Prognostic significance of age in 5631 patients with Wilms tumour prospectively registered in International Society of Paediatric Oncology (SIOP) 93-01 and 2001.

BACKGROUND: To enhance risk stratification for Wilms tumour (WT) in a pre-operative chemotherapy setting, we explored the prognostic significance and optimal age cutoffs in patients treated according to International Society of Paediatric Oncology Renal Tumour Study Group (SIOP-RTSG) protocols. METHODS: Patients(6 months-18 years) with unilateral WT were selected from prospective SIOP 93-01 and 2001 studies(1993-2016). Martingale residual analysis was used to explore optimal age cutoffs. Outcome according to age was analyzed by uni- and multivariable analysis, adjusted for sex, biopsy(yes/no), stage, histology and tumour volume at surgery. RESULTS: 5631 patients were included; median age was 3.4 years(IQR: 2-5.1). Estimated 5-year event-free survival (EFS) and overall survival (OS) were 85%(95%CI 83.5-85.5) and 93%(95%CI 92.0-93.4). Martingale residual plots detected no optimal age cutoffs. Multivariable analysis showed lower EFS with increasing age(linear trend P<0.001). Using previously described age categories, EFS was lower for patients aged 2-4(HR 1.34, P = 0.02), 4-10(HR 1.83, P<0.0001) and 10-18 years(HR 1.74, P = 0.01) as compared to patients aged 6 months-2 years. OS was lower for patients 4-10 years(HR 1.67, P = 0.01) and 10-18 years(HR 1.87, P = 0.04), but not for 2-4 years(HR 1.29, P = 0.23). Higher stage, histological risk group and tumour volume were independent adverse prognostic factors. CONCLUSION: Although optimal age cutoffs could not be identified, we demonstrated the prognostic significance of age as well as previously described cutoffs for EFS (2 and 4 years) and OS (4 years) in children with WT treated with pre-operative chemotherapy. These findings encourage the consideration of age in the design of future SIOP-RTSG protocols.

Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG).

Blastemal-type Wilms tumour (BT-WT) has been identified as a high risk histological subgroup in WT assessed after pre-nephrectomy chemotherapy in trials of the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group. Therefore, in SIOPWT2001, post-operative chemotherapy for BT-WT was intensified aiming to improve survival. Survival analysis of all unilateral BT-WT patients (SIOPWT2001) (n=238), was compared with historical BT-WT controls (SIOP93-01) (n=113). 351/4061 (8.6%) unilateral non-metastatic BT-WT patients (SIOP93-01/SIOPWT2001) were studied. Median age at diagnosis was 43 months (Inter Quartile Range (IQR) 24-68 months), stages: I (n=140, 40%), II (n=106, 30%), III (n=105, 30%). BT-WTs were higher staged, showed greater volume decrease after pre-operative chemotherapy and were diagnosed at an older median age compared to other WT patients. Patient characteristics did not differ substantially between SIOP93-01 and SIOPWT2001. Univariate analysis showed a 5-year event-free survival (EFS) of 80% (95% confidence interval (CI): 75-86%) (SIOPWT2001) compared to 67% in SIOP93-01 (95% CI: 59-76%; p=0.006) and overall survival (OS) of 88% (95% CI: 83-93%) (SIOPWT2001) compared to 84% (95% CI: 77-91%; p=0.4) in SIOP93-01. 95% of relapses were distant metastases (SIOP93-01/SIOPWT2001). Treatment protocol, age at diagnosis, tumour stage (III versus I/II) and volume (at surgery), were prognostic variables for EFS (uni- and multivariate Cox regression analysis). Independent prognosticators for OS were age at diagnosis, tumour stage and volume (at surgery). The most significant survival benefit of intensified treatment, was observed in Stage I (EFS 96% in SIOPWT2001 (OS 100%), 71% in SIOP93-01 (OS 90%)). BT-WT derived benefits from more intensive chemotherapy as reflected by a reduction in relapse risk. However, the benefit of the more intensive chemotherapy to improve OS was only observed in stage I BT-WTs, by adding doxorubicin.

Clear cell sarcomas of the kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: a report of the SIOP Renal Tumour Study Group.

PURPOSE: Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. PATIENTS AND METHODS: We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials. RESULTS: A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73-85%) and 86% (95% CI: 80-92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. CONCLUSION: In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK.

Physician, patient and family attitudes regarding information on prognosis: a Brazilian survey.

BACKGROUND: Communication between physicians and patients is a fundamental aspect of cancer care, yet most physicians' perceptions are often inconsistent with the patients' stated preferences while prognostic information is the most misunderstood. PATIENTS AND METHODS: Members of the Brazilian Society of Oncology Physicians (n=609) were identified and asked to complete a mailed questionnaire. Outpatients (n=150) and their family members (n=150), oncologists and fellows (n=55) from a public healthcare hospital and a tertiary cancer hospital in Sao Paulo were also personally invited to participate. RESULTS: A total of 202 physicians, 150 outpatients and 150 family members were participated. The majority of patients (92%) believe they should know about their terminal stage compared with 79.2% of physicians and 74.7% of families (P=0.0003). Cancer patients were most likely to support disclosure of diagnosis and terminality (P=0.001), to consider that this disclosure was not stressful (P<0.0001) and that this knowledge would improve their quality of life (P<0.0001). CONCLUSIONS: Cancer patients seen in these centers in Southeastern Brazil prefer to know the truth about their poor prognosis more than their physicians and families think. Further studies with larger samples of patients and physicians are necessary to show if our results are representative of all Brazilian situations.

Temporal blastemal cell gene expression analysis in the kidney reveals new Wnt and related signaling pathway genes to be essential for Wilms' tumor onset.

Wilms' tumors (WTs) originate from metanephric blastema cells that are unable to complete differentiation, resulting in triphasic tumors composed of epithelial, stromal and blastemal cells, with the latter harboring molecular characteristics similar to those of the earliest kidney development stages. Precise regulation of Wnt and related signaling pathways has been shown to be crucial for correct kidney differentiation. In this study, the gene expression profile of Wnt and related pathways was assessed in laser-microdissected blastemal cells in WTs and differentiated kidneys, in human and in four temporal kidney differentiation stages (i.e. E15.5, E17.5, P1.5 and P7.5) in mice, using an orthologous cDNA microarray platform. A signaling pathway-based gene signature was shared between cells of WT and of earliest kidney differentiation stages, revealing genes involved in the interruption of blastemal cell differentiation in WT. Reverse transcription-quantitative PCR showed high robustness of the microarray data demonstrating 75 and 56% agreement in the initial and independent sample sets, respectively. The protein expression of CRABP2, IGF2, GRK7, TESK1, HDGF, WNT5B, FZD2 and TIMP3 was characterized in WTs and in a panel of human fetal kidneys displaying remarkable aspects of differentiation, which was recapitulated in the tumor. Taken together, this study reveals new genes candidate for triggering WT onset and for therapeutic treatment targets.

DNA damage in lymphocytes and buccal mucosa cells of children with malignant tumours undergoing chemotherapy.

The aim of the present study was to evaluate DNA damage (micronucleus) in cytokinesis-blocked lymphocytes and exfoliated buccal mucosa cells from children with malignant tumours and under chemotherapy. Micronucleated cells (MNCs) were assessed from children before and during chemotherapy. A total of 21 healthy children (controls), matched for gender and age, were used as control. The results pointed out higher frequencies of micronucleated lymphocytes in children with malignant tumour before any therapy when compared to healthy probands. Furthermore an increase of micronucleated lymphocytes during chemotherapy was detected when compared to the data obtained before chemotherapy. No statistically significant increases of MNCs were noticed in buccal mucosa cells at any of the timepoints evaluated. Taken together, these data indicate that the presence of malignant tumours may increase the frequency of DNA damage in circulating lymphocytes, these cells being more sensitive for detecting chromosome aberrations caused by anti-cancer drugs.

Report of the second international symposium on molecular epidemiology in childhood leukaemia and embryonal tumours, Rio de Janeiro, Brazil.

The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4-6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms' tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below.

Trends in childhood leukemia mortality in Brazil and correlation with social inequalities

Mortality from childhood leukemia has declined substantially in developed countries but less markedly in the developing world. This study was designed to describe mortality trends in childhood leukemia and the impact of social inequalities on these trends in Brazil from 1980 to 2002. Cancer mortality data by cause and estimates of resident population stratified by age and sex were obtained from the Brazilian Mortality Information System (SIM) for the years 1980 to 2002. Age-standardized (ages 0-19 years) mortality rates were calculated by the direct method using the 1960 world standard population. Trends were modeled using linear regression with 3-year moving average rates as the dependent variable and with the midpoint of the calendar year interval (1991) as the independent variable. The Index of Social Exclusion was used to classify the 27 Brazilian states. Pearson correlation was used to describe the correlation between social exclusion and variations in mortality in each state. Age-standardized mortality rates for boys decreased from 2.05 per 100,000 habitants in 1984 to 1.44 100,000 habitants in 1995, whereas the observed corresponding decline among girls was from 1.60 per 100,000 habitants in 1986 to 1.14 per 100,000 habitants in 1995. Statistically significant declining trends in mortality rates were observed for boys (adjusted correlation coefficient [r2] = 0.68; P < .001) and girls (adjusted r2 = 0.62; P < .001). Significant negative correlations between social inequality and changes in mortality were noted for boys (r = −0.66; P = .001) and for girls (r = −0.78; P < .001). A consistent decrease in mortality rates from childhood leukemia was noted in Brazil. Higher decreases in mortality were observed in more developed states, possibly reflecting better health care. Cancer 2007. © 2007 American Cancer Society.

A proposed score for predicting severe infection complications in children with chemotherapy-induced febrile neutropenia

Febrile neutropenia (FN) is one of most common complications in patients with cancer during chemotherapy. Identifying factors associated with severe infectious complications (SICs) at time of admission for fever and neutropenia is necessary for better treatment.We revised all medical charts of patients under 18 years old who developed a first episode of FN present from January 2000 to December 2003. Criteria for a SIC were defined. These included the presence of bacteremia or fungemia, sepsis, septic shock, and/or death from infection. To identify risk factors SIC was associated with the first FN episode. Factors identified in univariate analysis were female sex, age less than 5 years old, acute myeloid leukemia, baseline disease activity, use of central venous catheter, hemoglobin level 38.5°C, a chemotherapy interval 38.5°C, hemoglobin level <7 g/dL, any clinical focus of infection on first examination and absence of upper respiratory tract infection. The FN population was than divided among 3 different risk groups as follows: group 1 (low risk), group 2 (intermediate risk), with a 13 (4.4 to 38.3)-fold risk for SIC; and group 3 (high risk) with a 50 (16.4 to 149.2)-fold risk for SIC. This study suggests that patients with FN can be stratified for risk of SIC using clinical parameters at hospital admission

Melanoma maligno na infância

Melanoma cutâneo é uma entidade rara na infância, particularmente na criança em puberdade, ocorrendo somente em 0,4 por cento de todos os casos. Objetivo: Rever nossa experiência como Instituição que recebe pacientes menores de 18 anos tratados durante o período de 1970 a janeiro de 2000. Métodos: Foi realizada uma análise retrospectiva de 37 pacientes com diagnóstico de melanoma maligno. As características clínicas, assim como a terapia e o "follow-up", foram revistas. A sobrevida média foi analisada. Os dados foram comparados pelo método Qui-quadrado, análise de variância e t teste; e a sobrevida, pelo método de Kaplan-Meier. Resultados: 22 pacientes eram do sexo feminino (60 por cento) e sexo masculino (40 por cento). A raça branca foi predominante (97,3 por cento). A idade média ao diagnóstico foi 11 anos. O principal sítio foi cabeça e pescoço (40 por cento), tronco e dorso (30 por cento) e extremidades (27 por cento). Nove pacientes tinham nevo melanocítico, 5 xeroderma pigmentoso e 4 nevo congênito gigante. A terapêutica inicial foi cirúrgica na maioria dos casos, e 54 por cento dos melanomas puderam ser completamente ressecados ao diagnóstico. Nos demais, ou seja, melanoma não completamente ressecado ou melanoma metastático, foi usada terapia complementar com quimioterapia e imunoterapia. Melanomas metastáticos ao diagnóstico (46 por cento) ou recidivados (27 por cento) apresentaram pior sobrevida (p=0,02 x p=0,03, respectivamente). A sobrevida global em nosso estudo foi 57 por cento em 5 anos. Conclusão: A sobrevida depende do estádio ao diagnóstico. Atraso no diagnóstico ainda ocorre. Estudos prospectivos adicionais usando o mesmo protocolo de tratamento são necessários para definir o comportamento deste tumor na infância.

Immunohistochemical detection of p53 protein expression as a prognostic indicator in Wilms tumor.

BACKGROUND: Mutations of the tumor suppressor gene p53 are commonly found in several kinds of human cancer. In some types of neoplasms, accumulation of p53 protein has been reported to correlate with more aggressive clinical behavior. The role of p53 expression in Wilms tumors (WT) is not clear yet, but most studies have confirmed its correlation with anaplasia and advanced stage disease. PROCEDURE: Ninety-seven WT were evaluated for p53 expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue and correlated with outcome. Tumors were classified as p53-Negative (p53-N) when no positivity was observed or only few cells showed weak positivity (0/1+) and p53-Positive (p53-P) when there was a diffuse and strong nuclear positivity (2+/3+). RESULTS: p53-P was detected in 13 out of 97 tumors and was associated with disease relapse (39 vs.17%; P = 0.06) but not with anaplasia. Among p53-N patients only 5% had metastatic disease compared with 31% of the p53-P sample. (P = 0.038). Overall survival was 94% for patients with p53-N vs. 85% for patients with p53-P at 1 year (P = 0.34). CONCLUSIONS: p53 expression in Wilms tumor detected by immunohistochemistry seems to be associated with advanced disease and relapse.

Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors.

BACKGROUND: The prognosis of children who are affected by hepatoblastoma (HB) that presents with lung metastases has always been considered very poor. In light of the overall improvement in the survival of HB patients since the introduction of cisplatin (CDDP) in the therapeutic armament of this tumor, the question has been raised whether patients with metastatic HB also would benefit from this drug. The purpose of the current study was to address this issue by analyzing the treatment outcome of those patients presenting with metastases who entered into the first HB study on childhood liver tumors conducted by the International Society of Paediatric Oncology (SIOPEL 1). METHODS: SIOPEL 1 was a prospective, international, multicentric, single-arm study based on preoperative chemotherapy that was open to patient registration from January 1990 to February 1994. After undergoing a biopsy, patients received four courses of CDDP (80 mg/m(2) in a 24-hour, continuous infusion) on Day 1 followed by doxorubicin (60 mg/m(2) in a 48-hour, continuous infusion) on Days 2 and 3 (PLADO). Surgery was performed after four courses of PLADO and was followed by two more courses. Untreated children age < 16 years with biopsy-proven HB were eligible for the study. Metastatic spread was assessed by chest X-ray and, where available, lung computed tomography scan. RESULTS: Thirty-one of 154 children that entered into the trial presented with metastases. Eight children presently are alive with no evidence of disease (NED) after being treated with protocol therapy only (median follow-up, 60 months); nine children are alive with NED after having failed PLADO and having been rescued with alternative therapies (median follow-up, 80 months). The 5-year overall and event free survival rates for these children were 57% (95% confidence interval, 39-75%) and 28% (95% confidence interval, 12-44%), respectively. Persistent lung disease was the main reason for PLADO failure (17 of 23 patients; 74%). CONCLUSIONS: The SIOPEL 1 therapeutic strategy seems to cure 25% of the HB patients who present with metastases. However, further chemotherapy and the use of thoracotomies still can save significant numbers of these children.