IMPORTANCE: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. OBJECTIVE: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. INTERVENTIONS: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. MAIN OUTCOMES AND MEASURES: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. RESULTS: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. CONCLUSIONS AND RELEVANCE: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01356290.

• MeSH
• dítě MeSH
• etoposid MeSH
• kvalita života MeSH
• lidé MeSH
• meduloblastom * farmakoterapie   etiologie   MeSH
• metronomické podávání léků MeSH
• mladiství MeSH
• nádory mozečku * farmakoterapie   etiologie   MeSH
• nádory mozku * farmakoterapie   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• multicentrická studie MeSH

INTRODUCTION: Very little is known about the characteristics of mesothelial tumours in the paediatric population. In adults with malignant mesothelioma, the pemetrexed-based regimen with cytoreductive surgery (CRS) is a standard of care in limited tumours, but long-term survival is uncommon. MATERIAL AND METHODS: The European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT) retrospectively reviewed children, adolescents and young adults (≤21 year) diagnosed with mesothelial tumours treated between 1987 and 2018. RESULTS: Thirty-three patients were identified, 15 male and 18 female patients. One patient's exposure to asbestos was documented. Primary tumour was mainly in the peritoneum (23 patients). Histology was multicystic mesothelioma of the peritoneum (MCM) (six patients) or malignant mesothelioma (MM) (27 patients). Among MM, the first-line treatment comprised preoperative chemotherapy (14 cases), surgery only (three cases), chemotherapy only (five cases), adjuvant chemotherapy (three cases) or palliative treatment (two cases). The response rate to cisplatin-pemetrexed was 50% (6/12 cases). CRS with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was performed in 19 patients (upfront in three, after neoadjuvant therapy in 12, or after tumour progression in six patients, including three twice). After a median follow-up of 6.7 years (range, 0-20), five-year overall and event-free survivals were 82.3% (95% CI, confidential interval ((CI), 67.8-99.9) and 45.1% (95% CI, 28.4-71.7), respectively. All patients with MCM are alive after surgery (five patients) and CRS-HIPEC (one patient). CONCLUSIONS: Paediatric mesothelioma is exceptional and seems to be different from its adult counterpart with few asbestos exposures, more peritoneal primary, and a better outcome. The cisplatin-pemetrexed regimen showed promising efficacy. Relapses could be salvaged with active therapy including CRS-HIPEC.

• MeSH
• adjuvantní chemoterapie metody   MeSH
• cisplatina terapeutické užití   MeSH
• cytoredukční chirurgie metody   MeSH
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• maligní mezoteliom farmakoterapie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• následné studie MeSH
• neoadjuvantní terapie metody   MeSH
• peritoneální nádory farmakoterapie   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH

The 5(th) Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6(th) - 8(th) May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

• Publikační typ
• časopisecké články MeSH

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.

• MeSH
• dítě MeSH
• individualizovaná medicína * MeSH
• klinické zkoušky jako téma MeSH
• lékařská onkologie * MeSH
• lidé MeSH
• nádory farmakoterapie   genetika   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• výzkumný projekt MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.

• Publikační typ
• časopisecké články MeSH

• MeSH
• analýza nákladů a výnosů * MeSH
• antitumorózní látky * aplikace a dávkování   ekonomika   MeSH
• dostupnost zdravotnických služeb * ekonomika   MeSH
• interinstitucionální vztahy MeSH
• kooperační chování MeSH
• lidé MeSH
• metronomické podávání léků * MeSH
• nádory ekonomika   farmakoterapie   mortalita   MeSH
• náklady na léky MeSH
• přehodnocení terapeutických indikací léčivého přípravku ekonomika   MeSH
• rozvojové země ekonomika   MeSH
• úspory nákladů MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Prognosis for children with relapsed medulloblastoma remains poor. Metronomic chemotherapy may offer some benefit to patients treated initially with intensive regimens. However, dosing and duration of such palliative treatment have not been systematically studied. Here we describe a child with medulloblastoma relapsing after initial high-dose chemotherapy and standard radiotherapy. The patient was then treated with metronomic chemotherapy and achieved second complete remission after 21 months of treatment. Three months off therapy he relapsed again and died from progressive disease. This case illustrates the potential benefit of metronomic chemotherapy but also shows the uncertainty of when to stop metronomic chemotherapy while balancing toxicity.

• MeSH
• dítě MeSH
• indukce remise MeSH
• kombinovaná terapie MeSH
• léková chronoterapie MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• meduloblastom farmakoterapie   MeSH
• nádory mozečku farmakoterapie   MeSH
• neurochirurgické výkony MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   MeSH
• radioterapie MeSH
• staging nádorů MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH