BACKGROUND: The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA-RMS). PATIENTS AND METHODS: Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA-RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event-free survival (EFS) and overall survival (OS). RESULTS: From October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non-bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5-81.6) and 93.5% (95% CI, 90.1-95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5-year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/- radiotherapy was not significant (p = 0.8003). Adjuvant radiotherapy improved EFS with 5-year estimates of 84.7% versus 65.2% for nonirradiated (p < .0001), but not OS (p = .9298). Omitting radiotherapy for orbital tumors reduced OS (5-year was 87.1% vs. 97.3% for irradiated, p = .0257). Following R0 resection (n = 60), radiotherapy did not significantly improve EFS or OS. CONCLUSIONS: Radiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS.
- MeSH
- daktinomycin * aplikace a dávkování terapeutické užití MeSH
- dítě MeSH
- ifosfamid * aplikace a dávkování MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- předškolní dítě MeSH
- prospektivní studie MeSH
- protokoly protinádorové kombinované chemoterapie * terapeutické užití MeSH
- rhabdomyosarkom * radioterapie terapie mortalita chirurgie farmakoterapie MeSH
- vinkristin * aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Infantile fibrosarcoma (IFS) is a very rare disease occurring in young infants characterised by a high local aggressiveness but overall with a favourable survival. To try to reduce the total burden of therapy, the European pediatric Soft tissue sarcoma Study Group has developed conservative therapeutic recommendations according to initial resectability. MATERIAL AND METHODS: Between 2005 and 2012, children with localised IFS were prospectively registered. Initial surgery was suggested only if possible without mutilation. Patients with initial complete (IRS-group I/R0) or microscopic incomplete (group II/R1) resection had no further therapy. Patients with initial inoperable tumour (group III/R2) received first-line vincristine-actinomycin-D chemotherapy (VA). Delayed conservative surgery was planned after tumour reduction. Aggressive local therapy (mutilating surgery or external radiotherapy) was discouraged. RESULTS: A total of 50 infants (median age 1.4 months), were included in the study. ETV6-NTRK3 transcript was present in 87.2% of patients where investigation was performed. According to initial surgery, 11 patients were classified as group I, 8 as group II and 31 as group III. VA chemotherapy was first delivered to 25 children with IRS-III/R2 and one with IRS-II/R1 disease. Response rate to VA was 68.0%. Mutilating surgery was only performed in three cases. After a median follow-up of 4.7 years (range 1.9-9.0), 3-year event-free survival and overall survival were respectively 84.0% (95% confidence interval [CI] 70.5-91.7) and 94.0% (95% CI 82.5-98.0). CONCLUSIONS: Conservative therapy is possible in IFS as only three children required mutilating surgery, and alkylating or anthracycline based chemotherapy was avoided in 71.0% of patients needing chemotherapy. VA regimen should be first line therapy in order to reduce long term effects.
- MeSH
- adjuvantní chemoterapie metody MeSH
- daktinomycin aplikace a dávkování MeSH
- fibrosarkom farmakoterapie patologie chirurgie MeSH
- kojenec MeSH
- kombinovaná terapie metody MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- nádory měkkých tkání farmakoterapie patologie chirurgie MeSH
- následné studie MeSH
- osobní újma zaviněná nemocí MeSH
- pozorné vyčkávání MeSH
- přežití bez známek nemoci MeSH
- prospektivní studie MeSH
- protinádorové látky terapeutické užití MeSH
- reoperace MeSH
- staging nádorů MeSH
- studie proveditelnosti MeSH
- vinkristin aplikace a dávkování MeSH
- výsledek terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We have examined the ability of actinomycin D to induce apoptosis in human peripheral blood lymphocytes. Run-On assays were performed to specify the primary molecular damage, reverse transcription-PCR, Western blots and flow cytometry studies were performed to ascertain which proteins of the apoptosis machinery were affected to cause actinomycin D-induced cell death. Expression of 23 apoptosis-related genes was investigated. The down-regulation of ribosomal RNA synthesis caused by actinomycin D induced a mitochondria-dependent apoptosis. Although the expression of the majority of examined genes remained indifferent against actinomycin D activity, the cellular level of p53 protein increased, subsequently upregulating both Puma mRNA and protein. Puma-mediated mitochondrial apoptosis was accompanied by nucleolin cleavage and Bcl-2 mRNA destabilization. The stability of the cellular level of Bcl-2 protein independent of a mRNA decrease suggests that protection of Bcl-2 protein against proteasomal degradation can moderate the apoptotic process. In peripheral blood lymphocytes cultured in vitro, the apoptosis induced by a low concentration of actinomycin D (10 nmol/l) is dependent on p53 and Puma activation. This apoptotic pathway is demonstrated in peripheral blood lymphocytes for the first time. A different apoptotic pathway induced in peripheral blood lymphocytes using this drug has, however, been previously revealed by other authors. The combination of cell specificity and dose-dependent effects can likely play a decisive role in apoptosis observed in peripheral blood lymphocytes after genotoxic drug application.
- MeSH
- apoptóza účinky léků MeSH
- daktinomycin aplikace a dávkování farmakologie MeSH
- down regulace MeSH
- financování organizované MeSH
- lidé MeSH
- lymfocyty účinky léků MeSH
- messenger RNA metabolismus MeSH
- mitochondrie metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- poškození DNA účinky léků MeSH
- proteiny regulující apoptózu metabolismus MeSH
- protinádorová antibiotika aplikace a dávkování farmakologie MeSH
- protoonkogenní proteiny c-bcl-2 metabolismus MeSH
- protoonkogenní proteiny metabolismus MeSH
- průtoková cytometrie MeSH
- ribozomální DNA účinky léků MeSH
- upregulace účinky léků MeSH
- viabilita buněk MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- MeSH
- daktinomycin aplikace a dávkování farmakologie MeSH
- kultivační média MeSH
- kultivační techniky MeSH
- kur domácí MeSH
- sérový albumin MeSH
- slezina MeSH
- triaziny farmakologie MeSH
- tvorba protilátek účinky záření MeSH
- uracil analogy a deriváty aplikace a dávkování farmakologie MeSH
- uridin aplikace a dávkování farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
