Vassilios Papadakis

Randomized trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: The European HR-NBL1/SIOPEN study

PURPOSE To reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim). PATIENTS AND METHODS From May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 microg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled. RESULTS The PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest. CONCLUSION Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Burnout, staff support, and coping in Pediatric Oncology.

Goals of workThe goals of the study were the following: (1) to study the rate of burnout of the staff in Pediatric Oncology and compare it with that of a group of staff in other pediatric specialties, (2) to find out if job satisfaction, role clarity, staff support, and ways of coping are related to the burnout of these two groups, and (3) as a secondary aim, to identify other parameters, i.e., profession, experience, having children, etc., which might affect burnout, staff support, and ways of coping.Materials and methodsThe study group (n = 58) consisted of the staff of two Pediatric Oncology units and a Bone Marrow Transplantation unit, and the control group (n = 55) consisted of the staff of two Pediatric departments and one Pediatric Orthopedics department. The Maslach Burnout Inventory, the Staff Support Questionnaire, the Shortened Ways of Coping Questionnaire—Revised, and the Social Readjustment Scale were used.Main resultsNo differences were found in burnout between Pediatric Oncology staff and that of other specialties, the existing staff support, and the ways of coping. Decreased role clarity and wishful thinking, as a way of coping, were positively correlated to emotional exhaustion, whereas a negative correlation of the lack of role clarity existed with personal accomplishment. Not having children and less experience increased burnout in both groups studied.ConclusionsThe hospital management and the heads of departments should be knowledgeable of ways to prevent burnout in their staff. Strategies targeting role clarity and wishful thinking are useful toward this goal.

Neuroblastoma mRNAs Predict Outcome in Children With Stage 4 Neuroblastoma: A European HR-NBL1/SIOPEN Study

PURPOSE To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. METHODS RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy. RESULTS High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value. CONCLUSION High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial

BACKGROUND High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. METHODS We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at 128 institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared. Patients (age 1-20 years) with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate disease response. Patients were randomly assigned (1:1) to busulfan and melphalan or to carboplatin, etoposide, and melphalan by minimisation, balancing age at diagnosis, stage, MYCN amplification, and national cooperative clinical group between groups. The busulfan and melphalan regimen comprised oral busulfan (150 mg/m2 given on 4 days consecutively in four equal doses); after Nov 8, 2007, intravenous busulfan was given (0·8-1·2 mg/kg per dose for 16 doses according to patient weight). After 24 h, an intravenous melphalan dose (140 mg/m2) was given. Doses of busulfan and melphalan were modified according to bodyweight. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin continuous infusion of area under the plasma concentration-time curve 4·1 mg/mL per min per day for 4 days, etoposide continuous infusion of 338 mg/m2 per day for 4 days, and melphalan 70 mg/m2 per day for 3 days, with doses for all three drugs modified according to bodyweight and glomerular filtration rate. Stem-cell rescue was given after the last dose of high-dose chemotherapy, at least 24 h after melphalan in patients who received busulfan and melphalan and at least 72 h after carboplatin etoposide, and melphalan. All patients received subsequent local radiotherapy to the primary tumour site followed by maintenance therapy. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17. FINDINGS Between June 24, 2002, and Oct 8, 2010, 1347 patients were enrolled and 676 were eligible for random allocation, 598 (88%) of whom were randomly assigned: 296 to busulfan and melphalan and 302 to carboplatin, etoposide, and melphalan. Median follow-up was 7·2 years (IQR 5·3-9·2). At 3 years, 146 of 296 patients in the busulfan and melphalan group and 188 of 302 in the carboplatin, etoposide, and melphalan group had an event; 3-year event-free survival was 50% (95% CI 45-56) versus 38% (32-43; p=0·0005). Nine patients in the busulfan and melphalan group and 11 in the carboplatin, etoposide, and melphalan group had died without relapse by 5 years. Severe life-threatening toxicities occurred in 13 (4%) patients who received busulfan and melphalan and 29 (10%) who received carboplatin, etoposide, and melphalan. The most frequent grade 3-4 adverse events were general condition (74 [26%] of 281 in the busulfan and melphalan group vs 103 [38%] of 270 in the carboplatin, etoposide, and melphalan group), infection (55 [19%] of 283 vs 74 [27%] of 271), and stomatitis (138 [49%] of 284 vs 162 [59%] of 273); 60 (22%) of 267 patients in the busulfan and melphalan group had Bearman grades 1-3 veno-occlusive disease versus 21 (9%) of 239 in the carboplatin, etoposide, and melphalan group. INTERPRETATION Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma. FUNDING European Commission 5th Framework Grant and the St Anna Kinderkrebsforschung.

Immunomodulatory intervention in sepsis by multidrug-resistant Pseudomonas aeruginosa with thalidomide: an experimental study.

BackgroundThalidomide is an inhibitor of tumour necrosis factor-alpha (TNFα) that has been proven effective for the treatment of experimental sepsis by Escherichia coli. It was tested whether it might behave as an effective immunomodulator in experimental sepsis by multidrug-resistant (MDR) Pseudomonas aeruginosa.MethodsSepsis was induced by the intraperitoneal injection of 1 × 108 cfu/kg inoculum of the test isolate in a total of 109 Wistar rats divided in three groups as follows: group A controls; group B administered seed oil 30 minutes before bacterial challenge; and group C administered 50 mg/kg of thalidomide diluted in seed oil 30 minutes before bacterial challenge. Blood was sampled for estimation of endotoxins (LPS), TNFα, interferon-gamma (IFNγ), nitric oxide (NO) and malondialdehyde (MDA). LPS was measured by the QCL-1000 LAL assay, TNFα and IFNγ by ELISA, NO by a colorimetric assay and MDA by the thiobarbiturate assay.ResultsMean (± SE) survival of groups A, B and C were 18.60 ± 1.84, 12.60 ± 0.60 and 30.50 ± 6.62 hours (p of comparisons A to C equal to 0.043 and B to C equal to 0.002). Decreased TNFα and NO levels were found in sera of animals of group C compared to group A. Plasma levels of LPS, MDA and IFNγ did not differ between groups.ConclusionIntake of thalidomide considerably prolonged survival in experimental sepsis by MDR P.aeruginosa an effect probably attributed to decrease of serum TNFα.

Fulminant Aeromonas hydrophila infection during acute lymphoblastic leukemia treatment

Aeromonas hydrophila septicemia has a fulminant course and it has been usually reported in immunocompromised hosts and rarely among children with leukemia. High morbidity and mortality is associated with A hydrophila infections. We describe the case of a child with acute lymphoblastic leukemia who presented with septicemia due to A hydrophila. The patient presented with fever and skin discoloration during a febrile neutropenia episode, which rapidly evolved into bacteremia and extensive thigh suppuration, fasciitis, and myonecrosis. Apart from antibiotic treatment, surgical debridement to relieve compartment pressure and prevent further lower extremity compromise was promptly performed. Despite long delays in chemotherapy and an extensive tissue gap, primary closure of the involved area was possible with full cosmetic and functional limb recovery, and the patient has remained in clinical remission for more than 7 years.

NASOPHARYNGEAL CARCINOMA IN CHILDHOOD AND ADOLESCENCE: A Single Institution's Experience with Treatment Modalities During the Last 15 Years

Pediatric nasopharyngeal carcinoma (NPC) represents a locally advanced undifferentiated tumor with widely varying epidemiological features and with a high cure rate when combined modality treatment is provided. Both local and systemic treatment is necessary, and additional treatment with biologic modifiers seems promising. In this study, clinical experience and therapeutic results of 10 children with newly diagnosed NPC, treated in a single pediatric hematology/oncology institution in Athens over a period of 15 years, are analyzed. Results from Greece on NPC in young patients are reported for the first time. Ten patients (6 male, 4 female) 7–14 years old (median = 12.5) with a nasopharyngeal tumor were retrospectively evaluated. Disease extent was staged according to the TNM system. EBV-DNA, EBERs, and LMP-1 from paraffin-embedded tissues were studied in 8 patients. All patients received both local and systemic treatment. All cases were classified as type WHO-3. The presence of EBV-DNA and expression of EBER 1–2 mRNAs was demonstrated in the 8 tumors examined, while LMP-1 protein was expressed in 4/8 of the studied cases. Disease stage was III in 4 and IV in 6 patients. Time from the onset of symptoms to diagnosis ranged from 4 to 24 weeks (mean 8 weeks). All patients received preradiation chemotherapy and radiotherapy, and 5/10 received postradiation chemotherapy due to either resistant or advanced disease. In 9/10 patients, complete locoregional control was achieved. In addition to chemotherapy and radiotherapy the latest patient of this series was treated with recombinant IFN-β (105 IU/Kg iv 3 times a week) for 6 months and at 18 months remains in continuous complete remission. One patient was lost to follow-up 3 years after cessation of treatment while remaining in complete remission. Of the remaining 9 patients, 7 are alive for a median follow-up of 54 months (range 18–186); 5/7 are free of disease, and 2/7 are with disease but stable. The median time for first relapse was 17 months. The data confirm the good results of combined chemo-radiotherapy treatment for high-risk NPC in young patients. The documented EBV latency underlying this tumor, which possibly critically mediates its pathogenesis, justifies the use of biological modifiers with antiviral and immunoregulatory activity, like the IFNs, which may offer better therapeutic results in the future.

Testicular microlithiasis in siblings: clinical implications

Testicular microlithiasis is a relatively uncommon condition in children. It is characterized by the presence of microcalcifications within the testicular parenchyma. Although it is a benign finding, underlying diseases and other conditions must be ruled out because testicular microlithiasis has been found in association with both benign and malignant lesions in the testes and other tissues. We present two brothers with testicular microlithiasis, and highlight the prevalence, natural history, associated malignant conditions and follow-up recommendations of children diagnosed with testicular microlithiasis.

Metastatic angiomatoid fibrous histiocytoma of the scalp, with EWSR1-CREB1 gene fusions in primary tumor and nodal metastasis.

Angiomatoid fibrous histiocytoma is a rare soft tissue tumor of intermediate biologic potential, predominantly arising in superficial extremities of children and young adults. Less than 5% metastasize. We describe a case of angiomatoid fibrous histiocytoma in the scalp of an 8-year-old boy, which metastasized to a postauricular lymph node 3 years after primary tumor excision. Histologically, primary and metastasis comprised nodules of bland ovoid cells, with primary additionally showing hemorrhagic cavities, fibrous capsule, and lymphoplasmacytic inflammation. Both strongly expressed desmin, with focal epithelial membrane antigen. Reverse transcription-polymerase chain reaction showed EWSR1-CREB1 fusion transcripts in both primary and metastasis. This is, to our knowledge, the first description of genetically proven metastatic angiomatoid fibrous histiocytoma. Angiomatoid fibrous histiocytoma can mimic both benign and malignant lesions, and although most behave indolently, it is important to recognize their metastatic potential.

Hepatitis C Treatment Concomitant To Chemotherapy As “salvage” Therapy In Children With Hematologic Malignancies

In patients with malignancies, chronic hepatitis C reactivation or severe flare is uncommon and antiviral treatment is deferred mainly due to underlying bone marrow and immune suppression. We report the use of antiviral treatment concomitantly to chemotherapy in 3 children with hematologic malignancies, chronic hepatitis C, and significant liver dysfunction.