Epidemiology of osteosarcoma and Ewing's sarcoma in childhood: a study of 305 cases by the Children's Cancer Group

BACKGROUND: The Children's Cancer Group conducted a case-control study to determine the role of a broad range of environmental and familial factors in the etiology of Ewing's sarcoma and osteosarcoma in children. These factors included radiation exposure and, for children with osteosarcoma, parental exposure to beryllium. METHODS: The parents of 152 children with osteosarcoma and 153 children with Ewing's sarcoma were interviewed by telephone. Controls were obtained by random digit dialing and were matched to cases by age and race. RESULTS: Female osteosarcoma patients had earlier onset of breast development (age 11.4 vs. 11.8 years, P=0.03) and menarche (age 12.1 vs. 12.5 years, P=0.002) but no significant differences in growth, whereas male osteosarcoma patients were similar in age at the onset of secondary sexual characteristics but reported significantly less weight gain during their growth spurt (6.6 vs. 11.7 kg, P=0.003). For children with Ewing's sarcoma, the growth spurt began earlier (age 12.1 vs. 12.7 years, P=0.12) and resulted in less weight and height gain (5.2 vs. 9.7 kg, P=0.002, and 10.2 vs. 12.7 cm, P=0.02, respectively) for males, but no differences were observed among females. For factors not related to growth and development (including a wide range of occupational, medical, and household exposures), there was little evidence of an etiologic role with respect to either tumor type. CONCLUSIONS: Differences between cases and controls with respect to growth and development showed no consistent pattern. This study did not identify any important risk factors for either type of childhood bone tumor.     

Does histology influence outcome in childhood Hodgkin's disease? Results from the United Kingdom Children's Cancer Study Group

PURPOSE: Histology has been identified as an important prognostic factor in Hodgkin's disease (HD) in adults. Information regarding the impact of histology on outcome in childhood HD is scarce. This study determines the effect of histology on the overall survival (OS) or progression-free survival (PFS) in a national series of children treated in a standardized manner. PATIENTS AND METHODS: The results of treatment of 331 assessable patients, treated between January 1, 1982 and June 30, 1992, in the United Kingdom Children's Cancer Study Group (UKCCSG) Hodgkin's study I were reviewed to evaluate OS, PFS, and deaths according to stage and histology. Treatment was either involved-field radiation alone (stage IA) or chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) chemotherapy with or without mediastinal radiation. All were clinically staged at diagnosis. RESULTS: Nodular sclerosing (NS) HD was the most common histologic subtype (155 of 331 patients [47%]) and was uniformly distributed through all stages. Lymphocyte-depletion (LD) HD was extremely uncommon (< 1%). Mixed-cellularity (MC) HD had the highest relapse rate, but this was only significant (P < .05) in stage I patients who received local irradiation alone. There was no other statistically significant difference in OS and PFS between the various histologic subtypes. Multivariate analysis for PFS and OS confirmed that stage was the most important prognostic factor and that histology did not have an effect after stratification by stage. CONCLUSION: This study demonstrates that with effective multiagent chemotherapy, histologic subtype does not influence outcome. The high relapse rates in stage I MC subtype indicates that MC HD is biologically aggressive and systemic treatment with or without local irradiation may be indicated. The high relapse rate in stage IV patients appeared to be independent of histology.     

Analysis of the immunophenotype of children treated on the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia Trial XI (MRC UKALLXI). Medical Research Council Childhood Leukaemia Working Party

Despite many years of meticulous immunophenotyping of childhood acute lymphoblastic leukaemia (ALL) cases the prognostic significance of some subtypes remains unclear. The Medical Research Council UKALLXI trial (1990-1996) in which uniform treatment has been given to 2090 children with ALL below the age of 18 years and above the age of 1 year, has afforded the opportunity to review these issues. Children with ALL of mature B cell type were not entered into this trial. Immunophenotype analysis was performed in each individual trial centre, but results were centrally reviewed in all cases, and were both available and considered adequate in 1934 (93%) of the first 2090 patients entered. The main diagnostic categories were early pre-B or null reported in 60 cases (3.1%), common ALL in 1242 (64.2%), pre-B in 252 (13.0%), 'common' or pre-B in 172 (8.9%) and T cell in 207 (10.7%) cases. Children with T cell disease were significantly more likely to be over the age of 10 years, with central nervous system disease at diagnosis and to be CD34 negative. They also had a higher incidence of high white cell count and were more likely to be of the French-American-British (FAB) L2 morphological subtype. Patients with 'null' cell disease tended to be less than 2 years or greater than 10 years of age, and CD13 and CD33 positive. CD10 was associated with lower white cell count (WBC) at diagnosis, younger age and FAB L1 morphological subtype. The presence of cytoplasmic immunoglobulin in pre-B cells was not associated with any specific clinical or laboratory features. CD34 positivity was less common in T cell patients and was associated with low WBC. Disease-free survival (DFS) and 95% confidence intervals (CI) at 5 years from diagnosis was 52% (95% CI: 44-59%) for T cell disease, 58% (95% CI: 43-73%) for early pre-B (or null cell) disease and 65% (95% CI: 62-68%) for common or pre-B disease; there being no significant difference between common and pre-B disease with regard to disease outcome. Patients with T cell disease had a worse prognosis than any other immunophenotype group (P < 0.00005). However this worse outcome was no longer significant after allowing for the other principal prognostic factors of age, gender and white cell count at diagnosis except for the very small number with WBC <20 x 10(9)/l and T cell disease. Those with CD10-positive leukaemia did better than those who were CD10 negative (P < 0.00005), with DFS at 5 years 64% (95% CI: 62-67%) for positive vs 56% (95% CI: 49-62%) for CD10 negative. CD10 positivity did not have independent significance when white count, gender and age were taken into account. CD13, CD33, and cytoplasmic mu positivity carried no prognostic significance.     

The National Treatment Outcome Research Study in the United Kingdom: Six-month follow-up outcomes.

The National Treatment Outcome Research Study is the first prospective, multisite treatment outcome investigation of drug users in the United Kingdom. The findings of this influential national study are being used by the Department of Health to formulate purchasing guidance. This article presents data on substance use problems for clients (N?=?1,075) in specialist inpatient, rehabilitation, methadone maintenance, and methadone reduction modalities. The most frequent problem was heroin addiction with associated polydrug use problems. There were differences between modalities in substance use at intake. Clients in residential modalities were older, were more likely to use cocaine and alcohol in addition to opiates, had longer drug careers, and had more previous treatment contact. Substantial improvements in a range of substance use problems were observed at 6-month follow-up among clients in all treatment modalities. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study

Cytogenetic and clinical details are presented for 66 patients with myeloid malignancy and chromosome abnormalities of 3q21 and/or 3q26 (3qabns). Bone marrow and/or peripheral blood morphology was assessed for 52 cases. 3qabns in Philadelphia negative (Ph-ve) and positive (Ph+ve) cases were inv(3)(q21q26), (21 Ph-ve, 6 Ph+ve); t(3;3)(q21;q26) (nine Ph-ve, four Ph+ve); and t(3;21)(q26;q22) (four Ph-ve, six Ph+ve). Ph-ve cases also had t(1;3)(p36;q21) (three cases), and t(3;5)(q21;q31)/(q21;q35)/(q26;q21) (five cases aged < 40 years). Three cases, aged < 30 years, had t(3;12)(q26;p13) which defines a new 3qabn subgroup. Monosomy 7 and/or 5q- accompanied inv(3) or t(3;3) in 17/30 cases. All cases had a myeloid malignancy (predominantly AML M1, M4 or M7), frequent trilineage myelodysplasia, and markedly abnormal megakaryopoiesis with micromegakaryocytes (< 30 microns). Thrombocytosis occurred in two cases only. Most Ph+ve cases were in myeloid blast crisis and in Ph+ve cases alone, micro-megakaryocytes were uniquely small (10 microns) in 7/11 cases. There were equal numbers of males and females. Seven secondary leukaemias were found in Ph-ve cases with inv(3), t(3;3), t(3;21), t(1;3) or del(3)(q21). Three cases with t(3;21) (one Ph+ve) were de novo AML or had de novo aplastic anaemia. Survival was rarely greater than 12 months from detection of the 3qabn.     

United Kingdom Cancer Research Campaign approach to quality-of-life research in cancer clinical trials

Clinical trials of new anticancer therapies form an important part of the research activity of the Cancer Research Campaign (United Kingdom), and quality-of-life (QOL) end points are being increasingly used in the evaluation of new treatment approaches. The Campaign has a unique policy of supporting a broad range of scientific and clinical research, including psychosocial studies, and thus QOL research is generated in a variety of clinical settings. The focus of interest for the Cancer Research Campaign lies in QOL design and assessment rather than the routine application of QOL protocols. Clinical investigators are free to adopt in individual approach, but the Campaign operates a strict peer-review system in protocol assessment. Some standardization of approach is being achieved through consensus of opinion and wide collaboration, both nationally and internationally.     

Treatment results of intermittent and cyclic regimen with ATRA and chemotherapy in childhood acute promyelocytic leukemia. Children's Cancer and Leukemia Study Group

An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.     

Cancer in human immunodeficiency virus-infected children: a case series from the Children's Cancer Group and the National Cancer Institute

PURPOSE: To describe the spectrum of malignancies in human immunodeficiency virus (HIV)-infected children and the clinical outcome of patients with these tumors. METHODS: We retrospectively surveyed the Children's Cancer Group (CCG) and the National Cancer Institute (NCI) for cases of cancer that occurred between July 1982 and February 1997 in children who were HIV seropositive before or at the time of cancer diagnosis. We used Kaplan-Meier survivorship curves, hazard function estimates, and Cox proportional hazards models to evaluate survival. RESULTS: Sixty-four children (39 boys, 25 girls) with 65 tumors were reported. Thirty-seven children (58%) acquired HIV infection vertically (median age at cancer diagnosis, 4.3 years); 22 children (34%) acquired HIV through transfusion of blood or blood products (median age at cancer diagnosis, 13.4 years). Forty-two children (65%) had non-Hodgkin's lymphoma (NHL). Eleven children (17%) had leiomyosarcomas (or leiomyomas), which are otherwise exceptionally rare in children. Other malignancies included acute leukemia (five children), Kaposi's sarcoma (KS; three children), Hodgkin's disease (two children), vaginal carcinoma in situ (one child), and tracheal neuroendocrine carcinoma (one child). Median survival after NHL diagnosis was 6 months (range, 1 day to 89 months) and after leiomyosarcoma was 12 months (range, 10 days to 19 months). The average monthly death rate after NHL diagnosis was 12% in the first 6 months, which decreased to about 2% thereafter. In contrast, the monthly death rate after leiomyosarcoma diagnosis increased from 5% in the first 6 months to about 20% thereafter. CONCLUSION: After NHL, leiomyosarcoma is the second leading cancer in children with HIV infection. Both cancers have high mortality rates; improved outcome for NHL, in particular, may depend on earlier diagnosis and therapy.     

Prognostic significance of B-lineage leukemic cell growth in SCID mice: a Children's Cancer Group Study

Primary leukemic cells isolated from children (N = 681 ) with newly diagnosed B-lineage ALL enrolled on risk-adjusted treatment protocols of the Children's Cancer Group (CCG) were injected via the tail vein into 7-10 week old SCID mice. Leukemic cells from 104 of 681 patients (15.3%) were able to engraft and proliferate in one or more SCID mouse organs. These SCID+ patients were somewhat more likely than SCID patients to be older than 10 years of age (p = 0.03) and have WBC counts >20,000/microL (p = 0.04), but the groups were similar with respect to all other presenting features. Event-free survival (EFS) outcome at 3 years of follow-up was similar for SCID+ patients compared with SCID- patients (79.2%, SD = 5. 1% vs. 84.8%, SD = 2.8%; p = 0.20). Overall survival also was similar between the two groups (p = 0.93). This result was maintained within the subgroups of lower risk (N = 448) and higher risk (N = 233) patients. However, there were trends for poorer outcome among patients whose cells caused overt leukemia in SCID mice and infiltrated either 6 or more organs (p = 0.03), skeletal muscle (p = 0.0003), kidney (p = 0.05), or spleen (p = 0.06). Thus, engraftment of primary leukemic cells in SCID mice was not a significant predictor of outcome for the aggregate population of B-lineage ALL patients, the majority of whom were low risk, treated according to contemporary intensive chemotherapy programs of the CCG. However, development of disseminated overt leukemia and infiltration of SCID mouse skeletal muscle by primary leukemic cells from adjacent bone marrow may reflect a biologically more aggressive disease and identify patients at higher risk for treatment failure.     

Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience

PURPOSE AND METHODS: We reviewed the clinical records and pathologic findings of 37 children and adolescents with synovial sarcoma treated at our institution over a 30-year period to evaluate the prognostic significance of tumor size, invasiveness, histology, and other features. RESULTS: The 20 male and 17 female patients with synovial sarcoma had a median age of 13.7 years at diagnosis. Primary tumor sites were the extremities (n = 27), trunk (n = 8), and head and neck (n = 2). Disease stage (clinical group) was as follows: group I, n = 21; group II, n = 7; group III, n = 4; and group IV, n = 5. Nineteen patients had invasive (T2) lesions, 20 had tumors more than 5 cm in diameter, and 14 had histologic grade 3 lesions. The estimated 5-year survival rate (+/- SE) for patients with group I or II disease was 80% +/- 9%, compared with 17% +/- 15% for those with group III or IV tumors (P = .0003). An exact log-rank test, adjusted for clinical group, showed that tumor invasiveness and grade independently predicted overall and progression-free survival (P < .05); tumor size was significantly correlated with progression-free survival. A borderline significant relationship with overall survival was found for both tumor size and histologic subtype (P = .09). CONCLUSION: A controlled trial of adjuvant chemotherapy is merited in children with resected synovial sarcoma (clinical group I or II) who present with unfavorable clinicopathologic features such as large, invasive, or grade 3 lesions. Children with unresected or metastatic disease fare poorly despite multimodality therapy and require novel treatment approaches.     

The type of local treatment conditions the prognosis in patients with nonmetastatic Ewing's sarcoma of the extremities treated with adjuvant chemotherapy

The results obtained in 172 cases of non metastatic Ewing's sarcoma of the extremities are reported. The patients were advised to undergo surgical treatment, followed by radiotherapy (40-45 Gy) in case of inadequate surgical margins. 48 patients who refused surgical treatment, were locally treated with radiotherapy alone (50-65 Gy). With a mean follow-up of 8 years (R. 3-15) 101 patients (58.7%) are free of disease and 68 relapsed with metastases and/or local recurrence. A radio-induced bone sarcoma developed in two patients, one patient died of ADM cardiomyopathy. No differences in terms of risk factors were observed between patients who were or were not treated with surgery. A better DFS was observed in the patients treated with surgery (66.9%) in comparison with those treated with radiotherapy alone. The higher percentage of local recurrences observed in patients treated with radiotherapy alone seems to be responsible for the worse prognosis observed in these patients. The authors' conclusion is that the local control in patients with non metastatic Ewing's sarcoma should always be achieved by means of surgery.     

Pediatric rheumatology in the United Kingdom: data from the British Pediatric Rheumatology Group National Diagnostic Register

OBJECTIVE: To establish a computerized national diagnostic register for pediatric rheumatology in the UK; to describe the demography and diagnostic classification of children referred to pediatric rheumatology clinics; to estimate the current incidence of juvenile arthritis (JA) in the UK. METHODS: A diagnostic register was established in 1989: 23 centers have contributed data on all new cases seen since they joined the register; 18 centers have also contributed data on all current attenders. For 2 centers with well defined catchment areas, the incidence of JA was estimated. RESULTS: A total of 4948 cases were registered, of whom 2962 (60%) were female. 1991 (40%) had a diagnosis of JA. The 2nd largest category was mechanical/orthopedic problems (24%). Pauciarticular juvenile chronic arthritis was the most common subtype of JA. Seropositive RA was rare. Tertiary referral centers saw proportionately more JA and district general hospitals saw proportionately more mechanical problems. The annual incidence rate for JA from 2 centers was 10/100,000, and for all rheumatic disorders was 32-42/100,000 children under age 16. CONCLUSION: The relative proportion of patient diagnoses varies between centers. Nevertheless, the incidence of hospital referred JA seems very uniform.     

Adjudication in the United Kingdom: Constitutional Implications

Good ideas are often overtaken by great events. That happened to adjudication. Originally envisaged as a single concept applying across the United Kingdom, it has been overtaken by more significant constitutional change. This paper takes a look at that process. Something of a parallel could perhaps be drawn with the individual states in the United States each introducing a similar form of legislation. The possibility exists, of course, of each area adopting a different approach but the indications are that certain communality is developing in adjudication and it is, perhaps, a measure of the success of the concept of adjudication that it is being voluntarily adopted in other dependency areas such as the Isle of Man.     

Ewing's sarcoma of the pelvis: changes over 25 years in treatment and results

The pelvic localisations of Ewing's sarcoma have the worst prognosis due to large size at diagnosis, frequent distant metastases, radiosensitive organs next to the tumour and difficult surgery. The purpose of the present study was to analyse treatment results over a period of 25 years and to investigate the impact of newer chemotherapy schedules, improved radiotherapy techniques and newer surgical methods on the prognosis. 35 children and young adults were identified from 1967 to 1994 for whom diagnosis, presentation, performed treatment and outcome were available. Tumour size, as measured from CT scans, response to chemotherapy and radiotherapy target volume, could be reviewed in the later years. Actuarial 5-year survival for the whole group was 31% and for the 24 non-metastatic patients 40%, with a disease-free interval of 19%. Tumour size could be measured in 27 patients and ranged from 36 to 1540 cm3. There were 12 local recurrences, 1 in the 4 patients treated with surgery. After 1983, 9 out of 17 irradiated patients developed local failure. 3 patients had adequate fields and one a close field which did not cover completely the prechemotherapy extent and 3 of these recurred. All 4 patients with stable disease after neoadjuvant CT failed locally, not withstanding high-dose radiotherapy. The mean length of neoadjuvant CT tended to be shorter in patients without local relapse. There was no significant difference in survival before and after 1983.     

Medical Research Council: Grants Committee for the Behavioural Sciences.

Describes the procedures used by the Grants Committee for the Behavioural Sciences of the Canadian Medical Research Council in reviewing and adjudicating applications for research grants. The author takes issue with the contention that the Council does not give adequate attention to applications that come from psychologists who are not associated with medical schools. (6 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)