Administration of Samital® in children with oral mucositis: a feasibility study.

OBJECTIVE: SAMITAL®, a botanical drug containing three highly standardized extracts (Vaccinium myrtillus, Macleaya cordata and Echinacea angustifolia), has shown promising results in treating or preventing oral mucositis (OM) in adult patients, but it has not been fully investigated in children. In this study, we assessed the feasibility of SAMITAL administration in pediatric patients receiving anticancer treatment to prevent or treat OM, focusing on identifying an appropriate dose and evaluating safety and tolerability and palatability and treatment compliance. PATIENTS AND METHODS: We conducted an open-label, monocentric, prospective study on 18 children receiving anticancer therapy to prevent or treat OM. RESULTS: No SAMITAL®-related side effects were observed or reported during the study; moreover, no systemic absorption of SAMITAL® metabolites was detected in the bloodstream. However, compliance to SAMITAL® was unsatisfactory and variable (from 2 to 100%), and patients reported low palatability (median taste of 4.8; range 1.0-8.0). CONCLUSIONS: SAMITAL® administration appears to be safe in the pediatric population, as it is not absorbed in the bloodstream and does not cause any local or systemic side effects. However, the current formulation is only partially suitable for children, and future studies on SAMITAL® in children would need an adapted formulation to increase compliance.

In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

Inequalities in diagnosis and registration of pediatric very rare tumors: a European study on pleuropulmonary blastoma.

Very rare tumors (VRTs) account for up to 11% of childhood cancers. Dedicated national groups and registries only exist in some European countries. Pleuropulmonary blastoma (PPB) is a very rare intrathoracic pediatric tumor with a potentially severe prognosis. Due to its rarity, it sometimes goes unrecognized. We investigated PPB diagnostic capability and possible correlations between diagnostic performance and VRT-dedicated activities. The number of cases of PPB registered between 2000 and 2014 at pediatric oncology centers in Europe was compared with the number of expected cases. Data sources included VRT registries, population-based cancer registries, and hospital registries. Data were obtained for 25 countries, grouped into 4 geographical regions. The expected cases were 111, and the observed cases were 129. The observed-to-expected ratio was 1.86 for Northern Europe, 1.33 for Southern Europe, 1.22 for Central Europe, and 0.65 for Eastern Europe. More cases than expected were registered in all countries with an official VRT registry.Conclusion: The number of cases observed is consistent with expectations, but disparities exist across Europe. Difficulties in diagnosing PPB emerged in most Eastern countries. The incidence rate of PPB may be underestimated. The creation of VRT-dedicated groups and a European Registry for VRTs could help to reduce inequalities.What is Known:• Very rare pediatric tumors are often not recognized, despite representing almost 11% of childhood cancers .• Pleuropulmonary blastoma is a rare pediatric tumor with a poor prognosis.What is New:• The ability to diagnose and register pleuropulmonary blastoma varies in Europe.Registries dedicated to very rare pediatric tumors improve the diagnostic rates.• The incidence rate of pleuropulmonary blastoma may currently be underestimated.

High dose chemotherapy and autologous hematopoietic cell transplantation for Wilms tumor: a study of the European Society for Blood and Marrow Transplantation.

Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.

Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

OBJECTIVE: Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT. METHODS: Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin-etoposide-cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease. RESULTS: Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4-92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II-IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6-100%) and 84.5% (95% CI: 76.5-93.5%). CONCLUSIONS: We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.

Extraskeletal osteosarcoma: A European Musculoskeletal Oncology Society study on 266 patients.

PURPOSE: Prognosis of extraskeletal osteosarcoma (ESOS) is reported to be poorer than that of skeletal osteosarcoma. This multicenter retrospective study aimed to evaluate factors influencing ESOS prognosis. PATIENTS AND METHODS: Members of the European Musculoskeletal Oncology Society (EMSOS) submitted institutional data on patients with ESOS. RESULTS: Data from 274 patients treated from 1981 to 2014 were collected from 16 EMSOS centres; 266 patients were eligible. Fifty (18.7%) had metastases at diagnosis. Of 216 patients with localised disease, 211 (98%) underwent surgery (R0 = 70.6%, R1 = 27%). Five-year overall survival (OS) for all 266 patients was 47% (95% CI 40-54%). Five-year OS for metastatic patients was 27% (95% CI 13-41%). In the analysis restricted to the 211 localised patients who achieved complete remission after surgery 5-year OS was 51.4% (95% CI 44-59%) and 5-year disease-free survival (DFS) was 43% (95% CI 35-51%). One hundred twenty-one patients (57.3%) received adjuvant or neoadjuvant chemotherapy and 80 patients (37.9%) received radiotherapy. A favourable trend was seen for osteosarcoma-type chemotherapy versus soft tissue sarcoma-type (doxorubicin ± ifosfamide) regimens. For the 211 patients in complete remission after surgery, patient age, tumour size, margins and chemotherapy were positive prognostic factors for DFS and OS by univariate analysis. At multivariate analysis, patient age (≤40 years versus >40 years) (P = 0.05), tumour size (P = 0.0001) and receipt of chemotherapy (P = 0.006) were statistically significant prognostic factors for survival. CONCLUSION: Patient age and tumour size are factors influencing ESOS prognosis. Higher survival was observed in patients who received perioperative chemotherapy with a trend in favour of multiagent osteosarcoma-type regimen which included doxorubicin, ifosfamide and cisplatin.

Global DNA methylation profiling uncovers distinct methylation patterns of protocadherin alpha4 in metastatic and non-metastatic rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma (RMS), which can be classified as embryonal RMS (ERMS) and alveolar RMS (ARMS), represents the most frequent soft tissue sarcoma in the pediatric population; the latter shows greater aggressiveness and metastatic potential with respect to the former. Epigenetic alterations in cancer include DNA methylation changes and histone modifications that influence overall gene expression patterns. Different tumor subtypes are characterized by distinct methylation signatures that could facilitate early disease detection and greater prognostic accuracy. METHODS: A genome-wide approach was used to examine methylation patterns associated with different prognoses, and DNA methylome analysis was carried out using the Agilent Human DNA Methylation platform. The results were validated using bisulfite sequencing and 5-aza-2'deoxycytidine treatment in RMS cell lines. Some in vitro functional studies were also performed to explore the involvement of a target gene in RMS tumor cells. RESULTS: In accordance with the Intergroup Rhabdomyosarcoma Study (IRS) grouping, study results showed that distinct methylation patterns distinguish RMS subgroups and that a cluster of protocadherin genes are hypermethylated in metastatic RMS. Among these, PCDHA4, whose expression was decreased by DNA methylation, emerged as a down-regulated gene in the metastatic samples. As PCDHA4-silenced cells have a significantly higher cell proliferation rate paralleled by higher cell invasiveness, PCDHA4 seems to behave as a tumor suppressor in metastatic RMS. CONCLUSION: Study results demonstrated that DNA methylation patterns distinguish between metastatic and non-metastatic RMS and suggest that epigenetic regulation of specific genes could represent a novel therapeutic target that could enhance the efficiency of RMS treatments.

Surgical management of papillary thyroid carcinoma in childhood and adolescence: an Italian multicenter study on 250 patients.

PURPOSE: The extent of surgery for pediatric papillary thyroid carcinoma is debatable. The aim of this study was to evaluate the feasibility of offering pediatric patients a tailored surgical approach based on certain clinical features. METHODS: A national multicenter retrospective review of 250 pediatric patients treated for papillary thyroid carcinoma in a 14-year period was performed. Outcomes of interest included tumor-related features, type of surgery, surgical morbidity, disease-free and overall survival rates. Recurrence was thoroughly analyzed with particular focus on how it correlated with certain patient- and tumor-related features. RESULTS: The majority of patients (58.8 %) had tumors >2 cm in size. Nodal involvement occurred in 115/250 (46 %) patients and distant metastasis in 4 % (10/250). Total thyroidectomy and lobectomy were performed in 90.4 % (226/250) and 9.6 % (24/250) of patients, respectively. The overall rate of surgical complications was 20.8 % (52/250). These included transient and permanent hypoparathyroidism (13.6 and 4.4 %, respectively), and vocal fold palsy (2.8 %). All surgical complications occurred exclusively in the total thyroidectomy group. The rate of recurrent disease was 12 % (30/250) with the vast majority of recurrences (96.6 %) occurring in the total thyroidectomy group. The risk of recurrence correlated significantly with certain tumor-related features (size > 2 cm, multifocality, extrathyroidal invasion, nodal positivity, and distant metastasis). However, it did not correlate with the patient's age or sex. Overall survival was 100 %. CONCLUSION: Pediatric patients are likely to benefit from a tailored surgical strategy. Uniformly offering patients total thyroidectomy seems to be an overly radical approach.

Synovial sarcoma in children and adolescents: the European Pediatric Soft Tissue Sarcoma Study Group prospective trial (EpSSG NRSTS 2005).

BACKGROUND: To report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma. PATIENTS AND METHODS: From August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement. RESULTS: With a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions. CONCLUSION: This study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists. CLINICAL TRIALS NUMBER: European Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx).

The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.

Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups.

BACKGROUND: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004. PATIENTS AND METHODS: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS). RESULTS: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%. CONCLUSIONS: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

High ALK mRNA expression has a negative prognostic significance in rhabdomyosarcoma.

BACKGROUND: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in cancer, but its clinical and functional importance remain controversial. Mutation or amplification of ALK, as well as its expression levels assessed by conventional immunohistochemistry methods, has been linked to prognosis in cancer, although with potential bias because of the semi-quantitative approaches. Herein, we measured ALK mRNA expression in rhabdomyosarcoma (RMS) and determined its clinical impact on patients' stratification and outcome. METHODS: Specimens were obtained from RMS patients and cell lines, and ALK expression was analysed by quantitative RT-PCR, western blotting, IHC, and copy number analysis. RESULTS: High ALK mRNA expression was detected in the vast majority of PAX3/7-FOXO1-positive tumours, whereas PAX3/7-FOXO1-negative RMS displayed considerably lower amounts of both mRNA and protein. Notably, ALK mRNA distinguished unfavourable PAX3/7-FOXO1-positive tumours from PAX3/7-FOXO1-negative RMS (P<0.0001), and also correlated with larger tumour size (P<0.05) and advanced clinical stage (P<0.01), independently of fusion gene status. High ALK mRNA levels were of prognostic relevance by Cox univariate regression analysis and correlated with increased risk of relapse (P=0.001) and survival (P=0.01), whereas by multivariate analysis elevated ALK mRNA expression resulted a negative prognostic marker when clinical stage was not included. CONCLUSION: Quantitative assessment of ALK mRNA expression helps to improve risk stratification of RMS patients and identifies tumours with adverse biological characteristics and aggressive behaviour.

Paediatric and adolescent alveolar soft part sarcoma: A joint series from European cooperative groups.

BACKGROUND: Alveolar soft part sarcomas (ASPS) are generally chemo- and radio-resistant mesenchymal tumours, with no standardized treatment guidelines. We describe the clinical behaviour of paediatric ASPS and compare these features to previously reported adult series. PATIENTS AND METHODS: The clinical data of 51 children and adolescents with ASPS, prospectively enrolled in or treated according to seven European Paediatric trials were analysed. RESULTS: Median age was 13 years [range: 2-21]. Primary sites included mostly limbs (63%). IRS post-surgical staging was: IRS-I (complete resection) 35%, II (microscopic residual disease) 20%, III (gross residual disease) 18% and IV (metastases) 27%. Only 3 of the 18 evaluable patients (17%) obtained a response to conventional chemotherapy. After a median follow-up of 126 months (range: 9-240), 14/18 patients with IRS-I tumour, 10/10 IRS-II, 7/9 IRS-III and 2/14 IRS-IV were alive in remission. Sunitinib treatment achieved two very good partial responses in four patients. Ten-year overall survival (OS) and event free survival (EFS) was 78.0 ± 7% and 62.8 ± 7% respectively. Stage IV, size >5 cm and T2 tumours had a poorer outcome, but only IRS staging was an independent prognostic factor. CONCLUSIONS: ASPS is a very rare tumour frequently arising in adolescents and in the extremities, and chemo resistant. Local surgical control is critical. ASPS is a poorly chemo sensitive tumour. For IRS-III/IV tumours, delayed radical local therapies including surgery are essential. Metastatic patients had a poor prognosis but targeted therapies showed promising results.

Rare cancers in children - The EXPeRT Initiative: a report from the European Cooperative Study Group on Pediatric Rare Tumors.

The low incidence and the heterogeneity of very rare tumors (VRTs) demand for international cooperation. In 2008, EXPeRT (European Cooperative Study Group for Pediatric Rare Tumors) was founded by national groups from Italy, France, United Kingdom, Poland and Germany. The first aims of EXPeRT were to agree on a uniform definition of VRTs and to develop the currently most relevant scientific questions. Current initiatives include international data exchange, retrospective and prospective studies of specific entities, and the development of harmonized and internationally recognized guidelines. Moreover, EXPeRT established a network for expert consultation to assist in clinical decision in VRTs.

Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation.

BACKGROUND: The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone. PATIENTS AND METHODS: The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation. RESULTS: During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24-124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded. CONCLUSIONS: This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Unusual neuroimaging in a young boy with cerebral X-linked adrenoleukodystrophy.

We describe the case of a 7-year-old boy with cerebral X-linked adrenoleukodystrophy presenting with neurobehavioral symptoms. Attention deficit with hyperactive behavior was followed by progressive memory retrieval deficits and difficulty in writing. A detailed review of the clinical history, clinical examination and contrast-enhanced brain nuclear magnetic resonance imaging disclosed indeed an atypical cerebral form of X-linked adrenoleukodystrophy with diffuse anterior and posterior white matter involvement with a typical rim of contrast enhancement. A severe clinical deterioration occurred despite dietary treatment and hormonal replacement therapy. These rare but severe forms of atypical cerebral X-linked adrenoleukodystrophy can more often mimic attention deficit/hyperactivity disorder and should, therefore, be considered in young males with progressive neurobehavioral symptoms, particularly when possibly related to frontal white matter involvement. An accurate clinical history and examination should determine whenever a contrast-enhanced head MRI should be indicated.

Sequential intensified chemotherapy with stem cell rescue for children and adolescents with desmoplastic small round-cell tumor.

The RMS4.99 study was designed to explore the role of early sequential intensified chemotherapy (SICT) with PBSC rescue in patients with soft tissue sarcoma with a poor prognosis. Fourteen patients with desmoplastic small round-cell tumor (DSRCT) were included in this study. Initial chemotherapy was followed by a course of CY and etoposide with subsequent PBSC harvest, then three consecutive intensified chemotherapy combinations followed by PBSC rescue and G-CSF administration: first cycle thiotepa (150 mg/m(2) x 2 on day 1) and melphalan (60 mg/m(2) on day 2), second cycle CY (2 g/m(2) on days 1 and 2) and thiotepa (150 mg/m(2) x 2 on day 3), third cycle melphalan (80 mg/m(2) on day 1). The interval between cycles had to be kept as short as possible. Then patients underwent surgery or radiotherapy or both, after which six courses of vincristine, actinomycin D, CY were administered. Ten patients received SICT, which was well tolerated. With a median follow-up of 27 months only three patients are alive without evidence of disease. The 3-year event-free and overall survival rates were 15.5 and 38.9%, respectively. The prognosis for pediatric patients with DSRCT did not improve after administering intensified chemotherapy early in their treatment, so different strategies are needed.

European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors.

PURPOSE: Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission. PATIENTS AND METHODS: A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response. RESULTS: At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with > or = two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively. CONCLUSION: A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.

Is alveolar histotype a prognostic factor in paratesticular rhabdomyosarcoma? The experience of Italian and German Soft Tissue Sarcoma Cooperative Group.

PURPOSE: To ascertain whether alveolar histology retains its adverse prognostic role in the subset of paratesticular rhabdomyosarcoma (RMS) patients, generally characterized by a very good outcome. PATIENTS AND METHODS: Twenty pediatric patients were treated over a 25-year period using the protocols of the Italian and German Soft Tissue Sarcoma Cooperative Groups. Clinical characteristics at presentation were much the same as in non-alveolar patients. RESULTS: The proportion of patients with alveolar histotype (8%) in paratesticular site was lower than in the general RMS population (20-30%). With a median follow-up of 122 months, 5-year EFS and OS were 78 and 89%, respectively. CONCLUSION: Our data suggest a distinctly better clinical behavior of paratesticular alveolar RMS than when the disease occurs at other sites. These patients were more intensively treated than the embryonal cases, however, so-although a treatment intensity reduction may be desiderable-the idea of eliminating the alkylating agents (as in low-risk embryonal paratesticular RMS) must be considered with great caution.