Sustainability assessment as problem structuring: three typical ways.

Sustainability assessment (SA) is an increasingly popular term referring to a broad range of approaches to align decision-making with the principles of sustainability. Nevertheless, in public and private sectors sustainability results are still disappointing, and this paper reflects on this problem and proposes a way forward. We argue that, because sustainability issues are generally wicked problems (i.e. a 'complex of interconnected factors in a pluralistic context'), effective assessments need to be reflexive about the definition of the issue and about the criteria for sustainable solutions. Based on a distinction of policy problems, we characterize SA as a form of problem structuring, and we distinguish three typical ways of problem structuring, corresponding to three different ways of integrating reflexivity in the assessment. We illustrate these routes in three examples. We discuss the way reflexivity is integrated in each example by discussing the mix of methods, SA process and epistemological balance. Rather than merely calling for more stakeholder participation, our aim is to call for more reflexivity integrated into the SA approach, and we conclude by proposing a process map for reflexive sustainability assessment to support this.

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.

Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols. PATIENTS AND METHODS: We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012. RESULTS: Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%-32%), and 5-year overall survival (OS) was 26% (95% CI: 10%-42%). CONCLUSIONS: In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.

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.

Incidence and outcomes of patients with late recurrence of Wilms' tumor.

BACKGROUND: Most relapses from Wilms' tumor occur within 2 years from diagnosis. This study aims to describe the incidence and outcome of patients who experienced a late recurrence (LR) more than 5 years after diagnosis across several clinical trials, and to develop evidence-based recommendations for follow-up surveillance. METHODS: Available records on children with Wilms' tumor enrolled onto 10 national or international cooperative clinical trials were reviewed to identify patients who experienced a LR. RESULTS: Seventy of 13,330 (0.5%) patients with Wilms' tumor experienced a LR. No gender bias was observed. Median time elapsing between initial Wilms' tumor diagnosis and first recurrence was 13.2 years (range: 5.1-17.3 years). Initial tumor stage was: stage I (15); stage II (19); stage III (14); stage IV (8); bilateral disease stage V (14). The most frequent sites of relapse were--abdomen: 21, lungs: 20, and contralateral kidney: 15. Thirty-five children died of disease progression. Recurrence in the contralateral kidney was associated with a better outcome (13/15 patients alive), while initial tumor stage did not seem to influence the post-recurrence outcome. Therapies administered at recurrence varied between centers, preventing any conclusion about the best salvage treatment. CONCLUSIONS: LR of Wilms' tumor is rare and associated with similar outcome to those experiencing earlier recurrence. The low rate of LR does not justify prolonged monitoring. Further study of the biology of these tumors may give us some insights in regards to mechanisms on tumor cell dormancy or cancer stem cell maintenance.

Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group.

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6-97) and 98.9% (95% CI: 97.7-100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2-89.5; OS 93.2%, 95% CI: 88.7-97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse.

Endocrine late effects from multi-modality treatment of neuroblastoma.

Thyroid dysfunction has been reported after 131I-MIBG-treatment for neuroblastoma. In this study, we have evaluated all endocrine functions from patients who were given multi-modality treatment including 131I-MIBG. Twenty-five neuroblastoma survivors who were off therapy for a median period of 6.0 years (range 1.3-11.1) were evaluated and their median age was 8.1 years (range 2.2-14.7). All patients had received 131I-MIBG, 16 chemotherapy, and 16 surgery. Fourteen patients (56%) had permanently elevated thyrotropin levels and 9 received thyroxine. Two patients had a small thyroid volume while 6 had thyroid nodules or cysts. Two boys showed hypergonadotropic hypogonadism. Growth was retarded in 39% of children. Mean Target Height Standard Deviation Score of patients with thyrotropin elevation was lower than those without (P=0.019). Children treated for neuroblastoma with 131I-MIBG, chemotherapy and surgery were seen to be at risk from developing irreversible thyroid function loss, thyroid nodules, hypergonadotropic hypogonadism, and growth retardation. We recommend that during follow-up of neuroblastoma children, special attention should be paid to their endocrine state.

Metastasized angiosarcoma of the spleen in a 2-year-old girl.

Primary angiosarcoma of the spleen is rare and the prognosis is very poor. The authors present a 2-year-old girl with spontaneous rupture of splenic angiosarcoma. At diagnosis there were liver metastases. After splenectomy she received chemotherapy with ifosfamide, vincristine, and actinomycine D combined with a partial liver resection. She remained in complete remission over 2 years from diagnosis.

Childhood paroxysmal nocturnal haemoglobinuria (PNH), a report of 11 cases in the Netherlands.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by intravascular haemolysis, nocturnal haemoglobinuria, thrombotic events, serious infections and bone marrow failure. This acquired disease, caused by a deficiency of glycosylphosphatidylinositol (GPI) anchored proteins on the haematopoietic cells, is rare in children. We describe 11 Dutch paediatric PNH patients (median age: 12 years, range 9-17 years) diagnosed since 1983, seven cases associated with aplastic anaemia (AA), four with myelodysplastic syndrome (MDS). Presenting symptoms were haemorrhagic diathesis (n = 10), palor/tiredness (n = 8), dark urine (n = 1), fever (n = 1) and serious weight loss (n = 1). Treatment consisted of prednisolone (n = 7), anti-thymocyte globulin (n = 3) and/or androgens (n = 5). Eventually, five patients received a bone marrow transplantation (BMT) (three matched unrelated donors/two matched family donors), of whom four are still alive. PNH, diagnosed by immunophenotypic GPI-linked anchor protein analysis, should be considered in all children with AA or MDS. BMT should be considered as a therapeutic option in every paediatric PNH patient with BM failure.

Changes in thyroid hormone state in children receiving chemotherapy.

OBJECTIVE: The concentrations of thyroid function determinants may change during severe illness. Our goal was to quantify their changes in children with cancer during chemotherapy, and to correlate them to clinical condition and type of drugs. DESIGN: During a 3-month period all patients admitted for chemotherapy to the paediatric oncology ward were evaluated for inclusion. Patients with brain tumours, neuroblastoma (cranio)spinal irradiation and use of dexamethasone before the first blood sample were excluded. MEASUREMENTS: Plasma concentrations of T4, T3, rT3, thyroxine-binding globulin (TBG), thyroglobulin (Tg), TSH, IGF-1, cortisol, PRL and physical well-being by means of questionnaires were measured before and during chemotherapy. RESULTS: In 19 children, 46 courses of chemotherapy and 123 plasma samples were analysed. During chemotherapy, mean concentrations of TSH, T3, Tg and cortisol decreased to 53, 67, 69 and 15% of the baseline value, respectively. Mean plasma rT3 increased to 217% of baseline. In 87% of all courses, one or more thyroid parameter(s) was aberrant. Furthermore, in 23 samples (19%) from 10 patients (53%), the concentration of IGF-1 was below the reference value (adjusted for sex and age). Small changes were seen in scores for clinical condition but none was related to a change in thyroid function determinant. Most changes in thyroid hormones could be attributed to using dexamethasone. CONCLUSIONS: These results demonstrate that, in children, thyroid hormone state changes significantly during chemotherapy, apparently not related to physical well-being but to the drugs administered. Future investigations should focus on the impact for patient care and possibilities of (preventive) intervention.

Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua.

An important group of antimalarial drugs consists of the endoperoxide sesquiterpene lactone artemisinin and its derivatives. Only little is known about the biosynthesis of artemisinin in Artemisia annua L., particularly about the early enzymatic steps between amorpha-4,11-diene and dihydroartemisinic acid. Analyses of the terpenoids from A. annua leaves and gland secretory cells revealed the presence of the oxygenated amorpha-4,11-diene derivatives artemisinic alcohol, dihydroartemisinic alcohol, artemisinic aldehyde, dihydroartemisinic aldehyde and dihydroartemisinic acid. We also demonstrated the presence of a number of biosynthetic enzymes such as the amorpha-4,11-diene synthase and the--so far unknown--amorpha-4,11-diene hydroxylase as well as artemisinic alcohol and dihydroartemisinic aldehyde dehydrogenase activities in both leaves and glandular trichomes. From these results, we hypothesise that the early steps in artemisinin biosynthesis involve amorpha-4,11-diene hydroxylation to artemisinic alcohol, followed by oxidation to artemisinic aldehyde, reduction of the C11-C13 double bond to dihydroartemisinic aldehyde and oxidation to dihydroartemisinic acid.

Reduction of postoperative chemotherapy in children with stage I intermediate-risk and anaplastic Wilms' tumour (SIOP 93-01 trial): a randomised controlled trial.

BACKGROUND: Present treatment for Wilms' tumour is very successful. Now, efforts are aimed at reducing toxicity and burden of treatment by shortening schedules without loss of effectiveness. The objective of this randomised trial was to assess whether postoperative chemotherapy for patients with stage I intermediate-risk and anaplastic Wilms' tumour could be shortened to only 4 weeks from the standard 18 weeks, while maintaining equivalent event-free survival. METHODS: Between June, 1993, and June, 2000, 410 patients were randomly assigned after four doses of vincristine plus one course of dactinomycin postoperatively either to stop further adjuvant chemotherapy (no further chemotherapy group, n=200), or to receive a further two courses of the same chemotherapy (standard group, n=210). Previous treatment consisted of chemotherapy before nephrectomy of four doses of vincristine and two courses of dactinomycin followed by surgical resection of the tumour. Eligible patients were at least 6 months old and had stage I tumours with either intermediate-risk histology or anaplasia. The primary endpoint of this equivalence trial was 2-year event-free survival. Both per-protocol and intention-to-treat analyses were done. FINDINGS: By 2 years, 18 recurrences were reported in the standard group, and 22 in the no further chemotherapy group. Event-free survival was 91.4% (95% CI 87.5-95.2) for the no further chemotherapy group and 88.8% (84.3-93.2) for the standard group (difference=2.6%, upper 97.5% confidence limit 8.4%). The null hypothesis, that experimental treatment is less effective than standard treatment, could be rejected (p=0.008). CONCLUSIONS: Shortening duration of chemotherapy could reduce acute and late side-effects and inconvenience for patient and parents while maintaining effectiveness, and could be beneficial in terms of health costs.

Intracranial relapse in Wilms tumor patients.

BACKGROUND: In children with nephroblastoma, recurrence with metastases in the central nervous system is rare. Recently, previous reports (NWTSG and UKCCSG) reported brain metastases with an incidence of respectively 0.5% and 0.6% in Wilms tumor (WT) patients (respectively n = 30/5,852 and n = 7/1,249). PROCEDURE: We retrospectively investigated the incidence and survival of patients with central nervous system relapse in WT patients, treated according to the consecutive SIOP protocols 1, 2, 5, 6, 9, and 93-01. All children with WT from 1971 until 2000 were enrolled in the study (3,040 eligible patients). Specimens at diagnosis and if possible at relapse were centrally reviewed. Patients with renal neoplasms other than WT were excluded. RESULTS: CNS relapse was documented in 14 patients (0.5%). Median time to CNS relapse was 16 months (3-69). The occurrence of relapse was not associated with specific histological subtypes. In seven patients intracranial metastases occurred at first relapse, of which two were isolated relapses. In five patients no treatment was started because of the poor condition of the patient, the other nine cases were treated with (a combination of) chemotherapy (n = 6), surgery (n = 4), and radiotherapy (n = 6). CONCLUSIONS: CNS relapse in WNT is rare. In contrast to reports of other Wilms tumor study groups, although four patients reached (local) CR, the SIOP registry showed that eventually none of the documented WT patients survived.

Carboplatin-epirubicin regimen for the treatment of hepatoblastoma.

BACKGROUND: In order to lower the long-term toxicity of chemotherapy for hepatoblastoma patients, a prospective study was designed based on pre-operative chemotherapy combining carboplatin and epirubicin (CE). PROCEDURES: Patients under 16 years of age with an epithelial hepatic tumor diagnosed by ultrasound or CT scan and a high serum alpha-foetoprotein (AFP) level were eligible. Patients were treated with a pre-operative chemotherapy regimen combining carboplatin 600 mg/m(2) and epirubicin 80 mg/m(2). Tumor resectability was assessed after four courses given at 3-week intervals. After surgery, patients were given two more courses of CE. Response was assessed based on a drop in serum AFP and tumor shrinkage. RESULTS: Between July 1988 and August 1995, 27 patients with a hepatoblastoma were included. The initial PRETEXT group according to the SIOPEL classification was: group 2 (5 pts), group 3 (15 pts), group 4 (5 pts), and 2 pts were not assessed. Six patients had lung metastases. Response was partial response (PR) in 20/27 (74%) patients, disease was stable in 3 and 4 had progressive disease (PD). A complete surgical resection was performed in 21 pts. Five-year overall and disease-free survival (DFS) were respectively 56% (95%CI: 37-72%) and 63% (95%CI: 44-78%). During the same time period, 7 pts with a hepatocellular carcinoma were treated according to this protocol. Only one achieved a PR. Toxicity was mostly hematologic with > or =grade 3 leukopenia in 23% of the courses, > or =grade 3 thrombocytopenia in 29% of the courses and anemia in 22%. CONCLUSION: The CE protocol is feasible and efficient in hepatoblastoma. However, only a randomized study will permit a valid comparison of the efficacy of cisplatin and carboplatin for the treatment of these patients.

[Therapeutic advances of nuclear medicine in oncology]. / Avances terapéuticos de medicina nuclear en Oncología.

With the development of new radiopharmaceuticals there is a tendency to apply nuclear medicine therapy for malignancies of higher incidence (lymphoma, prostate) than the ones which have been treated for many years (thyroid cancer, neuroendocrine tumours). One of the most important areas of current development in radionuclide cancer therapy is the monotherapeutic use of new or already available radiopharmaceuticals in preclinical or phase I studies and to a lesser degree in phase II trials. In this context, the radioimmunotherapy is showing important advances in the treatment of medullary thyroid carcinoma, malignant lymphomas en brain tumours with potential extension to neuroblastoma therapy. The development of DOTA as a chelating agent has lead to the use of Y-90-DOTATOC in the treatment of neuroendocrine tumours, particularly carcinoid tumours, and non-I131I-avid thyroid carcinomas. In an effort to improve tumour targeting together with simultaneous reduction of physiological organ uptake, 131I-MIBG is being used in combination with interferon a and pre-targeting with unlabelled MIBG in the treatment of carcinoid tumours. New routes of administration of radiopharmaceuticals (intratumoral, intra-arterial) have enhanced the treatment of malignancies of liver, pancreas and brain as well as the potential use of radioimmunotherapy by intravesical administration for bladder carcinoma. Another significant tendency in radionuclide therapy is its evolution from monotherapy towards a combined application with other anticancer modalities. Some recent examples of combined therapy with demonstrated anti-tumour effect are found in neuroblastoma (131I-MIBG and chemotherapy), bone metastases of prostatic carcinoma (addition of 89Sr to chemotherapy schedules), brain malignancies (adjuvant use of radioimmnunotherapy in relation to surgery and external radiotherapy) and lymphoma (radioimmunotherapy combined with chemotherapy or immunotherapy). Reinforcing this trend in phase II and III studies as well as the planning of multicenter trials following the guidelines and criteria of clinical oncology will determine the future advances in this field.

Risk of cancer in the offspring of women who underwent ovarian stimulation for IVF.

BACKGROUND: Over the past decade attention has been increasingly focused on the long-term health effects of assisted reproductive technologies (ART), such as IVF, in both women and their offspring. To determine the risk of cancer in children conceived by IVF we used a large population-based historical cohort that was initially designed to examine the risk of gynaecological disorders in women who underwent IVF. METHODS: Children were included in the exposed group if they were conceived by IVF or other related fertility techniques (n=9484). The unexposed group consisted of 7532 children whose mothers were diagnosed with subfertility disorders but who were conceived naturally. All cohort members were asked to complete a mailed questionnaire that inquired about reproductive variables and cancer in the offspring (response rate 66.9%). RESULTS: During an average follow-up period of 6.0 years, 16 cancers were observed in the exposed and unexposed group combined, whereas 15.5 were expected [standardized incidence ratio (SIR) = 1.0; 95% confidence interval (95% CI) 0.6-1.7]. A direct comparison between children conceived after ART and naturally conceived children revealed no increased risk for childhood malignancies [risk ratio (RR) = 0.8; 95% CI 0.3-2.3]. CONCLUSIONS: Despite the small numbers of observed cancer cases, these findings demonstrate that children conceived by ART have no greatly increased risk of cancer during childhood compared with the general population and the internal reference group.

Germacrenes from fresh costus roots.

Four germacrenes, previously shown to be intermediates in sesquiterpene lactone biosynthesis, were isolated from fresh costus roots (Saussurea lappa). The structures of (+)-germacrene A, germacra-1(10),4,11(13)-trien-12-ol, germacra-1(10),4,11(13)-trien-12-al, and germacra-1(10),4,11(13)-trien-12-oic acid were deduced by a combination of spectral data and chemical transformations. Heating of these compounds yields (-)-beta-elemene, (-)-elema-1,3,11(13)-trien-12-ol, (-)-elema-1,3,11(13)-trien-12-al, and elema-1,3,11(13)-trien-12-oic acid respectively, in addition to small amounts of their diastereomers. Acid induced cyclisation of the germacrenes yields selinene, costol, costal, and costic acid respectively. It is highly probable that the elemenes reported in literature for costus root oil are artefacts.

Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxylated metabolites in children with malignant disease: a sparse sampling approach.

OBJECTIVE: To assess the feasibility of a sparse sampling approach for the determination of the population pharmacokinetics of ifosfamide, 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide in children treated with single-agent ifosfamide against various malignant tumours. DESIGN: Pharmacokinetic assessment followed by model fitting. PATIENTS: The analysis included 32 patients aged between 1 and 18 years receiving a total of 45 courses of ifosfamide 1.2, 2 or 3 g/m2 in 1 or 3 hours on 1, 2 or 3 days. METHODS: A total of 133 blood samples (median of 3 per patient) were collected. Plasma concentrations of ifosfamide and its dechloroethylated metabolites were determined by gas chromatography. Plasma concentrations of 4-hydroxy-ifosfamide were measured by high-performance liquid chromatography. The models were fitted to the data using a nonlinear mixed effects model as implemented in the NONMEM program. A cross-validation was performed. RESULTS: Population values (mean +/- standard error) for the initial clearance and volume of distribution of ifosfamide were estimated at 2.36 +/- 0.33 L/h/m2 and 20.6 +/- 1.6 L/m2 with an interindividual variability of 43 and 32%, respectively. The enzyme induction constant was estimated at 0.0493 +/- 0.0104 L/h2/m2. The ratio of the fraction of ifosfamide metabolised to each metabolite to the volume of distribution of that metabolite, and the elimination rate constant, of 2- and 3-dechloroethyl-ifosfamide and 4-hydroxy-ifosfamide were 0.0976 +/- 0.0556, 0.0328 +/- 0.0102 and 0.0230 +/- 0.0083 m2/L and 3.64 +/- 2.04, 0.445 +/- 0.174 and 7.67 +/- 2.87 h(-1), respectively. Interindividual variability of the first parameter was 23, 34 and 53%, respectively. Cross-validation indicated no bias and minor imprecision (12.5 +/- 5.1%) for 4-hydroxy-ifosfamide only. CONCLUSIONS: We have developed and validated a model to estimate ifosfamide and metabolite concentrations in a paediatric population by using sparse sampling.

Primary nephrectomy for emergency: a rare event in the International Society of Paediatric Oncology Nephroblastoma Trial and Study no. 9.

Experience of the International Society of Paediatric Oncology (SIOP) Trials and Studies indicates that the preoperative chemotherapy in Wilms' tumour improves stage distribution, decreases complication rate and reduces postoperative treatment. However, some situations may lead to prompt primary surgery. The aim of the study is to assess reasons leading to primary emergency nephrectomy. Records of 720 patients with non-metastatic unilateral nephroblastoma who were registered in the SIOP Trial and Study 9 were reviewed. Twenty-four (3%) cases of primary emergency nephrectomy were identified. Reasons leading to emergency nephrectomy were massive bleedings from ruptured tumours in 13 patients, suspicion of an "acute abdomen" in 7, bowel occlusion in 2 and other in 2. Postoperative treatment included radiotherapy in 71% of cases and anthracyclines in 92%. Complications were frequent and happened in 25% of patients, the outcome however, was favourable and 22 of 24 patients are alive (from 9 to 79 months). The 7 patients with a suspicion of an "acute abdomen" probably constitute the group which could have been markedly reduced if adequately diagnosed and observed prior to surgery.

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients.

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131I-MIBG (110 MBq) and with 131I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131I-mAb chCE7 and of 24 days with 131I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131I-chCE7 compared with 131I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131I-MIBG and 131I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not accumulate 131I-MIBG, and the antibody may hold potential for radioimmunotherapy, either by itself or in combination with 131I-MIBG.