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Background: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort., Methods: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z -score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance., Results: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P =0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P =0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (β±SE, 0.19±0.02; P <0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P =0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed., Conclusions: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment., Competing Interests: Disclosures C. Teran is a former University of California Log Angeles Health employee supported by National Institutes of Health funding. Dr Liebeskind is scientific advisor and on the Board of Directors of Sage Cerebrovascular Diagnostics, Inc. Dr McGrath receives grant support from the Health Research Board. Dr DeCarli is a consultant to Eisai and Novo Nordisk. Dr Himali receives grant support from NIH, the Alzheimer’s Drug Discovery Foundation, and the Alzheimer’s Association. Dr Seshadri is a consultant for Biogen and Eisai. Dr Hinman is a listed inventor on the following patents held by the Regents of the University of California that include blood measurement of the molecules included in this study: Japan Patent No. 7211626; Korea Patent No. 10-2538752; US Application 62/461,161; Canada Application 3,054,083; EPO Application 18755090.0. Dr Hinman is also the founder of Sage Cerebrovascular Diagnostics, Inc. which has an exclusive license from the Regents to commercialize diagnostic tests using these markers. The other authors report no conflicts.

In clinical research and care, information notices are too often reduced to complicated and hard-to-understand mandatory documents. However, every person has the right to transparent and truthful information. These considerations prompted the creation of a multidisciplinary working group in the fall of 2020, headed by the College des relecteurs de l'Inserm. This group associates the different actors involved in the development, evaluation and use of information notices: Health and research professionals, representatives of patient associations or research foundations, ethicists, jurists, scientific educators and communicators. This group has created a set of texts, pictograms and illustrations, adapted to the people concerned and accepted by all actors. These contents will be easily used by professionals through the app Notice infobox© . A pilot phase was conducted to generate the notices of the France Genomic Medicine Plan 2025, used for genetic examinations. This app Notice infobox© is a response to society's request to be an actor in its own healthcare and to adopt more ethical and responsible research., (© 2023 médecine/sciences – Inserm.)

Objective: To test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI., Methods: We studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), APOE ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression., Results: Less slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], p = 0.015; percentage, 0.16 [0.08], p = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], p = 0.034), and higher white matter hyperintensities volume (absolute duration, -0.12 [0.05], p = 0.010; percentage, -0.10 [0.04], p = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts., Conclusion: Loss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep., (© 2020 American Academy of Neurology.)

Objectives: According to the Renal Tumor Study Group (RTSG) of the International Society of Paediatric Oncology (SIOP), diagnostic biopsy of renal tumors prior to neoadjuvant chemotherapy is not mandatory unless the presentation is atypical for a Wilms tumor (WT). This study addresses the relevance of this strategy as well as the accuracy and safety of image-guided needle biopsy., Methods: Clinical, radiological, and pathological data from 317 children (141 males/176 females, mean age: 4 years, range, 0-17.6) consecutively treated in one SIOP-affiliated institution were retrospectively analyzed., Results: Presumptive chemotherapy for WT was decided for 182 patients (57% of the cohort), 24 (8%) were operated upfront, and 111 (35%) were biopsied at diagnosis. A non-WT was confirmed after surgery in 5/182 (3%), 11/24 (46%), and 28/111 (25%), respectively. Age at diagnosis was the most commonly (46%) used criterion to go for biopsy but a nine-year threshold should be retrospectively considered more relevant. Tumor volumes of clear cell sarcoma of the kidney and WT were significantly higher than those of other tumors (P = 0.002). The agreement between core-needle biopsy (CNB) and final histology was 99%. No significant morbidity was associated with CNB., Conclusion: The use of SIOP criteria to identify patients eligible for presumptive WT neoadjuvant chemotherapy or upfront surgery avoided biopsy in 65% of children and led to a 97% rate of appropriate preoperative chemotherapy. Image-guided CNB is a safe and accurate diagnostic procedure. The relevance of SIOP biopsy criteria might be improved by using an older age threshold (9 years instead of 6 years) and by adding initial tumor volume., (© 2019 Wiley Periodicals, Inc.)

Medulloblastoma patients treated at the Institute Curie between 1980 and 2000 were reviewed. Only patients whose primary treatment included craniospinal radiation were considered. Surviving patients were identified and evaluated by means of self-report questionnaires using the Health Utility Index (HUI). Psychosocial functioning, employment, and other health-related indicators were recorded. Seventy-three patients were treated during the study period. At a median follow-up from diagnosis of 14.4 years, 49 patients were alive and 45 surviving patients could be contacted. Late sequelae were frequent, particularly neurological deficits (71%) and endocrine complications (52%). Impairments of psychosocial functioning, including employment, driving capacity, independent living, and marital status, were identified in most patients. Most long-term medulloblastoma survivors suffer persistent deficits in several domains, with a significant impact on their psychosocial functioning. These findings reinforce the importance of early intervention programs for all survivors in order to reduce the psychosocial impacts of their disease.

Background: Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease., Procedure: A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients., Results: The following is a summary of the classification system developed-Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes., Conclusions: The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease., ((c) 2005 Wiley-Liss, Inc.)

The aim of this study was to determine the therapy-related risk factors for the occurrence of leukaemia after childhood solid cancer. Among 4204 3-year survivors of a childhood cancer treated in eight French and British centres before 1986, 11 patients developed leukaemia as a second malignant neoplasm (SMN). Compared with the leukaemia incidence in the general French and British populations, the standardised incidence ratio (SIR) of leukaemia was 7.8 (95% CI 4.0-13.4). It decreased from 20.3 (95% CI 8.3-41.2) during the first years of follow-up, to 2.2 (95% CI 0.1-9.7) between 10 and 20 years, but rose again to 14.8 (95% CI 3.7-38.3) 20 or more years after the first cancer. Radiotherapy appeared to increase the risk of leukaemia at moderate weighted doses to active bone marrow; the relative risk (RR) was 4.2 (95% CI 0.8-20.7) for doses ranging from 3 to 6.6 Gy. A greater RR was observed for epipodophyllotoxins and for vinca alkaloids. No specific type of first malignant neoplasm (FMN) was found to lead to a higher risk of secondary leukaemia. Epipodophyllotoxins and vinca alkaloids at high doses and moderate weighted radiation doses to active bone marrow may contribute independently to an increased risk of leukaemia for patients treated for childhood cancer. Our results suggest that the long-term risk of secondary leukaemia could be higher than previously reported.

In developed countries, adolescent death rate is under 1%, predominantly due to accidents. Amongst chronic diseases cancer has a prevalent role. A severe disease plays against the normal subjectivation and autonomization adolescent process. It leads to unbearable restrictions in being on the move with their mates, being proud of their body image, attending school. It increases parents' dependency and induces multiple treatment discomforts. Nursing team has to consider the adolescent as its primary interlocutor, to fulfil his demands of autonomy and to validate his choices, and to contribute to maintaining his links with his parents. Moreover, specific expressions of adolescent's needs in the field of pain control, body intimacy, information, schooling, sublimation's behaviours, sexuality, have to be recognized and satisfied.

Purpose: To assess the specific role of treatment and type of first cancer (FC) in the risk of long-term subsequent breast cancer (BC) among childhood cancer survivors., Patients and Methods: In a cohort of 1,814 3-year female survivors treated between 1946 and 1986 in eight French and English centers, data on chemotherapy and radiotherapy were collected. Individual estimation of radiation dose to each breast was performed for the 1,258 patients treated by external radiotherapy; mean dose to breast was 5.06 Gy (range, 0.0 to 88.0 Gy) delivered in 20 fractions (mean)., Results: Mean follow-up was 16 years; 16 patients developed a clinical BC, 13 after radiotherapy. The cumulative incidence of BC was 2.8% (95% CI, 1.0% to 4.5%) 30 years after the FC and 5.1% (95% CI, 2.1% to 8.2%) at the age of 40 years. The annual excess incidence increased as age increased, whereas the standardized incidence ratio decreased. On average, each Gray unit received by any breast increased the excess relative risk of BC by 0.13 (< 0.0 to 0.75). After stratification on castration and attained age, and adjusting for radiation dose, FC type, and chemotherapy, a higher risk of a subsequent BC was associated with Hodgkin's disease (relative risk, 7.0; 95% CI, 1.4 to 30.9)., Conclusion: The reported high risk of BC after childhood Hodgkin's disease treatment seems to be due not only to a higher radiation dose to the breasts, but also to a specific susceptibility.

Retinoblastoma is usually curable in developed countries. The morbidity and mortality of patients with hereditary retinoblastoma is still threatened by the occurrence of secondary tumours. Between 1971 and 1988, 427 patients with retinoblastoma were treated in the ophthalmologic, paediatric and radiotherapy departments of the Institut Curie. In this study, we report the clinical and therapeutic features and the outcome of 25 patients treated for a second malignant neoplasm, diagnosed between 1997 and 1999 at the Institut Curie. The median time interval between the diagnosis of retinoblastoma and SMN was 11.2 years (range 3.8-20.6 years). Histopathological diagnoses included: 12 osteosarcomas, 12 soft tissue sarcomas and, 1 malignant oligodendroglioma. The second malignant neoplasm was located inside the radiation field in 21 cases and outside in 4. Twenty three patients received pre-operative chemotherapy. Surgery was performed in 16 patients. Post-operative chemotherapy was administered in 12 patients and external beam radiotherapy was used in 2 patients. Response to treatment was evaluable in 24 patients: complete remissions were observed in 14/24, partial remissions in 2/24 and progressive disease in 8/24. Nineteen patients died. Six are still alive, with 4 in complete remission (median follow-up 8.8 years; range 5.8-13.9 years). Despite aggressive therapy, the prognosis of patients with second malignant neoplasm occurring after retinoblastoma is very poor. It is important to provide information to retinoblastoma patients regarding the risk of a second tumour as this may facilitate an early tumour detection.

Soft tissue sarcoma (STS) is one of the most frequent second primary cancer that occurs during the first 20 years following treatment for a solid cancer in childhood. Our aim was to quantify the risk of STS as a second malignant neoplasm and to investigate its relationship with radiotherapy and chemotherapy. A cohort study of 4,400 3-year survivors of a first solid cancer diagnosed during childhood in France or the United Kingdom, between 1942 and 1985, was followed 15 years on average. In a partially nested case-control study, we matched 25 cases of STS and 121 controls for sex, type of first cancer, age at first cancer and duration of follow-up. Sixteen STS occurred in the cohort, as compared to 0.3 expected from the general population (Standardized Incidence Radio, SIR = 54 (95%CI: 34-89)). The SIR was 113 (95% CI: 62-185) after chemotherapy plus radiotherapy (13 STS), whereas it was 28 (95%CI: 2-125) after chemotherapy alone (1 STS) and 19 (95%CI: 3-60) after radiotherapy alone (2 STS). After adjustment for treatment, there was no evidence of variation in the annual excess of incidence or in the SIR with either age at first cancer or time since 1st cancer. In the case-control study, the risk of a STS was increased with the square of the dose of radiation to the site of STS development and with the administration of Procarbazine. The increased risk of soft tissue sarcoma that occurred after childhood cancer is independently related to exposure to radiotherapy and Procarbazine. A closer surveillance of children treated with this treatment combination is strongly recommended., (Copyright 2004 Wiley-Liss, Inc.)

Purpose: Metaiodobenzylguanidine (MIBG), specifically taken up in cells of sympathetic origin, provides a highly sensitive and specific indicator for the detection of metastases in neuroblastoma. The aim of this study was to correlate early response to therapy by MIBG scan, using a semiquantitative scoring method, with the end induction response and event-free survival (EFS) rate in stage IV neuroblastoma., Patients and Methods: Seventy-five children older than 1 year and with stage IV neuroblastoma had 123I-MIBG scans at diagnosis, after two and four cycles of induction therapy, and before autologous stem-cell transplantation. The scans were read by two independent observers (concordance > 95%) using a semiquantitative method. Absolute and relative (score divided by initial score) MIBG scores were then correlated with overall pretransplantation response, bone marrow response, and EFS., Results: The pretransplantation response rate was 81%, and the 3-year EFS rate was 32%, similar to a concomitant group of 375 stage IV patients. The median relative MIBG scores after two, four, and six cycles were 0.5, 0.24, and 0.12, respectively. The probability of having a complete response or very good partial response before transplantation was significantly higher if the relative score after two cycles was < or = 0.5, or, if after four cycles, the relative score was < or = 0.24. Patients with a relative score of < or = 0.5 after two cycles or a score of < or = 0.24 after four cycles had an improved EFS rate (P =.053 and.045, respectively)., Conclusion: Semiquantitative MIBG score early in therapy provides valuable prognostic information for overall response and EFS, which may be useful in tailoring treatment.

Unlabelled: Severe genital bleeding during adolescence can occur in the event of thrombocytopenia related to chemotherapy. Preventive hormonal treatment to induce therapeutic amenorrhea is recommended by some clinicians. Nevertheless, the adverse effects of oestroprogestative treatment, such as thromboembolic risk or hepatic toxicity, could potentialize the adverse effects of some chemotherapies., Aim of the Study: To assess retrospectively the risk of genital bleeding associated with thrombocytopenia secondary to chemotherapy in a population of adolescent girls for whom therapeutic amenorrhea was induced or not., Patients and Methods: Among 140 girls, 12 to 18 years old, who were subjected to chemotherapy between 1991 and 1998, 24 girls presented at least one thrombocytopenic event (platelet level < 20 x 10(9) l(-1)) and were included., Results: Six out of 24 adolescent girls received hormonal therapy to induce amenorrhea. Only one bleeding event was observed, in a girl who had not received preventive oestroprogestative treatment. Vital prognosis was preserved. Furthermore, spontaneous amenorrhea occurring before chemotherapy was observed in 33% of the patients and permanent secondary ovarian insufficiency in 17% of the patients., Conclusion: The risk of genital bleeding among adolescent population at risk of chemotherapy-induced thrombocytopenia is low. The high frequency of amenorrhea, secondary to weight loss or to chemotherapy toxicity, should raise questions as to the usefulness of preventive oestroprogestative treatment.

Peripheral blood stem cells (PBSC) harvest may be difficult in young children. Extracorporeal separator line priming by red blood cells is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 24 children weighing less than 15 kg treated between January 1997 and September 1999, in whom we tried to avoid systematic blood priming. The median age and weight at the time of apheresis were 2.4 years and 12 kg, respectively. A total of 48 PBSC were performed. When haemoglobin was less than 12 g/dl, packed red cells were transfused before collection (40% of aphereses). The median cell yield per apheresis was 7.1 (2.2-30.6)x10(6)/kg CD34(+) cells and 16.0 (3.3-44.3)x10(5) CFU-GM/kg. Initial collection failed in three cases. Four children required an additional haematopoietic progenitor mobilization. This procedure allowed PBSC collection without transfusion in 37.5% of children, and was safe (two serious and five mild transient side effects) and effective (median CD34(+) cells collected per child: 7.1 x 10(6)/kg (4.6-30.6) and CFU-GM: 15.1 x 10(5)/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter was avoided in 43% of children.

Introduction: The use of transpupillary thermotherapy alone or associated with systemic chemotherapy is a therapeutic modality of ocular retinoblastoma that allows ocular preservation without external beam irradiation of the eye. We present our experience with thermotherapy in the treatment of selected cases of retinoblastoma., Material and Methods: This paper reports a retrospective case series of patients treated for retinoblastoma by thermotherapy or chemothermotherapy (carboplatin IV followed by thermotherapy) in a single institution from October 1994 to December 2000. Data collected include general characteristics of the treated children, tumor characteristics, and the results of the treatments on local tumor control. Transpupillar thermotherapy was delivered with a diode laser through an operating microscope. Each tumor was treated separately and laser intensity, spot size, and duration were adapted to the size of the tumor and the clinical response. Chemothermotherapy consisted in thermotherapy delivered shortly after an intravenous injection of carboplatin (560 mg/m(2)) at day 1, followed by thermotherapy alone at day 8 if the lesion was 6mm or more in diameter. This cycle was administered every 28 days. The choice between thermotherapy and chemothermotherapy depended on the initial size of the lesions. Thermotherapy was used when the lesion measured 3mm or less. Lesions measuring more than 15 mm, or associated with substantial vitreous seeding, retinal detachment, or optic nerve head involvement are not suitable for these techniques., Results: During the study period, 239 children were treated in our institution and 109 of them (147 eyes, 372 tumors) could be treated conservatively without external beam radiation. The median tumor diameter at the moment of thermotherapy or chemothermotherapy was 2mm (range, 0.2-15.0mm). One hundred and ninety-four tumors were treated by chemothermotherapy and 18 by thermotherapy alone. In 75% of the cases, the treatment was administered after two courses of chemotherapy (etoposide and carboplatin). After a mean follow-up of 55 months (range, 16-89 months), tumor control was obtained in 87.1% of lesions after chemothermotherapy and 77.8% after thermotherapy. Salvage enucleation was necessary for seven lesions (seven eyes) but none in the cases where thermotherapy was used alone. No severe systemic side effects were noted., Discussion: Diode laser delivers hyperthermia on the tumor bed and its use alone or in association with systemic administration of carboplatin makes it possible to preserve the eye without external beam irradiation, with few side effects and less cumulative doses of chemotherapy., Conclusion: Thermotherapy and chemothermotherapy provide excellent local tumor control and eye preservation in selected cases of retinoblastoma.

Loss of heterozygosity of chromosome 16q occurs in 17-25% of Wilms' tumors. Two cadherin genes mapping to 16q22 were chosen as candidate gens: E-CAD, encoding epithelial cadherin, because it is involved in kidney development and it was recently reported to be a WT1 target; and KSP-CAD because it encodes a kidney-specific cadherin. By RT-PCR analysis in a series of 39 Wilms' tumors, we identified a very low expression of E-CAD and KSP-CAD in 72% and 95% of the tumors, respectively. To ascertain whether down-expression of these genes could be related to WT1 alterations in tumors, we looked for a relationship between WT1 and CAD expression. Our data suggest (i) the existence of alternative mechanisms for regulating E-CAD expression, and (ii) that E-CAD does not belong to the WT1 pathway that is altered in Wilms' tumorigenesis.

The Lyon-Marseille-Curie-Est (LMCE) of France cooperative group has previously reported successive series of unselected stage four children older than 1 year at diagnosis with metastatic neuroblastoma (LMCE 1 and 3). The goal of LMCE 5 study was to increase progression free survival rate as compared to LMCE 1 and 3. Based on improvements reported with post induction chemotherapy, the LMCE 5 used post induction for all children, but omitted total body irradiation and immunomagnetic purging in megatherapy regimen for all children. Twenty-five sequentially diagnosed children received an induction regimen which compared with previous induction included an increased dose of etoposide and cyclophosphamide, delivered similar dose of cisplatinum, and deleted doxorubicin and vincristin. After surgery treatment was stratified based on response and eligible children received etoposide carboplatin (LMCE 5A : n=10)+/-doxorubicin (LMCE 5B-C n=13) followed by megatherapy (melphalan without total body irradiation and unpurged peripheral blood stem cell rescue). The increase in drug doses during induction did not improve remission rate. The progression free survival at 6 years is 8%. It is significantly worse than LMCE 3, and equivalent to LMCE 1 study though toxic death rate has decreased with increasing experience. Failure to improve the response rate during induction and reducing the megatherapy regimen may be the main factors in this disappointing result. Modified strategies for induction, non toxic alternative to total body irradiation, and post megatherapy regimen should be developed.

Wilms' tumour (WT) or nephroblastoma is the most frequent kidney cancer in children. In a previous study, we reported alterations to WT1 transcription in 90% of WT tested, with decreased exon 5 +/- isoform ratio being the most frequent alteration (56% of WT). We now report an approach based on cDNA profiling of tumour pools to identify genes likely to be dysregulated in association with a decreased WT1 exon 5 +/- ratio. We compared the expression profiles of pools of tumours classified according to whether this isoform imbalance was present (five tumours) or not (four tumours), using Atlas Cancer cDNA expression arrays. Fourteen of 588 genes tested displayed specific up-regulation (CCND2, PCNA, N-MYC, E2F3, TOP2A, PAK1, DCC and PCDH2) or down-regulation (VEGF, IGFBP5, TIMP3, ARHB, C-FOS and CD9) in the pool of tumours with decreased exon 5 +/- ratio. These results were validated by RT-PCR analysis of four genes (CCND2, PCNA, VEGF and IGFBP5). We extended the analysis of VEGF expression to 51 tumours by real-time RT-PCR and ascertained differential expression of this gene associated with WT1 expression pattern. Moreover, our results suggest that the VEGF expression level may be of prognosis relevance for relapsed patients.

Objective: To evaluate the results of chemothermotherapy for the treatment of retinoblastoma., Design: Non-comparative interventional case series., Patients: Fifty-one children (65 eyes and 103 tumors) were treated with chemothermotherapy in a single institution from January 1995 to May 1998., Methods: Chemothermotherapy consists of a combination of transpupillary thermotherapy delivered shortly after intravenous (IV) injection of carboplatin (560 mg/m(2)). Each tumor is treated separately with a diode laser using a microscope. Laser intensity, spot size, and duration are adapted to the size of each tumor and to the clinical response. After 8 days, thermotherapy alone is repeated. This cycle is performed from one to six times, every 28 days. The treatment data and outcome are analyzed separately., Main Outcome Measures: Assessment of local tumor control., Results: One hundred three tumors were treated in 65 eyes of 51 children. Age at diagnosis was 0 to 60 months (median, 7 months). Median tumor diameter at the time of treatment was 3.5 mm (range, 1.5-12 mm). Laser modalities were as follows: median intensity, 450 mW (range, 150-1000 mW); median spot size, 1.2 mm (range, 0.3-2.0 mm); and median number of cycles required to obtain tumor control, three. Tumor regression was obtained for 99 tumors (96.1%) after a median follow-up of 30 months (17-61 months). Seven tumors relapsed after initial control (6.8%). Salvage treatment (external beam radiation, iodine plaques, or enucleation) was necessary for a total of 11 tumors (10.7%). The only risk factor for relapse was the initial diameter of the lesion greater than 3.5 mm, whereas the other tumor characteristics or treatment variables were not significantly correlated with relapse. Ninety-seven percent of treated eyes were able to be preserved, and 92% of cases were treated without external beam radiation., Conclusions: Chemothermotherapy is an effective technique to treat small- to medium-sized retinoblastomas in children, avoiding external beam irradiation.

Purpose: Because of the long-term complications associated with external beam radiation in retinoblastoma, alternative treatment methods have been investigated. We conducted a retrospective study to evaluate the functional results of new treatment modalities., Methods: Thirty-seven eyes were treated without external beam irradiation in 31 patients. The median diameter of the largest tumor in each eye was 6 mm. Primary chemotherapy was used in 25 cases, chemothermotherapy was used in 32 cases, cryotherapy was used in 28 cases, iodine 125 Plaques were used in 15 cases, diode laser thermotherapy was used alone in 11 cases, and photocoagulation was performed in 5 cases. The median follow-up after diagnosis of retinoblastoma was 41 months. The visual results were evaluated at a median age of 54 months., Results: The median visual acuity of the treated eyes was 20/33. Twenty-four eyes presented a visual acuity better than 20/40, 4 eyes had a visual acuity between 20/200 and 20/40, and 9 eyes had a visual acuity less than 20/200. Maculopathy was observed in 16 cases, associated with papillopathy in 1 case. A cataract was observed in 1 case and a vitreous hemorrhage was observed in another case. Twenty-one eyes did not develop any complications. No corneal dryness and very few lens changes were observed., Conclusion: The functional results after local treatments for retinoblastoma are very good. The most frequent complication is maculopathy, particularly when the tumor involves or is situated close to the macula.

Modern treatments are able to cure 3/4 of paediatric cancers, but on another hand there is still a too high number of patients which will enter a resistant phase and test the ability of the medical and nursing team to face together the new modalities of care. At diagnosis, the reasonable hope to cure the child and the exciting feeling to be endued with a repairing mission strengthen among the team both the self-esteem and a rational and emotional consensus. Conversely, at the time of relapse or resistant disease, the feeling of a failure, added to anxiety and reciprocal aggressiveness, will contradictorily affect the group. In this atmosphere of loss of control of reality and emotions, elaborating new priorities of care is mandatory: medical positions have of course to be in keeping, but this is not enough since the nursing team has, through sharing information and feeling, to give their cure project of the child's cancer as lost while retaining and expanding their ability to care the child with cancer. Thanks to an over-investment of the symptomatic, psychological, and affective help support to the child, the nursing team will succeed in regaining this self-esteem absolutely necessary to their own professional survival. Consensus in the team is ultimately linked to its empathic ability of exchanging with the families which in turn results in giving them guidelines for the last weeks and months of life and helping them to be less emotionally unprovided when bereavement time has come: a pedagogy of the continuity of care is thus taking place which, equally distant from forsaking and therapeutic relentlessness, chooses to give up the idea of curing in order to go on caring.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

From 1984 to 1997, 57 consecutive patients with non-metastatic Ewing's sarcoma of the ribs were treated according to multimodal French Society of Pediatric Oncology (SFOP) protocols EW 84, EW 88 and EW 93. The results of treatment were reviewed and analysed. Median age was 12 years. 34 patients had large tumours (greatest tumour dimension > or = 8 cm); pleural effusion was noted in 26. A tumour-positive margin after surgery was noted in 15 patients. Histological response after chemotherapy was assessed in 34 patients. 34 patients received radiation therapy. With a median follow-up of 5 years, the projected overall and relapse-free survival rates were 69 and 62%, respectively. The major site of relapse was local. None of the following was significant in predicting relapse: tumour size, gender, age at diagnosis, existence of pleural effusion, level of rib tumour, rib component, type of local control, surgical margin (positive or negative). Response to chemotherapy was the sole significant prognostic factor (P=0.004). Patients with pleural effusion had a higher percentage of relapse if they were treated without local radiation therapy. Our study confirms the prognostic significance of response to initial chemotherapy. Radiation therapy may be withheld in selected cases, but seems necessary in patients with pleural effusion.

Long term outcome and prognosis factors of patients with metastatic osteosarcoma were evaluated on 29 observations from 3 centres reviewed retrospectively. Twenty-nine patients less than 18 years old were treated from 1990 to 1998. Only 29 of these patients had received similar treatments associating chemotherapy and surgery, adapted according to histological and clinical response to treatment, as recommended by the SFOP. Overall survival at five years was 26%, and disease free survival 14%. Eight patients are alive, four in first complete remission (CR) and four in second CR. Three of the four patients alive in first CR had bone metastases at diagnosis. On univariate analysis, factors predicting survival are: the numbers of organs affected by metastatic lesions, the number of lung nodules and the type of surgery. This is, to our knowledge, the first report of long term survivors with bone metastases at diagnosis. Metastatic osteosarcoma prognosis remain poor. A randomised study would help to define the best possible treatment for this disease.

Cranial irradiation alters hypothalamic-pituitary function. We reevaluated 90 patients with GH deficiency caused by fractionated cranial irradiation performed at age 4.9 +/- 0.4 (SE) yr when they were 15.7 +/- 0.2 yr old. Group 1 received 18 Grays (Gy) (7 cases) or 24 Gy (21 cases) for acute lymphoblastic leukemia; group 2, 30-40 Gy for medulloblastoma (22 cases); group 3, 45-60 Gy for optic glioma and various tumors (30 cases); and group 4, 40-50 Gy for retinoblastoma (10 cases). The mean GH peaks after an arginine insulin test in group 3 (1.9 +/- 0.4 microg/liter) was lower than in groups 1 (4.8 +/- 0.5 microg/liter, P < 0.001) and 2 (3.4 +/- 0.5 microg/liter, P < 0.03). The mean plasma IGF-I concentrations in group 3 [-3.8 +/- 0.2 z score (zs)] was lower than in groups 1 (-2.4 +/- 0.3 zs, P < 0.001) and 2 (-3.1 +/- 0.2 zs, P < 0.02), as was the mean in group 4 (-3.9 +/- 0.3 zs, P < 0.01 compared with group 1 and P < 0.05 compared with group 2). GH peaks and IGF-I were correlated positively (P = 0.0001) and negatively with dose (P < 0.001 for GH and P = 0.0001 for IGF-I), but not with age at irradiation. Among the 43 patients with GH peaks below 3 microg/liter, 41 (95%) had plasma IGF-I less than -2 zs. The body mass index (BMI), plasma insulin, and leptin were similar in the four groups. They were positively correlated with each other (P < 0.001 for BMI compared with insulin and with leptin, respectively, and P < 0.01 for insulin compared with leptin), but not with age or dose of irradiation, or with markers of GH secretion. In conclusion, in patients with GH deficiency caused by cranial irradiation, the residual GH secretion and plasma IGF-I depend on the dose. Almost all the patients with severe GH deficiency had low plasma IGF-I. BMI, leptin, and insulin seem to be independent of GH status.

Purpose: To determine the optimal duration of preoperative chemotherapy to further increase the proportion of stage I tumors by comparison of two regimens in the treatment of patients older than 6 months who have unilateral Wilms' tumor., Patients and Methods: Eligible patients (n = 382) initially received four weekly doses of vincristine (VCR) and two courses of actinomycin D (AMD) and were randomized either to be operated on (4-week group [n = 193]) or to receive 4 more weeks of the same chemotherapy regimen (8-week group [n = 189]). The assessment criterion was the observed percentage of stage I tumors. After surgery, patients were assigned according to tumor stage and histology to four different treatment groups: stage I and favorable histology (n = 5) were to have no further treatment (NFT); stage I and standard histology or anaplasia (n = 244), VCR and AMD for 17 weeks (AV); stages II and III and favorable or standard histology, VCR, AMD, and an anthracycline for 27 weeks (AVE) with no abdominal radiotherapy for stage II N0 disease (n = 75) or with a 15-Gy dose of abdominal irradiation (RTH) in case of stages IIN1 and III (n = 56). Anaplastic tumors staged higher than I or clear-cell sarcoma of the kidney (14), AMD, VCR, an anthracycline, and ifosfamide for 36 weeks (DEVI)., Results: No advantage was found in favor of prolonged preoperative treatment. The percentages obtained for the 4-week and the 8-week groups, respectively, were as follows: stage I, 64% versus 62%; intraoperative tumor rupture rate, 1% versus 3%; 2-year EFS, 84% versus 83%; and 5-year OS, 92% versus 87%. Two-year EFS and 5-year OS rates, respectively, of the different treatment groups were as follows: NFT, 100% for both EFS and OS; AV, 88% and 93%; AVE, 84% and 88%; AVE RTH, 71% and 85%; and DEVI, 71% and 71%. The rate of abdominal recurrences in stage II N0 nonirradiated patients was 6.6%., Conclusion: The 4-week schedule pre-nephrectomy chemotherapy regimen should be considered the standard treatment. Clinical trials should continue to improve the cure rate of high-risk patients and the quality of life of children with a more favorable prognosis.