Showing papers in "Pediatric Blood & Cancer in 2004"

Liver transplantation for hepatoblastoma: Results from the International Society of Pediatric Oncology (SIOP) study SIOPEL‐1 and review of the world experience

Abstract: BACKGROUND: For hepatoblastoma (HB) that remains unresectable by partial hepatectomy after chemotherapy, total hepatectomy with orthotopic liver transplantation (LTX) has been advocated as the best treatment option. The role of LTX in the overall management of HB is still, however, unclear. PROCEDURE: The results of LTX from the first study of HB by the International Society of Pediatric Oncology, SIOPEL-1, were analyzed. In addition, the world experience of LTX for HB was extensively reviewed. Twelve patients in the SIOPEL-1 study underwent a LTX. Median (range) follow-up at Dec. 31, 2001 was 117 months (52-125) since LTX. RESULTS: Overall survival at 10 years post-LTX was 85% for the seven children who received a "primary LTX" and 40% for the 5 children who underwent a "rescue LTX" after previous partial hepatectomy. In the world experience (147 cases), the overall survival rate at 6 year post-LTX was 82% for 106 patients who received a "primary LTX" and 30% for 41 patients who underwent a "rescue LTX." Multivariate analysis of patients undergoing primary LTX showed that only macroscopic venous invasion had a significant impact (P-value: 0.045 with a hazard ratio of 2.96) on overall survival. CONCLUSIONS: Orthotopic LTX has added a new dimension to the treatment of HB unresectable by partial hepatectomy. Because of the rarity of the disease and to optimize results, children with extensive HB should be treated in centers with surgical expertise in pediatric major liver resection and LTX, in close collaboration with pediatric oncologists, radiologists, and histopathologists.

Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group.

Abstract: Background Permanent consequences (PC) are often described among subjects with Langerhans cell histiocytosis (LCH) but data on the real incidence are scarce. Within the Histiocyte Society (HS), and in order to design a definitive late effects study, a retrospective survey was organized to describe the prevalence of PC among long-term survivors of LCH. Methods Nine institutions contributed with their LCH patients having a minimum follow-up of 3 years. Information was collected on their disease-history, and on type and date of onset of any PC. Because of the retrospective type of this study, it was accepted that each institution might have used different criteria to assess PC. Results One hundred eighty-two subjects were registered and in 95 (52%) at least 1 PC was reported. For some specific PC (e.g., anterior pituitary dysfunction) information was too scarce to provide reliable data. PC were more frequent among subjects with multisystem (MS) disease (71%), compared to those with single system (SS) disease (24%); P < 0.0001. The most frequently reported PC were diabetes insipidus (DI) (24%) orthopedic abnormalities (20%), hearing loss (13%), and neurological consequences (11.0%). Analysis of cumulative risk showed that some types of PC may become manifest more than 10 years from diagnosis. Conclusions This survey on selected cases of LCH survivors has confirmed that late sequels are frequent, and that they are even more common among those with MS LCH. Our findings highlight the need for long-term and patient-oriented follow-up in children with LCH. © 2004 Wiley-Liss, Inc.

Effects of physical therapy intervention for children with acute lymphoblastic leukemia

Abstract: Background The purpose of this study was to examine the effects of physical therapy intervention in children with acute lymphoblastic leukemia (ALL). Procedure Twenty-eight children aged 4–15 years were randomly assigned to an intervention or control group. The intervention group received five sessions of physical therapy and was instructed to perform an individualized home exercise program consisting of ankle dorsiflexion stretching, lower extremity strengthening, and aerobic exercise. Results After 4 months children who received physical therapy intervention had significantly improved ankle dorsiflexion active range of motion and knee extension strength (P < 0.01). Differences were not found between the two groups for any of the other dependent variables. Conclusions Physical therapy intervention for children with ALL receiving maintenance chemotherapy improved two body functions important for normal gait. Physical therapy programs initiated earlier in treatment and with greater emphasis on endurance activities may also improve stamina and quality of life (QOL). © 2003 Wiley-Liss, Inc.

Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Abstract: Background Although age <1 year at diagnosis has been associated with a worse prognosis in rhabdomyosarcoma (RMS), the relationship of age at diagnosis to clinical presentation and outcome has not been evaluated carefully. We reviewed data from recent Intergroup Rhabdomyosarcoma Study Committee (later called Group, IRSG) trials to examine this relationship in order to estimate prognosis more accurately and further refine treatment. Procedure We used data from IRS-III, -IV Pilot, and -IV (1983–97, N = 2,343) to study the relationship of patient age with clinical features and prognosis in a large cohort of patients treated with contemporary therapy. Results We showed that, after adjusting for important prognostic factors, age was an independent risk factor for treatment failure and patients could be classified into three failure-risk categories based on age (i.e., 10 years). Infants and adolescents were more likely to have unfavorable features, including alveolar or undifferentiated tumors and advanced Group and Stage, and also had significantly poorer failure-free survival (FFS) than did children aged 1–9 (53 and 51% vs. 72%, P < 0.001). Although there was a difference in FFS among age categories, there was no evidence that age influences outcome within the three categories. Conclusions Since age relates independently to outcome after adjustment for known risk factors, it is likely that other factors, including perhaps patients' tolerance of protocol-specified therapy, explain this relationship. © 2003 Wiley-Liss, Inc.

Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols.

Abstract: Background Germ cell tumors (GCTs) constitute a heterogeneous group of tumors that significantly vary with respect to their clinical presentation and biology. The objective of this analysis was to analyze a large population-based pediatric cohort of GCTs and to evaluate the parameters age, sex, site of the tumor, histology, and potential correlations between these parameters. Procedure Between 1981 and 2000, 1,442 patients were prospectively enrolled onto the German protocols for testicular and non-testicular GCTs. Tumors were histologically classified according to the WHO. Results We observed a bimodal age distribution with a first peak during infancy and a second after the onset of puberty. At birth, almost all tumors were teratomas, sometimes with microfoci of yolk sac tumor, which on the other hand, was the predominant histology during childhood. After the onset of puberty, germinomatous GCTs represented the most frequent histological subtype, and malignant non-germinomatous GCTs often presented as mixed tumors with choriocarcinoma and embryonal carcinoma components. During infancy, non-gonadal GCTs accounted for the majority of GCTs, while after the onset of puberty, gonadal GCTs predominated. Notably, among non-gonadal GCTs, there was a female predominance during childhood and a strong male predominance during adolescence. Conclusions Two separate groups of GCTs with distinct clinical features relevant for differential diagnosis and the diagnostic assessment can be distinguished. This observation correlates with genetic studies that reveal different genetic changes in childhood and adolescence GCTs. Further studies are needed to elucidate the molecular mechanisms of germ cell and GCT development that account for the age- and sex-dependent clinical manifestation. © 2003 Wiley-Liss, Inc.

Cancer incidence among children in France, 1990-1999.

Abstract: Background Cancer is the second most important cause of death for children aged less than 15 years in France, unintentional injuries being the leading cause. The aim of the present study was to estimate the incidence of childhood cancer from six Childhood Cancer Registries covering 32% of France. Procedure Incident cancer cases diagnosed between 1990 and 1999 in children (0–14 years) resident in the administrative areas covered by each Registry were included. Annual age-standardized rates (ASRs) were adjusted by the world population. The estimated annual percent change (EAPC) was used to measure trend towards changes in the annual age-standardized incidence rate. Results With 4234 registered cases, the ASRs per million children were 137.5 for all cancers combined, 42.3 for leukemia, 29.1 for central-nervous-system tumors, 15.6 for lymphomas, 14.1 for sympathetic-nervous-system tumors, and 9.1 for renal tumors. The ASR of all cancers combined was slightly higher in males (145.8 per million children) than in females (128.7 per million children) with an M/F ratio of 1.2. No significant incidence trend was observed, with an EAPC of +0.2% [IC 95% (−2.5; +3.0); P = 0.89]. Conclusions The estimated incidence rates are similar to those reported in previous studies in European and North American countries. These results will contribute to the development of National Registration of Childhood Cancer in France and support the national research program on childhood cancer. © 2004 Wiley-Liss, Inc.

Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine.

Abstract: Background Differentiated thyroid carcinoma (DTC) in childhood has a good prognosis despite a high incidence of relapse. The use of radioactive iodine (RAI) has not been well established. Procedure This is a review of 60 patients less than 21 years of age; mean follow-up was 14 years. Results Patients had a higher relapse rate with papillary thyroid carcinoma (PTC) than with follicular thyroid carcinoma (FTC): 24.5 vs. 9.1%. Compared with 997 patients with age ≥ 21, patients <21 years of age had a higher female to male ratio (7.6 vs. 3.9), higher incidence of nodal metastasis (45 vs. 28%), and lung metastasis (15 vs. 7.8%), and improved 10-year cause-specific survival (CSS) (98.3 vs. 89.5%). The 10-year rates of CSS, local-regional failure-free survival (LRFFS), and distant metastasis failure-free survival (DMFFS) for the young patients were 98.3, 79.3, and 90.7%, respectively. In patients with no distant metastasis at presentation, RAI improved 10-year LRFFS (71.9 vs. 86.5%; P = 0.04). At last follow-up, 10 of 12 patients (80%) with local-regional (LR) relapse and five of nine patients (55.6%) with distant metastasis were rendered disease-free. No patient has experienced a second malignancy. Conclusions Prognosis of DTC in young patients was good. Patients with LR relapse and distant metastasis had a high rate of remission after treatment. RAI treatment can reduce the rate of LR relapse in patients with no distant metastasis and result in complete remission in half of those with distant metastasis. No patient experienced a second malignancy. © 2003 Wiley-Liss, Inc.

Stature of young people with malignant bone tumors.

Abstract: Background Little is known about the aetiology of primary bone tumours. There have been conflicting reports relating to stature in young people with bone cancer. Patients We analysed height data at diagnosis for 364 patients with osteosarcoma and 356 patients with Ewing sarcoma registered on clinical trials run by the Medical Research Council (MRC) and the United Kingdom Children's Cancer Study Group (UKCCSG). Main Outcome Measures Height at diagnosis for each patient was standardised for age and sex compared to national reference data with a standard deviation score (SDS) calculated for each subject. Results Those with osteosarcoma were significantly taller than the general population (mean height SDS 0.2, P = 0.001). Patients with osteosarcoma of the femur were significantly taller than patients with other primary sites (mean height SDS 0.45 vs. −0.06, P = 0.0001). Overall those with Ewing sarcoma were not significantly taller than the general population (mean height SDS 0.09, P = 0.1), but children presenting under 15 years were taller (SDS 0.2, P = 0.004) whilst older patients were not (SDS −0.07, P = 0.4). In both osteosarcoma and Ewing sarcoma the mean age at diagnosis for females was significantly younger than for males. Conclusions This study suggests that tall stature and an earlier pubertal growth spurt may be important factors in the aetiology of both osteosarcoma and Ewing sarcoma. © 2003 Wiley-Liss, Inc.

Posttraumatic stress symptoms in adult survivors of childhood cancer

Abstract: Background. Previous research suggests that posttraurnatic stress disorder (PTSD) is present in survivors of childhood cancer. The aim of the current study was to explore posttraurnatic stress symptoms in a sample of young adult survivors of childhood cancer. In addition, the impact of demographic, medical and treatment factors on survivors' posttraumatic stress symptoms was studied. Procedure. Participants were 500 long-term survivors of childhood cancer. The median age at follow-up was 24 years (age range, 1649 years, 47% female). To assess symptoms of posttraumatic stress, all participants completed the Impact of Event Scale (IES), a self-report instrument consisting of two subscales, intrusion and avoidance. Results. Twelve percent of this sample of adult survivors of childhood cancer had scores in the severe range, indicating they are unable to cope with the impact of their disease and need professional help. Twenty percent of the female survivors had scores in the severe range as compared with 6% of the male survivors. Linear regression models revealed that being female, unemployed, a lower educational level, type of diagnosis and severe late effects/health problems were associated with posttraurnatic stress symptoms. Conclusions. The results indicate that, although the proportion of survivors reporting symptoms is well within the proportions found in the general population, a substantial subset of survivors report symptoms of posttraumatic stress. This finding supports the outcomes reported previously that diagnosis and treatment for childhood cancer may have significant long-term effects, which are manifested in symptoms of posttraurnatic stress. The investigated factors could explain posttraurnatic stress symptoms only to a limited extent. Further research exploring symptoms of posttraumatic stress in childhood cancer survivors in more detail is clearly warranted. From a clinical perspective, health care providers must pay attention to these symptoms during evaluations in the follow-up clinic. Early identification and treatment of PTSD symptoms can enhance the quality of life for survivors of childhood cancer. (C) 2004 Wiley-Liss, Inc

Role of radiotherapy in Ewing tumors.

Abstract: Background The objective of this review article is to outline the role of radiotherapy in a curative multimodal treatment concept. Procedure We have analyzed the data from major multi-institutional prospective trials in Ewing tumors for to evaluate the impact of radiotherapy on local control and survival. Results Surgery yields in general better local control and survival figures as compared to radiotherapy. The efficacy of radiotherapy as compared to surgery varies among the studies and seems to be dependent on patient selection and sequencing with chemotherapy. Combined local therapy (surgery plus post- or pre-operative radiotherapy) has yielded excellent local control rates in patients with high-risk lesions (e.g., pelvic tumors); although not proven by randomized studies, an impact on survival is likely. Indications for post-operative radiotherapy are unradical or marginal resections and poor histological response. In patients with chest wall primaries, adjuvant hemithorax irradiation has reduced the relapse rate significantly. Pre-operative irradiation offers theoretical advantages. Bilateral lung irradiation (as consolidation after chemotherapy) seems to improve prognosis in patients with metastases at diagnosis. Conclusions Patients with high-risk lesions probably benefit from combined local treatment (surgery plus radiotherapy). Improving local control after radiotherapy is a major issue for future studies, and sequencing with chemotherapy seems to be critical factor. The possible curative potential of radiotherapy in metastatic disease requires further investigation. © 2004 Wiley-Liss, Inc.

Long-term cause-specific mortality among five-year survivors of childhood cancer

Abstract: BACKGROUND: The purpose of our study was to assess long-term cause-specific mortality of 5-year childhood cancer survivors. PROCEDURE: The study population consisted of 1,378 patients who had been treated for childhood cancer in The Netherlands between 1966 and 1996 and survived at least 5 years; follow-up was complete for 99% of survivors. Cause-specific mortality was compared with general population rates to assess relative and absolute excess risks of death (standardized mortality ratio (SMR) and AER). RESULTS: After a median follow-up of 16.1 years, 120 patients had died. The overall SMR was 17-fold (95% CI: 14.3-20.6) increased compared to the general population. Our cohort experienced an excess of 7 deaths per 1,000 person-years. Patients who received combined modality treatment and were treated for at least one recurrence experienced the highest risk of death (SMR = 92.3; AER = 37.0 per 1,000 person-years). The SMR appeared to stabilize at an about 4 to 5-fold increased risk of death after 20 years of follow-up. Only after more than 20 years of follow-up excess mortality due to other causes than the primary cancer exceeded mortality from the primary childhood cancer (2.3 vs. 0.3/1,000 patients/year). The SMR for all causes other than primary cancer was 5.4 in 25-year survivors. The overall risks of death strongly decreased with increasing attained age, with an SMR of 1.6 (n.s.) and an AER of 0.3 per 1,000 person-years for survivors of 30 years or older. CONCLUSIONS: The first primary cancer contributes most to the absolute excess risk of death in 5-year survivors of childhood cancer, but after 25 years childhood cancer mortality is negligible. Relative risk of death due to other causes is still significantly increased after 25 years of follow-up.

Long-term follow-up of survivors of childhood cancer in the UK.

Abstract: Background Childhood cancer is rare, but there are now good survival prospects and in the UK approximately 1 in 1,000 young adults is a survivor of childhood cancer. There are many adverse health outcomes associated with the treatment of childhood cancer often arising several years after completion of treatment. The aim of this study was to quantify the long-term clinical follow-up practices concerning survivors of childhood cancer. Procedure A cross-sectional postal survey of 22 treatment centres of the United Kingdom Children's Cancer Study Group (UKCCSG) clinicians was carried out as well as a cross-sectional postal survey of general practitioners of most adult survivors of childhood cancer in Britain. Results Subsequent to 5 years after the end of treatment: 52% of UKCCSG clinicians follow-up all survivors for life, while 45% discharge some patients. Of those clinicians discharging: over 50% discharged benign, stage I or tumors treated with surgery alone, in contrast 16% reported discharging all or most patients; almost all (97%) clinicians discharged to a general practitioner. Only 14% of clinicians reported nurses undertook a specialist role. Sixty-five percent of the 10,979 general practitioners reported that their patient was not on regular hospital follow-up. Conclusions There are wide variations in the extent to which survivors of childhood cancer are discharged from hospital follow-up. There is a need for regularly updated national guidelines concerning the levels of follow-up required for specific groups of survivors defined principally by the treatment they received. Pediatr Blood Cancer 2004;42:161–168. © 2003 Wiley-Liss, Inc.

Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children.

Abstract: Background Biotransformation plays a crucial role in carcinogen activity and many genetic polymorphisms in xenobiotic metabolising enzymes have been associated with an increased risk of cancer. Such polymorphisms can lead to considerable variation in the activities of these enzymes, which are crucial in carcinogen and drug metabolism. These variations could play a role in the risk of developing paediatric acute lymphoblastic leukaemia (ALL) by their varying action on environmental carcinogens. Procedure The present study looked for two polymorphisms (m1 and m2) in the CYP1A1, CYP2D6*4 genes and deletions of the glutathione S-transferases (GSTM1 and GSTT1) in 118 paediatric ALL patients and 118 age matched control children. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study gene polymorphisms. Results In children with ALL, CYP1A1 m1 polymorphism was evident in 42.4% of subjects and CYP1A1 m2 in 37.3%. These were significantly different from the results obtained for control children (20.3% for CYP1A1 m1 and 19.5% for m2). Subjects with CYP1A1 m1 homozygous variant had a sixfold risk and CYP1A1 m2 a fourfold risk. In contrast, CYP2D6*4 was more prevalent in the controls than in the cases. Subjects with GSTM1 deletions had increased risk of ALL (OR = 2.1, P = 0.009). The odds ratios for both CYP1A1 m1 and m2 homozygous polymorphisms being associated with childhood ALL was 5.67 (95% CI = 2.11–15.27). The odds ratios for both GSTM1 and GSTT1 deletions being associated with ALL was 2.78 (95% CI = 0.67–11.56). Conclusions These results suggest that genetic polymorphisms of xenobiotic metabolising enzymes appear to influence susceptibility to childhood ALL. © 2004 Wiley-Liss, Inc.

Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis

Abstract: Background and Objectives Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk. Study Design In this retrospective study we included 54 patients registered at the LCH study reference center in whom the onset of CDI preceded the diagnosis of LCH, and we investigated their presentation and course to define a clinical pattern characteristic for LCH. Results In 49/54 patients (91%) the detection and biopsy of extracranial lesions led to the diagnosis of LCH. The most frequently involved organs were bones, skin, and lungs; 86% of the patients with bone lesions had skull lesions. In 18% of the patients extracranial lesions were already found at presentation of CDI, in another 51% of the patients extracranial lesions were found within 1 year from onset of CDI. Conclusions These observations underline that a comprehensive search for extracranial lesions at presentation and during the first year thereafter may help to achieve a specific diagnosis without a pituitary stalk biopsy. © 2004 Wiley-Liss, Inc.

Outcome in children with pulmonary Langerhans cell Histiocytosis.

Abstract: Background The aim of this study was to evaluate features and outcome of children with Langerhans cell Histiocytosis (LCH) and pulmonary involvement. Procedure Retrospective evaluation of LCH patients was performed from 1987 to 2001. Multisystem patients were classified according to the pattern of organ system involvement into Groups: A (no pulmonary, hematologic, or hepatic involvement), B (pulmonary involvement), C (pulmonary and hematologic or hepatic involvement), and D (hematologic or hepatic involvement). All had skin, bone, or lymph node involvement. Chest X-ray was performed in all patients and computed tomography (CT) in 21. Diagnostic lung biopsy was performed in five patients. Results Pulmonary involvement was found in 36/220 patients studied. Two patients had isolated pulmonary involvement. Multisystem involvement was present in 83 patients, 34 of whom had pulmonary involvement. In 20/36 patients, tachypnea, cough, and thoracic pain occurred. Diffuse interstitial involvement was found in all cases. Pulmonary function tests were performed in nine patients, six of whom revealed mild to moderate restrictive respiratory involvement. The two patients having isolated pulmonary involvement survived 2 and 2.7 years after diagnosis. Median follow-up of all multisystem patients was 2.1 years, with a 5-year survival probability of 0.59. The 5-year survival probability of Groups A–D was 0.94, 0.83, 0.23, and 0.40, respectively. The survival difference between Groups B and C was statistically different (P < 0.0071). Conclusions According to our data, pulmonary compromise without other risk organ involvement does not appear to be a negative prognostic factor in our study. © 2004 Wiley-Liss, Inc.

Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach.

Abstract: Purpose. High rates of overall and event-free survival have been reported in patients with intracranial germinomas treated with craniospinal radiotherapy. More recently, similar results have been reported with chemotherapy combined with radiotherapy to more localized treatment volumes. Our interest in exploring chemotherapy without radiotherapy in patients with CNS germinomas was based on concerns about the late sequelae of radiotherapy to the brain or neuraxis and also the well documented success of chemotherapy alone in patients with disseminated extracranial germinomas. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy, without radiotherapy, was effective in patients with CNS germinomas. Patients and Methods. Nineteen patients were enrolled, ranging in age from 1 to 24 years (median, 14 years). Thirteen were male. Nine had diabetes insipidus. Therapy comprised two courses of Regimen 'A' (cisplatin, etoposide, cyclophosphamide, and bleomycin) followed by MRI evaluation. Patients achieving a complete remission (CR) completed all planned therapy with two courses of regimen 'B' (carboplatin, etoposide, and bleomycin). Patients achieving less than a CR received two courses of Regimen 'B' followed by another evaluation. Those in CR after four courses of treatment received one additional course of Regimen 'A' and Regimen 'B', while those not in CR after four treatment courses underwent second look surgery and/or radiation therapy. Results. Eleven of 11 patients with residual postoperative disease assessable for response achieved a CR. With a median follow-up of 6.5 years, eight out of 19 (0.42) patients remain in CR 1 without radiotherapy and another three patients are in stable second or subsequent remissions. Three patients died from treatment-related toxicity and another died in CR 1 from an uncharacterized leukoencephalopathy. The 5-year event-free survival (EFS) was 0.47 ± 0.23 and 5-year overall survival (OS) was 0.68 ± 0.22. Conclusions. Intensive cisplatin and cyclophosphamide-based chemotherapy was effective in achieving remissions, however, the long-term outcome using this treatment program was unsatisfactory and associated with unacceptable morbidity and mortality, particularly in patients with diabetes insipidus.

A new clinical score for disease activity in Langerhans cell histiocytosis.

Abstract: Objective To develop an objective tool for assessing disease activity in patients with Langerhans cell histiocytosis (LCH). Method Scoring system was developed and applied to a database containing information on 612 patients. Results At diagnosis, the score distribution was highly asymmetrical: the score was between 0 and 2 in 74% of cases, 3-6 in 16%, 7-10 in 3%, and more than 10 in 6%. The 5-year mortality rates were 1, 4.4, and 43.4%, respectively, among patients with initial scores of 0-2, 3-6, and >6. Stability or an increase of the score at 6 weeks was highly predictive of death among patients with initial scores above 6, while score stability had no significant impact on vital outcome among patients with low or moderate scores at diagnosis. Conclusions This LCH disease activity score provides an objective tool for assessing disease severity, both at diagnosis and during follow-up and treatment.

Course and clinical impact of magnetic resonance imaging findings in diabetes insipidus associated with Langerhans cell histiocytosis

Abstract: Background Diabetes insipidus (DI) is the most frequent sequela in Langerhans cell histiocytosis (LCH). The clinical relevance and therapeutic impact of brain magnetic resonance imaging (MRI) findings in LCH patients with LCH during the disease course is unclear. Procedure In this retrospective study, we reviewed 113 brain MRIs from 59 DI patients, in 17 of these serial follow up MR-examination findings were correlated to the clinical course and therapy. Results At DI diagnosis, 71% patients showed a thickened stalk, in 24% the stalk was still thickened on MRIs done more than 5 years after DI onset, and in two patients the stalk was already thickened several months before DI onset. The changes of the pituitary stalk thickness were highly variable and did not clearly correlate with the treatment. Regression of pituitary thickness on MRI did not concur with clinical recovery of DI, which persisted in all but one patient with initially partial DI. The occurrence of anterior pituitary hormone deficiencies appeared to be linked to a thickening of the stalk at DI diagnosis. LCH-lesions in the craniofacial bones were seen in 75% DI patients, and 76% of DI patients with follow up MRIs done 5 years or longer after DI diagnosis had parenchymal neurodegenerative brain changes. Conclusions Our study indicates that repeated MR-examinations in DI patients are of limited value for assessing a response to therapy in the pituitary stalk, but are important for the monitoring of craniofacial bone lesions and for the detection of parenchymal CNS disease. © 2004 Wiley-Liss, Inc.

Wnt/Frizzled signaling in Ewing sarcoma

Abstract: Background The Ewing sarcoma family of tumors (ESFT) is a set of neuroectodermal malignancies that typically presents in the second decade and has a poor prognosis due to metastatic disease. Wnt signaling has a critical role in the normal development of multiple neuroectodermal tissues and also contributes to the neoplastic properties of tumor cells of neuroectodermal origin. Procedure We surveyed the expression of Wnts and their receptors in nine ESFT cell lines by RT-PCR analysis. We also tested biological response of ESFT cell lines to exogenous Wnts in β-catenin stabilization, actin stress fiber formation, and chemotaxis assays. Results We detected Wnt-10b in all the lines, and most also expressed Wnt-5a, Wnt-11, and Wnt-13. Several Frizzleds (Fz) and the Wnt co-receptors, low density lipoprotein-receptor-like proteins 5 and 6 were also expressed. We observed a marked stimulation of the β-catenin/canonical Wnt pathway in ESFT cells treated with Wnt-3a. Wnt-3a induced morphologic changes characterized by the formation of long cytoplasmic extensions in ESFT cells. We also observed chemotaxis of ESFT cells in response to Wnt-3a. Conclusions These results provide evidence that components of Wnt/Fz pathway are expressed and an intact Wnt/Frizzled signaling pathway exists in ESFT cell lines. Activation of the Wnt pathway in ESFT suggests that Wnt modulates cell motility rather than cell proliferation. Hence, activation of this pathway may influence metastatic potential of ESFT. © 2004 Wiley-Liss, Inc.

Serum troponin T levels and echocardiographic evaluation in children treated with doxorubicin.

Abstract: Objective. We investigated the usefulness of serum cardiac Troponin T (cTnT) to detect doxorubicin related cardiotoxicity as a noninvasive and reliable method. Patients and Methods. Twenty-four patients who received doxorubicin for their solid tumors at cumulative doses of 400 mg/m 2 or higher, between June 1982 and August 2000, were included in this study. None of them had clinical signs or symptoms of cardiotoxicity. The age range was 3–31 years (median 14), and male to female ratio was 14/10. The systolic and diastolic cardiac functions were evaluated by twodimensional, M-mode, and Doppler echocardiography. Serum cTnT levels were measured by a third generation immunoassay method and the lowest detectable level was 0.010 ng/ml. Results. The cumulative doxorubicin doses were at the range of 400 and 840 mg/m 2 (median 480). The time past from the last doxorubicin dose was 1–168 months (median 12). All of the patients had normal chest X-rays, electrocardiograms, and nine patients (37.5%) had abnormal systolic or diastolic cardiac function parameters. The median cumulative doxorubicin doses of the patients with normal and abnormal echocardiographic parameters were 480 and 440 mg/m 2 , respectively. Serum cTnT values of 21 patients were below the detection limit (< 0.010 ng/ml). There was no statistical difference between serum cTnT levels of the patients with normal and abnormal echocardiographic findings (P ¼ 0.376). Conclusions. No correlation was found between serum cTnT values, cumulative doxorubicin doses, and systolic or diastolic cardiac functions. We can conclude that echocardiographic follow-up is more reliable than serum cTnT levels for detecting subclinical cardiac toxicity. Pediatr Blood Cancer 2004;42:220–224. 2003 Wiley-Liss, Inc.

Ewing sarcoma: radiation dose and target volume.

Abstract: Background The outcome of children and adolescents with Ewing sarcoma is impacted by many prognostic factors and often measured by estimates of: event-free, relapse-free, disease-free, or overall survival. However, the preferred assessment following radiation therapy is local control. Procedure A review of large group experiences over the past several decades was undertaken to assess the optimal radiation dose and volume for patients with localized, osseous Ewing sarcoma. New approaches and techniques to improve local control were also investigated. Results With multidisciplinary therapy, 5-year overall local control rates range from 58 to 93%. Following definitive irradiation, they are 53–86%. Recommended radiation therapy doses are 55.8–60.0 Gy. In the postoperative setting, gross disease requires 55.8 Gy; microscopic disease requires 45 Gy. Altered fractionation schemes have not improved local control. The appropriate irradiated volume is an involved field to the pretreatment tumor volume plus 2.0–2.5 cm margin, followed by a boost to the post-induction chemotherapy tumor volume with margin. Good radiation quality control with central review improves local control. Use of an involved radiation field requires accuracy in defining tumor volume. Techniques to improve local control include risk-adapted multidisciplinary therapy, intraoperative boost radiation, and high radiation doses as delivered by 3-dimensional conformal radiation. Intensity modulated and proton beam radiotherapy may offer an advantage at special sites. Conclusions Innovative uses of radiation in the multidisciplinary setting will continue to provide excellent local control, improved function, and quality of life for young patients with localized Ewing sarcoma of bone. © 2004 Wiley-Liss, Inc.

Surgery of cavoatrial tumor thrombus in nephroblastoma: a report of the SIOP/GPOH study.

Abstract: Background Resection of a Wilms tumor extending through the inferior vena cava into the right atrium represents a challenge to the pediatric surgeon. Exact preoperative diagnosis is essential to identify the tumor and its in travascular extension. To achieve a complete excision of the tumor cardiopulmonary bypass and hypothermia may be required. The feasibility of a complete resection is important as it guides subsequent therapy such as chemotherapy and radiation. Procedure In order to define these issues, we reviewed the records of 33 of 1,151. Patients enrolled in the SIOP 93-01/GPOH Study and the SIOP 2001/GPOH Study who had a tumor thrombus into the inferior venacava and into the right atrium. Results The median age at diagnosis was 3.73 years. Twenty-four patients had a tumor thrombus into the inferior vena cava, in nine patients the thrombus reached into the right atrium. All patients were operated on; cardiopulmonary bypass was used in nine patients. There were no deaths intraoperatively. Twenty-nine children are still alive; four patients died, one patient due to aspiration and failed resuscitation, two patients died from a recurrent tumor, and one child due to an unresectable primary tumor. Conclusion Our report suggests that Wilms tumor extending to the inferior vena cava and the right atrium is technical challenging, but with adequate preoperative diagnosis and a multidisciplinary surgical approach including cardiopulmonary bypass and hypothermia, the prognosis is favorable. © 2004 Wiley-Liss, Inc.

Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines.

Abstract: Background Osteosarcoma is the most common malignant bone tumor of childhood. Significant proportions of these patients eventually develop pulmonary metastases and succumb to their disease even after conventional multi-agent chemotherapy and surgical excision. Matrix metalloproteinase (MMP)-2 induced degradation of blood vessel basement membranes is an important pre-requisite for tumor invasion and metastasis. Bisphosphonates (BPs) have been known to inhibit tumor growth and metastasis in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer, and may do so through inhibition of MMP secretion. We, therefore, tested the effect of BPs on tumor cell invasion, MMP-2 secretion, and apoptosis of osteosarcoma cell lines. Procedure Two osteosarcoma cell lines (SaOS-2, U2OS) were treated with alendronate (50, 100, and 150 μM) for 24 and 48 hr. Matrigel invasion assay was used to investigate the invasive potential of osteosarcoma cell lines before and after alendronate treatment. Real-time quantitative RT-PCR was used to determine the mRNA level of MMP-2 with and without alendronate treatment. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the cytokine level of MMP-2 secreted in the condition medium. BP-induced cell apoptosis was evaluated by fluorescent flow cytometric analysis. Results and Conclusions The results showed that alendronate inhibited cell invasion of both osteosarcoma cell lines in a dose-dependent manner. Alendronate reduced the mRNA level and cellular level of MMP-2 in both cell lines in a time and dose-dependent manner. Alendronate also induced significant apoptosis in both cell lines. Our finding suggests that alendronate downregulates MMP-2 secretion and induces apoptosis in osteosarcoma cells, which may both contribute to the reduction of invasive potential of the tumor cells. © 2004 Wiley-Liss, Inc.

Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood

Abstract: Fertility impairments among men treated during childhood for cancer are known to occur after some, but not all, types of anti-cancer therapy. This is the first study to evaluate proven fertility among adult male survivors of childhood acute lymphoblastic leukemia (ALL). In a retrospective cohort study, proven fertility (ever fathered a pregnancy) was evaluated by self-report among 213 men treated for ALL before age 18 on protocols of the Children's Cancer Group (CCG). Controls (N = 145) were drawn from among male siblings. Overall, with a proportional hazards analysis, proven fertility of male survivors was not different from that of controls (relative fertility (RF) = 0.95, 95% CI 0.63-1.43). However, married men treated before age 10 with high dose (24 cGy) cranial radiotherapy (RT), without spinal RT, had only 9% of the fertility of controls (Relative risk, RR = 0.09, 95% CI 0.01-0.82). High dose cranial RT at older ages was not associated with a statistically significant fertility deficit (RR = 0.56, 95% CI 0.25-1.28). In this first study of proven fertility among men treated for childhood leukemia, the majority of survivors showed no evidence of fertility impairment compared to controls. However, men treated at a young age with high dose cranial RT may have impaired fertility. These results suggest that further investigation of men with these treatments is needed to confirm and extend these findings.

Immune responses to influenza immunization in children receiving maintenance chemotherapy for acute lymphoblastic leukemia.

Abstract: Purpose To compare the immune responses to influenza vaccine in children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy with those in healthy children. Methods Hemagglutinin-inhibition (HAI) antibody titers were determined before and after influenza vaccination in children with ALL and healthy controls. Immune responses were measured as geometric mean titers (GMT) and 4-fold rises in HAI titers. Results Although post-immunization GMT were lower in children with ALL compared to healthy children for the H1N1 antigen (P < 0.001), the H3N2 antigen (P = 0.03), and for the influenza B antigen (P = 0.003), at least 60% of children with ALL had at least a 4-fold rise in HAI titers to each of the influenza antigens. Conclusions While the GMT after trivalent influenza immunization in children with ALL were significantly lower than those seen in healthy children, the majority of children with ALL had 4-fold rises in HAI titers. Children receiving maintenance chemotherapy for ALL should receive yearly influenza vaccine. © 2003 Wiley-Liss, Inc.

Factors influencing central line infections in children with acute lymphoblastic leukemia: results of a single institutional study.

Abstract: INTRODUCTIONThe use of central lines or venous access devices(VADs) in children with malignancies, which has faci-litated the administration of intensive chemotherapy, isassociated with an increased risk of infection [1,2].Several reports in children indicate that external catheters(ECs)suchastheHickmanorBroviachaveahigherrateofvenous access device related infections (VADRIs) thantotally implanted devices (TIDs) such as the Port-a-Cath[3–6]. Most VADRIs occur within 100 days of insertion[5,7]. Many of our patients with acute lymphoblasticleukemia (ALL) are febrile at presentation and neutrope-nia that occurs within a few days of starting therapypersistsfor2–3weeks.WehadtheclinicalimpressionthatVADs inserted during this first 3 week induction period,when neutropenia was present, were more likely tobecome infected than those inserted subsequently. Wecould find no published data regarding the effect of timingof VAD insertions on the infection rate in children withALL. Shaul [8] had demonstrated that lines insertedduring neutropenic episodes were more likely to becomeinfected. Rackoff [2], however, had shown that theincidence of infected lines was highest during interimmaintenance and least during induction and delayedintensification, the more myelosuppressive phases. Sinceyoung age had also been associated with an increasedincidence in some series, we evaluated both the effect ofage and timing of insertion on the rate of VADRIs [7,9].We also compared the rate of VADRIs in the two types ofVADs in children with ALL.MATERIALS AND METHODSPatient PopulationBetween January 1996 and June 2001, 154 patients age<13 years with ALL were referred to our center. VADs

Limb sparing surgery for pediatric musculoskeletal tumors.

Abstract: There has been an unprecedented improvement in the survival outcome of children with extremity sarcoma as well as a corresponding increase in percentage of limb-sparing surgeries being performed over the past many decades. This has been, in part, due to the improved imaging modalities, newer surgical techniques, and advences in neoadjuvant chemotherapy. Limb-sparing surgery for primary bone and soft-tissue malignancies in children is becoming an acceptable option of surgical treatment in most cases today. This article outlines the demographics, classification, clinical presentation, imaging, and molecular genetics of pediatric mosculoskeletal tumors and discusses the current treatment principles with emphasis on the state-of-the-art surgical management and limb-sparing techniques for children with extremity sarcoma. © 2004 Wiley-Liss, Inc.

High-dose chemotherapy with autologous stem-cell rescue in the treatment of patients with recurrent non-cerebellar primitive neuroectodermal tumors.

Abstract: Background Recurrent non-cerebellar primitive neuroectodermal tumors (PNETs) carry a dismal prognosis when treated with conventional chemotherapy alone. XSWe tested the efficacy of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in this setting. Procedure Eligibility mandated either minimal residual disease or evidence of chemosensitivity before HDC. Conditioning consisted of carboplatin (CBDCA) (500 mg/m2 or AUC = 7 mg/ml min using the Calvert formula) on days −8 to −6, thiotepa (300 mg/m2), and etoposide (250 mg/m2) on days −5 to −3. Irradiation was given post HDC selectively. Results Among 17 patients treated in this study, there were eight pineoblastoma(s) (pineo), seven cortical PNETs, and two arising elsewhere. Relapse was either local (nine) or metastatic to the brain (four) or spine (four). Two patients received HDC as the sole therapy for recurrence; additionally, eight underwent surgical debulking before HDC, and nine received irradiation, including six after HDC. Median age at ASCR was 3.9 years. Two patients died of toxicity (11%) and ten experienced tumor relapse (range: 23–361 days post ASCR). Five patients with cortical PNETs remain alive disease-free (median follow-up: 8.3 years); four of them received irradiation post HDC. The difference in 5-year event-free survival (EFS) between patients with pineo and other supratentorial PNETs was significant (0 vs. 62.5 ± 17%, P = 0.0065). Both surgery at relapse and irradiation post HDC were favorable prognostic factors (P = 0.006 and 0.01, respectively). Conclusions Patients with recurrent cortical PNETs can be cured with this strategy. Surgical debulking before, and irradiation after HDC play an important role in treatment success. © 2003 Wiley-Liss, Inc.

Intramedullary spinal cord astrocytomas in children.

Abstract: Background Intramedullary spinal cord astrocytomas are uncommon tumors in childhood. There is little information on therapy and outcome of astrocytomas in this location. Procedure A retrospective review was performed for the 10 children who were treated between 1996 and 2003 for spinal cord astrocytomas in our institution. Only one had metastatic disease. All ten patients underwent surgical resection, nine partial and one total. Eight had low-grade tumors, and two high-grade tumors. Two had surgery only, four had chemotherapy only, two had radiation only, and two had both radiation and chemotherapy. Results Progression free survival was 58% and survival was 68% at 4 years. Four patients had disease progression, of which three died. Both children with high-grade astrocytomas died. Two of eight of the children with low-grade astrocytomas of the cord recurred, one having received radiation as initial therapy and the other chemotherapy. The child, who relapsed after radiation, had a spastic quadriplegia from radiation myelitis and no salvage therapy was attempted. The four patients, all with low-grade astrocytomas, who treated with chemotherapy alone, received carboplatin and vincristine. Of these four, three are in continuous remission and one relapsed, but was salvaged with radiation. Conclusions Chemotherapy and radiation did not benefit those with high-grade astrocytomas of the spinal cord. Good outcomes can be achieved by conservative surgery for low-grade astrocytomas of the cord when adjuvant therapy is given. Carboplatin and vincristine appeared to be effective, safe therapy for those with low-grade astrocytomas of the cord. © 2004 Wiley-Liss, Inc.