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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.

Background: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (≤12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS)., Methods: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgene ™ blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures., Results: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up., Conclusions: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted., (© 2018 Wiley Periodicals, Inc.)

Background: Recently biosimilars of granulocyte-colony-stimulating factor (G-CSF) became available for prophylaxis and treatment of postchemotherapy neutropenia and for mobilization of peripheral blood CD34+ cells for either autologous or allogeneic hematopoietic stem cell transplant. Most of the data on the mobilization efficacy and safety of biosimilar G-CSF are from adult patients, whereas no data are available in pediatric patients., Study Design and Methods: This was a retrospective study on cases treated at three Italian pediatric transplant centers, from January 2011 to October 2013. Data were collected on all children undergoing first peripheral blood stem cell (PBSC) mobilization after stimulation with biosimilar G-CSF and chemotherapy. The results were compared with a historical control group., Results: Twenty-nine children underwent mobilization with biosimilar G-CSF. Peak peripheral blood CD34+ cell count of 20 × 10(6) /L was achieved in 90% of patients, with a median value of 71 × 10(6) /L. Eighty-three percent reached the desired target (CD34+/kg) dose. The median number of collected CD34+ cells was 10 × 10(6) /kg (range, 4.8 × 10(6) -68.8 × 10(6) /kg). No difference was observed in comparison with historical control group mobilized with originator filgrastim. Moreover, no major and/or unexpected side effects were reported., Conclusion: Biosimilar G-CSF resulted as effective and safe as originator filgrastim molecule in mobilizing PBSCs in children, with the advantage of a reduced cost., (© 2014 AABB.)

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.

Background: A mobile clinical pathology laboratory (MoLab) was designed, outfitted and evaluated to improve the turnaround time (TAT) of laboratory tests performed in patients who receive follow-up care at home., Methods: Full blood counts (FBCs), basic clinical biochemistry tests on blood and urine, and basic coagulation and blood gases were measured using bench-top laboratory analyzers to perform point-of-care tests in a mobile setting. The quality of the results was evaluated on the instruments both while the vehicle was at rest and following movement during the course of routine activity., Results: The equivalence of the values produced by the point-of-care testing (POCT) and central laboratory (CL) measurement procedures was demonstrated and remained stable after movement in city traffic. The TATs ranged from a few minutes for FBCs to <20 min for extended clinical biochemistry tests., Conclusions: During the first 6 months of activity, the MoLab assured the provision of laboratory results for home care patients in a matter of minutes. This approach not only allowed for real-time modifications in therapy but also reduced the number of second visits by the home care medical team. Point-of-care tests performed on the MoLab were significantly more expensive than the same tests performed in the CL. However, the savings in patient hospitalization expenses and the reduced costs resulting from fewer second daily visits completely offset the costs of using the MoLab during the first 6-month pilot phase.

Background: Peripheral blood stem cells (PBSCs) are the preferred source in autologous transplantation. We assessed prospectively the efficacy of mobilization in pediatric patients and risk factors associated with its failure., Study Design and Methods: Patients, aged 0 to 17 years, needing a first collection of PBSCs for autologous stem cell transplantation were eligible. The study period was from July 2008 to September 2010. A blood peak of fewer than 20 × 10(6) CD34+ cells/L was used as the cutoff to define a poor mobilizer., Results: A total of 145 patients, 57% male (82) and 43% female (63), with a median age of 7 years, affected by solid tumor, 79% (114), and acute leukemia or lymphoma, 21% (31), were enrolled. Granulocyte-colony-stimulating factor used was filgrastim in 69%, lenograstim in 26%, and pegfilgrastim in 5% of patients. A total of 83% (121) of patients mobilized successfully, the median CD34+ count being 120 × 10(6) /L (range, 23 × 10(6) -1840 × 10(6) /L). A single leukapheresis procedure was sufficient to achieve the target CD34+ cell dose in 82% (99/121) of patients. Among 24 poor mobilizer patients, 15 underwent a second mobilizing course and nine required a marrow harvest. Factors associated with poor mobilization were metastatic disease and relapse. Among 99 patients who underwent autologous stem cell transplantation, the median times to neutrophil and platelet engraftment and of hospitalization were longer by 2, 12, and 6 days in poor versus good mobilizer group., Conclusions: In pediatric patients undergoing a first mobilization, the incidence of poor mobilization was 17%. Failure of mobilization resulted in an increase in health costs and a longer hospitalization for those who underwent autologous stem cell transplantation., (© 2012 American Association of Blood Banks.)

Purpose: To review event-free (EFS) and overall survival (OS) from publications describing outcome for children with relapsed Wilms' tumour. Comparisons are made between those receiving myeloablative high dose chemotherapy with autologous stem-cell rescue (HDT) and those not (NoHDT)., Materials and Methods: Relevant information was extracted from individual patient or summary data and 3-year EFS and OS rates established. These rates were combined in a weighted manner to derive hazard ratios (HRs)., Results: Nineteen publications were identified (5 HDT, 6 NoHDT, 8 both). Pooling all studies suggested an advantage to HDT with a hazard ratio (HR) for EFS of 0.87 (95% confidence interval (CI) 0.67-1.12) and 0.94 (0.71-1.24) for OS. A stratified analysis confined to studies that provided individual patient data on both HDT and NoHDT gave HRs of 0.83 (0.56-1.24) and 0.92 (0.59-1.41). Further, analyses of risk groups, defined by treatment and/or histology prior to first relapse, suggested a HR for EFS of 0.90 (95% CI 0.62-1.31) for those of high and 0.50 (CI 0.31-0.82) for the very high risk patients., Conclusion: The evidence suggests, although there are many caveats since the information summarised here is not from randomised trials, a great deal of uncertainty concerning the role of HDT in patients following relapse after treatment for their Wilms' tumour. For each risk group we propose a randomised trial comparing a standard with a more intensive therapy with specific choice of regimen tailored to the risk group (and co-operative groups) concerned. A synthesis of updated evidence from studies in this overview together with any emerging studies and future trial information will form the basis for future evidence-based clinical decision-making., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The results obtained by protocols for children with rhabdomyosarcoma (RMS) have improved in recent decades. Survival curves usually reach a plateau 3 years after the diagnosis, suggesting that long-term survival can be expected, but late events are known to occur. We analyzed the long-term results of the RMS 79 protocol to investigate the type and impact of such events., Procedure: From 1979 to 1987, 163 children with RMS diagnosed at 21 Italian institutions were registered. Each institution was contacted every year to record patients' status after the end of treatment. When patients were lost to follow-up, their status was checked by inquiring at the Registry Offices of the towns of residence and the cause of death or occurrence of second cancers was investigated by contacting the patients or their family by phone., Results: Overall, 16 patients had late events, that is, 7 tumor recurrences, 6 second tumors, and 3 deaths due to treatment-related complications. The overall survival rates dropped from 62.6 at 3 years to 52.8 at 20 years. By multivariate analysis, the characteristics influencing long-term survival were histology, tumor site and size, and IRS group. Factors predictive of any kind of late event were tumor site and IRS group., Conclusions: Major late events can significantly affect the long-term survival of children with RMS. Modern protocols should provide for a much longer follow-up than is usually considered to confirm the results achieved and enable possible correlations between primary treatment and late events to be investigated., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Limited data are available on the use of pegfilgrastim in pediatric patients as a mobilizing agent in association with chemotherapy., Study Design and Methods: This was a prospective, multicenter, Phase II study to evaluate the safety and efficacy of a single dose of 100 µg/kg pegfilgrastim in mobilizing peripheral blood stem cells (PBSCs) in pediatric patients. The primary endpoint of the study was the percentage of good mobilizers with pegfilgrastim (blood peak of CD34+ cells ≥ 20 × 10(6) /L). The results were compared with a historical control group., Results: Thirty of 36 recruited patients were classified as good mobilizers (83%). The median value of circulating CD34+ at leukapheresis was 143 × 10(6) /L (range, 20 × 10(6) -1988 × 10(6) /L). No significant adverse effects were associated with the use of pegfilgrastim and no patient was withdrawn from using the drug. A blood peak of 20 × 10(6) /L or more CD34+ was observed in 33 of 36 control patients (92%) and the median CD34+ count at leukapheresis was 158 × 10(6) /kg (range, 28 × 10(6) -4529 × 10(6) /kg; p = 0.7). No significant differences were found between the two groups in terms of toxicity or other variables of mobilization. As at October 2008, 23 patients of the pegfilgrastim group and 32 patients of the filgrastim group underwent autologous transplant. No significant differences were found in terms of early toxicity, myeloid recovery, and Day 100 survival., Conclusion: A single dose of 100 µg/kg pegfilgrastim was safe and effective for PBSC collection in pediatric patients. We suggest that these results support the use of pegfilgrastim for pediatric patients., (© 2011 American Association of Blood Banks.)

Treatment regimens for recurrent Wilms tumor (WT) are currently designed to include drugs that are not used during primary chemotherapy, using a risk-stratified approach. Therapy of recurrent disease depends on the nature of initial treatment, and of recognized prognostic indicators inherent in the primary tumor. Several highly effective chemotherapy regimens, including ifosfamide-carboplatin-etoposide, cyclophosphamide-etoposide and carboplatin-etoposide, are considered first treatment choice for recurrent disease. While intense-dose chemotherapy is uniformly accepted to treat high-risk recurrent WTs, the optimal therapy for standard-risk children has yet to be defined, owing to the small number of such patients and their relatively better prognosis compared with high-risk recurrences. Recurrent tumors among those defined as very-high risk are likely to develop chemoresistant disease, and novel therapeutic strategies will be necessary to cure these patients. Evidence on how to properly administer surgery and radiotherapy at relapse is more fragmentary. The authors have reviewed the available experiences concerning the treatment of recurrent WT, and have attempted to provide the most up-to-date recommendations regarding the optimal risk-based treatment for these patients.

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS)., Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages <14 years diagnosed at the Giannina Gaslini Children's Hospital, Genoa, between 1987 and 2004., Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages

We describe a single-center pediatric experience with 1 mg/kg/wk cidofovir without probenecid in 7 children with BK virus-associated hemorrhagic cystitis. Clinical improvement was observed in all cases, without adverse events, although significant reduction of urinary viral load was observed 2 weeks after the end of cidofovir in 5 out of 6 patients who completed the treatment.

Background: We evaluated an intensified chemotherapy strategy in children with Wilms tumor who relapsed with high-risk features., Procedures: From January 2001 to June 2006, we treated 20 consecutive children with reinduction chemotherapy (using ifosfamide/carboplatin/etoposide in 15/20 cases), with (n = 15) or without (n = 5) subsequent high-dose chemotherapy and hematopoietic stem cell support, surgery where feasible, and radiation therapy. The median time to relapse was 10 months after nephrectomy. All but two children initially received doxorubicin as first-line therapy., Results: All patients were assessed for outcome: 13 are currently alive, 12 of them in remission a median 25 months since their relapse, one with progressing tumor. The treatment was unsuccessful in eight children: the disease progressed during reinduction in three, and relapsed in five. There was one toxic death. All transplanted patients engrafted to a neutrophil count >0.5 x 10(3)/microl after a median 11 days, and to an unsustained platelet count >25,000/microl after a median of 13 days. Three-year disease-free and overall survival rates were 56 +/- 12% and 55 +/- 13%, respectively. Neither recurrence within 12 months of nephrectomy nor extra-lung recurrence negatively affected outcome. A survival advantage was demonstrated in patients without disease evidence prior to transplant., Conclusion: A disease-free survival rate nearing 50% is a realistic target in children with high-risk recurrent Wilms tumor. The benefit of autologous hematopoietic stem cell transplantation for consolidation deserves to be investigated in a randomized, controlled study., ((c) 2008 Wiley-Liss, Inc.)

Background: Parameningeal rhabdomyosarcoma (PM-RMS) is a rare, highly malignant pediatric tumor arising from locations adjacent to the meninges, from where it can spread intracranially., Procedure: We reviewed 109 children with non-metastatic PM-RMS enrolled in the Italian RMS79, RMS88 and RMS96 protocols over a 24-year period. All patients received intensive chemotherapy and standard or hyperfractionated and accelerated radiotherapy. Some had delayed surgery., Results: Five-year overall survival rose from 40% in the RMS79 to 72% in the RMS88 and RMS96 protocols (P = 0.01), where more intensive chemotherapy and hyperfractionated accelerated radiotherapy (HART) was used. Delayed surgery after initial treatment was statistically associated with a better prognosis. Unfavorable tumor characteristics for RMS arising in other sites, for example, histology, invasiveness or node involvement, did not predict outcome for PM-RMS., Conclusion: Outcome in PM-RMS patients enrolled in three consecutive Italian protocols has progressively improved, as a result of intensive chemotherapy, delayed surgery and, possibly, HART, though improved imaging and radiotherapeutic tools may have had a role as well., ((c) 2007 Wiley-Liss, Inc.)

CEP is a rare inborn error of porphyrin-heme synthesis. Clinical manifestations can range from mild to severe and include erythrodontia, reddish-colored urine, and hemolytic anemia that can be mild or severe and may result in splenomegaly. Completely avoiding exposure to the sun is crucial. Attempts to reduce erythropoiesis and to lower circulating porphyrin levels by means of erythrocyte transfusions have been successful in reducing the expression of the disease. However, the complications of a chronic transfusion regimen are potentially severe. Successful bone marrow transplantation has been reported in CEP. We report a case of successful bone marrow transplantation and prolonged follow-up in an adolescent CEP patient.

Purpose: Contribution of peripheral blood stem cell (PBSC) contaminating tumor cells to subsequent relapse and overall survival of neuroblastoma patients remains controversial., Experimental Design: Neuroblastoma cell contamination of 27 PBSC harvests from stage IV neuroblastoma patients was assessed by quantitative RT-PCR for both tyrosine hydroxylase (TH) and GD2 synthase (GD2-s). The effect of PBSC contamination on survival was then analyzed., Results: Seven PBSC tested negative for both markers; 19 were positive for GD2-s, 6 for TH, with 5 positive for both. Survival of the 20 patients with positive PBSC did not differ from that of the patients with negative PBSC (log-rank test, P = 0.134 and 0.218 for event-free survival and overall survival, respectively). By considering the TH and GD2-s results independently, a borderline (P = 0.053) negative effect on event-free survival was observed in patients reinfused with GD2-s-positive PBSC. When the status at transplant was taken into account, only the event-free survival of the patients rescued when in complete remission with GD2-s-negative PBSC was better, although not significantly, than that of patients infused with GD2-s-positive PBSC., Conclusions: Our results obtained in a small cohort of homogeneously treated stage IV patients suggest that patient survival is not affected by PBSC contamination with the exception of a borderline negative effect on event-free survival in patients rescued when in complete remission.

The long-term evolution to intractable epilepsy in children treated with cyclosporine administered for graft-versus-host-disease after hematopoietic stem cell transplantation was evaluated. In a group of 185 children treated with cyclosporine after bone marrow transplantation, 15 (8%) presented with acute seizures that were generalized in 7 and focal in 7 and had absence status in 1. Electroencephalography (EEG) and neuroimaging showed predominant abnormalities in the occipital regions. One patient died shortly after the seizure; in seven cases, seizures remitted, whereas relapses were observed in seven others. After the first year, seizures persisted chronically in four cases and evolved to intractable epilepsy. Focal temporal epilepsy was diagnosed in three cases, whereas in the fourth case, a multifocal epilepsy was observed. Magnetic resonance imaging (MRI) detected mesial temporal sclerosis in all of these cases. The risk factors associated with evolution to epilepsy included lower age at transplantation (3-5 years), more than one relapsing seizure in the first year after transplantation, and longer treatment with cyclosporine. Not only can cyclosporine cause acute central nervous system toxicity, it can also determine intractable epilepsy associated with mesial temporal sclerosis.

Newly diagnosed patients with acute graft-versus-host disease (GvHD, grades I-IV; n = 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day +5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P = .009), and the 5-year survival is 53% and 35% (P = .007). Nonresponders on day +5 (n = 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n = 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n = 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group. In conclusion, 5 days of prednisolone as first-line therapy of acute GvHD identifies patients with different risk of TRM, and second-line therapy with a combination of 6MPred + ATG does not improve patient outcome, compared with 6MPred alone.

The treatment of brain tumors in infants (children <3 years of age) in the last 15-20 years has been a special field of interest for clinical investigation and research, since infants affected by brain tumors are an ideal experimental group of patients. New treatment strategies (conventional, myeloablative and intraventricular chemotherapy) have been tested on these patients in an effort to avoid or delay conventional irradiation. The amazing amount of knowledge that has been acquired from neuropathological and biological studies, as well as from the first generation treatment baby protocols, which were designed between 1985 and 2000, is now leading to a new approach whereby treatment strategies are tailored to the patient's clinicopathological features.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only cure for juvenile myelomonocytic leukaemia (JMML), but relapse remains the major cause of failure. A second transplant may be considered a way to induce the graft vs. leukaemia effect in patients who relapse after their first HSCT. We describe a 7-month-old girl with JMML who relapsed after a first, related allo-HSCT, and who again relapsed 8 months after the second transplant, despite discontinuation of immusuppressive therapy. She underwent a third allogeneic transplant from another related donor. At the time of this report the patient is in complete remission 26 months after the third transplant. We suggest that a third allo-HSCT may be taken into consideration for JMML patients who experience relapse, even after two previous transplants.

Purpose: To describe long-term late consequences in children who received total body irradiation (TBI) for hematopoietic stem cell transplantation 10 years earlier., Methods and Materials: A cohort of 42 children treated with TBI between 1985 and 1993, still alive at least 10 years after fractionated TBI (FTBI), was evaluated. Twenty-five patients received FTBI at 330 cGy/day for 3 days (total dose 990 cGy), whereas 17 children were administered fractions of 200 cGy twice daily for 3 days (total dose 1200 cGy). Twenty-seven patients received autologous and 16 allogeneic hematopoietic stem cell transplantation. Median age at TBI was 6.3 years, and 18.4 years at most recent follow-up., Results: Cataract was diagnosed in 78% of patients after a median of 5.7 years. Hypothyroidism was detected in 12%, whereas thyroid nodules were observed in 60% of our population after a median interval of 10.2 years. Patients treated with 990 cGy developed thyroid nodules more frequently than those treated with 1200 cGy (p = 0.0002). Thyroid carcinoma was diagnosed in 14% of the total population. Females who received FTBI after menarche more frequently developed temporary ovarian dysfunction than those treated before menarche, but cases of persistent ovarian dysfunction did not differ between the two groups. Indirect signs of germinal testicular dysfunction were detected in 87% of males. Restrictive pulmonary disease was observed in 74% of patients. Osteochondroma was found in 29% of patients after a median interval of 9.2 years. This latter complication appeared more frequently in patients irradiated before the age of 3 years (p < 0.001)., Conclusions: This study shows that late effects that are likely permanent, although not fatal, are frequent in survivors 10 years after TBI. However, some of the side effects observed shortly after TBI either disappeared or remained unchanged without signs of evolution. Monitoring is recommended to pursue secondary prevention strategies and counseling on family planning.

Background: Immune reconstitution after hematopoietic stem-cell transplantation (HSCT) occurs gradually. Thus, a variable period of immunodeficiency may be present, leading to immunomediated complications, such as graft-versus-host disease (GVHD) and opportunistic infections., Methods: To better understand the kinetics of B-cell repertoire reconstitution in children, 49 pediatric patients were analyzed before and after transplantation by immunoglobulin (Ig) HCDR3 fingerprinting, which is a molecular technique that analyzes one of the hypervariable segments of the Ig heavy chain, which provides the amino acid residues that are essential to interact with antigens., Results: In healthy donors, the CDR3 fingerprinting profile shows 16 to 20 bands, and each band corresponds to a particular length of CDR3. This situation is considered polyclonal. Patients analyzed just after transplantation show strong oligoclonality, because only a few CDR3 bands are detected within the first 3 to 6 months., Conclusions: The authors' data show a significant lag in diversification of the B-cell repertoire, which reaches the polyclonal situation of normal healthy donors approximately 6 months after HSCT. This period may vary depending on the type of transplant (autologous vs. allogeneic) and on the immunosuppressive therapy related to GVHD.

Gastrointestinal acute graft-versus-host disease (GI-aGvHD) is still a common complication of allogeneic stem cell transplantation. Surgical management is an unusual approach, reserved for patients with intestinal occlusion, severe profuse rectal bleeding, or both. The authors describe a child with severe GI-aGvHD who did not respond to common immunosuppressive drugs and procedures and therefore underwent subtotal colectomy due to untreatable rectal bleeding. The bowel resection was followed by three "surgical looks" for occlusive intestinal episodes. In the end, a cholecystectomy for cholelithiasis was performed. The patient is still alive 41 months after stem cell transplantation, and although the terminal ileostomy is not closed yet, his quality of life is good. This experience suggests that surgery can be performed on children with severe, unresponsive GI-aGvHD.

Abdominal irradiation, especially if associated with doxorubicin administration, increases the risk of a secondary malignant neoplasm (SMN) after treatment of nephroblastoma. Secondary malignant salivary tumors are rare and usually occur in patients with previous cranial irradiation. The authors describe the case of a parotid mucoepidermoid carcinoma arising 13 years after diagnosis of nephroblastoma. This patient showed no characteristics reported in the literature as statistically significant for the development of an SMN. The authors believe that long-term, regular clinical examination is necessary even in patients at low risk of developing an SMN.

Kostmann syndrome (KS) is an inherited hematological disorder characterized by an absolute neutrophil count (ANC) <0.2 x 109/L and life-threatening bacterial infections. Granulocyte-colony stimulating factor (G-CSF) makes it possible to reach an ANC of 1.0 x 109/L and consequently to reduce significantly the occurrence of severe infections. Absence of response to G-CSF, G-CSF receptor mutation, and leukemic transformation are absolute indications to perform hematopoietic stem cell transplantation (HSCT). Pulmonary mycosis does not represent an absolute contraindication to bone marrow transplantation (BMT), although a relapse rate of 30-50% has been reported, despite adequate medical and surgical treatment. Mycotic pneumonia recurrence shows a mortality rate above 80%, especially in the presence of persisting immunosuppression. We report on a KS patient with long-lasting fungal pneumonia who developed myelodysplasia and subsequent acute myeliod leukemia (AML) conversion resistant to antiblastic therapy. Despite surgical excision and secondary prophylaxis, recurrence of the pulmonary lesion occurred prior to the unrelated HSCT. In spite of these poor prognostic characteristics, outcome was uneventful and the patient is alive and well in continuous complete remission with no signs of fungal infection.

Purpose: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma., Patients and Methods: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two., Results: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively., Conclusion: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

Background and Objectives: Hematopoietic stem cell transplantation (HSCT) is associated with profound neutropenia and significant morbidity and mortality. To evaluate the safety and efficacy of non-glycosylated recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in accelerating myeloid recovery and its influence on infections, supportive therapy, and transplant-related mortality we carried out a randomized study in pediatric patients receiving HSCT., Design and Methods: Two hundred and twenty-one consecutive children, recipients of an allogeneic or autologous bone marrow (BM) or peripheral blood progenitor cell (PBPC) transplant, were randomized to either receive rHuG-CSF 10 mg/kg (n=110) or not (n=111)., Results: Myeloid engraftment was faster in the treated arm (14 vs 20 days, p=0.0001). Neutrophil recovery was accelerated both in the BM subgroups (allogeneic and autologous, p=0.002) and in the PBPC group (p=0.0005). All the other evaluated variables showed an advantage in favor of rHuG-CSF treated patients that was significant for platelet transfusion independence and time to discharge (p=0.02 and p=0.04, respectively) only in the BM subgroup., Interpretation and Conclusions: We conclude that faster neutrophil recovery in BM recipients receiving rHuG-CSF led to clinical benefits, while, in the PBPC subgroup, it did not translate into clinical advantages.

In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBTs) or bone marrow transplants, 541 children with acute leukemia (AL) transplanted with umbilical cord blood (n = 99), T-cell-depleted unrelated bone marrow transplants (T-UBMT) (n = 180), or nonmanipulated (UBMT) (n = 262), were analyzed in a retrospective multicenter study. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference between the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMTs (P <.001). Other significant differences were observed in pretransplant disease characteristics, preparative regimens, graft-versus-host disease (GVHD) prophylaxis, and number of cells infused. Nonadjusted estimates of 2-year survival and event-free survival rates were 49% and 43%, respectively, in the UBMT group, 41% and 37% in the T-UBMT group, and 35% and 31% in the UCBT group. After adjustment, differences in outcomes appeared in the first 100 days after the transplantation. Compared with UBMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR] = 0.37; 95% confidence interval [95CI]: 0.27-0.52; P <.001), increased 100 day transplant-related mortality (HR = 2.13; 95CI: 1.20-3.76; P <.01) and decreased acute graft-versus-host disease (aGVHD) (HR = 0.50; 95CI: 0.34-0.73; P <.001). T-UBMT recipients had decreased aGVHD (HR = 0.25; 95CI: 0.17-0.36; P <.0001) and increased risk of relapse (HR = 1.96; 95CI: 1.11-3.45; P =.02). After day 100 posttransplant, the 3 groups achieved similar results in terms of relapse. Chronic GVHD was decreased after T-UBMT (HR = 0.21; 95CI: 0.11-0.37; P <.0001) and UCBT (HR = 0.24; 95CI: 0.01-0.66; P =.002), and overall mortality was higher in T-UBMT recipients (HR = 1.39; 95CI: 0.97-1.99; P <.07). In conclusion, the use of UCBT, as a source of hematopoietic stem cells, is a reasonable option for children with AL lacking an acceptably matched unrelated marrow donor.

In the last two decades autologous hematopoietic stem cell transplantation (HSCT) has been increasingly used in the treatment of several poor risk solid tumors of childhood. Examples are recurrent or resistant cancers, metastatic presentation at diagnosis, incomplete surgical resection, unfavorable histologic and biological features. Results from the Children's Cancer Group randomized trial confirm the data from retrospective studies which reported the superiority of HSCT over standard chemotherapy for neuroblastoma. Several retrospective analyses support the use of HSCT in Ewing's sarcoma and in some brain tumors. No evidence of utility has been reported for rhabdomyosarcoma. The most widely utilized source of stem cells is peripheral blood, while there are conflicting data regarding the use of total body irradiation and purging of stem cells.

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)

Thirty-one fiberoptic bronchoscopies and BAL performed within 4 days after the appearance of pulmonary infiltrates in 28 children who received BMT were reviewed. A causative agent was identified in 67% of patients with diffuse infiltrates (Cytomegalovirus in 8 cases, Pneumocystis carinii in 4) and in 31% of those with localized infiltrates (Aspergillus in 2, bacteria in 2). No relevant side effect was reported. The results obtained from cytological and microbiological testing provided relevant informations for the management of most cases, regardless to the identification of a specific pathogen. We conclude that BAL is a safe diagnostic procedure that should be considered early after the onset of pulmonary complications in BMT recipients.

Twenty-three children with congenital or acquired hematological disorders and 8 children with solid tumors received filgrastim at a dose of 5 micrograms/Kg by a daily 2-hour infusion following allogeneic (18 cases) or autologous (13 cases) bone marrow transplantation (group I). The results were compared with those of a disease, age and type of transplant matched cohort of 31 children treated in the same institution who did not receive the growth factor (group II). Filgrastim treatment was started within 24 hours of completion of the marrow infusion and lasted for 21 consecutive days or until the absolute neutrophil count reached 10 x 10(9)/l for 3 consecutive days. Twelve variables were evaluated prospectively in Group I and retrospectively in Group II. Myeloid reconstitution with peripheral granulocyte counts > 0.5 x 10(9)/L was achieved at a median time of 13 days in group I and of 14 days in group II (p = ns). Platelet recovery to > 50 x 10(9)/L was slower in group I (43 vs 30 days: p < .05). Median time to last platelet and red blood cell infusion was higher in group I (33 vs 18 days for platelets, p < .05; 45 vs 25 for red blood cells, p < .005). Filgrastim-treated children undergoing autologous BMT had fewer days of fever (6 vs 10 days, p < .05). There was no significant toxicity ascribable to filgrastim. Clinically and microbiologically documented infections, days of antibiotic therapy, duration of total parenteral nutrition and median time in hospital were similar in both groups. We conclude that in children undergoing autologous BMT for malignancies, filgrastim significantly reduced the number of febrile days. Similar benefits were not observed in children undergoing allogeneic BMT. Children receiving filgrastim experienced a delay in erythrocyte and platelet recovery. A prospective randomized study is required to better define the cost-benefit of filgrastim in children undergoing autologous or allogeneic BMT.

The role of autologous bone marrow transplantation (ABMT) in childhood ALL after an isolated extramedullary (IE) relapse is controversial. Between December 1984 and November 1995, 52 children underwent ABMT because of an IE relapse. The data were stored in the AIEOP-BMT Registry. Thirty four children were transplanted in 2nd CR; eighteen > 2nd CR. The median duration of 1st CR was 24 (range 3-69) and 18 (range 3-59) months, respectively. The median interval from last CR to ABMT was 6 (range 1-28) and 3 (range 1-81) months, respectively. The 5 year EFS for patients transplanted in 2nd CR was 67.7%, while the 3 year EFS for patients in > 2nd CR was 16.7%. In conclusion, ABMT was an effective treatment in early IE relapse only if performed in 2nd CR.

This study reports a large cooperative experience in myeloablative therapy and bone marrow rescue undertaken to define better the outcome of children with disseminated neuroblastoma after megatherapy. Between 1984 and 1993, 135 children underwent myeloablative therapy with bone marrow transplantation (BMT) in nine Italian Centres. One hundred and seventeen children received unpurged autologous BMT, five allogeneic BMT and 13 peripheral blood progenitor cells as rescue. Of these 135 children, 57 were in 1st CR, 11 in 2nd or subsequent CR, 42 in 1st PR, and 25 had more advanced disease. Twelve children (9%) died of toxicity, 86 relapsed or progressed at 1-68 months (median 7 months) and 80 of these subsequently died of progressive disease. Forty-three children are still alive with 37 in continuous remission at a median of 65 months (30-123 months) after BMT. Overall and disease-free survival at 8 years are 28.5% (s.e. 4.3) and 26% (s.e. 4), respectively. Disease-free survival is 34.6% (s.e. 6.7) for the patients grafted in 1st complete remission, 23.6% (s.e. 6.6) for patients grafted in 1st partial remission, 36.4% (s.e. 14.5) for patients grafted in 2nd or subsequent CR, and 8% (5.4) for patients with advanced disease. We conclude these data confirm that early toxicity of myeloablative therapy is manageable and that myeloablative therapy with bone marrow rescue may contribute to an improved long-term survival of children with disseminated neuroblastoma but the objective of cure of all patients remains distant.

We have examined data reported in the AIEOP-BMT Registry in order to determine the incidence, causes and risk factors for fatal pneumopathy after bone marrow transplantation in a pediatric population. Overall, in the Registry 1134 children are reported, 531 of whom received an autologous BMT, 468 allomatched BMT, eight syngeneic, 75 mismatched, 29 unrelated and 23 peripheral blood progenitor cells as rescue after myeloablative therapy in the period 1983-1993. 198 patients out of 1134 (17%) died of transplant-related causes and 86 of them died of pulmonary complications: 12 were recorded as fungal pneumonia, eight bacterial, four bacterial and fungal, six viral, two Pneumocystis carinii pneumonia, 12 ARDS, 13 interstitial, 29 unspecified 'respiratory failure'. Multivariate analysis showed that only type of graft and presence or absence of Pneumocystis carinii prophylaxis influence the cumulative incidence of fatal pneumonia. After autologous BMTs only Pneumocystis carinii prophylaxis was significant in multivariate analysis. After allogeneic BMTs multivariate analysis showed that BMT type, Pneumocystis carinii prophylaxis and GVHD grade seem to maintain their influence on cumulative incidence of fatal pneumonia. After BMT the incidence of fatal pneumopathy in children is low (9%), but it represents the second cause of death after primary disease. Pneumocysti carinii prophylaxis should also be given after autologous BMT.

Authors report a case of P. carinii pneumonia in a child with 5% CD4 lymphocytes (absolute number 5/microliters) after autologous bone marrow transplantation followed by pulmonary irradiation. Serial evaluation of CD4 lymphocyte count or percentage or, at least, detection of significant and persistent lymphopenia could be useful for detecting a high risk of developing P. carinii pneumonia.

The European BMT Solid Tumour Registry (EBMT-STR) received reports from 21 European transplant centers on 63 patients (50 Ewing's sarcomas and 13 peripheral neuroectodermal tumours) in first (n = 32) or second CR (n = 31) consolidated with megatherapy and BM and/or PSC rescue between December 1982 and November 1992. There were 31 males and 32 females with a median age of 12 years (range 1-30 years) at megatherapy. The median follow-up time since megatherapy is 4 years (range 1 month to 10 years), Thirty-two patients with metastatic disease at diagnosis (22 had metastases to the bone and/or bone marrow) and consolidated in CR1 reached an actuarial event-free survival (EFS) of 21% at 5 years. Thirty one patients in CR2 achieved an actuarial EFS of 32% at 5 years. Favourable outcome was limited to relapse patients with localised disease at initial diagnosis. Distant relapse had a more favourable prognosis than local failure. Analysis of the different megatherapy strategies could not identify a significantly superior approach, nor is there convincing evidence in favour of double graft procedures. From the above results it appears that consolidation treatment by megatherapy contributes to improved EFS rates in high-risk patients compared with historical experience. Major questions for the future to be addressed prior to randomised studies include agreement on the definition of high-risk patients and the most efficient megatherapy procedure.