Publications by authors named "Felix Niggli"

151 Publications

Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2021 Oct 11:e29403. Epub 2021 Oct 11.

Pädiatrie 5 (Pädiatrische Onkologie, Hämatologie, Immunologie), Klinikum der Landeshauptstadt Stuttgart gKAöR, Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart, Germany.

Background: Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD).

Methods: Treatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated.

Results: LD was diagnosed in 71 patients at a median age of 0.4 years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n = 77) and partial remission (n = 10) at a median follow-up time of 3.4 years after diagnosis (range 0.01-19.4); no data available (n = 5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%).

Conclusion: Prognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29403DOI Listing
October 2021

Treatment of children with acute lymphoblastic leukemia in Cambodia.

Pediatr Blood Cancer 2021 Oct 28;68(10):e29184. Epub 2021 Jul 28.

Kantha Bopha Hospital, Phnom Penh, Cambodia.

We report a retrospective analysis of 110 unselected pediatric patients with acute lymphoblastic leukemia (ALL) treated during 2015-2017 in a charity-funded public institution in Cambodia with a reduced intensity ALL-Moscow Berlin (MB)-91 protocol. No patient abandoned treatment. Sixty-three patients (57%) were high risk (HR). Seventy-two patients (65.5%) reached complete remission (CR) on day 36. The 3-year event-free survival (EFS) and overall survival (OS) was 34.9% (50.5% for standard risk [SR]). Most deaths resulted from infections (40 [53.3%]) and bleeding (15 [20%]). With further selective reduction of treatment intensity and access to platelet infusion, leukemia therapy is justified in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29184DOI Listing
October 2021

The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents.

J Cancer Res Clin Oncol 2021 Jul 17. Epub 2021 Jul 17.

Hospital for Children and Adolescents, Goethe-University Frankfurt (Main), Frankfurt, Germany.

Background: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.

Methods: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.

Results: Median age of 185 patients was 13.9 years (0.1-56)-with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3-5 cm in 59 (32%), 5-10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.

Discussion: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03614-6DOI Listing
July 2021

Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS).

Pediatr Blood Cancer 2021 Oct 5;68(10):e29145. Epub 2021 Jun 5.

Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt, Germany.

Background: We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P.

Methods: Patients were treated in CWS-91 with four- (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five-drug (+etoposide [EVAIA]) cycles, in CWS-96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS-2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT).

Results: Two hundred forty-three patients fulfilled the eligibility criteria. The 5-year event-free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57-69) and 73% (95% CI 67-79), respectively. The 5-year EFS by study was 64% (95% CI 54-74) in CWS-91, 57% (95% CI 48-66) in CWS-96, and 79% (95% CI 67-91) in CWS-2002P (n.s.). The 5-year OS was 72% (95% CI 62-82) in CWS-91, 70% (95% CI 61-79) in CWS-96, and 86% (95% CI 76-96) in CWS-2002P (n.s.). In CWS-96, 5-year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52-81) versus 55% (95% CI 39-76) log-rank p = .13, and 85% (95% CI 75-96) versus 61% (95% CI 45-82), log-rank p = .09.

Conclusion: Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET-ETS fusion positive tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29145DOI Listing
October 2021

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Department of Pediatric Hematology, Oncology and BMT, University Hospital Muenster, 48149 Münster, Germany.

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13092075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123268PMC
April 2021

Support of BCP-ALL-cells by autologous bone marrow Th-cells involves induction of AID expression but not widespread AID off-target mutagenesis.

Cancer Immunol Immunother 2021 Aug 28;70(8):2275-2289. Epub 2021 Jan 28.

Experimental Infectious Diseases and Cancer Research, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFβ/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02835-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289808PMC
August 2021

Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity.

Nat Commun 2020 09 15;11(1):4629. Epub 2020 Sep 15.

University Children's Hospital, Department of Oncology and Children's Research Center, Steinwiesstrasse 75, CH-8032, Zurich, Switzerland.

Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18388-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492191PMC
September 2020

The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL.

Blood Adv 2020 09;4(17):4052-4064

Department of Stem Cell Transplantation, University Children's Hospital Zurich, Zurich, Switzerland; and.

Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479947PMC
September 2020

Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

J Surg Oncol 2020 Dec 18;122(7):1337-1347. Epub 2020 Aug 18.

Department of Pediatric Oncology and Hematology, University Hospital Frankfurt, Frankfurt/Main, Germany.

Background And Objectives: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that present as large, invasive tumors. Our aim was to assess outcomes, identify prognostic factors, and analyze treatment strategies in a prospectively collected pediatric cohort.

Methods: Patients less than 21 years with MPNST treated in the consecutive prospective European Cooperative Weichteilsarkom Studiengruppe (CWS)-trials (1981-2009) and the CWS-SoTiSaR registry (2009-2015) were analyzed.

Results: A total of 159 patients were analyzed. Neurofibromatosis type I (NF1) was reported in thirty-eight patients (24%). Most were adolescents (67%) with large (>10 cm, 65%) tumors located at extremities (42%). Nodal involvement was documented in 15 (9%) and distant metastases in 15 (9%) upon diagnosis. Overall, event-free survival (EFS) was 40.5% at 5 and 36.3% at 10 years, and overall survival (OS) was 54.6% at 5 and 47.1% at 10 years. Age, NF1 status, tumor site, tumor size, Intergroup Rhabdomyosarcoma Study (IRS) group, metastatic disease, and achieving first complete remission (CR1) were identified as prognostic factors for EFS and/or OS in the univariate analysis.

Conclusions: Prognostic factors were identified and research questions for future clinical trials were addressed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.26153DOI Listing
December 2020

Lineage-restricted sympathoadrenal progenitors confer neuroblastoma origin and its tumorigenicity.

Oncotarget 2020 Jun 16;11(24):2357-2371. Epub 2020 Jun 16.

Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.

Neuroblastoma (NB) is the most common cancer in infants and it accounts for six percent of all pediatric malignancies. There are several hypotheses proposed on the origins of NB. While there is little genetic evidence to support this, the prevailing model is that NB originates from neural crest stem cells (NCSCs). Utilizing mouse models, we demonstrate that targeting oncogene to NCSCs causes perinatal lethality. During sympathoadrenal (SA) lineage development, SOX transcriptional factors drive the transition from NCSCs to lineage-specific progenitors, characterized by the sequential activation of genes. We find the NCSCs factor SOX10 is not expressed in neuroblasts, but rather restricted to the Schwannian stroma and is associated with a good prognosis. On the other hand, SOX9 expression in NB cells was associated with several key biological processes including migration, invasion and differentiation. Moreover, manipulating gene predominantly affects lineage-restricted SA progenitors. Our findings highlight a unique molecular SOX signature associated with NB that is highly reminiscent of SA progenitor transcriptional program during embryonic development, providing novel insights into NB pathobiology. In summary, we provide multiple lines of evidence suggesting that multipotent NCSCs do not contribute to NB initiation and maintenance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299536PMC
June 2020

39·0°C versus 38·5°C ear temperature as fever limit in children with neutropenia undergoing chemotherapy for cancer: a multicentre, cluster-randomised, multiple-crossover, non-inferiority trial.

Lancet Child Adolesc Health 2020 07 1;4(7):495-502. Epub 2020 Jun 1.

Pediatric Hematology and Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address:

Background: Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety.

Methods: This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to <18 years) with any malignancy and treated with myelosuppressive chemotherapy expected to last 2 months or more were repeatedly randomly assigned (1:1), at the cluster level, to either monthly 39·0°C or 38·5°C ear temperature limits for diagnosis of fever in neutropenia. Diagnosis below the randomised limit was allowed for clinical reasons. Such a diagnosis implied emergency hospitalisation, examinations (including blood culture), as-needed antipyretics, and empirical intravenous broad-spectrum antibiotics. The primary outcome was the rate of fever in neutropenia with safety relevant events (SRE) per chemotherapy year; we also assessed efficacy in terms of rate of fever in neutropenia. The non-inferiority margin was 1·33 for safety, and for effiacy, the superiority margin was 1·00. This trial is registered at ClinicalTrials.gov, number NCT02324231.

Findings: 269 patients were recruited between April 28, 2016, to Aug 27, 2018, until the trial was stopped for success after the second interim analysis. Patients were repeatedly randomly assigned, with 1210 (48%) of 2547 randomisation periods and 92 (47%) of 195 chemotherapy years randomised to 39·0°C. SREs were diagnosed in 72 (20%) of 360 fever in neutropenia episodes (zero deaths, 16 intensive care unit admissions, 22 cases of severe sepsis, and 56 cases of bacteraemia). In 92 chemotherapy years randomised to the 39·0°C fever limit, 151 episodes of fever with neutropenia were diagnosed (1·64 per year), including 22 (15%) with SRE (0·24 per year). In 103 chemotherapy years randomised to 38·5°C, 209 episodes were diagnosed (2·03 per year), including 50 (24%) with SRE (0·49 per year). The mixed Poisson regression rate ratio (RR) of fever in neutropenia with SRE in 39·0°C versus 38·5°C was 0·56 (95% upper confidence bound 0·72). The corresponding RR of fever in neutropenia was 0·83 (95% upper confidence bound 0·98).

Interpretation: In children with neutropenia and chemotherapy for cancer, 39·0°C ear temperature was safe and seemed efficacious. For Switzerland and comparable settings, 39·0°C can be recommended as new evidence-based standard fever limit except for patients with acute myeloid leukaemia or haematopoietic stem cell transplantation.

Funding: Swiss Cancer League (KLS-3645-02-2015).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(20)30092-4DOI Listing
July 2020

Dermatofibrosarcoma protuberans in children and adolescents: Primary and Relapsed disease-Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).

J Surg Oncol 2020 Aug 19;122(2):263-272. Epub 2020 May 19.

Klinikum Stuttgart-Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade tumor. Little is known about best treatment of primary and relapsed disease (RD).

Methods: Treatment and outcome of 40 patients with DFSP prospectively registered within the CWS-96 and -2002P trials and the registry SoTiSaR (1996-2016) were analysed.

Results: Median age was 8 years (range, 0.64-17.77). Fluorescence in situ hybridization analysis to detect COL1A1-PDGFB fusion genes was positive in 86% (12/14) of evaluated patients. Primary resection was performed in all patients. Patients had IRS group I (n = 28), II (n = 9), and III (n = 2); not available (n = 1). To achieve complete remission (CR), a secondary resection was performed in 18 patients resulting in microscopically complete (R0, n = 34/40) and microscopically incomplete (R1, n = 5/40) resection. All patients achieved CR. The 5-year event-free survival (EFS) and overall survival was 86% (±12; CI, 95%) and 100% (±0; CI, 95%), respectively. R0 resection/IRS I was significantly favorable for the 5-year EFS. Local relapse occurred after a median time of 1.1 years (range, 0.04-5.1) in 15% (6/40) after CR. All patients with RD underwent resection and achieved CR. Three patients had fibrosarcomatous DFSP, two were alive after R0 resection.

Conclusion: Complete surgical resection is mandatory to prevent relapse of DFSP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25943DOI Listing
August 2020

Second malignancies after treatment of childhood non-Hodgkin lymphoma: a report of the Berlin-Frankfurt-Muenster study group.

Haematologica 2021 05 1;106(5):1390-1400. Epub 2021 May 1.

DEpt. of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Germany.

Second malignant neoplasms pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for second malignant neoplasms in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma. 3590 patients <15 years of age at diagnosis registered between 01/1981 and 06/2010 were analyzed. Second malignant neoplasms were reported by the treating institutions and the German Childhood Cancer Registry. After median follow-up of 9.4 years (Quartile, Q1 6.7 and Q3 12.1) 95 second malignant neoplasms were registered (26 carcinomas including 9 basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 CNS-tumors, and 16 other). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio excluding basal cell carcinomas was 19.8 (95% CI 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range: 0.2-30.3). Acute-lymphoblastic-leukemia-type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (HR 1.87, 95% CI 1.23-2.86, p=0.004), CNS-involvement (HR 2.24, 95% CI 1.03-4.88, p=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI 1.69-3.97, p<0.001), and cancer-predisposing condition (HR 11.2, 95% CI 5.52-22.75, p<0.001) retained an independent risk. Carcinomas were the most frequent second malignant neoplasms after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for second malignant neoplasm-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.244780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094109PMC
May 2021

Progressive or relapsed Burkitt lymphoma or leukemia in children and adolescents after BFM-type first-line therapy.

Blood 2020 04;135(14):1124-1132

NHL-BFM Study Center and Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

Children with refractory or relapsed Burkitt lymphoma (BL) or Burkitt leukemia (B-AL) have a poor chance to survive. We describe characteristics, outcome, reinduction, and transplantation approaches and evaluate risk factors among children with progression of a BL/B-AL included in Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Münster studies between 1986 and 2016. Treatment recommendation was reinduction including rituximab from the early 2000s followed by blood stem cell transplantation. The 3-year survival of the 157 children was 18.5 ± 3%. Survival significantly improved from 11 ± 3% before to 27 ± 5% after 2000 (P < .001), allowing for risk factor analyses among the latter 75 patients. Survival of 14 patients with relapse after initial therapy for low-risk disease (R1/R2) was 50 ± 13% compared with 21 ± 5% for 61 patients progressing after R3/R4 therapy (P < .02). A total of 25 of 28 patients with progression during first-line therapy, 31 of 32 with progression during reinduction, 15 of 16 not reaching a complete remission (CR) before transplantation, 9 of 10 treated with rituximab front-line, and all 13 patients not receiving rituximab during reinduction died. Forty-six patients received stem cell transplantation (20 autologous, 26 allogeneic). Survival after a regimen combining rituximab with continuous-infusion chemotherapy followed by allogeneic transplantation was 67 ± 12% compared with 18 ± 5% for all other regimen and transplantations (P = .003). Patients with relapsed BL/B-AL have a poor chance to survive after current effective front-line therapies. Progression during initial or reinduction chemotherapy and initial high-risk disease are risk factors in relapse. Time-condensed continuous-infusion reinduction followed by stem cell transplantation forms the basis for testing new drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019003591DOI Listing
April 2020

Synovial sarcoma disease characteristics and primary tumor sites differ between patient age groups: a report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

J Cancer Res Clin Oncol 2020 Apr 13;146(4):953-960. Epub 2020 Jan 13.

Hospital for Children and Adolescents, Goethe-University, Frankfurt (Main), Germany.

Background: Older age is associated with worse outcome in synovial sarcoma (SS) patients. Differences in disease presentation among distinct age groups, however, are currently unknown.

Methods: SS patients < 21 years registered in consecutive CWS trials over the period of 1981-2018 were evaluated. Characteristics were analyzed according to age groups using the Fisher's exact test.

Results: The study population included 432 SS patients. Disease characteristics differed according to age groups of children (0-12 years, n = 176), adolescents (13-16 years, n = 178), and young adults (17-21 years, n = 78). The proportion of invasive tumors (T2) was significantly higher in older patients: children 33%, adolescents 39% and young adults 54%, p = 0.009805. Similarly, the proportion of tumors > 10 cm was higher (13%, 21%, 31%; p = 0.005657) whereas conversely, the proportion of small tumors < 3 cm was lower in older patients (29%, 24%, 6%; p = 0.000104). The presence of metastases at first diagnosis was also highest in older patients (6%, 10%, 21%, p = 0.000963). Notably, the proportion of thigh tumors was higher in older patients (p = 0.04173), whereas the proportion of head-neck tumors was lower in older patients (p = 0.08896).

Conclusions: The rates of large, invasive tumors and the presence of metastases are significantly associated with older patient age. Localization to the thigh is more frequent in older patients.

Discussion: The causes for these variations require further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-019-03121-9DOI Listing
April 2020

Endothelial cell malignancies in infants, children and adolescents: Treatment results of three Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2020 03 8;67(3):e28095. Epub 2019 Dec 8.

Department for Children and Adolescents, University of Frankfurt, Frankfurt am Main, Germany.

Background: Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients.

Methods: Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019).

Results: Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE.

Conclusions: Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28095DOI Listing
March 2020

The impact of local control in the treatment of children with advanced infantile and adult-type fibrosarcoma: Experience of the cooperative weichteilsarkom studiengruppe (CWS).

J Pediatr Surg 2020 Sep 9;55(9):1740-1747. Epub 2019 Nov 9.

Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; Children's Hospital, Department of Pediatric Hematology and Oncology, Tuebingen, Germany.

Background And Objectives: This study aims at examining the potential survival benefits of primary versus secondary surgery of children diagnosed with advanced infantile (iFS) and adult-type fibrosarcoma (aFS).

Methods: Treatment and outcome of 89 children with FS treated within prospective Cooperative Studiengruppe (CWS) trials (1981-2016) were analyzed retrospectively.

Results: Localized disease (LD) was diagnosed in 87 patients: 64/66 patients with iFS (≤2 years) and 23 with aFS (>2 ≤ 18 years). Two patients (iFS) had metastatic disease. Resection was the mainstay of therapy of patients with LD resulting in microscopically complete (R0, IRS group I) (n = 29/87, 33%), microscopically incomplete (R1, IRS group II) (n = 17/87, 20%) and macroscopically incomplete (R2, IRS group III) (n = 41/87, 47%). Advanced LD (IRS group III) was present in 32/64 (50%) patients with iFS and in 9/23 (39%) with aFS. Chemotherapy was added predominantly in patients with advanced disease and an assessable objective response to CHT was seen in 71% iFS and 75% aFS. The 5-year event-free survival (EFS) of patients with iFS and aFS was 81% (±10, 95% CI) and 70% (±19, 95% CI) (p = 0.24); the 5-year overall survival (OS) was 98% (±3, 95% CI) and 82% (±16, 95% CI) (p = 0.02). Primary resection was no prognostic factor. Secondary R0/ R1 resection in patients with advanced disease improved 5-year EFS and OS in aFS (p = 0.002 and p = 0.000) but not in infants.

Conclusions: Secondary resection improves outcome in advanced aFS but not in infants. Mutilating surgery in infants should be avoided.

Type Of Study And Level Of Evidence: Treatment study: patients were enrolled in five prospective studies and one registry, prognosis study: retrospective study.

Level Of Evidence: II/ III.

Mini-abstract: Fibrosarcoma is a very rare malignant tumor. Little is known about differences of local treatment of advanced infantile and adult-type. Data of 89 patients registered in five prospective trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981-2016) were analyzed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2019.10.051DOI Listing
September 2020

Low-grade fibromyxoid sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer 2020 02 17;67(2):e28009. Epub 2019 Nov 17.

Department of Pediatric Oncology, University of Tuebingen, Tuebingen, Germany.

Background: Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue tumor with benign histologic appearance, though fully malignant behavior is possible.

Methods: Patients with LGFMS <21 years registered in Cooperative Weichteilsarkom Studiengruppe trials until 2017 were analyzed. Firstline treatment consisted of complete surgical resection whenever possible.

Results: Median age of 31 patients was 10.9 years (first month to 17.1 years). Twenty-six tumors were confirmed to the tissue of origin (T1), four invaded contiguous structures (T2), one was TX. Eight were >5 cm. The best surgical result was resection with free margins (R0) in 24 and microscopic residuals (R1) in seven. Five-year event-free (EFS), 5-year local-relapse-free (LRFS), and 5-year overall-survival were 71 ± 18.6% confidence interval (CI) 95%, 76 ± 17.6% CI 95%, and 100%, respectively. Six patients suffered local relapse in a median of 1 year, one combined within 1.3 year and one metastatic relapse with lesions in the lung, back muscles, and thigh discovered in whole-body imaging 6 years after the first diagnosis. In univariate analysis, T status correlated with EFS (T1 79.6 ± 18.6%, T2 50.0 ± 49.0%, P = .038). Resection with free margins tends to be associated with better LRFS (R0 82.4 ± 18.6%, R1 53.6 ± 39.4%, P = .053). Among 24 patients with R0 resection, five (21%) suffered relapse, thereof three local, one metastatic, and one combined. Among seven patients with R1-resection, three (43%) suffered local relapse.

Conclusion: Special caution is advisable in T2 tumors. The metastatic potential with lesions in unusual sites indicates that affected patients need to be informed. If long-term follow-up with whole-body imaging is beneficial, it may be addressed in larger intergroup analyses. Further research in disease biology is essential for optimal treatment and follow-up care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28009DOI Listing
February 2020

Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study.

Eur J Cancer 2019 11 17;122:61-71. Epub 2019 Oct 17.

Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

Background: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years.

Methods: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years.

Findings: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm.

Interpretation: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.09.004DOI Listing
November 2019

Rhabdomyosarcoma diagnosed in the first year of life: Localized, metastatic, and relapsed disease. Outcome data from five trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS).

Pediatr Blood Cancer 2019 06 14;66(6):e27652. Epub 2019 Feb 14.

Department for Children and Adolescents, University Hospital of Frankfurt, Frankfurt/M., Germany.

Background: Rhabdomyosarcoma (RMS) diagnosed during the first year of life is reported to have poor outcome. Little is known about treatment and outcome data of relapsed disease (RD).

Methods: Characteristics, treatment, and outcome of 155 patients ≤ 12 months registered within the Cooperative Weichteilsarkom Studiengruppe (CWS) between 1981 and 2016 were evaluated.

Results: Localized disease (LD) was diagnosed in 144 patients and metastatic disease (MD) in 11. The histological diagnosis was alveolar (RMA) (n = 38, 23/25 examined patients PAX7/3:FOXO1-positive), embryonal (RME) (n = 100), botryoid (n = 10), anaplastic (n = 1), and spindle-cell RMS (n = 6). Multimodal treatment including conventional (age-adjusted) chemotherapy (CHT) (n = 150), resection (n = 137), and radiotherapy (RT) (n = 37) was administered. Complete remission was achieved in 129 of 144 patients with LD. RD occurred in 51 infants at a median age of 1.7 years (range, 0.3-8.8). Sixty-three percent of patients with RMA suffered RD, in contrast to 28% of patients with RME. Relapse treatment consisted of conventional CHT (n = 48), resection (n = 28), and RT (n = 21). The pattern of relapse and best resection were significant prognostic factors for patients with RD (P = 0.000 and P = 0.002). Late effects occurred as secondary malignancies in 6%, long-term toxicity in 21%, and resection-related impairment in 33% of the 105 surviving patients. The 5-year event-free survival and overall survival for infants with initial LD were 51% and 69%, 14% and 14% for patients with initial MD and 39% and 41% for relapsed patients, respectively.

Conclusion: Multimodal treatment including microscopically complete resection is strongly recommended to achieve a good prognosis in LD and RD of infants with RMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27652DOI Listing
June 2019

USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth.

Sci Rep 2019 01 30;9(1):951. Epub 2019 Jan 30.

Department of Oncology and Children's Research Center, University Children´s Hospital, Steinwiesstrasse 32, 8032, Zurich, Switzerland.

Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-37264-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353870PMC
January 2019

Desmoplastic small round cell tumors: Multimodality treatment and new risk factors.

Cancer Med 2019 02 16;8(2):527-542. Epub 2019 Jan 16.

Pediatrics 5, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.

Background: To evaluate optimal therapy and potential risk factors.

Methods: Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed.

Results: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.

Conclusion: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.1940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382921PMC
February 2019

Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients.

Oncogene 2019 03 7;38(13):2420-2431. Epub 2018 Dec 7.

Experimental Infectious Diseases and Cancer Research, Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0594-4DOI Listing
March 2019

Localized synovial sarcoma of the foot or ankle: A series of 32 Cooperative Weichteilsarkom Study Group patients.

J Surg Oncol 2019 Jan 13;119(1):109-119. Epub 2018 Nov 13.

Pediatrics 5 (Oncology, Hematology, Immunology), Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.

Background: Synovial sarcoma of the foot/ankle is rare. Mutilating surgery is often discussed.

Methods: Patients registered from 1981 to 2013 were analyzed. Cooperative Weichteilsarkom Studiengruppe (CWS) protocols recommend chemotherapy for all synovial sarcoma patients.

Results: Thirty-two of 330 patients with localized synovial sarcoma had their tumor at the foot/ankle. Eleven of thirty-two tumors were >5 cm. Twenty were T1, 11 T2, and one TX, respectively. Eight (25%) patients underwent primary complete resection with free margins (Intergroup Rhabdomyosarcoma Study [IRS] I), 12 of 32 (38%) primary complete resection with positive margins (IRS II), and 12 of 32 (38%) had macroscopic residuals (IRS III). The best surgical result at any time was R0 in 19, R1 in 10 and R2 in one patient, and missing in two. Mutilation was documented in 14 of 32 (44%). Radiotherapy was conducted in 20 patients. All patients achieved a first complete remission. Five-year-event-free survival and overall survival rates were 80% and 86%, respectively. Four patients suffered local and four other metastatic recurrences. IRS and the best surgical result at any time did not correlate with survival. There was no prognostic difference between R0- and R1-resection.

Conclusion: Survival expectancies for patients with localized synovial sarcomas of the foot/ankle compare favorably to that of those with other affected sites.

Discussion: Further studies are needed to set the limits of minimally required aggressiveness of local therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25284DOI Listing
January 2019

Alveolar soft-part sarcoma: Primary metastatic disease and metastatic relapse occurring during long-term follow-up: Treatment results of four Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

Pediatr Blood Cancer 2018 12 19;65(12):e27405. Epub 2018 Aug 19.

Klinikum Stuttgart-Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend-und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.

Background: Patients with metastatic alveolar soft-part sarcoma (ASPS) are known to have a very poor prognosis. Little is known about best treatment of primary metastatic disease (MD) or relapsed metastatic disease (rMD).

Patients And Methods: Patients with localized disease (LD), primary MD, and metastatic recurrence after complete remission (CR) treated within the CWS-86, -91, -96, -2002P trials and the recent registry SoTiSaR (1985-2016) were analyzed.

Results: Fifteen of 61 patients had primary metastases at initial diagnosis at the age of 14.6 years (range, 7.8-19.7). Nine of 46 patients with initial LD suffered of rMD at a median age of 9.9 years (range, 3.5-30), 3.75 years (0.75-21) after CR of primary disease. Complete resection (microscopically or macroscopically) was possible in 2 of 15 patients with MD and in 5 of 9 with rMD. RT was administered in 4 of 15 MD and 1 of 9 rMD. Chemotherapy was administered to 11 of 15 MD and 3 of 9 rMD, targeted therapy to 3 of 15 MD and 1 of 9 rMD. Median time to progression of patients treated with targeted therapy (n = 4), CHT (n = 14), and resection only (n = 6) was 56, 17, and 23 months, respectively. The 5-year event-free survival and overall survival (OS) rates were 19.8% and 61%, respectively, for patients with MD compared with 79% and 98% for patients with LD. The 5-year progression-free survival and OS were 67% and 100% for patients with rMD.

Conclusions: Complete tumor resection correlates with long-term survival in patients with primary and relapsed MD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27405DOI Listing
December 2018

Inflammatory myofibroblastic tumors-A retrospective analysis of the Cooperative Weichteilsarkom Studiengruppe.

Pediatr Blood Cancer 2018 06 26;65(6):e27012. Epub 2018 Feb 26.

Pediatrics 5 (Oncology, Hematology, and Immunology), Stuttgart Cancer Center, Klinikum Stuttgart, Olgahospital, Stuttgart, Germany.

Background: Inflammatory myofibroblastic tumors (IMTs) are a rare subgroup of soft tissue tumors. The outcome of patients with IMT has been reported as favorable when the tumor is completely resected. If surgical resection is not possible, systemic therapy has to be considered. However, the best systemic treatment and response rates are currently unclear.

Methods: Thirty-eight patients under the age of 21, who were registered between 2000 and 2014 with a primary diagnosis of IMT, were analyzed.

Results: IMT was typically localized intra-abdominally or in the pelvis. In 20 patients, the tumor was resected without further therapy; 17 patients were in complete remission at last evaluation and two patients were in partial remission. Eighteen patients received systemic therapy, 15 of whom had macroscopically incomplete resection. Systemic therapy most commonly consisted of regimens with dactinomycin, ifosfamide or cyclophosphamide, and vincristine, with or without doxorubicin, and it seemed to reduce tumor extension in individual cases. Five-year event-free survival was 74 ± 14% and 5-year overall survival was 91 ± 10% for all patients. The patients who died due to the disease were those with incomplete resection (n = 3).

Conclusions: Surgery without further systemic therapy was a feasible and acceptable therapeutic option for every second patient with IMT. Standard chemotherapy for pediatric soft tissue sarcoma produced favorable results in individual cases and was able to shrink the tumor enough to enable resection. Superior efficacy of new targeted therapies such as anaplastic lymphoma kinase-inhibitors compared to standard chemotherapy has to be proven in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27012DOI Listing
June 2018

Palliative care in Swiss pediatric oncology settings: a retrospective analysis of medical records.

Support Care Cancer 2018 Aug 24;26(8):2707-2715. Epub 2018 Feb 24.

Institute for Biomedical Ethics, University of Basel, Bernoullistrasse 28, -4056, Basel, CH, Switzerland.

Purpose: This study examined the provision of palliative care and related decision-making in Swiss pediatric oncology settings. The aim was to determine if and when children who died from cancer received palliative care, whether there were differences by cancer diagnosis, and inclusion of children in decision-making regarding palliative care.

Methods: Using a standardized data extraction form, a retrospective review of medical records of deceased pediatric patients was conducted. The form captured information on demographics, diagnosis, relapse(s), treatments, decision-making during palliative care, and circumstances surrounding a child's death.

Results: For 170 patients, there was information on whether the child received palliative care. Among those, 38 cases (22%) did not receive palliative care. For 16 patients, palliative care began at diagnosis. The mean duration of palliative care was 145 days (Mdn = 89.5, SD = 183.4). Decision to begin palliative care was discussed solely with parent(s) in 60.9% of the cases. In 39.1%, the child was involved. These children were 13.6 years of age (SD = 4.6), whereas those not included were 7.16 years old (SD = 3.9). Leukemia patients were less likely to receive palliative care than the overall sample, and patients with CNS neoplasms received palliative care for a longer time than other patients.

Conclusions: There are still high numbers of late or non-referrals, and even children older than 12 years were not involved in decision-making regarding palliative care. These results do not align with international organizational guidelines which recommend that palliative care should begin at diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-018-4100-xDOI Listing
August 2018

Patterns of paediatric end-of-life care: a chart review across different care settings in Switzerland.

BMC Pediatr 2018 02 16;18(1):67. Epub 2018 Feb 16.

Department of Pediatrics, Inselspital Bern University Hospital, Bern, Switzerland.

Background: Paediatric end-of-life care is challenging and requires a high level of professional expertise. It is important that healthcare teams have a thorough understanding of paediatric subspecialties and related knowledge of disease-specific aspects of paediatric end-of-life care. The aim of this study was to comprehensively describe, explore and compare current practices in paediatric end-of-life care in four distinct diagnostic groups across healthcare settings including all relevant levels of healthcare providers in Switzerland.

Methods: In this nationwide retrospective chart review study, data from paediatric patients who died in the years 2011 or 2012 due to a cardiac, neurological or oncological condition, or during the neonatal period were collected in 13 hospitals, two long-term institutions and 10 community-based healthcare service providers throughout Switzerland.

Results: Ninety-three (62%) of the 149 reviewed patients died in intensive care units, 78 (84%) of them following withdrawal of life-sustaining treatment. Reliance on invasive medical interventions was prevalent, and the use of medication was high, with a median count of 12 different drugs during the last week of life. Patients experienced an average number of 6.42 symptoms. The prevalence of various types of symptoms differed significantly among the four diagnostic groups. Overall, our study patients stayed in the hospital for a median of six days during their last four weeks of life. Seventy-two patients (48%) stayed at home for at least one day and only half of those received community-based healthcare.

Conclusions: The study provides a wide-ranging overview of current end-of-life care practices in a real-life setting of different healthcare providers. The inclusion of patients with all major diagnoses leading to disease- and prematurity-related childhood deaths, as well as comparisons across the diagnostic groups, provides additional insight and understanding for healthcare professionals. The provision of specialised palliative and end-of-life care services in Switzerland, including the capacity of community healthcare services, need to be expanded to meet the specific needs of seriously ill children and their families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-018-1021-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816353PMC
February 2018

Spatial clustering of childhood cancers in Switzerland: a nationwide study.

Cancer Causes Control 2018 03 13;29(3):353-362. Epub 2018 Feb 13.

Faculty of Medicine, Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012, Bern, Switzerland.

Purpose: Childhood cancers are rare and little is known about their etiology. Potential risk factors include environmental exposures that might implicate spatial variation of cancer risk. Previous studies of spatial clustering have mainly focused on childhood leukemia. We investigated spatial clustering of different childhood cancers in Switzerland using exact geocodes of place of residence.

Methods: We included 6,034 cancer cases diagnosed at age 0-15 years during 1985-2015 from the Swiss Childhood Cancer Registry. Age and sex-matched controls (10 per case) were randomly sampled from the national censuses (1990, 2000, 2010). Geocodes of place of residence were available at birth and diagnosis for both cases and controls. We used the difference in k-functions and Cuzick-Edwards test to assess global clustering and Kulldorff's circular scan to detect individual clusters. We also carefully adjusted for multiple testing.

Results: After adjusting for multiple testing, we found no evidence of spatial clustering of childhood cancers neither at birth (p = 0.43) nor diagnosis (p = 0.13). Disregarding multiple testing, results of individual tests indicated spatial clustering of all childhood cancers combined (p < 0.01), childhood lymphoma (p = 0.01), due to Hodgkin lymphoma (HL) (p = 0.02) at diagnosis, and embryonal tumors of the central nervous system (CNS) at birth and diagnosis, respectively (p = 0.05 and p = 0.02).

Conclusions: This study provides weak evidence of spatial clustering of childhood cancers. Evidence was strongest for HL and embryonal CNS tumors, adding to the current literature that these cancers cluster in space.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10552-018-1011-6DOI Listing
March 2018
-->