Beatriz de Camargo

Successful Treatment of Childhood High-Risk Hepatoblastoma With Dose-Intensive Multiagent Chemotherapy and Surgery: Final Results of the SIOPEL-3HR Study

PURPOSE The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

Cisplatin versus Cisplatin plus Doxorubicin for Standard-Risk Hepatoblastoma

BACKGROUND Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

Results of the brazilian osteosarcoma treatment group studies III and IV : Prognostic factors and impact on survival

PURPOSE To evaluate the impact of chemotherapy and surgery on the outcome of osteosarcoma (OS) of the extremities and to identify prognostic factors in Brazilian patients. PATIENTS AND METHODS A total of 225 patients with metastatic and nonmetastatic OS of the extremities were enrolled and assessed in two consecutive studies designed and implemented by the Brazilian Osteosarcoma Treatment Group. RESULTS The 5-year survival and event-free survival rates for the 209 assessable patients were 50.1% and 39%, respectively; for the 178 patients with nonmetastatic disease at diagnosis, the rates were 60.5% and 45.5%, respectively. The multivariate analysis showed that the following variables were associated with a shorter survival: metastases at diagnosis (P < .001), necrosis grades 1 and 2 (P = .046), and tumor size (P = .0071). CONCLUSION The overall 5- and 10-year survival rates were lower than the rates reported in North American and European trials. A pattern of advanced disease at diagnosis was often present, with a high proportion of patients having metastases (20.8%) and large tumor size (42.9%). However, these features were not necessarily associated with longer duration of prediagnostic symptoms. These findings were considered in the strategic planning of the current Brazilian cooperative study, with the aim of improving survival and quality of life of a large number of patients with OS.

Extraocular retinoblastoma: a 13-year experience.

The current study was performed to evaluate two regimens of treatment and to describe clinical and epidemiologic characteristics in patients with extraocular retinoblastoma.

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA.

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

Background 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. Procedure 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. Results 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 <7 g/dL, leukocytes count <500 cells/mm3, granulocytes count <500 cells/mm3, monocytes count <100 cells/mm3, platelets <20,000, and body temperature >38.5°C, a chemotherapy interval <7 days, presence of mucositis, pneumonia, absence of upper respiratory tract infection, or the presence of any clinical focus on first physical examination. In multivariate analysis the variables that remained as independent predictive risk factors for SIC were age less than 5 years, use of central venous catheter, body temperature >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. Conclusions This study suggests that patients with FN can be stratified for risk of SIC using clinical parameters at hospital admission.

Prognostic stratification for children with hepatoblastoma: The SIOPEL experience

PURPOSE To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Hepatoblastoma presenting with lung metastases

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).

Noninvasive ventilation in immunocompromised pediatric patients: Eight years of experience in a pediatric oncology intensive care unit

Objective The experience of noninvasive positive pressure ventilation (NPPV) in the pediatric setting is limited. The aim of the present study is to retrospectively evaluate the effectiveness of NPPV in pediatric immunocompromised patient admitted in our PICU (Pediatric Intensive Care Unit) for acute respiratory failure. Design/Setting Retrospective cohort study of children admitted to the PICU of Hospital do Cancer between June 1997 and May 2005 requiring ventilatory support. Results A total of 239 admissions were included. The first mechanical ventilation (MV) technique used was NPPV in 120 (50.2%) patients [noninvasive ventilation (NIV) group] and conventional MV in 119 (49.8%) [invasive ventilation (IV) group]; 25.8% of the patients from the NIV group subsequently required intubation. Patients in the IV group were more likely to be in a severe clinical status. Characteristics associated with severe clinical status were median value for therapeutic intervention scoring system score (37.5 points IV vs. 29 points NIV, P<0.0001), presence of >2 organs failure (63.6% IV vs. 36.4% NIV, P<0.0001), cardiac failure (62.5% IV vs. 37.5% NIV, P<0.0001), and septic shock (63.9% IV vs. 36.1% NIV, P<0.0001). Documented severe pulmonary disease was significantly higher (67.6%) in IV group, P=0.02. Baseline values of arterial pCO2, hypoxemia, arterial pH, and respiratory rate did not differ between the groups. Multivariate analysis showed that independent predictive factors for intubation were solid tumors (P=0.012), cardiovascular dysfunction (P<0.0001), and therapeutic intervention scoring system score ≥40 points (P=0.018). Conclusions Our results encourage the use of NPPV as a first-line treatment in children with malignancies who develops acute respiratory failure, except in those with severe hemodynamic status.

Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: A report of the SIOP renal tumour study group

Survival data of malignant rhabdoid tumour of the kidney (MRTK) registered in SIOP trials, advocating preoperative chemotherapy, are not available. Aim To evaluate characteristics, response and survival of MRTK patients registered in recent SIOP protocols.