Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.

Variations of sex development: The first German interdisciplinary consensus paper.

INTRODUCTION: The term variations of sex development subsumes a large number of congenital conditions including chromosomal mosaics and variations of chromosomal, gonadal, and phenotypic sex. A situation of this nature may cause severe distress to both, parents and affected persons. One of the reasons for this is the binary form of gender classification in the society. In the past, because of a fear of possible stigmatization and an inability to cope with complex situations, it has been medical policy and practice for newborns to undergo early, mostly 'feminizing' elective surgery with the aim of achieving an outer genital appearance that is unambiguously male or female. Protests by advocacy groups for the most part as well as the results of outcome studies have shown that the development of affected persons may be very different to what has been expected and often does not result in the intended clear female or male gender identity as had been intended. It, therefore, seemed a matter of urgency to implement this new awareness as well as the ethical and personal human rights perspectives in the recommendations for the medical and psychosocial management of diverse sex development (DSD) in the future. STUDY DESIGN: In 2012, an interdisciplinary group of German academics engaged in the field of DSD decided to work on a consensus paper for this topic. It involved the participation of all faculties and non-scientific groups dealing with DSD, in particular advocacy and service-user groups. In a structured consensus, process recommendations were developed based on scientific literature as well as personal experiences of clinicians and affected individuals. RESULTS: Finally, 37 recommendations were agreed on. The strength of consensus is reflected in the degree of agreement as expressed in percentages. CONCLUSION: The introduction of the consensus paper reflects on the emerging paradigm shift and the necessity for a more open view of gender within society. The paper is intended to aid the performance of appropriate diagnostics in DSD-affected newborns and especially to help parents and affected persons cope with the biological and social consequences of DSD. With regard to medical or surgical therapy, it gives information about the most recent treatment trends.

[Infantile hemangiopericytoma of the nasal cavity]. / Infantiles Hämangioperizytom der Nasenhaupthöhle.

An infantile sinunasal hemangiopericytoma as a variant of infantile myofibroma is a rare finding. The observation of a sinunasal, infantile hemangiopericytoma affecting the anterior skull base and ethmoid bone in a female infant is presented. Chromosomal gains (6q14q16.2 und 18q22qter) as well as chromosomal losses (5q33.3q35.2, 10p11.2p12.2, 10q24.3q26.1, 15q23q25, 17p12pter and 22q11.2q13.2) were present. Endonasal tumor resection was achieved.

Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.

Differential expression of antimicrobial peptides in psoriasis and psoriatic arthritis as a novel contributory mechanism for skin and joint disease heterogeneity.

OBJECTIVES: This study tested the hypothesis that a differential innate immune antimicrobial peptide (AMP) profile was evident between the skin and joints in psoriasis and psoriatic arthritis (PsA) and that PsA synovitis may have a distinct AMP pattern compared to other arthropathies. METHOD: Twenty-two cases had knee biopsies [10 PsA, eight rheumatoid arthritis (RA), and four osteoarthritis (OA)]. Lesional and non-lesional skin biopsies in psoriasis and control tissue were also obtained (n = 4 each). Immunohistochemistry with semi-quantitative scoring of both synovium and skin was performed using the following panel of AMPs: S100 A8, S100 A9, human neutrophil peptides 1-3 (HNP1-3), human ß-defensins 2 and 3 (hBD-2 and hBD-3), cathelicidin LL-37, psoriasin (S100 A7), and ribonuclease 7 (RNase 7). RESULTS: Similar expression of S100 A8, S100 A9, and HNP1-3 was detectable in PsA and RA synovium but only in the synovium sublining layer (SSL). No expression of psoriasin, RNase 7, hBD-2, and hBD-3 could be detected in the synovial tissue of PsA, RA, or OA. All psoriasis skin samples exhibited broad expression of all investigated AMPs, with strong keratinocyte expression. CONCLUSIONS: Given that some AMPs, especially hBD-2, are genetically linked to psoriasis and are only expressed in the skin, these findings show how differential AMP expression in innate immune responses may contribute to disease heterogeneity between PsA and psoriasis and provides a genetic basis for the non-progression of psoriasis subgroups to PsA.

[Primary liver tumours in childhood]. / Primäre Lebertumoren im Kindesalter.

The reported prevalence of focal liver lesions in adult patients and children is different. The article discusses pediatric liver tumors under the criteria of histopathology and contrast enhanced ultrasound (CEUS) features. Aim of this article is also to support the already established Pediatric Registry of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to collect data on safety and applications of ultrasound contrast agents in children (www.efsumb.org).

[Histiocytic diseases in childhood and adolescence]. / Histiozytäre Erkrankung des Kindes- und Jugendalters.

Histiocytic diseases are generally rare with a variable clinical course and variable morphology which often have a peak frequency of occurrence in childhood and adolescence. Histiocytoses are subdivided into Langerhans cell histiocytosis and the so-called non-Langerhans cell histiocytosis, such as juvenile xanthogranuloma, Erdheim-Chester disease and Rosai-Dorfman disease. The most common forms of histiocytosis in childhood are Langerhans cell histiocytosis and juvenile xanthogranuloma. In contrast, forms of histiocytosis which occur more frequently in adulthood, such as Erdheim-Chester disease and Rosai-Dorfman disease are rare in childhood. Some forms of histiocytosis harbor BRAFv600E mutations. In Langerhans cell histiocytosis they have been found in 50-55 % of the cases examined and in Erdheim-Chester disease in up to 100 % of cases. In the remaining forms of histiocytosis (especially juvenile xanthogranuloma and Rosai-Dorfman disease) BRAF mutations could not be detected. A prognostic relevance could not be shown so far; however, in individual cases a mutation analysis of BRAF could provide help in the differential diagnostic considerations or the option of a therapy approach with BRAF inhibitors.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG).

Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) (n=238), was compared with historical BT-WT controls (SIOP93-01) (n=113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43 months (Inter Quartile Range (IQR) 24-68 months), stages: I (n=140, 40%), II (n=106, 30%), III (n=105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75-86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59-76%; p=0.006) and overall survival (OS) of 88% (95% CI: 83-93%) (SIOPWT2001) compared to 84% (95% CI: 77-91%; p=0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin.

Testicular germ cell tumors in adolescents - results of the protocol MAHO 98 and the identification of good risk patients.

BACKGROUND: In adolescents aged 10-15 years germ cell tumors of the testis (TGCT) are rare and information for a risk adapted therapy limited. AIMS OF THE STUDY: The protocol MAHO 98 for patients (pts) with TGCTs is stratified according to age, stage and histology. Pts ≥ 10 years received after tumororchiectomy 2 courses (crs) PVB and restaging. Residual tumor was resected and therapy continued in regard to inital stage and response. Chemotherapy: PVB: cisplatin (20 mg/m²/day 1-5), vinblastine (3 mg/m²/day 1+2), and bleomycin (15 U/m²/day 1-3). For consolidation 1 crs PVB has been given to stage II patients with CR. In case of PR, 2 crs PEB (vinblastine substituted by etoposide 100 mg/m²/day 1-3) or relapse 3 crs PEI (bleomycin substituted by ifosfamide 1 500 mg/m²/day 1-5) were given. RESULTS: Between Jan 1998 and Dec 2005, 34 pts (≥ 10 year) were registered, 31 fulfilled the inclusion criteria. Median age: 15;6 years; months (range 13;5-20;2 ). Lugano staging: IA n=14, IB n=2, IC n=3, IIA n=4, IIB n=6, IIC n=1, IIIC n=1. The stage IIIC pt received preoperative chemotherapy, all other pts had tumororchiectomy first. Residual tumor after 2 crs PVB was detected in 4 pts and was resected. Late relapses occurred in 2 pts and were cured by additional therapy. All patients are surviving. CONCLUSION: Young patients with TGCT stage I and II have an excellent prognosis and further reduction of therapy has to be considered.

Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols. PATIENTS AND METHODS: We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012. RESULTS: Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%-32%), and 5-year overall survival (OS) was 26% (95% CI: 10%-42%). CONCLUSIONS: In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

Pretreatment for bilateral nephroblastomatosis is an independent risk factor for progressive disease in patients with stage V nephroblastoma.

BACKGROUND: Treatment of stage V nephroblastoma is less established and more complex than in unilateral nephroblastoma. METHODS: Retrospective analysis of 121 consecutive patients with stage V nephroblastoma registered from January 1989 to May 2005. Registration, prospective data collection and treatment were carried out within the framework of 3 consecutive SIOP/GPOH-nephroblastoma-trials. RESULTS: 19 patients had metastasis and 29 syndromes at diagnosis. 13 patients had been pretreated for bilateral nephroblastomatosis. 1 patient was not treated and 17 patients had upfront surgery. Preoperative treatment duration ranged from 1-12 weeks (n=103). 1-3 preoperative treatment-cycles resulted in average tumor-volume-reduction of 45%. 1 patient underwent bilateral nephrectomy. 52% of the patients had 2 functioning kidneys after the end of treatment. 20 patients had died after mean follow-up of 8.6 years. 5y-Progression-Free (PFS) and Overall-Survival (OS) were excellent for patients having a localized disease without pretreatment for nephroblastomatosis (5yPFS/OS: 80±4%/93±3%). Metastasis at diagnosis (51±12%/56±12%; p=0.003) and pretreatment for nephroblastomatosis (37±14%/67±13%; p<0.001) were associated with significantly poorer outcome. Cox-regression analysis revealed an independent influence of pretreatment for nephroblastomatosis, metastasis and syndromes on PFS. The latter 2 as well as anaplasia and age (<2 years or >3 years) had an independent influence on OS. CONCLUSIONS: Pretreatment for nephroblastomatosis, metastasis and syndromes are independent risk factors. 1-3 preoperative treatment-cycles are sufficient to achieve save nephron-sparing-surgery in most patients.

Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2-12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants.

Extra-appendiceal neuroendocrine neoplasms in children - data from the GPOH-MET 97 Study.

Neuroendocrine neoplasms (NEN) in children are rare. In Germany, children with NEN of the gastroenteropancreatic system are prospectively registered since 1997. The objective of this study was to evaluate diagnostics, treatment and outcome in children with extra-appendiceal NEN.Clinical data of 39 patients with NEN registered in the GPOH-MET 97 trial from 1997 to 2012 were analyzed. Children with NEN of the appendix were excluded.14 patients with pancreatic, 12 patients with bronchial, 6 patients with gastrointestinal, 2 patients with nasopharyngeal and 5 patients with NEN of unknown primary were registered. About half of the patients had localized disease and rather low grade tumors, including all bronchial NEN, 5 of 14 pancreatic and 2 of 6 gastrointestinal tumors. Metastatic disease and high grade tumors were stated in cases with nasopharyngeal tumors, NEN of unknown -primary and in part of pancreatic and gastrointestinal NEN. Complete surgical resection was performed in patients with localized NEN with an overall survival of 100%. In contrast, overall survival in metastatic disease was 26%.Outcome in children with low grade NEN and localized disease is excellent. Management of high grade tumors and metastatic disease remains challenging. Establishing international registries is inevitable for further improvements.

Clear cell sarcomas of the kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: a report of the SIOP Renal Tumour Study Group.

PURPOSE: Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. PATIENTS AND METHODS: We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials. RESULTS: A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73-85%) and 86% (95% CI: 80-92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. CONCLUSION: In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK.

Testicular sex cord stromal tumors: analysis of patients from the MAKEI study.

BACKGROUND: In children and adolescents, testicular sex cord stromal tumors (TSCSTs) are rare. There is only limited information available regarding their clinical presentation, biology, and prognosis. METHODS: Between 1993 and 2009, 42 patients were prospectively reported to the cooperative MAHO and MAKEI studies on childhood germ cell tumors. Based on standardized documentation, data on epidemiology, clinical presentation, diagnostic features, histopathological differentiation, therapy, and follow-up were evaluated. RESULTS: During the study period, a gradual increase of the documentation of these rare tumors was observed. Palpable, indolent testicular swelling was the most common clinical finding. In three patients, retention of the testis was observed. Two patients showed sexual precocity, and one patient showed a 45X/46XY mosaic. Juvenile granulosa cell tumors (n = 16) and Sertoli cell tumor (n = 15) were the leading histopathological subtypes. The first were commonly diagnosed during the first weeks of life (median age: 6(0-162) days, the latter during infancy (median 7(0-14) months, P < 0.05). Other histological diagnoses included Leydig cell and Large Cell Calcifying Sertoli cell tumors (both n = 3) and not-otherwise-specified TSCSTs (n = 5), which were diagnosed during childhood and adolescence. All tumors were limited to the testis; there were no metastases. Treatment was surgical, only. After a median follow-up of 3.8 years, no relapse was observed. CONCLUSIONS: Diagnosis and therapy of testicular tumors should be planned in accordance with the recommendations of the respective childhood germ cell tumor protocols. High inguinal orchiectomy is safe and constitutes definitive therapy. Diagnostic work-up and follow-up should also consider potentially associated tumor predisposition syndromes.

Lung metastasis of primary alveolar soft-part sarcoma occurring 20 years after initial treatment.

A 30-year old woman was referred to our center because of suspicion of a primary lung tumor of the right upper lobe. Histological examination of the lung lesion revealed lung metastasis of a previously treated alveolar soft part sarcoma of the musculus vastus medialis of the right femur, which was resected 20 years ago. Alveolar soft-part sarcoma is a rare malignant tumor that occurs most often in the soft tissue of lower limbs. It is a slow-growing malignant soft tissue tumor arising in muscle tissue, usually in young adults. Due to pleural and extensive mediastinal infiltration with bilateral lung metastases, a systemic treatment with chemotherapy doxorubicin and ifosfamide was initiated. Late metastases from previously treated alveolar part sarcoma should be considered in patients with suspicious lung lesions even if surgical treatment was performed a long time ago.

Molecular genetic analysis of bilateral ovarian germ cell tumors.

BACKGROUND: Ovarian germ cell tumors (oGCTs) are rare and highly heterogeneous with regard to their clinical and histologic appearance. The risk of tumor development is higher in children with aberrant sexual differentiation. Development of gonadoblastomas is seen in young women with 46,XY gonadal dysgenesis. At least 50 % of gonadoblastomas may develop into malignant oGCTs, mostly dysgerminomas. In this study, we evaluated bilateral oGCTs in clinically inapparent patients for sex chromosomal aberrations. PATIENTS AND METHODS: We analyzed tumor samples of 15 patients with synchronous bilateral oGCTs enrolled onto the consecutive MAKEI trials for non-testicular GCTs. Paraffin embedded samples from the Kiel German Childhood Tumor Registry were evaluated for the presence of Y-chromosomal sequences. Molecular genetic techniques included comparative genomic hybridization, polymerase chain reaction, and fluorescence in situ hybridization. RESULTS: Among 15 patients with bilateral oGCTs, Y-chromosomal DNA sequences were detected in 6 tumors. Both mature teratomas were negative for Y-chromosomal DNA. Thus, 5 of 12 malignant oGCTs and 1 immature teratoma (with elevated AFP) showed Y-chromosomal material. A 45(X,0) karyotype could not be demonstrated. CONCLUSIONS: These investigations provide additional insight into the development of oGCTs: mature teratomas, which develop from postmeiotic germ cells, are not associated with gonadal dysgenesis. Bilateral immature teratomas, dysgerminomas and mixed malignant oGCTs may frequently show Y-chromosomal DNA, indicating underlying but clinically inapparent gonadal dysgenesis. Thus, the presence of aberrant Y-chromosomal sequences appears to be involved in tumor development in about half of these patients.

Systemic treatment of adrenocortical carcinoma in children: data from the German GPOH-MET 97 trial.

BACKGROUND: Adrenocortical cancer (ACC) in childhood is a rare disease with poor prognosis. Complete surgical resection, systemic chemotherapy, and mitotane therapy are important curative treatment options for patients with advanced-stage tumors. Since 1997, pediatric ACC patients in Germany have been treated according to the non-randomized, single arm study GPOH-MET-97. PATIENTS AND METHODS: Data regarding disease course, treatment, and survival rates of 60 patients (age 0.24-17.8 years) with ACC treated according to the GPOH-MET-97 protocol were collected and analyzed to determine outcome, with a focus on examining the effectiveness of mitotane therapy. RESULTS: Among all patients, event-free survival and overall survival were found to be 43.3% and 64.8%, respectively. Chemotherapy with VCR, IFO, ADR, CARBO, and VP16 had been provided to 34 patients (56.6%) in different settings (neoadjuvant, adjuvant, and salvage) and mitotane therapy to 32 patients (53.3%). Duration of mitotane treatment longer than 6 months and mitotane levels greater than 14 mg/l were found to be associated with significantly better survival. Local relapse was found to be associated with a worse prognosis compared to distant metastasis only. CONCLUSIONS: Systemic chemotherapy and mitotane therapy are important therapeutic options in the treatment of advanced pediatric ACC patients. Neoadjuvant therapy should be considered for patients with primarily incomplete resectable or inoperable tumors, and tumor spillage is an indication for adjuvant chemo- and mitotane therapy. All pediatric ACC patients should be treated in pediatric oncological centers according to a consistent protocol in a highly interdisciplinary setting.

Primary lung metastases in pediatric malignant non-Wilms renal tumors: data from SIOP 93-01/GPOH and SIOP 2001/GPOH.

Malignant non-Wilms renal tumors (NWRT) are a small but relevant subgroup of renal neoplasms in children. In this study we analyzed corresponding data from the trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the Society of Pediatric Oncology and Hematology.Data of 22 patients with NWRT and primary lung metastases were retrospectively reviewed. Analyses included epidemiology, tumor characteristics, chemotherapy, local treatment, and outcome.The following diagnoses were registered: Malignant Rhabdoid tumor of the kidney (MRTK, n=15), Renal-cell carcinoma (RCC, n=3), Clear-cell sarcoma of the kidney (CCSK, n=3), and primitive neuro ectodermal tumor (PNET, n=1). Median age of patients at diagnosis was 14 months. Overall survival was 36.36% (8/22). Of the 15 children with MRTK 3 survived, 3/3 patients with RCC, 1/3 patients with CCSK, and 1/1 patient with PNET survived. Lung metastases disappeared in 6 patients after initial chemotherapy, 6/8 patients undergoing local treatment of lung metastases (surgery, irradiation, or both) achieved complete remission. Only patients with complete clearance of lung lesions, either through neoadjuvant chemotherapy or subsequent local treatment, survived. Mean Follow up was 31 months (1-137).Survival of patients with stage IV NWRT is dismal. Complete removal of lung metastases seems mandatory for survival. An aggressive diagnostic and therapeutic approach seems justified in affected children.