Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal n... more Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6‐NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4‐ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4‐ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.
9511 Background: A semi-quantitative reporting method developed by an international expert panel ... more 9511 Background: A semi-quantitative reporting method developed by an international expert panel (J Nucl Med 2009;50:1379) was used to evaluate the role ofI-123 meta-IodoBenzylGuanidine [123I mIBG] imaging in high risk neuroblastoma [HR-NBL]. METHOD Patterns of skeletal 123I mIBG uptake were assignednumerical scores (Mscore) ranging from 0 (no metastasis) to 72 (diffuse metastases) within 12 body areas as described previously (J Nucl Med 2009;50:1379). 271 anonymised, paired image data sets acquired at diagnosis and on completion of Rapid COJEC induction chemotherapy were reviewed, constituting a representative sample of 1602 children treated prospectively within the HR-NBL1/SIOPEN trial. Pre-and post-treatment Mscores were compared with bone marrow cytology (BM) and 3 year event free survival (EFS). RESULTS 224/271 patients showed skeletal mIBG uptake at diagnosis and were evaluable for mIBG response. Complete skeletal mIBG response (CR) to Rapid COJEC induction was achieved by 66%, 34% and 15% of patients who had pre-treatment Mscores of <18 (n=65, 29%), 18-44 (n=95,42%) and ≥45 (n=64, 28.5%) respectively (p<.0001). Mscore at diagnosis correlated with post treatment score (p<0.001) and with BM involvement (p<0.0001). The 3 year EFS in 47 children with Mscore 0 at diagnosis was 0.68 (±0.07), by comparison with 0.42 (±0.06), 0.35 (±0.05) and 0.25 (±0.06) for patients in pre-treatment Mscore groups <18, 18-44 and ≥45, respectively (p<0.001). An Mscore threshold of ≥45 at diagnosis was associated with significantly worse outcome by comparison with all other Mscore groups (p=0.029). Patients who achieved metastatic CR (mIBG and BM) after Rapid COJEC had a significantly longer 3 year EFS of 0.53 (±0.07) compared with 0.24 (±0.04) observed in children who did not reach CR (p=0.005). CONCLUSIONS SIOPEN scoring of 123I mIBG imaging at diagnosis in children with HR-NBL predicts response to induction chemotherapy and outcome. (1) Lewington V et al. Development of a semi-quantitative I -123 mIBG reporting method in HR-NBL.
2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimen... more 2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS). Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m2 in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m2/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m2day or 4x200mg/m2/day*], melphalan [3x70mg/m2/day or 3x60mg/m2/day*. *reduced if ...
Klinická onkologie : casopis Ceské a Slovenské onkologické spolecnosti, 2009
We evaluated the therapeutic results in 44 patients (17 girls and 27 boys) with osteosarcoma from... more We evaluated the therapeutic results in 44 patients (17 girls and 27 boys) with osteosarcoma from 1997 to 2006.Their average age was 12.8 years (2.5-20.2). 41 patients had localised disease and 3 had primary metastases. We treated our 44 patients using CCG 7921 POG 9351 INT 0133, the therapeutic protocol of the North American cooperative Children's Oncology Group.The median of the follow up was 5.5 years (2-11 years). 40 patients went into complete remission. 19 patients suffered relapses. Of these, 17 patients died - 15 progressed, 1 died due to treatment-related toxicity, 1 died due to secondary acute myeloid leukaemia. As a whole, the patients had a 5-year overall survival rate (OS) of 58.4% and a 5-year event free survival rate (EFS) of 46.7%. The patients with localised extremity osteosarcoma (n = 40) had a 5-year EFS rate of 51%. The patients with good histological response (n = 22) had a 5-year EFS rate of 63.6%, while patients with poor histological response (n = 18) ach...
Children with primary refractory or recurrent malignant lymphoma have usually poor prognosis. Les... more Children with primary refractory or recurrent malignant lymphoma have usually poor prognosis. Less than 10% of those, who were treated with conventional-dose regimens had survived for 2 years. In an attempt to improve the outcome for these patients, we explored the role of consolidation high-dose chemotherapy with autografting. Forty-five patients with poor-prognosis lymphoma, of whom 27 were males, underwent megatherapy between January 1992 and December 1999. High-dose chemotherapy was indicated in patients with poor initial response to first-line chemotherapy (14 cases) or in the relapse (31 cases). The group consisted of 27 patients with Hodgkin's disease and 18 patients with non-Hodgkin's lymphoma. The median age was 14.7 years. The conditioning for Hodgkin's disease patients contained cyclophosphamide, etoposide and busulfan or carmustine. Patients with non-Hodgkin's lymphomas received cyclophosphamide, etoposide and busulfan or total body irradiation. Bone marr...
Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dos... more Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; ...
PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated t... more PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS Genomic ALK amplification ( ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no- ALKa [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of...
PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local pro... more PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patient...
Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to... more Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios. The cohort included 1053 patients with medi...
High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patient... more High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and m...
Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare... more Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The thir...
Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal n... more Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6‐NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4‐ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4‐ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities.
9511 Background: A semi-quantitative reporting method developed by an international expert panel ... more 9511 Background: A semi-quantitative reporting method developed by an international expert panel (J Nucl Med 2009;50:1379) was used to evaluate the role ofI-123 meta-IodoBenzylGuanidine [123I mIBG] imaging in high risk neuroblastoma [HR-NBL]. METHOD Patterns of skeletal 123I mIBG uptake were assignednumerical scores (Mscore) ranging from 0 (no metastasis) to 72 (diffuse metastases) within 12 body areas as described previously (J Nucl Med 2009;50:1379). 271 anonymised, paired image data sets acquired at diagnosis and on completion of Rapid COJEC induction chemotherapy were reviewed, constituting a representative sample of 1602 children treated prospectively within the HR-NBL1/SIOPEN trial. Pre-and post-treatment Mscores were compared with bone marrow cytology (BM) and 3 year event free survival (EFS). RESULTS 224/271 patients showed skeletal mIBG uptake at diagnosis and were evaluable for mIBG response. Complete skeletal mIBG response (CR) to Rapid COJEC induction was achieved by 66%, 34% and 15% of patients who had pre-treatment Mscores of <18 (n=65, 29%), 18-44 (n=95,42%) and ≥45 (n=64, 28.5%) respectively (p<.0001). Mscore at diagnosis correlated with post treatment score (p<0.001) and with BM involvement (p<0.0001). The 3 year EFS in 47 children with Mscore 0 at diagnosis was 0.68 (±0.07), by comparison with 0.42 (±0.06), 0.35 (±0.05) and 0.25 (±0.06) for patients in pre-treatment Mscore groups <18, 18-44 and ≥45, respectively (p<0.001). An Mscore threshold of ≥45 at diagnosis was associated with significantly worse outcome by comparison with all other Mscore groups (p=0.029). Patients who achieved metastatic CR (mIBG and BM) after Rapid COJEC had a significantly longer 3 year EFS of 0.53 (±0.07) compared with 0.24 (±0.04) observed in children who did not reach CR (p=0.005). CONCLUSIONS SIOPEN scoring of 123I mIBG imaging at diagnosis in children with HR-NBL predicts response to induction chemotherapy and outcome. (1) Lewington V et al. Development of a semi-quantitative I -123 mIBG reporting method in HR-NBL.
2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimen... more 2 Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS). Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m2 in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m2/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m2day or 4x200mg/m2/day*], melphalan [3x70mg/m2/day or 3x60mg/m2/day*. *reduced if ...
Klinická onkologie : casopis Ceské a Slovenské onkologické spolecnosti, 2009
We evaluated the therapeutic results in 44 patients (17 girls and 27 boys) with osteosarcoma from... more We evaluated the therapeutic results in 44 patients (17 girls and 27 boys) with osteosarcoma from 1997 to 2006.Their average age was 12.8 years (2.5-20.2). 41 patients had localised disease and 3 had primary metastases. We treated our 44 patients using CCG 7921 POG 9351 INT 0133, the therapeutic protocol of the North American cooperative Children's Oncology Group.The median of the follow up was 5.5 years (2-11 years). 40 patients went into complete remission. 19 patients suffered relapses. Of these, 17 patients died - 15 progressed, 1 died due to treatment-related toxicity, 1 died due to secondary acute myeloid leukaemia. As a whole, the patients had a 5-year overall survival rate (OS) of 58.4% and a 5-year event free survival rate (EFS) of 46.7%. The patients with localised extremity osteosarcoma (n = 40) had a 5-year EFS rate of 51%. The patients with good histological response (n = 22) had a 5-year EFS rate of 63.6%, while patients with poor histological response (n = 18) ach...
Children with primary refractory or recurrent malignant lymphoma have usually poor prognosis. Les... more Children with primary refractory or recurrent malignant lymphoma have usually poor prognosis. Less than 10% of those, who were treated with conventional-dose regimens had survived for 2 years. In an attempt to improve the outcome for these patients, we explored the role of consolidation high-dose chemotherapy with autografting. Forty-five patients with poor-prognosis lymphoma, of whom 27 were males, underwent megatherapy between January 1992 and December 1999. High-dose chemotherapy was indicated in patients with poor initial response to first-line chemotherapy (14 cases) or in the relapse (31 cases). The group consisted of 27 patients with Hodgkin's disease and 18 patients with non-Hodgkin's lymphoma. The median age was 14.7 years. The conditioning for Hodgkin's disease patients contained cyclophosphamide, etoposide and busulfan or carmustine. Patients with non-Hodgkin's lymphomas received cyclophosphamide, etoposide and busulfan or total body irradiation. Bone marr...
Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dos... more Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; ...
PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated t... more PURPOSE In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS Genomic ALK amplification ( ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no- ALKa [n = 860] 51% [95% CI, 47 to 54], [ P < .001]), particularly in cases with metastatic disease. ALK mutations ( ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of...
PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local pro... more PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patient...
Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to... more Risk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. Data were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios. The cohort included 1053 patients with medi...
High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patient... more High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and m...
Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare... more Fanconi anemia, complementation group D1 with bi-allelic FANCD1 (BRCA2) mutations, is a very rare genetic disorder characterized by early onset of childhood malignancies, including acute leukemia, brain cancer and nephroblastoma. Here, we present a case report of a family with 3 affected children in terms of treatment outcome, toxicity and characterization of the malignancies using comprehensive cytogenetic analysis. The first child was diagnosed with T-cell acute lymphoblastic leukemia when he was 11 months old. During chemotherapy, he suffered from repeated pancytopenia, sepsis and severe vincristine polyneuropathy, and 18 months after primary diagnosis, he succumbed to secondary acute monocytic leukemia. The second child was diagnosed with stage 2 triphasic nephroblastoma (Wilms tumor), when he was 3 years and 11 months old. During chemotherapy, he suffered from vincristine polyneuropathy. Currently, he is in complete remission, 29 months following the initial diagnosis. The thir...
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