Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 µg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. FUNDING: See Acknowledgments for funders.

From amino acid to glucosinolate biosynthesis: protein sequence changes in the evolution of methylthioalkylmalate synthase in Arabidopsis.

Methylthioalkylmalate synthase (MAM) catalyzes the committed step in the side chain elongation of Met, yielding important precursors for glucosinolate biosynthesis in Arabidopsis thaliana and other Brassicaceae species. MAM is believed to have evolved from isopropylmalate synthase (IPMS), an enzyme involved in Leu biosynthesis, based on phylogenetic analyses and an overlap of catalytic abilities. Here, we investigated the changes in protein structure that have occurred during the recruitment of IPMS from amino acid to glucosinolate metabolism. The major sequence difference between IPMS and MAM is the absence of 120 amino acids at the C-terminal end of MAM that constitute a regulatory domain for Leu-mediated feedback inhibition. Truncation of this domain in Arabidopsis IPMS2 results in loss of Leu feedback inhibition and quaternary structure, two features common to MAM enzymes, plus an 8.4-fold increase in the k(cat)/K(m) for a MAM substrate. Additional exchange of two amino acids in the active site resulted in a MAM-like enzyme that had little residual IPMS activity. Hence, combination of the loss of the regulatory domain and a few additional amino acid exchanges can explain the evolution of MAM from IPMS during its recruitment from primary to secondary metabolism.

Nephron sparing surgery (NSS) for unilateral wilms tumor (UWT): the SIOP 2001 experience.

BACKGROUND: Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT-2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non-infiltrating tumors. AIM: Inventory of the current SIOP NSS-experience. PROCEDURES: 2,800 patients with a unilateral, localized or metastatic and an unequivocal surgical technique recorded were included. All had neo-adjuvant chemotherapy and delayed surgery. In 91 (3%) NSS was performed and in 2709 TN. Data was retrieved from the SIOP WT 2001 database. RESULTS: NSS group contained 65% stage I tumours and the TN group 48%. Tumor volume (at diagnosis and surgery) was significantly smaller in the NSS group. Within stage III, after NSS, 7/12 (58%) had positive margins (M +), 5 with tumor negative lymph nodes (LN-). After TN, 355/712 (55%) had M + , 182 were LN-. Treatment of M+ in the NSS group resulted in two conversions to TN (one combined with radiotherapy), three patients had radiotherapy only and in two patients local therapy, if given, was not recorded. After NSS, four recurrences occurred. For localized disease the 5-year overall (OS) and event free survival (EFS) in NSS group was 100 and 94.8 (95% CI:89.9-99.9), respectively, while OS and EFS in the TN group were 94.4 (95% CI: 93.2-95.5, log-rank test P = 0.06) and 86.5 (95% CI:85.0-88.1, log-rank test P = 0.06), respectively. CONCLUSIONS: NSS was only performed in 3% of patients with uWT. Despite excellent survival with few relapses, the gain of nephrons needs to be weighed against the risk to induce stage III with intensified therapy.

The role of 131I-metaiodobenzylguanidine (MIBG) therapy in unresectable and compromising localised neuroblastoma.

PURPOSE: In patients with localised neuroblastoma without adverse genetic aberrations, observational treatment is justified. Therapy is required when organ or respiratory functions have become compromised. As the outcome is good, side effects of treatment should be prevented. The aim of this retrospective study was to evaluate response and outcome in patients treated with (131)I-metaiodobenzylguanidine (MIBG) for unresectable localised neuroblastoma, with compromised organ functions. METHODS: Patients with localised neuroblastoma [median age 1.6 years (0-5.5 years)] diagnosed between 1989 and 2008 were included in this retrospective study (n = 21). Primary tumours were unresectable and there was a compromised organ or respiratory function. Diagnosis and staging were performed according to the International Neuroblastoma Staging System. Fixed doses of (131)I-MIBG therapy (50-200 mCi) were given. The median number of infusions was two (range one to seven). Response was graded according to the International Neuroblastoma Response Criteria. RESULTS: Of the 21 patients, 14 did not need any chemotherapy. Patients were treated with (131)I-MIBG therapy and, in most cases, with additional surgery and/or chemotherapy. Sixteen achieved complete response (CR), three very good partial response (VGPR), one partial response (PR) and one progressive disease (PD). Two patients died of PD after having achieved CR initially and due to surgical complications a few months after resection. Ten-year overall survival and event-free survival were 90.5 %. The median follow-up was 8.5 years (range 0.4-19.6 years). CONCLUSION: (131)I-MIBG therapy is an effective treatment modality for unresectable localised neuroblastoma with compromised organ functions. However, this was a small and heterogeneous cohort and further studies are needed.

Toxicity of upfront ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) therapy in newly diagnosed neuroblastoma patients: a retrospective analysis.

PURPOSE: In the treatment of patients with high-risk neuroblastoma, different doses of (131)I-metaiodobenzylguanidine ((131)I-MIBG) are administered at different time points during treatment. Toxicity, mainly haematological (thrombocytopenia), from (131)I-MIBG therapy is known to occur in extensively chemotherapy pretreated neuroblastoma patients. Up to now, acute toxicity from (131)I-MIBG as initial treatment has never been studied in a large cohort. The aim of this retrospective study was to document acute toxicity related to upfront (131)I-MIBG. METHODS: All neuroblastoma patients (stages 1-4 and 4S) treated upfront with (131)I-MIBG at the Emma Children's Hospital, Academic Medical Centre (1992 - 2008) were included in this retrospective analysis. The acute toxicity (during therapy) and short-term toxicity (1st month following therapy) of the first two (131)I-MIBG therapies were studied. RESULTS: Of 66 patients (34 boys, 32 girls; median age 2.2 years, range 0.1 - 9.4 years), 49 had stage 4 disease, 5 stage 4S, 6 stage 3, 1 stage 2 and 5 stage 1. The median first dose was 441 MBq/kg (range 157 - 804 MBq/kg). The median second dose was 328 MBq/kg (range 113 - 727 MBq/kg). The most frequently observed symptoms were nausea and vomiting (21 %, maximum grade II). The main toxicity was grade IV haematological, occurring only in stage 4 patients, after the first and second (131)I-MIBG therapies: anaemia (5 % and 4 %, respectively), leucocytopenia (3 % and 4 %) and thrombocytopenia (2 % and 4 %). No stem cell rescue was needed. CONCLUSION: The main acute toxicity observed was haematological followed by nausea and vomiting. One patient developed posterior reversible encephalopathy syndrome during (131)I-MIBG therapy, possibly related to (131)I-MIBG. We consider (131)I-MIBG therapy to be a safe treatment modality.

The efficacy and toxicity of SIOP preoperative chemotherapy in Malawian children with a Wilms tumour.

BACKGROUND: In Malawi, preoperative chemotherapy for Wilms tumour is a logical strategy, but detailed information on toxicity and efficacy in such a resource limited setting has been unavailable. PROCEDURE: Patients diagnosed with a unilateral Wilms tumour received preoperative chemotherapy-a two-drug 4-week regimen for localized disease and 6 weeks of a three-drug regimen for metastatic disease. Estimated maximum tumour diameter, decrease in tumour size, resectability, stage distribution and haematological toxicity during therapy were documented. RESULTS: At diagnosis, 28% of 72 patients had an estimated maximum tumour diameter of more than 25 cm; 29% of patients had metastases. Eight children (11%) died during preoperative chemotherapy. More than half (59%) of the patients developed moderate neutropenia (neutrophils <1.0 × 10(9) /L; CTC grade 3) and 27% severe neutropenia (CTC grade 4 neutrophils <0.5 × 10.9/L). Grade 4 neutropenia occurred significantly more frequently in children receiving the three-drug regimen compared to the two-drug regimen; 50% (10/20) versus 15% (6/40) (P = 0.004). Fifty-seven percent of all patients had CTC grade 4 anaemia (Hb < 6.5 g/dL) during treatment. Most tumours (92%, 56/61) showed a response to chemotherapy but 14% (8/58) remained unresectable. CONCLUSION: Preoperative chemotherapy for Wilms tumour causes considerable haematological toxicity and treatment-related mortality in malnourished Malawian children. A significant number of children have unresectable disease despite preoperative chemotherapy. To reduce treatment related mortality, consideration should be given to starting treatment with reduced doses in acutely malnourished patients.

Management of children with a Wilms tumor in Malawi, sub-Saharan Africa.

Wilms tumor has a survival rate of 85% to 90% in well-resourced countries. Malawi is a country in Sub-Saharan Africa with very limited resources. We evaluated the outcome of a treatment guideline including preoperative chemotherapy, supportive care, and strategies to enable parents to complete treatment. Between 2006 and 2011, 95 patients were initially diagnosed with a Wilms tumor; 11 were later excluded due to misdiagnosis. In 31% of patients, metastases were detected at presentation. Treatment outcomes in 8 patients with bilateral tumors and 3 patients who were referred after nephrectomy are analyzed separately. Treatment failed in 51% of 73 remaining patients. Reasons for failure were: 1) incomplete treatment (7%); 2) treatment-related deaths (15%); and 3) disease-related deaths (28%) with 11% unresectable tumors or metastases after preoperative chemotherapy and 17% relapse of disease. Projected survival is 46%. Challenges remain to improve survival for children with Wilms tumor in Malawi. Earlier diagnosis would reduce disease-related deaths as numbers of unresectable disease and relapse are high. Effective strategies, including social support, to enable parents to complete treatment need to be continued. Improved supportive care and nutritional support and possibly less intense preoperative chemotherapy are needed to reduce treatment-related deaths.

Long-term outcome of bilateral Wilms tumors (BWT).

BACKGROUND: Modern WT management consist of ample chemotherapy, nephron-sparing surgery, and, when indicated, radiotherapy. Survivors may develop renal failure or secondary tumors due to anticancer treatment. We analyzed long-term outcome (follow-up >5 years) after bilateral Wilms tumor (BWT) treatment with respect to survival, renal function, and secondary malignancies. METHODS: From 41 patients (23 females, 28 synchronous tumors) diagnosed with BWT between 1967 and 2007, 25 (18 females, 14 synchronous) with a follow-up >5 years could be included. Of this subgroup, median age at diagnosis was 1.64 years (range 0.27-5.35), and at maximum follow-up 14.99 years (range 5.40-33.99). Data were retrospectively collected and analyzed. RESULTS: One patient (4%) died 17.75 years after diagnosis, five (20%) had renal transplants: 3/5 after bilateral nephrectomy for Denys-Drash syndrome (DDS), and 2/5 for ESRD after an interval of 7 and 18 years, respectively. All transplanted patients remained in CR. Another three patients developed mild renal insufficiency (creatinine levels 1.3, 1.8, and 2.8 mg/100 ml, respectively; N = 0.5-1.2), combined with hypertension in 1; neither of them was transplanted. Sixteen (64%) had normal renal function and were in CR. Long-term renal function appeared significantly better after bilateral nephron sparing surgery (NSS) then after other surgical procedures (P < 0.0001). Seven secondary tumors were found in five (20%) patients, one of whom had a DDS. CONCLUSION: Long-term 10-year overall survival was 78%. There was significant morbidity (13/25, 52%), in terms of renal failure (8/25, 32%) including renal transplantation (5/25, 20%), and secondary tumors (5/25). These findings necessitate long-term follow-up beyond childhood. Future work should be directed at reducing the harmful effects of treatment, including the increased use of NSS.

Nephroblastoma: does the decrease in tumor volume under preoperative chemotherapy predict the lymph nodes status at surgery?

BACKGROUND: Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN. PROCEDURE: SIOP 9301 (1993-2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed. RESULTS: Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318-772) to 192 (63-458) ml = 67% (27-88%) during preoperative ChT. In the LN(-) group-377 (200-612) to 130 (44-294) ml = 62% (28-83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(-) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751). CONCLUSIONS: Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low.

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.

BACKGROUND: 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. METHODS: An evaluation of all MRTK patients treated from 1993 to 2005 (SIOP trials 93-01 and 2001) was performed. Data were obtained from study specific case record forms and entered centrally in a database. RESULTS: Hundred and seven patients were identified (57 male), with a median age at diagnosis of 13 months (interquartile range 6-27 months), and a median follow-up time of 60 months. Left and right kidneys were equally affected. Tumour stage distribution was stage I (6%), stage II (22%), stage III (43%), stage IV (22%) and stage V (3%). Stage IV patients included 17 with pulmonary metastasis (8 lung-only) and 12 with multiple organ metastases (bone, brain and liver). Primary surgery was the upfront treatment approach in 22/107 patients (21%), by which 19 patients reached a complete remission (CR). Median difference in tumour volume before and after preoperative chemotherapy was 69 ml (interquartile range: 4.5-158.0, P < 0.0001), indicating marked chemosensitivity. The 5-year event-free survival (EFS) of the total group was 22% (95% CI: 15-33) and overall survival 26% (95% CI: 18-37). Most events (86%) occurred within the first 2 years after diagnosis. Younger age at diagnosis was an important adverse prognostic factors for survival. In contrast, tumour volume at diagnosis, nor volume reduction was associated with outcome. CONCLUSION: MRTK has a poor outcome especially in young and advanced-stage disease patients. Neither tumour volume at diagnosis, nor pre-operative chemosensitivity are prognostic factors for survival.

Stromal and epithelial predominant Wilms tumours have an excellent outcome: the SIOP 93 01 experience.

BACKGROUND: Wilms tumour (WT) has various subtypes that are correlated with prognosis and require distinct therapy. Stromal predominant (SpWT) and epithelial WT (EpWT) have previously been associated with a good outcome. The current analysis describes the outcome and (tumour) characteristics of all patients with SpWT, EpWT, including highly differentiated epithelial type (HDET), treated according to the International Society of Pediatric Oncology (SIOP) 93-01 study. PROCEDURE: All children older than 6 months and below 18 years of age with localized or metastatic WT and intermediate risk (IR) histology or HDET treated with pre-operative chemotherapy were included in the present analysis. RESULTS: A total of 1,389 eligible patients had IR or HDET histology: 1% HDET, 4% EpWT, 10% SpWT, and 85% other IR. For EpWT/HDET, 93% had stage I/IIN-, 5-year EFS was 90.2% and overall survival of (OS) 98.4%, as compared to 84.0% and 92.5% in other IR histology (NS). Stage I EpWT/HDET had a significant better outcome than stage I of other IR. In SpWT 82% of cases had stage I/IIN-; 5-year EFS was 94.3% and OS 99.2%, significantly better compared to other IR histology. All patients with stage I are alive (2/149 relapses); 3/52 stage IIN-, 2/21 stage IIN+/III, and 6/12 stage IV patients relapsed (1 deceased per stage group). CONCLUSIONS: The good outcome for EpWT and SpWT generally is very good which may be related to low age and low stage in most cases. A reduction of treatment intensity and/or duration may be justified especially for low stage SpWT that has an EFS close to 100%.

Fanconi anemia gene mutations are not involved in sporadic Wilms tumor.

Bi-allelic germline mutations of the Fanconi anemia (FA) genes, PALB2/FANCN and BRCA2/FANCD1, have been reported in a few Wilms tumor (WT) patients with an atypical FA phenotype. Therefore, we screened a random cohort of 47 Dutch WT cases for germline mutations in these two FA-genes by DNA sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Although several cases appeared to carry missense variants, no bi-allelic pathogenic mutations were identified, indicating that bi-allelic mutations in these FA-genes do not contribute significantly to the occurrence of WT.

Malignant tumours of the kidney: imaging strategy.

Primitive malignant renal tumours comprise 6% of all childhood cancers. Wilms tumour (WT) or nephroblastoma is the most frequent type accounting for more than 90%. Imaging alone cannot differentiate between these tumours with certainty but it plays an important role in screening, diagnostic workup, assessment of therapy response, preoperative evaluation and follow-up. The outcome of WT after therapy is excellent with an overall survival around 90%. In tumours such as those where the outcome is extremely good, focus can be shifted to a risk-based stratification to maintain excellent outcome in children with low risk tumours while improving quality of life and decreasing toxicity and costs. This review will discuss the imaging issues for WT from the European perspective and briefly discuss the characteristics of other malignant renal tumours occurring in children and new imaging techniques with potential in this matter.

Acute malnutrition is common in Malawian patients with a Wilms tumour: A role for peanut butter.

BACKGROUND: Children with cancer in resource limited countries are often malnourished at diagnosis. Acute malnutrition is associated with more infectious complications and an increased risk of morbidity and mortality in major surgery. METHODS: All new patients with the clinical diagnosis of a Wilms tumour admitted in the Queen Elizabeth Central Hospital, Blantyre, Malawi from January 2007 until June 2008 were included. We documented anthropometric parameters, tumour size and serum levels of micronutrients at diagnosis. Corrected weight (body weight - tumour weight) was repeated after 4 weeks of preoperative chemotherapy. During therapy oral feeds were encouraged and a locally made ready to use therapeutic peanut butter-based food (chiponde) supplied. RESULTS: A high rate of acute malnutrition was found in patients with Wilms tumour at diagnosis (45-55%), much higher than in community controls (11%). Patients (40%) and community controls (37%) had a similar, high rate of stunting (low height for age), a sign of chronic malnutrition. Tumour size at diagnosis and the degree of acute malnutrition at diagnosis was correlated; patients with a larger tumour had more severe acute malnutrition (r = -0.88, P < 0.01). With a supply of chiponde, 7 of 18 patients had a >5% increase in corrected weight during preoperative chemotherapy. Patients with a more positive nutritional course had a better tumour response to chemotherapy (r = 0.52, P < 0.05). Surprisingly, few micronutrient deficiencies were found, except for low serum levels of vitamin A (44% of patients). CONCLUSION: Acute malnutrition, superimposed on chronic malnutrition, is common in patients with Wilms tumour in Malawi. Earlier presentation needs to be encouraged. Chiponde, a peanut butter based ready-to-use-therapeutic-food, is an attractive means of nutritional support which needs further study.

Veno-occlusive disease as a complication of preoperative chemotherapy for Wilms tumor: A clinico-pathological analysis.

BACKGROUND: Vincristine (VCR) and actinomycin D (ACD) form the backbone of chemotherapeutic regimens of Wilms tumor treatment. Veno-occlusive disease (VOD) is a potentially life-threatening complication of ACD. OBJECTIVES: To investigate the incidence of VOD after preoperative chemotherapy and assess the effect of dose and frequency of administrating ACD on the occurrence of VOD. METHODS: A single-center retrospective study of patients where liver biopsies were performed after 4 or 8 weeks of preoperative chemotherapy. Patients had localized or metastatic Wilms tumor and were treated according to SIOP 9, 93-1, or 2001 protocol. A correlation was analyzed between histologically confirmed VOD, laboratory parameters, and mode and frequency of ACD administration. Long-term hepatic toxicity was assessed 5 years after the end of therapy. RESULTS: Ninety-one patients were included in this analysis. Forty-one patients (45.1%) had histological evidence of VOD. The incidence of histologically proven VOD was significantly correlated with single administration of 45 microg/kg ACD (SIOP 2001 protocol) as compared to repeated dosing of l5 microg/kg (P = 0.003). Fifty-two percent of all patients had mild-to-severe abnormal liver enzymes 5 years after accomplishing therapy. CONCLUSION: Despite short-course preoperative chemotherapy regimen, patients are at risk of developing histological VOD. This risk is higher when ACD is administered in a 1-day 45 microg/kg regimen as compared to 3 days l5 microg/kg.

Preoperative chemotherapy for patients with Wilms tumor in Malawi is feasible and efficacious.

BACKGROUND: Wilms tumor has a survival rate of 85-90% in well resourced countries but in low income countries survival is lower. Malawi is a country with very limited resources. We studied the feasibility, toxicity and efficacy of preoperative chemotherapy for Wilms tumor in Malawian children. METHODS: All patients diagnosed with a Wilms tumor, admitted in Blantyre, Malawi, from 2006 to 2008, were included. These patients received SIOP-based preoperative chemotherapy followed by surgery and risk-stratified post-operative chemotherapy. Social support and counseling were provided to prevent abandonment of treatment. RESULTS: Twenty patients were included. Mean tumor volume at diagnosis was 2,500 ml and eight patients (40%) had metastases. Ninety-five percent of patients presented with hypertension, 80% with microscopic hematuria and 60% with a raised platelet count. Preoperative chemotherapy resulted in >50% tumor reduction in 55% of patients with localized disease and 75% of patients with metastatic disease. During preoperative chemotherapy, 11 of 18 patients experienced >or= grade 3 anaemia, 7 patients experienced >or= grade 3 neutropenia. In 12 patients the tumor was resected. Reasons of treatment failure were: abandonment of treatment (N = 3), death during anaesthesia induction (N = 1), inoperability (N = 5, due to metastatic disease in N = 4) and relapse (N = 2). One patient died of malaria 2 months after completion of chemotherapy. Eight patients (40%) are alive with a median follow up of 8 months (range 0-1.5 years). CONCLUSION: Preoperative chemotherapy for Wilms tumor is feasible, tolerated and efficacious in Malawi. Continued efforts are needed to encourage early presentation and to prevent abandonment.

High-resolution molecular cytogenetic analysis of Wilms tumors highlights diagnostic difficulties among small round cell kidney tumors.

Many solid tumors exhibit characteristic gene fusions, which are reflected by balanced translocations at the cytogenetic level. These changes might be useful diagnostic and prognostic tools. In Wilms tumor (WT, nephroblastoma) no fusions genes or recurrent balanced translocations have been described thus far. To screen for cryptic balanced translocations, we have analyzed 17 renal neoplasms, histopathologically classified as WT, by a combination of G-banding, multicolor FISH, and subtelomeric FISH. This approach revealed several submicroscopic chromosomal aberrations and three different seemingly balanced translocations, resulting in a heterozygous deletion of HACE1, an EWSR1/ERG fusion, and an EWSR1/FLI1 fusion, respectively. As EWSR1 rearrangements are known to be a characteristic of Ewing tumors (ET), our findings illustrate the diagnostic problems regarding small cell kidney tumors and strongly argue for the need of adjuvant diagnostic techniques in this group of neoplasms. In summary, our genomic screening approach proved efficient in finding structural chromosomal aberrations. The fact that no recurrent translocations were found in the WTs of this study argues against the presence of a frequent pathognomonic translocation in this disease entity.

Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age.

PURPOSE: To determine the response to radionuclide targeted therapy with I-131-metaiodobenzylguanidine ((131)I-MIBG) as induction therapy in high-risk neuroblastoma patients. PATIENTS AND METHODS: The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months. RESULTS: Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%. CONCLUSION: First line (131)I-MIBG-targeted therapy is a valuable tool in the treatment of MIBG-positive high-risk neuroblastoma patients.

The guardians' perspective on paediatric cancer treatment in Malawi and factors affecting adherence.

BACKGROUND: Abandonment of paediatric cancer treatment is a common problem in developing countries. Little is known about the guardians' perspective on cancer treatment in these countries, especially the factors that affect adherence. METHODS: Following a pilot study enquiring into the possible causes of abandonment, a problem analysis diagram was drawn which helped to develop the questionnaires. Semi-structured interviews (n = 83) and focus group discussions (n = 8) were held with the guardians of 25 Burkitt lymphoma patients and 7 Wilms tumour patients at different phases of therapy in Malawi. RESULTS: Parents in Malawi are very motivated to continue treatment if they think that it will cure their child. Financial costs are important concerns. Not all tasks at home are assumed by other household members. The diagnosis of cancer was unknown before being told about it in hospital and caused fear of recurrence and death. Guardians are reluctant to ask the health personnel questions. They worry that taking frequent blood samples will weaken their child. The side effects of the chemotherapy are seen as a proof of efficacy. CONCLUSION: It is important to appreciate the guardians' concerns when offering treatment that requires their sustained commitment. It is necessary to provide not only medical treatment, but also travel allowances and adequate nutritional support during long hospital stays to impoverished families. Information should be given proactively.

Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: A collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups.

BACKGROUND: To review the clinical characteristics and survival of infants diagnosed with a primary renal tumor in the first 7 months of life. PROCEDURE: A retrospective data review of patients registered in five large international protocols (SFOP/GPOH/SIOP9/93-01, UKW3 and NWTSG 4 and 5) spanning 1985-2002. RESULTS: 750 (7.2%) of 10,430 registered patients were diagnosed with a renal tumor before age 213 days. Tumor types were Wilms tumor (WT) 58%; congenital mesoblastic nephroma (CMN) 18%; malignant rhabdoid tumor (MRTK) 8%; clear cell sarcoma (CCSK) 2%; non-Wilms tumor (unspecified) 6%; histology unknown, 9%. CMN predominated among tumors diagnosed in the first month of life (54%) but its relative contribution diminished to <10% of all cases diagnosed after the age of 3 months (P < 0.001). Among 639 cases with specified histology and stage, 9/11 stage IV tumors were MRTK, 37/39 bilateral tumors were WT. In 626 children where surgical approach was specified, 522 had immediate nephrectomy. For all cases, 5 years event-free survival (EFS) was 80% and overall survival (OS) 86%. Five years EFS and OS respectively by tumor type were WT (86%, 93%), CMN (94%, 96%), CCSK (49%, 51%), MRTK (16%, 16%). CONCLUSION: Renal tumors diagnosed in the first 7 months of life generally have an excellent prognosis though histology is an important prognostic factor. In the first 2 months of life the prevalence of CMN is high. The relative occurrence of WT increases rapidly with age thereafter. Bilateral tumors are usually WT. Tumors with metastases at diagnosis are usually MRTK.