An undifferentiated sarcoma with BCOR-CCNB3 fusion transcript - pathological and clinical retrospective study.

The BCOR-CCNB3 positive sarcoma is a recently identified sarcoma morphologically and clinically similar to Ewing sarcoma in adolescents and young adults. The BCOR-CCNB3 fusion transcript originates from a paracentric inversion on the X chromosome with an in-frame fusion between the last codon of BCOR and the exon 5 of CCNB3 gene. We report morphological and molecular genetic analysis of 8 undifferentiated sarcomas positive for the BCOR-CCNB3 fusion. Six of the eight BCOR-CCNB3 positive sarcoma patients were male. Five of the eight patients were in their second decade of life (median of all patients 14 years at diagnosis). The bone marrow involvement was demonstrated in 2 of 4 patients tested. Detection of the fusion transcripts BCOR-CCNB3 in the bone marrow suggests that patients with positive findings are at high risk of the tumor progression.

Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

Teenagers and young adults with cancer in Europe: from national programmes to a European integrated coordinated project.

Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer.

Burkitt lymphoma (BL): reclassification of 39 lymphomas diagnosed as BL or Burkitt-like lymphoma in the past based on immunohistochemistry and fluorescence in situ hybridization.

Burkitt lymphoma (BL) is a well characterized entity. For atypical findings a term Burkitt-like lymphoma (B-LL) was applied in the past, but the interpretation of the morphological appearances was subjective and poorly reproducible. We used a combined approach (morphology using classical histological staining; immunohistochemistry-IHC; fluorescence in situ hybridization-FISH on interphase nuclei; cytogenetics) to perform a retrospective study on 39 patients diagnosed as BL and B-LL at our department in the years 1982 to 2002. By FISH we demonstrated t(8;14)(q24;q32) in 31 patients; in further two we found a break at 8q24, suggestive of a variant translocation. In three patients with the cytogenetic investigation available we confirmed the findings of FISH--two lymphomas had the t(8;14)(q24;q32), one had t(2;8)(p12;q24). IHC showed CD20, CD10, BCL-6, p53 expression, and Ki-67 antigen in > 95% of the tumor cell population in a majority of the patients. There was a group of 4 patients in whom the t(8;14)(q24;q32) or a break at 8q24 were not found (FISH). These cases were reclassified within the WHO defined grey zone subgroup of B-cell lymphoma unclassifiable with features intermediate between diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma--I-DLBCL/BL. Two further cases were reclassified as DLBCL based on a combined IHC and FISH findings. A lymphoma of one of these patients had breaks at 3q27 (BCL6) and at 14q32 (IGH) suggestive of t(3;14)(q27;q32). The overall survival estimate of 33 patients with the diagnosis of BL was 54%. Most of deaths occurred within 6 months after the tumor diagnosis. The unfavorable clinical outcome appears to be associated with a strong expression of the p53 protein in the tumor cell population. Individually utilized methods in the diagnosis of BL may lead to false diagnostic conclusions. A combined approach helps to establish a more reliable diagnosis of BL and to separate grey zone lymphomas I-DLBCL/BL and DLBCL with morphological mimics of BL to start adequate treatment. I-DLBCL/BL is a non-homogenous group of lymphomas necessitating further analysis in a prospective study.

[Staging of non-Hodgkin's lymphoma--recommendations of the Czech Lymphoma Study Group]. / Urcování rozsahu onemocnení u non-Hodgkinových lymfomu--doporucení Kooperativní lymfomové skupiny.

BACKGROUNDS: The Ann Arbor system is typically used for the staging of Non-Hodgkin's lymphomas. This classification was nevertheless originally developed in the 1970s for Hodgkin's lymphoma, a disease usually confined to the lymph nodes with less frequent dissemination to extralymphatic organs/tissues and extremely rare primary extranodal involvement. Non-Hodgkin's lymphomas, however, are more often associated with extralymphatic involvement and primary extranodal lymphomas are relatively common (approximately 1/3 of cases). Therefore, the value of the Ann Arbor staging system appears to be limited in these cases. An analysis of data from centres participating within the Czech Lymphoma Study Group showed that staging of Non-Hodgkin's lymphomas with extranodal involvement is not uniform. DESIGN: At the end of 2009, a draft for a Non-Hodgkin's lymphomas staging system was put forward for use by the lymphoma register of the Czech Lymphoma Study Group with special regard paid to the involvement of extralymphatic organs/tissues. This draft was further refined following comments from members of the Czech Lymphoma Study Group committee and the final form was accepted at the meeting of the Czech Lymphoma Study Group committee in January 2010. RESULTS: A consensus was reached at the meeting of the Czech Lymphoma Study Group committee regarding the staging of various combinations of nodal and extranodal involvement. For the purpose of suitable staging and appropriate treatment intensity, extranodal organs were divided into "major"--liver, lungs, bones, mesothelium (pleura, peritoneum, pericardium) and soft tissues. All other organs were defined as "minor". CONCLUSION: The Ann Arbor staging system is suitable for the staging of Non-Hodgkin's lymphomas with lymph node/lymphatic tissue involvement. As regards the extralymphatic spread of the disease or primary extranodal lymphomas, this classification should rather be adapted to practical needs. The validity of the updated classification system will be assessed in both prospective and retrospective Czech Lymphoma Study Group studies.

[Mixed germ cell tumours of the ovary in childhood and adolescence]. / Smísené germinální nádory ovaria u detí a dospívajících. Retrospektivní klinicko-patologická studie.

Mixed germ cell tumours of the ovary are rare malignant neoplasms containing combinations of two or more types of germ cell elements. The aim of the study was to review biopsy examinations, medical records, treatment strategy, follow-up and outcome of all girls treated for mixed germ cell tumour of the ovary at the Department of Pediatric Oncology, University Hospital Motol during the period 1979-2002. Archival slides of all tumours were reviewed and tumours were classified according to the WHO system. The clinical data on surgical treatment, chemotherapy and radiotherapy used and follow-up information were obtained in all girls. The staging was reviewed retrospectively on the basis of surgical and pathological findings and results of imaging investigations, and it was outlined according to the most recent FIGO criteria and TNM classification. Sixteen girls with mixed germ cell tumour of the ovary, age range 3 years 11 months to 17 years 8 months (median 12 years) were treated. All girls presented with unilateral tumour of the ovary and all underwent surgery as an initial treatment. The most common presenting symptom was abdominal pain, occurring in ten patients. The original diagnosis of mixed histology was confirmed in all cases; in five cases the tumour contained three histologic components, in eleven cases the tumour consisted of two germ cell types. All tumours contained elements of yolk sac tumour, followed by immature teratoma, embryonal carcinoma, dysgerminoma and mature teratoma. At the time of diagnosis three patients had stage I disease, four patients stage II, seven stage III and two stage IV disease. All patients were treated with chemotherapy after surgery, predominantly with platinum-based regimens (PVB, BEP). Three patients treated initially with MAC (metothrexate, dactinomycin, cyclophosphamide) were diagnosed in the early eighties. In seven girls with advanced disease treated in the early years, radiotherapy was administered to the pelvis or whole abdomen. Overall survival and event-free survival were 80% and 81.3% respectively (median follow-up time 7.6 years). Three patients have died from the disease, two progressed on treatment (MAC), one girl relapsed three months after finishing therapy, no further therapy was administered. One girl underwent resection of tumour of her remaining ovary 24 months after original diagnosis. Histology showed mixed serous and mucinous cystadenoma. The latest examinations revealed that all other patients were in good health. Microscopic examination should be extensive and careful to find out all types of malignant germ cell elements. Platinum based chemotherapy is effective in the management of children and adolescents with mixed germ cell tumors of the ovary. Chemosensitivity of these tumours allows most girls to have conservative surgery with possible preservation of reproductive function.

[Cardiac damage in a young woman with Hodgkin's disease and long term survival after combination therapy and bone marrow transplantation]. / Poskození srdce u mladé zeny s Hodgkinovou chorobou dlouhodobe prezívající po kombinované lécbe a transplantaci kostní drene.

The authors describe the disease of a 22-year-old woman treated from the age of 13 years on account of Hodgkin's lymphoma by irradiation and cytostatic treatment. On account of a relapse of lymphoma at the age of 14 years megachemotherapy with subsequent transplantation of autologous bone marrow. In the course of eight years of the follow up gradual development of constrictive pericarditis with exsudate. Concurrently progression of mitral insufficiency based on valvular prolapse resulting from radiation. During the last two years refractory systemic hypertension resistant to treatment. At the peak of the disease development of cardiac tamponade and cardiac cachexia with anasarca. After anamnestic, clinical and haemodynamic analysis total pericardetomy was indicated and mitral valve replacement performed. The operation led to improvement of the patient's condition, systemic hypertension receded completely. The patient is in permanent remission.

[Effect of amifostine on reducing acute toxicity of megachemotherapy of tumors in children]. / Vliv amifostinu na redukci akutní toxicity pri protinádorové megachemoterapii detí.

BACKGROUND: Amifostine (WR-2721, Ethyol) is a chemoprotective agent. There is little experiences with amifostine application in megachemotherapy in children. We evaluated amifostine effect on the reduction of the acute toxicity. METHODS AND RESULTS: Retrospective comparison of patients who received amifostine with the control group (72 vs. 72). Amifostine 750 mg/m2 was given 15 minute before cytostatic dose and regularly each eight hours if we administered cytostatics continuously. Megachemotherapy schedule included melfalan, carboplatin, cyklophosphamid, vepesid, busulfan, thiotepa and karmustin. Type of graft: peripheral stem cells 56 vs. 29, bone marrow 8 vs. 30, combination 8 vs. 13. Nonhematological toxicity: mucositis p = 0.047, hepatotoxicity p < 0.001, nephrotoxicity p = 0.005. Hematological toxicity: engraftment D + 12 vs. D + 15 (p < 0.001), amount of erythrocyte transfusions 3 vs. 6 (p < 0.001), platelet transfusions 7 vs. 9 (p = 0.06), days when number of platelets reaches 20,000 without substitution D + 15 vs. D + 22 (p < 0.001). The only statistically difference was in the in total amount of platelets (p = 0.032), when we calculated patients, who received peripheral stem cells. Number of hospitalization days 14 vs. 18 (p = 0.016), days with antibiotics 14 vs. 18 (p = 0.016), number of febrile days 6 vs. 7 (p = 0.51). CONCLUSIONS: Amifostine reduces mucosal, liver and kidney damage. The graft type could affect hematological results.

Clinical ineffectiveness of IL-2 and/or IFN alpha administration after autologous PBSC transplantation in pediatric oncological patients.

Clinical impact of s.c. administration of IL-2 and/or IFN alpha was studied in 23 pediatric patients with Hodgkin lymphoma (IFN alpha group) and sarcoma, non-Hodgkin lymphoma, peripheral neuroepitelioma, neuroblastoma, and embryonic carcinoma (IL-2 + IFN alpha group) after autologous PBSC transplantation. Expression of CD3, CD4, CD8, CD25, CD38, CD56, CD71, CD122, and HLA-DR antigens, serum level of the soluble IL-2R alpha, and NK activity against K562 cell line were evaluated in 11 patients representative for both types of immunotherapy. T and, more markedly, NK cell proliferation, induction of activation markers on the surface of T and NK subsets, and elevation of sIL-2R alpha concentrations were seen in the IL-2 + IFN alpha subgroup. In the IFN alpha subgroup, the total number of lymphocytes and expression of activation markers remained unchanged, but the number of CD8+ T cells increased at the expense of CD4+ T and NK cells during the therapy. Cytotoxic activity against K562 cells was not influenced by the immunotherapy in either subgroup. No significant clinical benefit of the immunotherapy was seen in these patients compared to 27 control patients with relevant diagnoses who did not receive immunotherapy.

[High-dose chemotherapy in the treatment of children with malignant lymphoma]. / Vysokodávkovaná chemoterapie v lécbe detí s maligním lymfomem.

BACKGROUND: 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. METHODS AND RESULTS: 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 marrow was used as the source of haemopoietic stem cells in ten patients, peripheral blood in twenty-eight, and both sources were used in seven patients. After the median follow-up of 47 months, the final survival was 61%. Eleven patients died of the disease progression, four of the infectious complications, one at a car accident. Median time to relapse after the transplantation was 7.5 months. CONCLUSIONS: Further improvement of these results will require earlier transplantation, improved preparative regiments or early posttransplant immunotherapy.

Treatment of children and adolescents with non-Hodgkin's lymphoma (results based on the NHL Berlin-Frankfurt-Münster 90 protocols).

BACKGROUND: To determine the feasibility and results of treating children with non-Hodgkin's lymphomas (NHL) according to very intensive protocols based on the German Berlin Frankfurt Münster NHL 90 study. METHODS AND RESULTS: From 1991 until 1995 eighty two patients less than 18 years of age with NHL were admitted to our department. Sixty three of them were eligible for the study. The entire group consisted of 43 males and 20 females (ratio 2.1:1). Median age was 10 2/12 years. Eleven had stage I disease, 4 stage II, 29 stage III and 19 stage IV disease. Histologies represented were: large cell lymphoma 22, lymphoblastic lymphoma 19, and Burkitt lymphoma 10 patients. In 12 cases the immunophenotype was not further classified as to B-cell or T-cell subtype. Patients were stratified into the therapy groups "B" or "non B" according to histopathology, clinical stage and LDH level. Therapy for the B group consisted of 2, 4 or 6 courses of intensive 5 day pulses of 6 drugs. Patients in the non B group received the protocol for acute lymphoblastic leukemia including reinduction and CNS irradiation for advanced stages. At a median follow-up of 35 months the probability of event free survival (pEFS) at 5 years 70% and overall survival 73% for entire group. For therapy group B pEFS was 76%. The non B therapy group had a pEFS 60% (p = 0.22). There was a significantly better outcome for children classified as stage I and II. There was no statistical difference between stage III and IV. Treatment results were comparable between NHL subtypes, except for large cell lymphomas, which did significantly better (pEFS 90%). CONCLUSIONS: The use of protocols based on BFM 90 study in the Czech Republic was feasible. The pEFS are approximately 10% lower than the German study but comparable to some other studies. Outcome for large cell lymphomas was excellent. Reduction of treatment related complication and mortality rate as well as more precise classification are required.

Treatment of pediatric B-cell non-Hodgkin's lymphomas at the Motol Hospital in Prague, Czech Republic: results based on the NHL BFM 90 protocols.

Malignant non-Hodgkin's lymphomas (NHL) of childhood and adolescence are a heterogeneous group of diseases originating from the lymphoid cells. Unlike adults with non-Hodgkin's lymphoma, children typically have extranodal disseminated disease of high grade (Burkitt's lymphoma, large cell lymphoma, or lymphoblastic lymphoma). This study was conducted to determine the feasibility of treating children in the Czech Republic with B-cell non-Hodgkin's lymphomas according to very intensive protocols based on the German Berlin Frankfurt Munster (BFM) NHL 90 study. Treatments are divided in the BFM studies according to "B" and "non-B" immunophenotypes. The authors report only those treated according to the BFM B-cell protocol. From 1991 through 1997 eighty-two patients less than 18 years with NHL were admitted to the department. Seventy-three of them were classified as B-cell lymphoma and 54 were thus eligible for the BFM B-cell treatment. The entire group consisted of 38 males and 16 females (ratio 2.38). Median age was 11.6 years. Twelve had stage I disease, 3 stage II, 30 stage III, and 9 stage IV lymphoma. There were 21 patients with Burkitt's lymphoma, 29 with large cell lymphoma, of which 5 were patients with MALT lymphoma. In 3 cases B-cell NHL was not further classified and one child had a mediastinal B lymphoma. Patients were further stratified according to clinical stage and lactate dehydrogenase (LDH) level. Therapy consisted of a prephase and short (2, 4, or 6 courses), intensive 5-day therapy with 6 drugs. The probability of event-free survival (pEFS) for the entire group was 74% and overall survival at 5 years was 80%. There was a significantly better outcome for children classified as stage I. No difference was observed between the EFS of stage III and IV patients. Four patients died from treatment-related complications in complete remission. Treatment results were not identical between NHL subtypes, with large cell lymphoma patients doing significantly better (pEFS 90%, p = .008). The use of protocols based on BFM 90 study was feasible at this center. The treatment results are approximately 10% lower than those reported by BFM investigators, but comparable to results from other centers.

Treatment of Hodgkin's disease in children with VAMP (vinblastine, adriamycin, methotrexate, prednisone) and VEPA (vinblastine, etoposide, prednisone, adriamycin).

Treatment of Hodgkin's disease in children should be directed at maximizing cures and minimizing the long-term effects of alkylating agents, anthracyclines, and bleomycin. In this study methotrexate and etoposide were used in the VAMP/VEPA regimens to treat 60 clinically staged pediatric patients with Hodgkin's disease. Twenty-nine patients with stages I-IIA received four courses of VAMP plus low-dose radiotherapy. Thirty-one IIA bulky disease and IIB-IVB patients received four or six courses of VEPA plus low-dose radiotherapy. There were 6 partial remissions after the completion of chemotherapy and all of these patients relapsed, but 4 were successfully salvaged with ABMT. Two patients have died. The 3.1-year overall survival rate is 97% (100% VAMP, 94% VEPA) and the event-free survival rate is 88% (97% VAMP, 77% VEPA). These results suggest that VAMP is a reasonable treatment for low stages of Hodgkin's disease, but more advanced disease is not adequately treated by VEPA and low-dose radiotherapy.