[Nephroblastoma -  30-years period of its treatment in the University Hospital Motol, Prague]. / Nefroblastom -  30 let lécby ve Fakultní nemocnici v Motole.

INTRODUCTION: Nephroblastoma (Wilms tumor - WT) is the most common solid tumor of kidney in children. We present treatment development of WT at the Department of Pediatric Hematology and Oncology, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol (KDHO) in the Czech Republic over 30 years. Patients that were treated prior to access to the International Society of Pediatric Oncology (SIOP) protocols are considered to be the historical group, then we have patients treated according to SIOP 9, SIOP 93-01 and SIOP 2001 protocols as full participants of SIOP studies. PATIENTS AND METHODS: Between January 1980 and April 2009, we treated 330 patients with WT at KDHO: 91 patients in historical group (1980-1988), 94 pts in SIOP 9 (1988-1993), 80 pts in SIOP 93-01 (1994-2001) and 65 pts in SIOP 2001 (2002-2009). Overall survival (OS) and event-free survival (EFS) were analyzed by Kaplan-Meier test. RESULTS: The overall ten-year EFS was 81.2% and OS 87.6%. Fifty-eight patients from the 330 (17.6%) had metastases at diagnosis, EFS without metastatic process was 84.6% compared to 65.4% with metastasis presented at diagnosis (p = 0.0003), OS was 70.7% compared to 91.2% (p < 0.0001). One hundred and seventy patients (51.5%) were treated with preoperative chemotherapy and/or radiotherapy, whereas 158 patients (47.5%) underwent primary nephrectomy; EFS and OS did not differ: neoadjuvant vs primary nephrectomy EFS was 81.2% vs 80.9% (p = 0.85), OS 89.4% vs 85.4% (p = 0.38). Sixty (18%) patients experienced disease recurrence; OS after relapse was 33%. In the historical group, EFS and OS were 85.7% and 91.2%. In patients treated according to the SIOP 9 protocol, EFS and OS were 68.1% and 74.5%, resp. In patients treated according to SIOP 93-01, it was 83.6% and 93.7%, resp. and in patients treated according to 87 SIOP 2001, it was 7% and 95.4% (p = 0.001 and p = 0.0008), resp. CONCLUSION: WT is a well treatable disease. The aim for the future is to maintain the current very good survival while minimizing the treatment intensity.

[Radical surgery in the complex treatment of hepatoblastoma]. / Chirurgická radikalita v komplexní lécbe hepatoblastomu.

BACKGROUND: Evaluation of treatment results in children with hepatoblastoma--a retrospective study of clinical and pathological data of surgically treated children. METHODS AND RESULTS: At the clinic of authors, 28 children were operated for hepatoblastoma during 1991 to 2002. Average age of patients was 2.2 years. When tumors were classified according to PRETEX system, 3 children were in the stadium I, 12 children in stadium II, 12 children in stadium III, and one child in the stadium IV. At the diagnosis, lung metastases were found in 3 children. Till 1996 the treatment was initiated by a primary operation, since 1996 by a preoperative chemotherapy. Chemotherapy was administered according to the SIOP protocols. Primary operation was done in 13 children, 15 children were operated after the pre-operation chemotherapy. Liver resection included right-sided lobectomy in 7 cases, extended right-sided lobectomy in 4 cases, left-sided lobectomy in 8 cases, right-sided trisegmentectomy in 5 cases, left-sided trisegmentectomy in 3 cases. In our studied group the three years of event free survival was achieved in 75%, overall survival in 86%. Four children died, two of them because of the progression of the disease, two for the complication during the therapy. CONCLUSIONS: Combination of the radical surgical resection with preoperative and postoperative chemotherapy enables successful treatment of the childhood hepatoblastoma.

[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.

[Ovarian dysgerminoma in children and adolescents. Retrospective clinico-pathologic study]. / Dysgerminomy ovaria u detí a dospívajících. Retrospektivní klinicko-patologická studie.

BACKGROUND: To review the treatment strategy, follow up and outcome for all patients with pure ovarian dysgerminoma treated in childhood and adolescence. METHODS AND RESULTS: Twenty-one patients younger than 18 years were treated between 1979-2002 in Faculty Hospital Motol for newly diagnosed pure ovarian dysgerminoma. Patients were included into the cohort on the basis of revision of archival biopsy specimens deposited in Institute of Pathology and in Molecular Medicine tumor registry. The staging was reviewed retrospectively on the basis of surgical and pathological findings and on results of imaging investigations and outlined according to the TNM and International Federation of Gynecology and Obstetrics (FIGO) classification. The median age at the time of diagnosis was 12.5 years (range 6 years, 5 months--17 years, 11 months). There were ten FIGO stage IA tumors, one stage IB, two of stage IIC, one stage IIIB and seven IIIC tumors. All patients, except two girls with bilateral dysgerminoma, underwent unilateral adnexectomy or ovarectomy. Ten girls were treated postoperatively with chemotherapy, eight with chemotherapy and radiotherapy (eleven with cisplatine based chemotherapy). Three girls with dysgerminoma confined to the ovary (stage IA) have not received adjuvant chemotherapy. With a median follow up 7.1 years all girls remained continuously disease free. The 5-year overall and event free survival is 100%. Majority of patients does not have severe treatment sequelae, three pregnancies have occurred so far. CONCLUSIONS: Most patients with dysgerminoma, including those with metastases can expect cure when treated with conservative surgery and cisplatine based chemotherapy. Reduction of treatment toxicity and preservation of reproductive function is a main task. The girls with dysgerminoma confined to the ovary (stage IA) can be treated with fertility sparing surgery, other should be treated with cisplatine based chemotherapy.

[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.

[Detection of minimal residual disease in Ewing's sarcoma using RT-PCR]. / Detekce minimální reziduální nemoci u Ewingova sarkomu pomocí RT-PCR.

BACKGROUND: More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and FLI-1 genes, due to the t(11;22)(q23;q12) translocation. At the molecular level, the EWS-FLI-1 rearrangement shows great diversity. Specifically, many different combinations of exons from EWS-FLI-1 encode in-frame fusion transcripts and result in differences in length and composition of the chimeric protein, which function as an oncogenic aberrant transcription factor. The finding of this translocation gives evidence for the presence of ES cells. The aim of this prospective study was to verify applicability of the RT-PCR method for the detection of minimal residual disease in patients with ES. METHODS AND RESULTS: Conditions for the detection of Ewing's sarcoma cells by means of the reverse-transcriptase polymerase chain reaction (RT-PCR) at fusion transcripts in peripheral blood, bone marrow (BM) and autologous hematopoietic stem cell grafts in patients with ES were appointed. 31 samples of BM, 5 samples of blood and 7 peripheral blood grafts obtained from 23 patients were investigated. Presence of tumor cells was identified in 7 BM samples from 7 different patients (31 samples from 16 patients), all the peripheral blood and graft samples were negative. CONCLUSIONS: The high sensitivity of RT-PCR method in detection of cells bearing t(11;22)(q23;q12) was demonstrated in the experimental model and clinical samples. Likewise the literary statements, the RT-PCR method was found to be more sensitive than cytology.

[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.

Papillary cystic and solid tumor of the pancreas--surgical therapy with the use of CUSA, and a review of the pediatric literature.

Papillary cystic and solid tumor of the pancreas (PCSTP), so-called Frantz tumor, is a very rare tumor in children. Only 62 cases, 57 girls and 5 boys, have been reported in children since 1959. The tumor presents usually as a slowly growing abdominal mass with or without abdominal pain. Surgical resection of the tumor is an adequate mode of treatment, and the prognosis is excellent. The authors present 4 girls and 1 boy with PCSTP and demonstrate that the Cavitron Ultrasonic Surgical Aspirator (CUSA, Valleylab) is successfully used in surgical therapy.

[Advances in the diagnosis and treatment of neuroblastoma]. / Pokroky v diagnostic a lécbe neuroblastomu.

Neuroblastoma is the second most common solid tumor in children. The prognosis is poor for approximately 70% of patients who have widespread disease at the time of diagnosis. The use of new strategies for classification and therapy has raised expectations for cure in advanced neuroblastoma. We summarise results and experiences reached during the last decade.

Pseudomembraneous clostridium after autologous bone marrow transplantation.

Clostridium difficile (C. difficile) pseudomembraneous colitis was diagnosed in a 13-year-old boy with Hodgkin's disease 3 months after autologous bone marrow transplantation. Hematopoiesis was fully reconstituted at the time. C. difficile infection occurred after gall bladder empyema had been treated conservatively with i.v. antibiotics and prophylactic 4-week administration of oral amoxicillin. C. difficile colitis was diagnosed early and intensive supportive therapy combined with administration of i.v. and subsequently oral vancomycin therapy failed. It is a phenomenon rarely seen and successful eradication of the clostridium infection was only achieved by a combination of higher dose vancomycin with metronidazole. During the post-colitis recovery the patient experienced a relapse of Hodgkin's disease and died following further surgical intervention 137 days post-transplantation.

Treatment of spinal cord tumors in children.

BACKGROUND: A retrospective review was carried out of nine children under 17 years of age with a diagnosis of intramedullary tumor seen during the period 1989-1995. Six had astrocytomas; one each had an ependymoma, a PNET, and a choroid plexus papilloma. Five patients had back pain, 3 others had mild pareses and the ninth had incapacitating defects. Seven of the 9 were treated by subtotal extirpation of the lesion, and biopsy alone was performed in the other two. All tumors were low grade (grade I or II) and therefore radiation therapy (RT) was performed as the only postoperative treatment in 8 of the 9 children. RESULTS: In February 1996, seven (77.8%) children were alive and two (22.2%) died of recurrent tumor (7 months and 5 years after diagnosis, respectively). Median follow-up was 3 years 4 months (range: 1 year 6 months to 7 years 3 months). CONCLUSION: Surgical removal of intraspinal tumors provides the best hope of control, but spinal column deformity after laminectomy and irradiation is a serious long-term problem in children. Orthopedic supervision for the prevention of these deformities; e.g., by external immobilization, is mandatory.

[N-myc oncogene amplification in tumors of the sympathetic nervous system: preliminary study of methods and clinico-pathologic correlations]. / Amplifikace N-myc onkogenu u nádoru sympatického nervového systému: Predbezná studie s metodickým aspektem a klinickopatologickou korelací.

Tumors of the sympathetic nervous system (NT), namely neuroblastoma (NB) and ganglioneuroblastoma (GNB), have a variable clinical course. Prognostic factors include clinical stage, age of the patient, histological grade, and changes at the genomic level, of which amplification of N-myc oncogene is a well recognized phenomenon. The aim of this study was to establish the status of the N-myc oncogene in NT and to compare the results with histopathological grading, with risk groups according to criteria outlined by Joshi et al., and with the clinical stage. To detect the amplification of N-myc oncogene we used differential polymerase chain reaction (D-PCR). Amplified N-myc oncogene was found in 10 out of 31 investigated children with NB (32%). The result of D-PCR could not be interpreted reliably in two patients. Of seven children with GNB the N-myc amplification was found in one case. None of seven children with ganglioneuroma was found to have amplified N-myc oncogene. The tumors with N-myc amplification were histologically poorly differentiated of undifferentiated with a high mitotic activity-8 children were classified as a high risk category; in two we had not enough surgical material to evaluate the histological prognostic factors. The correlation of N-myc status with clinical stage revealed N-myc amplification in two of 9 children classified as clinical stage III, and in eight of 11 children classified as clinical stage IV. The N-myc amplification was not found in any child diagnosed at stage I, II and IV. Five of 10 children with NB and N-myc amplification died of the disease progression. Four children died in the group of 19 children without N-myc amplification. The median of follow-up was 18 months. The patient with GNB and N-myc amplification also died of the disease progression. Although the follow-up period of the investigated group of patients was short, the results showed that the amplification of N-myc oncogene was associated with tumors of patients diagnosed at a late clinical stage (III and IV), and with tumors whose morphology and age were assessed collectively under the term "high risk group".