of telomere-related genes: Prevalence, clinical, radiological, pathological features, outcome, and risk factors

International audienceBackground and aim: Germline mutations of telomere-related genes (TRG) induce multiorgan dysfunction, and liver-specific manifestations have not been clearly outlined. We aimed to describe TRG mutations-associated liver diseases. Approach and results: Retrospective multicentre analysis of liver disease (transaminases>30 IU/L and/or abnormal liver imaging) in patients with TRG mutations. Main measurements were characteristics, outcomes, and risk factors of liver disease in a TRG mutations cohort. The prevalence of liver disease was compared to a community-based control group (n=1190) stratified for age and matched 1:3 for known risk factors of liver disease. Among 132 patients with TRG mutations, 95 (72%) had liver disease, with associated lung, blood, skin, rheumatological and ophthalmological TRG diseases in 82%, 77%, 55%, 39%, and 30% of cases, respectively. Liver biopsy was performed in 52/95 patients, identifying porto-sinusoidal vascular disease (PSVD) in 48%, and advanced fibrosis/cirrhosis in 15%. After a follow-up of 21 months (12-54), ascites, hepato-pulmonary syndrome, variceal bleeding, and hepatocellular carcinoma occurred in 14%, 13%, 13%, and 2% of cases, respectively. Five-year liver transplantation-free survival was 69%. A FIB-4 score ≥3·25 and ≥1 risk factor for cirrhosis were associated with poor liver transplantation-free survival. Liver disease was more frequent in patients with TRG mutations than in the paired control group (80/396, (20%)), OR 12.9 (CI95% 7.8-21.3, p <0.001). Conclusions: TRG mutations significantly increase the risk of developing liver disease. Although symptoms may be mild they may be associated with severe disease. PSVD and cirrhosis were the most frequent lesions suggesting that the mechanism of action is multifactorial