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Biomedical subjects

P A Voute

Publications and source records attributed to P A Voute.

At least 19 recordsLinked to original sources
PubMed2000

In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia.

Cytidine triphosphate (CTP) synthetase is a key enzyme for the synthesis of cytosine (deoxy)ribonucleotides, catalysing the conversion of uridine triphosphate (UTP) into CTP, and has a high activity in several malignancies. In this preclinical study, the enzyme activity and mRNA expression of the enzyme and (deoxy)ribonucleotide concentrations were analysed in leukaemic cells of 57 children suffering from acute lymphocytic leukaemia (ALL). In addition, in vitro experiments were performed with the CTP synthetase inhibitor cyclopentenyl cytosine (CPEC). A significantly higher activity of CTP synthetase (6.5 +/- 3.9 nmol CTP/mg/h) was detected in ALL cells than in lymphocytes of healthy controls (1.8 +/- 0.9 nmol CTP/mg/h, P < 0.001) that was independent of white blood cell (WBC) count, blast percentage, age, gender or type of ALL. The enzyme activity was not correlated with the CTP synthetase mRNA expression. The activity of CTP synthetase in ALL cells compared with non-malignant CD34+ bone marrow controls (5.6 +/- 2.4 nmol CTP/mg/h) was not statistically different. In vitro treatment of ALL cells with CPEC induced a dose-dependent decrease of the CTP concentration. The lowest concentration of CPEC (0.63 microM) induced a depletion of CTP of 41 +/- 20% and a depletion of dCTP of 27 +/- 21%. The degree of CTP depletion of ALL cells after treatment with CPEC was positively correlated with the activity of CTP synthetase. The inhibition of CTP synthetase in situ was confirmed by flux studies using radiolabelled uridine. From these results, it can be expected that CPEC has a cytostatic effect on lymphoblasts of children with ALL.

Adult↗
PubMed1999

Pelvic Ewing sarcoma: a retrospective analysis of 241 cases.

BACKGROUND: This article reports on 241 patients each with pelvic Ewing sarcoma registered for studies in Germany, Austria, and the Netherlands from January 1, 1981, until January 31, 1994. One hundred sixty-four patients had localized disease and 87 had metastases at diagnosis (PMP). Eighty-four patients with localized disease were entered on protocol (PP) and 80 were followed (FP). METHODS: Statistics included an analysis of event free survival by the Kaplan-Meier method and a Cox regression analysis of factors influencing prognosis. RESULTS: In the Kaplan-Meier analysis, on February 1, 1995, the event free survival (EFS) rate was 32% at 12 years for all patients, 54% for PP, 25% for FP, and 13% for PMP. Cox regression analysis showed that response to chemotherapy, initial metastases, and less intense therapy were significant prognostic factors. Among patients who had surgery for local control, the histologic response to chemotherapy was analyzed in the surgical specimen and had a significant influence on survival: EFS 69% for PP with good response compared with 47% (P = 0.11) for patients with poor response, and for FP 56% versus 13% (P = 0.002). All PP with small tumors had relapse free survival, compared with 69% of patients with medium-sized tumors and 36% of patients with tumors larger than 200 mL (P = 0.006). The initial tumor volume was a significant predictor of survival. CONCLUSIONS: Combined modality treatment has resulted in definitive improvement of prognosis for patients with localized pelvic Ewing sarcoma. However, the results for patients with metastases at diagnosis are still discouraging, and their treatment requires new approaches. Tumor load, responsiveness to chemotherapy, and adequate surgical margins are the major factors influencing the prognosis of patients with localized Ewing sarcoma of the pelvis.

Adolescent↗
PubMed1999

The role of preoperative chemotherapy in the treatment of nephroblastoma: the SIOP experience. Societe Internationale d'Oncologie Pediatrique.

Treatment of Wilms' tumor is an example of success of modern oncology. A combination of surgery, radiotherapy, and chemotherapy is widely accepted as the efficacious treatment of nephroblastoma. However, timing of each part of the treatment differs, in various protocols: the Societe Internationale d'Oncologie Pediatrique (SIOP) recommends the diagnosis based on imaging and metabolic exclusion of neuroblastoma to reduce the biopsy-related risk of spillage. In patients more than 6 months old, the treatment starts with the preoperative chemotherapy to improve the stage distribution at surgery and decrease the complications rate. Patients with advanced nephroblastoma, as those with vena cava thrombus and lung metastases, can benefit the most from the pretreatment. Results from the SIOP studies 6 and 9 confirm these statements: the stage distribution after the pretreatment reveals more than 50% of cases staged I, the 4-year disease-free survival in pulmonary stages IV was 83%, and of 42 patients with vena cava thrombus still present at surgery, 38 are alive from 27 to 109 months.

Child↗
PubMed1998

Rarity of surgical complications after postchemotherapy nephrectomy for nephroblastoma. Experience of the International Society of Paediatric Oncology-Trial and Study "SIOP-9". International Society of Paediatric Oncology Nephroblastoma Trial and Study Committee.

The aim of the study was to assess rates and types of nephrectomy-related complications in children nephrectomized for nephroblastoma after preoperative chemotherapy. Records of 598 Wilms' tumour patients registered in the International Society of Paediatric Oncology Trial & Study No. 9 (SIOP-9), and pretreated correctly according to the protocol with vincristine + actinomycin D +/- epirubicine or adriamycin prior to nephrectomy, were retrospectively reviewed. Forty-nine patients (8%), who suffered from 54 complications, were identified. Most frequent events were small-bowel occlusions (3.7%) and tumour ruptures (2.8%). Other complications were registered in 2.0% of cases. The low rate of nephrectomy complications and no deaths related to registered ones, are another argument for preoperative chemotherapy in Wilms' tumour patients.

Adolescent↗
PubMed1997

Three germline mutations in the TP53 gene.

Three germline mutations in the TP53 tumor-suppressor gene are reported, two of which are not reported previously. A missense mutation at codon 265 of TP53 was found in three patients of a family that complied with the definition of the Li-Fraumeni syndrome. A nonsense mutation in codon 306 was found in a woman who had had a rhabdomyosarcoma at age 4 and a subsequent breast cancer at age 22. She was part of a Li-Fraumeni-like family, but the parental origin of the mutation could not be traced. Finally, while screening for somatic alterations in TP53 in a series of 141 sporadic breast tumors, we detected a constitutional missense mutation in codon 235 in a woman diagnosed with breast cancer at age 26 and a recurrence 4 years later. The recurrence, but not the primary tumor, showed an additional missense mutation at codon 245 as well as loss of the wild-type allele. This suggests that the 245 mutation was particularly important for tumor progression and that there might exist heterogeneity in terms of cancer predisposition potential among the various germline TP53 mutations.

Breast Neoplasms↗
PubMed1995

Paediatric surgical oncology. 5--Nephroblastoma. International Society of Paediatric Oncology (SIOP) Nephroblastoma Trial & Study Committee.

The favourable results from the treatment of Wilms' tumour are an example of the success of multimodal therapy in paediatric oncology. The epidemiology, methods of diagnosis, benefits of pre-operative chemotherapy, basic principles of surgery and post-operative treatment modalities are presented. The approach to the management of Wilms' tumour considered in this paper is mainly that of the International Society of Paediatric Oncology.

Chemotherapy, Adjuvant↗
PubMed1994

The expression pattern of contractile and intermediate filament proteins in developing skeletal muscle and rhabdomyosarcoma of childhood: diagnostic and prognostic utility.

In order to investigate whether rhabdomyosarcoma (RMS) can be related to equivalent stages of skeletal muscle development, muscle tissue of 21 human foetuses and 112 primary RMSs were characterized immunohistochemically using antibodies directed against vimentin, desmin, muscle-specific actin (HHF35), sarcomeric actin (sr-actin), smooth muscle actin (sm-actin), and troponin-T. During fetal skeletal muscle development, all myotubes/fibres of the first and second generations expressed desmin, HHF35, and sr-actin. Vimentin was almost exclusively present in immature primary and secondary myotubes/fibres. Troponin-T was expressed in immature myotubes/fibres of the first and second generations as well as mature fibres of the second generation. Sm-actin was never expressed. Vimentin was expressed in 96 per cent of primary and 98 per cent of relapsed RMS; HHF35 in 96 and 98 per cent, respectively; desmin in 95 and 100 per cent; troponin-T in 82 and 75 per cent; sr-actin in 71 and 86 per cent; and sm-actin in 13 and 17 per cent. The proportion of RMS cells reacting with vimentin, HHF35, and desmin was consistently higher than those expressing sr-actin and troponin-T. Neither the shape nor size of neoplastic RMS cells nor the histopathological types were related to the expression pattern of the investigated markers. RMS with aberrant expression of two or more markers predicted a worse prognosis than RMS in which at most one marker was aberrantly expressed (25 per cent and 54 per cent 10-year survival, P = 0.01). These results demonstrate that HHF35, desmin, sr-actin, and troponin-T have the potential to confirm the commitment of the tumours to the myogenic pathway which supports the diagnosis of RMS. However, it was impossible to relate RMS to equivalent stages of skeletal muscle development. Aberrant marker expression by RMS cells correlated significantly with patients' survival.

Actins↗
PubMed1994

Histopathological classification of childhood rhabdomyosarcomas: relationship with clinical parameters and prognosis.

To define a useful and prognostically relevant classification system for rhabdomyosarcomas (RMSs), tissue sections of 113 well-documented, protocol-treated cases were retrieved from the files of the Emma Kinderziekenhuis Amsterdam, the Netherlands, and reclassified by a panel of pediatric pathologists. The following subtypes were recognized: embryonal RMS (n = 66), alveolar RMS (including the solid variant) (n = 16), botryoid RMS (n = 11), embryonal sarcoma (n = 6), and spindle cell RMS (n = 5). Nine cases were classified as RMS not otherwise specified (NOS). The above-mentioned histopathological subtypes correlated significantly with survival (P = .005) in patients with nonparameningeal tumors. Indeed, the best prognosis was observed in patients with spindle cell RMS, embryonal sarcoma, and botryoid RMS (10-year survival rates of 80% to 86%). Patients with embryonal RMS had an intermediate prognosis (10-year survival rate of 55%) and patients with alveolar RMS fared poorly (10-year survival rate of 9%). Survival rate was poor in patients with a localized parameningeal tumor, irrespective of histopathological subtype (10-year survival rate of 33%). Furthermore, this study confirmed the known impact on prognosis of localization (P = .008) and tumor node metastasis (TNM) stage (P = .0005). Classification of RMS subtypes proved to be fairly well reproducible (kappa ranging from 0.47 to 0.85 and percentage of concordance ranging from 50% to 85%). The best agreement was noted in botryoid RMS and the worst in embryonal sarcoma. However, improvement of agreement was noted for the latter subtype during the consecutive classification sessions. In summary, this study shows the strong prognostic value of histopathological subtypes and parameningeal tumor localization.

Child↗
PubMed1994

Histopathological features and grading in rhabdomyosarcomas of childhood.

Rhabdomyosarcoma represents a large group of soft tissue sarcomas displaying heterogeneous histopathological features. In addition to their histopathological classification, the variable expression of a number of histopathological features may contribute to the heterogeneity and may be related to prognosis. Tissue sections of 113 well-documented, protocol-treated patients with long term follow-up (mean 6 years) were analysed by a panel of four paediatric pathologists. The following features were assessed: presence of rhabdomyoblasts, degree of maturation of rhabdomyoblasts, heterogeneous maturation patterns, mitotic activity, tumour necrosis, myxoid component, and septa. A scoring system was allocated to each index. High degree of maturation (amount of cytoplasm greater than surface area of the nucleus), absence of tumour necrosis (< 10% of tumour surface), and absence of septa (< 10% of tumour surface) significantly correlated with a favourable clinical course. Reproducibility in the assessment of these three features was good: mean kappa varying from 0.53 to 0.64. A rhabdomyosarcoma score function for survival was defined by: (-0.27 x degree of maturation score) + (0.007 x percentage septated area) + (0.031 x percentage tumour necrosis). Based on the score a two-grade system was elaborated, i.e. grade I (score < -0.20) v. grade II (score > or = -0.20). Rhabdomyosarcoma grade appeared to be the best factor in predicting patients survival: 69% long-term survival in patients with grade I v. 33% in patients with grade II (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Primary chemotherapy in rhabdomyosarcomas and other malignant mesenchymal tumors of the orbit: results of the International Society of Pediatric Oncology MMT 84 Study.

PURPOSE: The MMT 84 multicentric prospective trial of the International Society of Pediatric Oncology (SIOP) was designed to (1) test the effectiveness of ifosfamide 3 g/m2 on days 1 and 2, vincristine 1.5 mg/m2 on days 1 and 14, and dactinomycin 0.9 mg/m2 on days 1 and 2 (IVA) repeated every 21 days; and (2) reduce late effects of treatment by reserving radiation therapy to the primary site for patients not achieving a complete response (CR) to primary chemotherapy. MATERIALS AND METHODS: Between 1984 and 1989, the MMT 84 study registered 34 children with nonmetastatic rhabdomyosarcomas (RMSs) and other malignant mesenchymal tumors (MMTs) of the orbit in this trial. RESULTS: The 4-year event-free survival rate is 62% +/- 9% (SD) and the 4-year survival rate 86% +/- 7% (SD). A total of 11 local recurrences occurred, 10 among 22 patients treated without initial radiation. Salvage of local failure was achieved in nine of 11 patients with the use of radiation and additional chemotherapy, but three later developed distant metastases and two have died. One isolated regional lymph node failure has occurred, while no patient relapsed with isolated distant metastases. Six of 12 patients who failed are alive with no evidence of disease from 16 to 50 months after relapse. The treatment was well tolerated in all patients, except for one with renal tubular acidosis and one who died of cardiotoxicity. Twelve patients remain in first remission without the use of radiation to the primary tumor from 27 to 84 months. CONCLUSION: Despite a higher incidence of local recurrence when treated by primary chemotherapy, early survival rates were not compromised and a significant number of patients avoided the late effects of radiation. However, longer follow-up is required to assess the ultimate outcome of patients treated in this manner.

Adolescent↗
PubMed1993

Excess of multifocal tumors in nephroblastoma: implications for mechanisms of tumor development and genetic counseling.

Referring to the mutational theory of carcinogenesis in embryonal tumors, it is commonly accepted that patients with multifocal tumors are hereditary cases. This is based on the implicit assumption that each tumor results from a single mutational event occurring in a cell that has already inherited a mutation, and that these tumors are independent. We studied the distribution of tumors in 1,868 cases where the focality was known (SIOP 1, 2, 5 and 6). Using all the supposed gene carriers (bilateral and unilateral multifocal cases), and assuming a Poisson distribution of tumors, we estimated the mean number m of tumors in each kidney to be 0.37. Comparing the observed distribution of cases to the expected one, we found a very bad fit to this hypothesis (P < 10(-9)). This is due to an excess of multifocal tumors, particularly in unilateral cases. These findings have important implications in genetic counseling, since the usual practice of considering multifocal tumor patients as hereditary cases may result in a large overestimate of the recurrence risk in such cases. The implications for the mechanisms of tumor development are also discussed.

Chi-Square Distribution↗
PubMed1993

Urogenital rhabdomyosarcoma in children: is a conservative surgical approach justified?

Between 1970 and 1990, 23 patients were treated for embryonal rhabdomyosarcoma of the bladder (8), prostate (7), uterus (4) or vagina (4). One girl underwent exenteration without chemotherapy. Of the patients 22 received chemotherapy as initial treatment. There was 1 treatment-related death. A total of 21 patients completed the first phase: 4 were treated with chemotherapy alone and 17 subsequently underwent an operation. Three boys underwent total cystoprostatectomy and local resection was performed in 14 patients. One boy was lost to followup. Mean followup was 11.2 +/- 6.3 years in 15 survivors. Complete remission was achieved in 19 patients, while 11 (53%) had relapse at an interval of 3 to 102 months. Of 13 patients with bladder and prostate tumors 8 had relapse and 7 survived. Of 8 patients with uterus and vagina tumors 3 had relapse and all survived. Six patients died of recurrent disease (overall mortality rate 32%). The interval from initial diagnosis until death was always less than 5 years. The mortality rate was greater in boys (5 of 12) than in girls (1 of 9). Preservation of pelvic organs in girls was 75%, while of the boys 44% retained the bladder. Since disease relapsed in patients in whom no tumor was found in the resection specimen after chemotherapy, we conclude that a conservative surgical approach combined with chemotherapy towards urogenital rhabdomyosarcoma is justified. Although late relapses do occur, they can usually be salvaged by a combination of chemotherapy, radiotherapy and surgery.

Adolescent↗
PubMed1988

Epidemiological features of Wilms' tumor: results of studies by the International Society of Paediatric Oncology (SIOP).

This descriptive epidemiology study of 1,040 children with Wilms' tumor (WT) registered in the International Society of Paediatric Oncology (SIOP) clinical trials confirms the findings reported by the National Wilms' Tumor Study. The male:female rate was 0.89:1. The mean age at diagnosis of the 43 bilateral cases was significantly younger than children with unilateral renal involvement (32.4 vs 45 months). However, the mean ages of diagnosis for unilateral multicentric and for unicentric WT were very similar. On the other hand, the mean age at diagnosis of children with sporadic aniridia and hypospadias was younger than the mean age of patients with or without other congenital malformations. Thus aniridia as well as hypospadias could be indices of the first mutation, according to the Knudson and Stron hypothesis. WT was reported in two members of each of five families. However, these familial cases were comparable in terms of demographic and clinical features to the nonfamilial ones. These data suggest that the heritable fraction of WT is relatively small and that genetic and environmental factors interact in the development of WT.

Congenital Abnormalities↗
PubMed1988

Prognostic factors in 281 children with nonmetastatic rhabdomyosarcoma (RMS) at diagnosis.

Pretreatment characteristics of 281 children with nonmetastatic rhabdomyosarcoma, included in the registry of the International Society of Pediatric Oncology (SIOP) between January 1975 and December 1983, were examined to study the children's prognosis. The multivariate statistical method (Cox regression model) was used for each of two endpoints: survival time and disease-free time. The three most important predictors for survival time were primary site (p less than .001), clinical stage (p = .009), and sex (p = .020). The best results involved paratesticular and orbital primary sites, regardless of the clinical stage; males fared slightly better than females. These same three factors were also significant predictors for disease-free time.

Adolescent↗
PubMed1985

Primary chemotherapy in the treatment of rhabdomyosarcoma in children: trial of the International Society of Pediatric Oncology (SIOP) preliminary results.

This therapeutic trial deals with 81 patients with stage III rhabdomyosarcoma (RMS), from different centers of the International Society of Pediatric Oncology. These patients were included between October 1975 and March 1983. The aim of this work is to minimize the sequelae of treatment without jeopardizing the survival rate. After a pretrial course of VAC, two groups of patients are compared: the first treated with systematic extensive surgery or radiotherapy on the initial tumor volume, and the second treated with combined chemotherapy using vincristine, dactinomycin, adriamycin, cyclophosphamide until maximum tumor reduction, followed by radiotherapy or surgery on the residual mass only. Eighty one patients were included in the trail; 15 patients were not randomized due to the failure of the pretrial course of chemotherapy, 3 were excluded after randomization (2 were found not to have RMS, and in one case the protocol was not observed). The preliminary results for the 63 patients show a survival rate of 40% at 3 years. The sequential scheme for patients at 3 years follow-up does not show a superiority in either arm.

Adolescent↗