Showing papers in "Medical and Pediatric Oncology in 2002"

Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project.

Abstract: Background Increased attention has been directed toward the long-term health outcomes of survivors of childhood cancer. To facilitate such research, a multi-institutional consortium established the Childhood Cancer Survivor Study (CCSS), a large, diverse, and well-characterized cohort of 5-year survivors of childhood and adolescent cancer. Procedure Eligibility for the CCSS cohort included a selected group of cancer diagnoses prior to age 21 years between 1970–1986 and survival for at least 5 years. Results A total of 20,276 eligible subjects were identified from the 25 contributing institutions, of whom 15% are considered lost to follow-up. Currently, 14,054 subjects (69.3% of the eligible cohort) have participated by completing a 24-page baseline questionnaire. The distribution of first diagnoses includes leukemia (33%), lymphoma (21%), neuroblastoma (7%), CNS tumor (13%), bone tumor (8%), kidney tumor (9%), and soft-tissue sarcoma (9%). Abstraction of medical records for chemotherapy, radiation therapy, and surgical procedures has been successfully completed for 98% of study participants. Overall, 78% received radiotherapy and 73% chemotherapy. Conclusion The CCSS represents the largest and most extensively characterized cohort of childhood and adolescent cancer survivors in North America. It serves as a resource for addressing important issues such as risk of second malignancies, endocrine and reproductive outcome, cardiopulmonary complications, and psychosocial implications, among this unique and ever-growing population. Med. Pediatr. Oncol. 2002;38:229–239. © 2002 Wiley-Liss, Inc.

Cancer in older adolescents and young adults: Epidemiology, diagnosis, treatment, survival, and importance of clinical trials

Abstract: Cancer in adolescents and young adults has unique features in addition to the special medical, physical, psychological, and social needs of patients in this age group. The spectrum of malignant diseases is different from that in any other period in life, and it is strikingly different from the pattern in older persons. More people 15-25 years of age are diagnosed to have cancer than during the first 15 years of life. During the last 25 years, the incidence of cancer in this age range has increased faster while the increase in their cancer survival rates has been significantly lower than in younger or older patients, especially in comparison to results of the national pediatric cooperative cancer groups. Thus the 5-year outcome in 15-19 year olds with leukemias and sarcomas is not only worse than in younger patients, but also lower in this population at large than in patients of the same age treated at Children's Cancer Group institutions. In the United States, only approximately 5% of 15-25 year olds with cancer are entered onto clinical trials, in contrast to 60-65% of younger patients. Thus, cancer during adolescence and early adult life is an underestimated challenge that merits specific resources, solutions, and an international focus.

Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood.

Abstract: The previous International Society of Paediatric Oncology (SIOP) trials and studies recognized three prognostic groups of renal tumors of childhood: low risk, intermediate risk, and high risk tumors, which were further defined in the SIOP (Stockholm) Working Classification of Renal Tumors of Childhood (1994). The results of the latest SIOP Trials and Studies showed that certain histological features which remain after preoperative chemotherapy, such as blastema, are of prognostic significance while others are not. Therefore, in the next SIOP Trials and Study a revised classification of renal tumors will be followed. It still recognizes the three tumor risk groups with different types in each of them, but for treatment purposes, only three major types of nephroblastoma need to be recognized: completely necrotic (low risk tumor), blastemal (high risk tumor), and others (intermediate risk tumors). Patients will be treated according to tumor histology and stage. Trials which include preoperative chemotherapy have shown that the presence of necrotic tumor or chemotherapy induced changes in the renal sinus or perirenal fat can be ignored for distinguishing between stage I and II, but if present at resection margins or lymph nodes, it should be regarded as stage III. Prognostic significance of all histological component of Wilms tumors will be studied prospectively in the new trial.

CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments of concentration, attention, and memory.

Abstract: Purpose To date, the event free survival (EFS) after treatment of childhood acute lymphoblastic leukemia (ALL) attains 80%. The survivor group is growing steadily. Therefore, the primary purpose of our study is to define the neuropsychological function and to describe which central nervous system (CNS) functions are impaired following the German ALL-BFM and COALL protocols for CNS-negative patients. Patients and Methods In a cross-sectional multicenter study 121 subjects, long-term survivors of childhood ALL in first continuous complete remission were investigated. Seven years ago, the subjects were treated as standard or medium risk patients according to ALL-BFM 81, ALL-BFM 83, or COALL 82 protocols, receiving comparable treatments. According to different CNS-prophylaxes, two subgroups were compared in the study: the non-cranially irradiated MTX-group (methotrexate-group) (n = 38) and the cranially irradiated RT-group (radiotherapy-group) (with MTX i.th.) (n = 83). Intellectual and cognitive abilities of these groups were evaluated using standardized psychometric techniques. The Kaufman factors Verbal Comprehension, Perceptual Organisation and Freedom from Distractibility were calculated. Demographical and clinical data collected at the time of the diagnosis were compared between both groups. The different prognoses for patients within both groups were taken into account using a defined risk factor. Analysis of variance was conducted to relate intellectual performance to age, gender, and CNS-treatment. Results The RT-group exhibited a lower Full Scale IQ than the MTX-group (101.2 ± 15.9 vs. 109.9 ± 14.9, P = 0.031). Particularly for the Kaufman factor Freedom from Distractibility the RT-group showed the lower scores (96.9 ± 14.1 vs. 105.5 ± 12.6, P = 0.037). Significant interactions between gender and CNS prophylactic treatment were observed for Full Scale IQ (P = 0.008), Verbal IQ (P = 0.012), Performance IQ (P = 0.024), Verbal Comprehension (P = 0.004), and Perceptual Organisation (P = 0.032). Conclusions Cranial irradiation in combination with MTX therapy was associated with deficits in attention, concentration, and the ability of sequencing and processing, measured by the Kaufman factor Freedom from Distractibility. Our results support the strategy of avoiding prophylactic CNS irradiation in low risk patients. Med. Pediatr. Oncol. 2002;38:320–328. © 2002 Wiley-Liss, Inc.

Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Surveillance Epidemiology and End Results.

Abstract: Background It has been suggested that cerebellar medulloblastoma (M) and primitive neuroectodermal tumors (PNET) arising elsewhere in the nervous system, represent a single entity (M/PNET), although this concept is controversial. Cancer registries permit population-based description of cases reported as medulloblastoma, those reported as PNET and description of the aggregate, M/PNET. Procedure We reviewed the 768 cases of M/PNET (633 diagnosed medulloblastoma and 135 diagnosed PNET) among persons under 20 years of age in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. Results The incidence of M/PNET rose 23%, from 4 per 106 person-years in 1973–77 to 4.9 per 106 person-years in 1993–98. Cases reported as PNET were more likely than those reported as medulloblastoma to be supratentorial (30.4% vs. 1.9%, P < 0.001) and to be female (42.2% vs. 35.4%, P = 0.13). The difference in 5-year survival between the 600 children with infratentorial medulloblastoma vs. the 49 children with infratentorial PNET was not statistically significant (55% vs. 43%). Regardless of reporting diagnosis, survival was poorer among children age 0–3 years and those with supratentorial tumors. Children diagnosed in the more recent period from 1985–1998 had a longer median survival than children diagnosed in 1973–84 (4.9 years vs. 10 years, P < 0.05). Rates were 42% higher among Whites compared to Blacks (4.5/106 person-years vs. 3.1/106 person-years, P < 0.01). Conclusions We found M/PNET is increasing in incidence and more frequent among Whites. Given that medulloblastoma and PNET are histologically identical and have similar epidemiologic profiles, future studies should provide analyses that combine these entities. Med Pediatr Oncol 2002;39:190–194. Published 2002 Wiley-Liss, Inc.

Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study.

Abstract: Background Patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma have poor prognoses and limited therapeutic options. We have investigated the use of peptide pulsed vaccination in an attempt to immunologically target the breakpoint region of tumor specific fusion proteins expressed in these tumors. Procedure Sixteen patients with recurrent, translocation positive, Ewing sarcoma, and alveolar rhabdomyosarcoma underwent apheresis for collection of peripheral blood mononuclear cells. Following countercurrent centrifugal elutriation, an apheresis product comprised predominantly of monocytes but containing small numbers of circulating immature dendritic cells was pulsed with peptides derived from the breakpoint region of the fusion proteins. Vaccines were administered intravenously concomitant with continuous intravenous rhIL-2 at 9 × 106 IU/m2/day. Results Toxicity was limited to IL-2 related effects and was generally mild. Following vaccination, all patients showed progressive disease, most in a rapid fashion following the first vaccine. One patient showed evidence of an immunologic response and another showed a mixed clinical response. Patients enrolled on this tumor vaccine trial showed significant immunosuppression and large bulky tumors. Conclusions Peptide vaccination as administered in this trial did not alter the dismal clinical outcome for patients with recurrent pediatric sarcomas. Future trials of tumor vaccines in this population should target patient populations with improved immune competence and smaller tumor burdens. Furthermore, optimization of the antigen presenting cell populations may be important for inducing immune responses to peptide antigens. Med Pediatr Oncol 2002;38:158–164. Published 2002 Wiley-Liss, Inc.

Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects.

Abstract: Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are two different subtypes of primary tumors arising from liver parenchymal cells. These tumors differ by many histoclinical characteristics, and comparative analysis of genetic alterations in HB and HCC might provide some clues on the molecular oncogenic pathways leading to hepatocyte transformation. Recent outcomes have been provided by the assessment of global genetic changes in tumor cells, using conventional cytogenetic approaches, PCR-based microsatellite analysis and Comparative genomic Hybridization (CGH). Cytogenetic studies of HB, microsatellite analysis of HCC and recent CHG data have outlined common and distinctive characters between the two tumor types. HBs are characterized by a low number of chromosomal changes, consisting mainly of gains at chromosomes 1q, 2, 8q, 17q, and 20. By contrast, HCCs harbor multiple chromosomal abnormalities, predominantly losses, with increased chromosomal instability in tumors associated with hepatitis B virus infection. Common alterations in HB and HCC include gain of chromosomes 1q, 8q, and 17q, and loss of 4q. Another important common feature shared by the two tumor types is the frequent activation of Wnt/beta-catenin signaling by stabilizing mutations of beta-catenin. Immunohistochemical analysis of beta-catenin has demonstrated nuclear/cytoplasmic accumulation of the protein in most HBs and in more than one third of HCCs. Strikingly, beta-catenin mutations are associated with chromosomal stability in both tumor types. Together, these studies define different pathways in liver cell transformation, reflecting various developmental stages and multiple risk factors. A detailed understanding of the molecular hits underlying liver tumorigenesis, combined with clinicopathological parameters, will permit an accurate evaluation of major targets for prognostic and therapeutic intervention.

Multi-component behavioral intervention to promote health protective behaviors in childhood cancer survivors: the protect study.

Abstract: Background Improved cure rates for childhood cancer have produced a growing population of survivors at risk for late toxicities of chemotherapy and radiation therapy. Healthy behaviors can modify these risks. We initiated a controlled prospective trial to determine if a multi-component behavioral intervention could induce change in childhood cancer survivors' health knowledge, health perceptions, and practice of health-protective behaviors. Procedure Adolescent cancer survivors attending a long-term follow-up clinic were randomized to receive standard follow-up care or standard care plus the educational intervention. Baseline measures were obtained at randomization (T0) and repeated 1 year (T1) later during the survivors' annual check-up. Results Of 272 patients enrolled and randomized, 251 are evaluable at both time points. Treatment and control groups were similar in regards to diagnosis, gender, race, and age. The change in outcome measures over the year (T1−T0) was not significantly different between the two groups as assessed by a two-sample pooled t test. However, additional exploratory analyses indicated a significant gender difference in knowledge with female survivors in the intervention group having higher scores. In addition, patients who choose certain individual health goals, such as breast/testicular self-examination, showed improved practice of the health behavior. In addition, in a very exploratory analysis, a gender difference in response to the intervention was noted, with females exhibiting a greater improvement in knowledge scores than did males. Conclusions Although the multi-behavioral educational intervention did not induce change in health knowledge, perceptions, and behaviors of childhood cancer survivors for the treatment group as a whole, gender differences and specific health goal differences were found. These findings suggest that future interventions should be tailored to reflect gender differences and the nature of the health goal under assessment. Med Pediatr Oncol 2002;39:2–11. © 2002 Wiley-Liss, Inc.

Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator.

Abstract: Background Reliable prediction of prognosis allowing risk-adapted therapy remains a major issue in the management of multisystem Langerhans cell histiocytosis (LCH). In a recent publication of the International LCH Study Group, response to initial therapy appears to be a reliable outcome predictor. The aim of this study is to test this observation in a cohort of patients treated with more intensive initial therapy. Furthermore, we compare the predictive value of response to initial therapy to some other well-established stratification systems. Procedure Response to initial combination chemotherapy (prednisolone, vinblastine, and etoposide) at 6 weeks and its prognostic value was evaluated retrospectively in 63 patients with multisystem LCH from the DAL-HX 83 and 90 Studies, and correlated to some established scoring systems from the literature. Results After 6 weeks of therapy, 50/63 (79%) patients qualified as responders, 4/63 (7%) patients showed intermediate response, and 9/63 (14%) patients did not respond. Probability of survival at 5 years was 0.94 ± 0.03 for responders, 0.75 ± 0.22 for patients with intermediate response, and only 0.11 ± 0.10 for non-responders. Conclusions Response to initial therapy appears to be a reliable prognostic predictor. Compared to the published international LCH-I Study, our results suggest that more intensive initial treatment allows a better discrimination between responders and non-responders. This allows to identify a subgroup of patients with extremely poor prognosis (mortality rate 90%) relatively early in the disease course. Med Pediatr Oncol 2002;39:581–585. © 2002 Wiley-Liss, Inc.

Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin.

Abstract: Background. We encountered on seven malignant hepatocellular tumors developing in older children and adolescents. Results. These tumors exhibit an unusual phenotype with respect to clinical presentation, histopathology, immunohistochemistry, and treatment response. As a working hypothesis, we suggest that these apparently novel, unusual, and aggressive tumors occurring in older children and adolescents may form a transition in the putative developmental pathway of hepatocarcinogenesis. Conclusion. We therefore propose the term, transitional liver cell tumors (TLCT), to denote these lesions.

Cholestasis, sclerosing cholangitis, and liver transplantation in Langerhans cell Histiocytosis.

Abstract: Objective To analyze features and outcomes of cholestasis, sclerosing cholangitis (SC), and liver transplantation (LTx) in patients with Langerhans cell Histiocytosis (LCH) between October 1987 and June 1999. Study design Of 182 cases with LCH, 36 had hepatic involvement and 12 of those presented with cholestasis. These 12 were the focus of our study. Their median age was 23 months (range: 3–36). Hepatomegaly or hepatosplenomegaly was found in 11 of the 12; elevations of alkaline phosphatase, transaminases, gamma glutamyl transpeptidase (GGT), and less frequently direct bilirubin were detected. Sonography, liver biopsy, and cholangiography were consistent with the diagnosis of SC in 11 patients. None of the biopsies revealed Langerhans cells (LC). Frequently associated lesions of skin, bone, and ear were noted. Early patients were treated with Vinblastine/prednisone for 8 weeks, later patients with the LCH I and LCH II protocols of the Histiocyte Society (HS). Results Median follow-up was 28 months (range: 10–86). Three patients improved and remained without signs of progressive SC at 27, 32, and 86 months. Nine had progressive liver sequelae resistant to chemotherapy. Of these nine, five received LTx, three died before LTx with progressive SC, and one awaits LTx. Three LTx patients survive without disease reactivation 14, 25, and 37 months post-transplant. Two patients died less than one month after LTx, due to renal failure and sepsis in the first patient and bowel volvulus with perforation followed by sepsis in the second one. Conclusions SC is a frequent and usually progressive sequela of multisystem LCH in our institution. LTx has become the treatment of choice for the majority of patientsand should be considered early in cases with severe hepatic involvement. Med Pediatr Oncol 2002;38:178–182. © 2002 Wiley-Liss, Inc.

Treatment of children and adolescents with localized parameningeal sarcoma: Experience of the Intergroup Rhabdomyosarcoma Study Group protocols IRS‐II through ‐IV, 1978–1997*†

Abstract: Background We reviewed 611 patients with parameningeal sarcoma entered on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-II through-IV (1978–1997), to delineate treatment results and evaluate prognostic factors. Procedure Primary sites were the middle ear/mastoid (N = 138), nasopharynx/nasal cavity (N = 235), paranasal sinuses (N = 132), parapharyngeal region (N = 29), and the pterygopalatine/infratemporal fossa (N = 77). Treatment was initial biopsy or surgery followed by multiagent chemotherapy and radiation therapy (XRT). Beginning in 1977, patients with cranial nerve palsy, cranial base bony erosion, and/or intracranial extension at diagnosis were considered as having meningeal involvement. They received triple intrathecal medications, whole brain XRT, and then spinal XRT. These treatments were successively eliminated from 1980 to 1991. Results The 611 patients' overall survival rate at 5 years was 73% (95% confidence interval, 70–77%). Favorable prognostic factors were: age 1–9 years at diagnosis; primary tumor in the nasopharynx/nasal cavity, middle ear/mastoid, or parapharyngeal areas; no meningeal involvement; and non-invasive tumors (T1). Thirty-five of 526 patients (6.7%) with information about presence/absence of meningeal involvement at diagnosis developed central nervous system (CNS) extension at 5–164 weeks (median, 46 weeks) after starting therapy. The estimated 5-year cumulative incidence rate of CNS extension during the study period was 5–7% (P = 0.88). Conclusions Biopsy, XRT to the target volume, and systemic chemotherapy are successful treatments for the large majority of patients with localized parameningeal sarcoma. Carefully defining and irradiating the initial volume should reduce the risk of CNS failure. Aggressive initial surgical management of these patients is unnecessary. Med Pediatr Oncol 2002;38:22–32. © 2002 Wiley-Liss, Inc.

Clinical and social factors that affect the time to diagnosis of Mexican children with cancer

Abstract: Background There are few studies on the factors that influence the time to diagnosis (TD) in childhood cancer. The object of the present study was to determine the influence of some clinical and social factors associated to TD in children with cancer seen at Mexico City (MC) hospitals. Procedure A retrospective study was performed. A total of 4,940 clinical records of children with cancer were reviewed. Cases of cancer were grouped, according to the International Classification of Childhood Cancer. The median (med) TD was calculated for each group (type) of cancer. The association between delayed TD (longer than 1 month) and type, age at diagnosis, parental educational level, medical institution, and place of residence was analyzed, for which the odds ratio (OR) and 95% confidence intervals (CI) were obtained. Results Leukemias had the shortest TD (med = 1 month), while Hodgkin disease (HD) and retinoblastoma had the longest TD (med = 5 months). The highest risk for delayed TD was in children with HD (OR = 7.0; 95% CI 5.3–9.3), in the 10–14 age group (OR = 1.8; 95% CI 1.4–2.3), with low maternal educational level (OR = 1.5; 95% CI 1.2–2.1), in the population with no access to social security (OR = 1.3; 95% CI 1.1–1.4), and whose place of residence is far from MC (OR = 1.5; 95% CI 1.2–2.1). Conclusions In Mexican children with cancer, age at diagnosis, and societal characteristics are important factors affecting timely diagnosis. Med Pediatr Oncol 2002;39:25–31. © 2002 Wiley-Liss, Inc.

SEER update of incidence and trends in pediatric malignancies: acute lymphoblastic leukemia.

Abstract: Background Acute lymphoblastic leukemia (ALL) represents the most common malignancy of childhood. Its incidence peaks in children just before school entry age; i.e., in 2–3 year olds. It is known to be more common in white children in the USA; the incidence is also higher in boys than girls. Procedure We reviewed the 5,379 cases of ALL among persons under 20 years of age in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database. Results The overall incidence of ALL was 26/106 person-years between 1973 and 1998, but increased from 19/106 person-years in 1973–77 to 28/106 person-years in 1993–98 (P < 0.0001). Rates were 44% higher among Whites compared to Blacks (27/106 person-years vs. 15/106 person-years, P < 0.0001). In 1992–1998, the incidence rate for Hispanics was 43/106 person-years, significantly higher than non-Hispanics (28/106, P < 0.0001). White children with ALL had better 5-year survival rates than Black children with ALL (71% vs. 58%, P < 0.0001), and 5-year survival was poorest among black males. Conclusions ALL incidence has increased over the examined 25-year period. The rate in US whites is higher than that of US Blacks, and the rates in the Hispanic subgroup are the highest of all. While the median survival period is now more than 10 years overall, the 5-year survival rate remains poor for Black males under 4 years of age. Socioeconomic factors do not account for this difference, which may relate to ALL subtype distribution. Med Pediatr Oncol 2002;39:554–557. © 2002 Wiley-Liss, Inc.

Epithelial salivary glands neoplasms in children and adolescents: A forty‐four‐year experience

Abstract: Background Epithelial neoplasms of salivary gland origin are relatively uncommon in children and adolescents. Over a 44-year period, there were 38 cases affecting children under 19 years of age in our Pediatric Hospital-Based Tumor Registry. Procedure Medical charts of 38 patients with epithelial neoplasms of salivary glands were reviewed. Data collected included demographic, clinical, and histological characteristics. Statistical analysis included descriptive statistics, Student t-test, and Kaplan–Meier method was used for survival analysis. Results The mean age was 11.8 years. There was a female preponderance of 1.9:1. The parotid gland was affected in most cases (65.8%). Twenty-seven patients had malignant tumors and eleven patients presented benign neoplasms. Pleomorphic adenoma was the most frequent benign tumor (7 out of 11) and mucoepidermoid carcinoma was the most frequent malignancy (17 out of 27). Five-year overall survival rate was 81.6% for patients with malignant tumors. Grade of differentiation was the only significant prognostic factor for patients with mucoepidermoid carcinomas. Conclusions Epithelial salivary gland tumors are very rare in children. Surgery is the best option to achieve high cure rates and radiotherapy must have precise indications because of their long-term side effects in young age. Med Pediatr Oncol 2002;39:594–600. © 2002 Wiley-Liss, Inc.

Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study.

Abstract: Background, In adults, it has been shown that the pharmacokinetics of doxorubicin are highly variable, despite standardization of the dose based on body surface area (BSA). The purpose of this study was to determine the plasma concentrations of doxorubicin and its active metabolite doxorubicinol in children treated for acute lymphoblastic leukemia (ALL). Procedure. Children, 107 in number, aged 1.3-17.3 years, were studied at Day 1 of induction therapy according to the current Nordic protocol. Five infants, 3-9 months old, were also included. Plasma samples were drawn 23 hr after the start of a 24-hr infusion of doxorubicin 40 mg/m(2), and analyzed by reversed-phase liquid chromatography. Results. There was a more than 10-fold difference between patients in dose normalized plasma concentration of doxorubicin, median 62.8 ng/ml, range 22.6-334 ng/ml. The doxorubicin concentrations differed significantly between age groups (P=0.003). Children aged 4-6 years had the highest doxorubicin concentrations, median 77.9 ng/ml, followed by 2-4-year-old children, median 64.3 ng/ml. Both younger and older children had median values of about 50 ng/ml. Patients with white blood cell (WBC) count > 50 x 10(9)/L at diagnosis had significantly lower doxorubicin concentrations, median 55.3 ng/ml, than those with WBC count < 10 x 10(9)/L, median 64.4 ng/ml (P 0,015). There was no difference in doxorubicin concentration between boys and girls. No correlation was found between doxorubicin levels and serum aminotransferases or serum creatinine. The concentration of doxorubicinol was 13% (median value) of that of doxorubicin. Four infants, 7-9 months old, had plasma clearance between 350-431 ml/min/m(2), which is in the same range as in older children. A 3-month-old infant had a clearance of 181 ml/min/m(2). Conclusions. The age groups who had the highest doxorubicin concentrations, (2-) 4-6-year-old children, are known to make up a large proportion of standard risk ALL cases with good prognosis. The correlation between doxorubicin plasma levels and clinical effect needs further study. The influence of age, body composition, and tumor burden on the pharmacokinetics of antineoplastic drugs should also be further explored, aiming at improvements in the current dosing regimen based on BSA. (C) 2002 Wiley-Liss, Inc.

Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group.

Abstract: Background Malignant vascular tumors are extremely rare in childhood and few data on their clinical management are available. We report on a series of 18 children who had malignant vascular tumors, treated from 1980 to 2000 by the Italian and German Soft Tissue Sarcoma Cooperative Group. Procedure Twelve patients had angiosarcoma, four had malignant hemangioendothelioma, and two had Kaposi's sarcoma. Surgical resection was completed in six cases; radiotherapy was administered to 6 children, and chemotherapy to 14. Results After a median follow-up of 208 months, the 5-year survival and event-free survival rates were 30.9 and 20.8%. Six patients were alive, four in first remission (three had tumor < 5 cm, grossly completely resected), and two in second remission. Response to chemotherapy was evaluable in nine cases and was: six no response, two partial remission, one complete remission. Conclusions Angiosarcoma and related malignant vascular tumors are aggressive neoplasms with a poor prognosis; their behavior in children seems no different from their adult counterparts. Complete surgical resection remains the mainstay of treatment, but is probably sufficient in only a minority of cases. Postoperative radiotherapy may have a role and could be added to improve local control. The role of chemotherapy is uncertain, but the high rate of metastatic spread prompts investigation into new chemotherapeutic approaches. Med Pediatr Oncol 2002;39:109–114. © 2002 Wiley-Liss, Inc.

Adult type vs. Childhood hepatocellular carcinoma--are they the same or different lesions? Biology, natural history, prognosis, and treatment.

Abstract: Background. Differences in the biology, natural history, and treatment results of hepatocellular carcinoma (HCC) in children and adults were sought based on the literature and experience resulting from SIOPEL 1 trial. Procedure. In the SIOPEL1 study, 40 children with HCC were registered from January 1990 to February 1994. Outcome was analyzed in 39. In most cases, disease was advanced at diagnosis: 31% had metastases and 39% had extrahepatic tumor extension and/or vascular invasion. More than 50% of patients had multifocal tumors; 39% of tumors were associated with hepatic cirrhosis. All, but two patients, received preoperative chemotherapy (PLADO-cisplatin and doxorubicin). Outcome, response to treatment, and prognostic factors were analyzed using the SAS statistical package. Results. Overall survival (OS) at 5 years is 28% and EFS is 17% at median follow-up of 75 months (49-90). Partial response to chemotherapy was observed in 18 of 37 cases evaluated (49%). Complete tumor resection was achieved in 14 of the 39 patients (36%). Twenty (51%) never became operable. Multifocality of the tumor, presence of metastases, and PRETEXT grouping adversely influenced OS. A large number of "de novo" HCC cases, fairly high response rate to preoperative chemotherapy (49%) and 54% survival after complete resection constitute a significant difference in comparison with adult HCC series. Conclusions. Survival for pediatric HCC patients is below 30%. Radical tumor resection remains the only chance for survival. New multi-center prospective studies in children with HCC are required to better results and to allow further study of differences between adult and pediatric HCC should they exist.

Combined chemotherapy and local treatment in the management of intraocular retinoblastoma.

Abstract: BACKGROUND: To assess the efficacy of chemotherapy (chemoreduction) plus local treatments as an alternative to external beam and enucleation for intraocular retinoblastoma. MATERIALS AND METHODS: A prospective study was performed on 21 patients with retinoblastoma treated in our institution from September 1997 to December 2000 to study the ocular outcome of those 33 eyes. RESULTS: There were 9 unilateral and 12 bilateral retinoblastoma cases. There were 12 eyes with Reese-Ellsworth group I-IV and 21 eyes with group V. Among 33 eyes, nine eyes (27%) were initially managed by enucleation. The remaining 24 eyes (73%) were initially treated with chemoreduction (maximum of six cycles of carboplatin, vincristine, etoposide) or chemothermotherapy. Among those 24 eyes, 20 were successfully treated with local treatments (thermotherapy plus cryotherapy in 16 eyes and thermotherapy plus cryotherapy plus (125)I plaque radiotherapy in 4 eyes), enucleation eventually underwent in two eyes and was proposed but refused in one child with bilateral group V retinoblastoma. With a median follow-up of 21 months, conservative management without external beam radiation was successful in all 12 eyes with group I-IV and in a total of 20/33 eyes (60%). Among the nine cases of unilateral retinoblastoma, eight were enucleated but among the 24 eyes with bilateral retinoblastoma, 19 (79%) were successfully treated with conservative therapy. CONCLUSIONS: It may be possible to eradicate viable tumor in all eyes with Reese-Ellsworth group I-IV retinoblastoma by chemoreduction followed by local treatments. Although 8 out of 21 eyes (38%) with group V retinoblastoma may be salvaged after chemoreduction and local therapies, enucleation remained the treatment of choice in those eyes with total retinal detachment and diffuse vitreous seeding.

Body composition of long-term survivors of acute lymphoblastic leukaemia.

Abstract: Background Long-term quality of life is of growing importance in children previously treated for malignancy. Obesity defined indirectly from indices of height and weight, has been described in long-term survivors of acute lymphoblastic leukaemia (ALL) and hypothesised to be a consequence of previous cranial irradiation. Procedure In this study, measures of whole and regional body composition using skinfold and dual energy X-ray absorptiometry (DEXA) measurements have been made in 35 long-term survivors of ALL who had received cranial irradiation and chemotherapy. To assess the influence of cranial irradiation, results were compared with those obtained in 21 children treated for other malignancies, who received chemotherapy alone and with 31 healthy sibling controls. Results Girls treated for ALL were significantly fatter than those treated for other malignancies or healthy control siblings whether measured by skinfold thickness (median (range) 37.4% (17.9–41.3) vs. 24.6% (19.1–35.0) and 28.8% (19.6–43.1), respectively, P < 0.01) or DEXA (33.5% (20.5–42.8) vs. 25.5% (16.5–31.0) and 24.5% (18.8–53.6), respectively, P < 0.01). Boys treated for ALL were not significantly fatter than boys in the other two groups. Measures of whole body percent fat derived from DEXA were persistently less than those derived from skinfold measurements with a mean (95% CI) difference of 2.4% (1.7–3.1, P < 0.001) for all groups combined. In ALL survivors, using regression equations for skinfold thicknesses derived from controls with DEXA as the ‘gold standard’ method, fat mass was significantly overestimated. Conclusion Female survivors of ALL are significantly fatter than those of other malignancies and healthy sibling controls. Caution should be observed in the application of published equations, derived from the normal population, for the calculation of body composition in children treated for ALL. The mechanism of onset of obesity remains unclear, but is probably multifactorial and related to previous cranial irradiation. Med Pediatr Oncol 2002;38:165–172. © 2002 Wiley-Liss, Inc.

Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis.

Abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is, without treatment, an invariably fatal disease of infancy and early childhood characterized by fever, hepatosplenomegaly, pancytopenia, and a widespread accumulation of T-lymphocytes and macrophages. During recent years, the diagnosis and the survival as well as the understanding of the disease have improved dramatically. Recent studies suggest that FHL is caused by impaired lymphocyte-mediated cytotoxicity and defective triggering of apoptosis, and that the symptoms are mediated by a pro-inflammatory hypercytokinemia. Moreover, specific genetic alterations, mutations in the perforin gene, have been revealed in FHL patients. Perforin, which normally is secreted from cytotoxic T-lymphocytes and natural killer (NK) cells upon conjugation between effector and target cells, is able to insert into the membrane of the target cell. It there polymerizes to form a cell death-inducing pore through which toxic granzymes may enter the cell and trigger apoptosis. The establishment of perforin deficiency as a cause of the rapidly fatal disease FHL has demonstrated the essential role of perforin in human immune homeostasis.

Evolving concepts of management of febrile neutropenia in children with cancer.

Abstract: Background Recent investigations of febrile neutropenia in pediatric cancer patients have identified subsets of low-risk patients who can be managed with less antibiotic therapy than previously recommended standards. Methods and Materials PubMed and Medline were searched for prospective trials and reviews of febrile neutropenia in children. Magnitude and duration of fever and neutropenia, comorbidities, and therapeutic strategies were examined. Results Twenty-seven prospective trials and five reviews were identified. The child with cancer and low-risk febrile neutropenia is clinically well and afebrile within 24–96 hr of antibiotic therapy and has evidence of marrow recovery with a rising phagocyte count. Disqualifying comorbidities include leukemia at diagnosis or in relapse, uncontrolled cancer, age under 1 year, medical condition(s) that would otherwise require hospitalization and social or economic conditions that may potentially compromise access to care or compliance. Therapeutic strategies include parenteral or oral antibiotics in the hospital with early discharge or parenteral antibiotics in the outpatient setting followed by oral or parenteral therapy and daily reassessment. Although as many as 25% of low-risk patients require modification of therapy and/or hospitalization, life-threatening or fatal infection is exceptional. Conclusion One-third to one-half the children with febrile neutropenia are at low-risk of serious infection. In the context of clinic trials, they can be safely managed with inpatient or outpatient strategies that maintain close follow-up and reduce the burden of antibiotic therapy. Adoption of these alternative strategies as the standard of care should proceed with caution guided by written protocols. Med Pediatr Oncol 2002;39:77–85. © 2002 Wiley-Liss, Inc.

Cytogenetic abnormalities and clinical outcome in Wilms tumor: a study by the U.K. cancer cytogenetics group and the U.K. Children's Cancer Study Group.

Abstract: Background Tumor genetic features reported to correlate with adverse outcome in Wilms tumor include karyotype complexity, losses of material from the short arm of chromosome 1 and from the long arms of chromosomes 11, 16 and 22 and gain of material from the long arm of chromosome 1. This study sought to test these associations in a large series of tumors studied by cytogenetic analysis. Identification of markers associated with elevated risk of relapse and fatal outcome could allow more effective treatment stratification at presentation. Procedure Thirteen member laboratories of the U.K. Cancer Cytogenetics Group provided results from a 12-year period. Karyotype abnormalities were correlated with clinical data (age, tumor stage, and histology) and outcome data provided by the central register of the U.K. Children's Cancer Study Group. Results Of 127 abnormal karyotypes, 78 included a reputedly “poor prognosis” feature. Univariate survival analysis showed no significant adverse effect for karyotype complexity, 1p loss or 11q loss. The poor outcome of cases with 16q loss was of borderline significance, but this effect was restricted to those tumors with unbalanced translocation der(16)t(1q;16q). The association between relapse risk and gain of 1q material was not significant. Only monosomy 22 was a significant marker of poor outcome in univariate analysis (13 cases showing 50% relapse free survival at 5 years compared to 79% survival for the remaining 114 cases, P = 0.02). In multivariate analysis, significant independent predictors of poor outcome were 1q gain (Hazard Ratio 3.4), stage IV disease (HR 5.0), and monosomy 22 (HR 5.9). Conclusions Loss of chromosome 22 identifies high risk Wilms tumors. The prognostic significance of 1q gain, 16q loss and unbalanced translocation der(16)t(1q;16q) is unresolved and warrants further investigation. Med Pediatr Oncol 2002;38:11–21. © 2002 Wiley-Liss, Inc.

Epidemiology of cancer in adolescents.

Abstract: In western populations, the annual incidence rate of cancer among adolescents aged 15-19 years is around 150-200 per million, intermediate between the rates for older children and young adults. The most frequent diagnostic groups are acute leukemia, lymphomas, central nervous system tumors, bone and soft tissue sarcomas, germ cell tumors, thyroid carcinoma, and malignant melanoma. While the causes of most cancers in teenagers are still unknown, health education and promotion and public health programs offer some scope for prevention among people of this age group. Reduction in sun exposure should lead to a reduction in incidence of melanoma, and elimination of hepatitis B in regions where it is endemic should result in a decrease in hepatic carcinoma. Five-year survival of patients diagnosed around 1990 exceeded 70% in the USA and UK. Entry to clinical trials appears to be much less frequent for adolescents with cancer than for children. There is some evidence that higher survival is associated with entry to trials or centralized treatment for certain cancers in this age group.

Radiotherapy for medulloblastoma in children: A perspective on current international clinical research efforts

Abstract: Background The North America and four European pediatric cooperative groups have undertaken prospective studies for medulloblastoma continuously since the 1970s. In this article, we will review the results of these studies with respect specifically to the use of radiotherapy, and trace the developments that have led up to the present trials for patients with this tumor. Procedure Published and unpublished data from the North American CCG and POG and now COG studies, from the UKCCG and SIOP groups, as well as from the French and German groups were reviewed. Issues of especial interest included radiotherapy dose and dose fractionation schedules, scheduling of chemotherapy and radiotherapy, and technical aspects of treatment with radiotherapy that might impact on outcome. Results and Conclusions Much progress has been made in the management of medulloblastoma in childhood as a consequence of the studies undertaken sequentially by these groups over the past two decades. It now seems clear that chemotherapy plays an important role for all patients. In patients with average risk disease, the use of chemotherapy has allowed a reduction in the dose of radiotherapy to the craniospinal axis and the combination of chemotherapy with radiotherapy appears to have brought about a significant improvement in disease-free and overall survival in this patient population. Patients with high-risk disease fare better now than in the past as a consequence of the routine use of aggressive chemotherapy and preliminary data suggest that the use of higher doses of radiation as in the POG studies is associated with a particularly favorable outcome. Accurate delivery of radiotherapy is essential for optimal results. The avail-ability of better tools at the treating centres and quality control as an integral part of cooperative studies are likely to bring about further improvements in outcome in the future. Med Pediatr Oncol 2002;39:99–108. © 2002 Wiley-Liss, Inc.

Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor.

Abstract: Background Desmoplastic small round cell tumor (DSRCT) is an aggressive and often misdiagnosed neoplasm of children and young adults. It is chemotherapy-sensitive, yet patients often relapse off therapy because of residual microscopic disease at distant sites: peritoneum, liver, lymph node, and lung. Strategies directed at minimal residual disease (MRD) may be necessary for cure. Monoclonal antibodies selective for cell surface tumor-associated antigens may have utility for diagnosis and therapy of MRD, as recently demonstrated in advanced-stage neuroblastoma (JCO 16: 3053, 1998). We examined DSRCT samples for the expression of two tumor antigens that could serve as possible targets for antibody-based immunotherapeutic approaches. Procedures Using immunohistochemistry, we studied the expression of two antigens: (1) GD2 using antibody 3F8 and (2) a novel antigen using antibody 8H9 in a panel of 46 freshly frozen DSRCT. GD2 is a disialoganglioside, which is widely expressed among neuroectodermal tumors as well as adult sarcomas. 8H9 recognizes a 58 kDa surface antigen expressed among neuroectodermal, mesenchymal, and epithelial tumors with restricted expression on normal tissues. Results Thirty-two of 46 (70%) tumors were reactive with 3F8, and 44 of 46 (96%) with 8H9. Both GD2 and the 58 kDa antigen were localized to tumor cell membrane and stroma. In general, immunoreactivity was stronger and more homogeneous with 8H9 than with 3F8. There was no correlation between expression of either antigen or clinical outcome. Conclusions GD2 and the novel tumor antigen recognized by 8H9 are potential targets for immunodiagnosis and antibody-based therapy of DSRCT. Med Pediatr Oncol 2002;39:547–551. © 2002 Wiley-Liss, Inc.

Supratentorial embryonal tumors in children under 5 years of age: an SFOP study of treatment with postoperative chemotherapy alone.

Abstract: Background To determine the effectiveness of multiagent chemotherapy as sole post-operative treatment of supratentorial central nervous system (CNS) embryonal tumors in young children. Procedure The data of 25 children under 5 years of age diagnosed with supratentorial embryonal tumors (17 primitive neuroectodermal tumors, four pinealoblastomas, and four medulloepitheliomas) treated exclusively by postoperative chemotherapy (CT) between 1990 and 1997 were reviewed. Results Fifteen tumors were hemispheric and 10 were deeply seated. Four children presented with disseminated leptomeningeal disease. Total resection was performed in nine patients, subtotal in 9, partial in 3, and a diagnostic biopsy only in 2. Two children did not undergo surgery. Twenty-four children relapsed with a median time of 5.5 months. The median overall survival was 12 months, and the 2-, and 5- year survivals were 30 and 14y, respectively. The 2- year disease-free survival was 4%. There was a significantly worse prognosis in patients undergoing incomplete resection and in the group with deeply situated tumors. Four relapses were treated by second surgery followed by high-dose chemotherapy and radiotherapy. Two of them remain in CR2, and all these children are free of late sequelae. Conclusions CT alone failed to maintain disease-free survival in most of the children, although, disease progression was delayed to some extent. Children under 5 years with supratentorial embryonal tumors should undergo total surgical resection if possible. Med Pediatr Oncol 2002;38:83–90. © 2002 Wiley-Liss, Inc.

Prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in 41 children with cancer--a prospective study.

Abstract: Background This study was designed to prospectively evaluate the prevalence of thrombophilia and central venous catheter-associated neck vein thrombosis in children with cancer. Procedure Children with cancer and central lines, treated at the National Hospital in Norway, were consecutively enrolled in the study. Biochemical analysis of thrombophilia and Doppler ultrasonography of neck veins were performed at inclusion, and ultrasonography was repeated 3–5 months later. We recorded systematically positive blood-cultures and days with intravenous antibiotics. In a subgroup of 13 patients with acute lymphoblastic leukaemia, the thrombophilia parameters were re-evaluated during asparaginase therapy. Results Forty-one children were included in the study and observed for a mean of 266 days (range 95–569 days). Eighteen patients (44%) developed venous thrombosis (VT), visualized by Doppler ultrasonography of the catheterized vein. Some clots were transient, but blood clots with diameters > 0.5 cm (n = 11) had a tendency to remain (P = 0.14). Twelve children (29%) were classified as thrombophilic at inclusion, with elevated serum levels of homocysteine and lipoprotein (a) as the most frequent alterations. Transient thrombophilia developed in all patients during asparaginase-therapy. Within the limitations of our study, we did not find any significant correlation between thrombophilia and development of VT, nor thrombosis and infectious disease. Conclusions VT develops frequently in paediatric cancer patients with central lines, but the clinical implication of this observation remains to be clarified. Med Pediatr Oncol 2002;38:405–410. © 2002 Wiley-Liss, Inc.

Antibody formation during intravenous and intramuscular therapy with Erwinia asparaginase.

Abstract: Background Determination of the frequency of antibody formation during first and second exposure to Erwinia asparaginase after i.v. and i.m. administration. Procedure Thirty-nine children with newly diagnosed acute lymphoblastic leukemia (ALL) were included in this prospective study. Antibodies were determined (ELISA method) in plasma from these patients on specific days during and after therapy with 30,000 IU/m2 i.v. or i.m. every day for ten days during the induction phase (first exposure). For 19 children, antibodies were measured in plasma during and after the re-induction phase (second exposure) following treatment with 30,000 IU/m2 i.v. or i.m. twice a week for two weeks (Mondays and Thursdays). On the same days of therapy, enzyme activity (spectrophotometric method) and the concentration of asparagine (HPLC) was determined. Results During the first exposure, none of the patients developed anti-Erwinia asparaginase antibodies. During the second exposure, one patient (1 of 8 patients) treated intravenously developed antibodies, which were associated with disappearance of enzyme activity and reappearance of asparagine. Three of eleven patients developed antibodies of pharmacokinetic importance after i.m. therapy. None of the children had any clinical symptoms of hypersensitivity. Conclusions The formation of antibodies and subsequently altered pharmacokinetics of Erwinia asparaginase seemed to be of importance only during a second period of asparaginase therapy. Med. Pediatr. Oncol. 2002;38:310–316. © 2002 Wiley-Liss, Inc.