Long-term results of the combination of the N7 induction chemotherapy and the busulfan-melphalan high dose chemotherapy.

BACKGROUND: To evaluate long-term survival of the first cohort of stage-4 neuroblastoma patients treated with the N7 induction chemotherapy, surgery of the primary tumor and high-dose chemotherapy (HDC) containing Busulfan-Melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT). PROCEDURE: From 1998 to 1999, 47 children were included in the NB97 trial and treated with induction chemotherapy according to the N7 protocol, followed by surgery of the primary tumor. HDC (Busulfan, 600 mg/m(2) Melphalan, 140 mg/m(2) ) was administered in patients with partial response of metastases with no more than 3 mIBG spots. Radiotherapy was delivered to the primary tumor site when tumors displayed MYCN amplification. RESULTS: Thirty-nine patients received Bu-Mel (83%): 23 who had achieved complete response (CR) of metastases, 20 after induction treatment and 3 after second-line chemotherapy, and 16 in partial response (PR). The toxicity of the whole treatment was manageable. The main HDC related-toxicity was hepatic veno-occlusive disease grade > 2 occurring in 15% of the patients. The 8-year EFS of the whole cohort was 34% (95% CI, 22-48%). The 8-year EFS of the 39 patients who received Bu-Mel and ASCT was 41% (95% CI, 27-57%). Patients who achieved a CR of metastases at the end of induction chemotherapy had a significantly better outcome than the others (8-year EFS, 52% vs. 20%; P = 0.02). CONCLUSIONS: The long-term results of this first prospective cohort of patients with metastatic disease treated with the N7 induction chemotherapy and HDC (Bu-Mel) confirm published data with stable survival curves but with a longer follow-up.

A dose-intensive approach (NB96) for induction therapy utilizing sequential high-dose chemotherapy and stem cell rescue in high-risk neuroblastoma in children over 1 year of age.

BACKGROUND: To improve outcome and overall survival (OS) in high-risk neuroblastoma, NB96 induction therapy was intensified using sequential high-dose chemotherapy and autologous stem cell rescue. PROCEDURE: Twenty children were included in this pilot study undertaken at seven reference centers in France, between May 1995 and October 1996. Induction began with one cycle of conventional chemotherapy followed by six sequential cycles of high-dose chemotherapy comprising two cycles of etoposide 800 mg/m(2)/day over 3 days, two cycles of cyclophosphamide 2,000 mg/m(2)/day over 3 days, and two cycles of carboplatin 400 mg/m(2)/day over 5 days, followed by stem cell rescue. RESULTS: Thirteen patients (13/20) received this induction with acceptable toxicity and adequate stem cell harvest. Of these, nine (9/13) underwent surgery according to the protocol, while one patient was given a consolidation regimen prior to surgery. No toxic death was recorded. At the end of induction, complete remission was achieved in 10 cases (50%), with six still alive in July 2009. The 5-year event-free survival and OS were 35 ± 11% and 40 ± 11%, respectively. CONCLUSION: NB96 therapy is feasible and tolerated without lethal toxicity. Nevertheless, given the small sample size and absence of randomization in our study, the effectiveness of this strategy based on metastasis complete response rates and long-term outcome was not superior to other intensive chemotherapy regimens.

PCA analgesia for children with chemotherapy-related mucositis: a double-blind randomized comparison of morphine and pethidine.

AIMS: This study aimed to compare pethidine and morphine on efficacy and toxicity in children with severe mucositis following chemotherapies. PATIENTS AND METHODS: From March 2000 to November 2003, 35 hospitalized children with chemotherapy-related mucositis were randomly assigned to receive double blindly "patient-controlled analgesia" (PCA) bolus doses of morphine or pethidine. The mucositis pain score was the mean of pain measured four times a day with a Visual Analogue Scale from day 2 to 5 of PCA. RESULTS: Study stops before total accrual for difficulties of recruitment. Out of the 29 patients with more than one day of PCA, the median (range) of the Mean Pain Score was 44 (13-72) and 33 (3-89) in the morphine (n = 14) and pethidine (n = 15) groups, respectively (P = 0.32). PCA was stopped for failure in 10 cases (five in each group). Constipation requiring specific treatment was higher in the morphine group (43% versus 0%). CONCLUSIONS: PCA with pethidine appears not inferior to morphine, with less constipation requiring specific treatment, but a larger study is warranted to confirm this.

Phacomatosis pigmentokeratotica with nephroblastoma and juvenile hypertension.

Phacomatosis pigmentokeratotica is characterized by the coexistence of an organoid epidermal naevus, follow-ing Blaschko's lines, and a large speckled lentiginous naevus, typically arranged in a chequerboard pattern. This entity has been isolated from the group of epidermal naevus syndromes and is frequently associated with extracutaneous anomalies. We report here the first observation of phacomatosis pigmentokeratotica associated with nephroblastoma. In addition to this paediatric renal tumour, the coexistence of juvenile arterial hypertension suggests an associated vascular defect. The link between the extracutaneous manifestations and cutaneous twin spot phenotype is discussed.

A predictor of unfavourable outcome in neutropenic paediatric patients presenting with fever of unknown origin.

BACKGROUND: No sensitive, specific marker able to discriminate favourable or unfavourable outcome of fever of unknown origin (FUO) at diagnosis has been identified. Procalcitonin, a recently assessed infection marker, may be useful in predicting the outcome of FUO. METHODS: We conducted a prospective study examining the following variables: age 0.5-22 years; solid tumour diagnosis; chemotherapy-related grade-4 febrile neutropenia (FN). A complete clinical, bacteriological and biological evaluation was performed at hospital admission (H0). Other investigations depended on clinical status. FUO was considered to be of unfavourable outcome if the fever was persistent or re-appeared at day 3 (or later), or if secondary clinical or microbiological infection occurred. To validate the results of the analysis the data set was randomly split into a training set and a validation set. RESULTS: Out of 172 episodes of FN, 136 episodes were classified as FUO (80%). Seventy-two (53%) were included in this study. PCT values were significantly higher in episodes of unfavourable outcome (P < 0.001). None of the other prediction candidates appeared to be significantly linked to the risk of unfavourable outcome. In the validation set, the best PCT cut-off was 0.12 micro/L, which was associated with a sensitivity of 80% and specificity of 64%. CONCLUSIONS: PCT-H0 level can predict FUO outcome. A protocol based on PCT-H0 measurement, integrating clinical and bacteriological evaluation, facilitates shorter hospital stays and less antibiotic treatment. Patients with a PCT-H0 value <0.12 micro/L could benefit from an outpatient treatment starting at H48 thus reducing hospitalisation costs and improving quality of life.

High levels of circulating VEGFR2+ Bone marrow-derived progenitor cells correlate with metastatic disease in patients with pediatric solid malignancies.

PURPOSE: Pediatric solid malignancies display important angiogenic potential, and blocking tumor angiogenesis represents a new therapeutic approach for these patients. Recent studies have evidenced rare circulating cells with endothelial features contributing to tumor neovascularization and have shown the pivotal role of bone marrow-derived (BMD) progenitor cells in metastatic disease progression. We measured these cells in patients with pediatric solid malignancies as a prerequisite to clinical trials with antiangiogenic therapy. PATIENTS AND METHODS: Peripheral blood was drawn from 45 patients with localized (n = 23) or metastatic (n = 22) disease, and 20 healthy subjects. Subsets of circulating vascular endothelial growth factor receptor (VEGFR)2+-BMD progenitor cells, defined as CD45-CD34+VEGFR2(KDR)+7AAD- and CD45(dim)CD34+VEGFR2+7AAD- events, were measured in progenitor-enriched fractions by flow cytometry. Mature circulating endothelial cells (CEC) were measured in whole blood as CD31+CD146+CD45-7AAD- viable events. Data were correlated with VEGF and sVEGFR2 plasma levels. RESULTS: The CD45-CD34+VEGFR2(KDR)+7AAD- subset represented <0.003% of circulating BMD progenitor cells (< or =0.05 cells/mL). However, the median level (range) of the CD45(dim)CD34+VEGFR2+7AAD- subset was higher in patients compared with healthy subjects, 1.5% (0%-10.3%) versus 0.3% (0%-1.6%) of circulating BMD progenitors (P < 0.0001), and differed significantly between patients with localized and metastatic disease, 0.7% (0%-8.6%) versus 2.9% (0.6%-10.3%) of circulating BMD progenitors (P < 0.001). Median CEC value was 7 cells/mL (0-152 cells/mL) and similar in all groups. Unlike VEGFR2+-BMD progenitors, neither CECs, VEGF, or sVEGFR2 plasma levels correlated with disease status. CONCLUSION: High levels of circulating VEGFR2+-BMD progenitor cells correlated with metastatic disease. Our study provides novel insights for angiogenesis mechanisms in pediatric solid malignancies for which antiangiogenic targeting of VEGFR2+-BMD progenitors could be of interest.

Bilateral adrenal neuroblastoma.

BACKGROUND: Bilateral adrenal neuroblastoma is extremely rare. To date, 45 cases have been reported in the literature. PROCEDURES: We retrospectively identified and reviewed 15 cases of bilateral adrenal neuroblastoma, treated between 1988 and 2004, by the French Society of Pediatric Oncology. We then compared our cohort to the 45 cases reported in literature. RESULTS: Median age at diagnosis was 4 months in our cohort whereas it was 3 months in the literature. The same percentage of infants was found in both series (86.6%). Disease had generally been detected due to metastasis-related symptoms. Ten out of 15 patients in our cohort and 18/39 cases in the literature were classified as stage 4S according to the International Neuroblastoma Staging System (INSS). The incidence of stage 4S was significantly higher than that described in other neuroblastoma cohorts (P = 10(-4)). Five-year overall survival was 90% for stage 4S. In our series, bilateral neuroblastoma was neither associated with familial cases nor with any risk factors. CONCLUSIONS: The majority of bilateral neuroblastoma carry a favorable prognosis. Exceptional cases exhibiting risk factors, such as amplified MYCN, are comparable to high-risk unilateral neuroblastoma cases with the same poor prognostic features. The therapeutic strategy could be similar to that used against unilateral neuroblastoma, except for surgery. However, the low incidence of relapse and the risk of adrenal failure if radical surgery is performed, argue against an aggressive surgical approach.

Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE).

Parental smoking and maternal alcohol and caffeinated beverage consumption are prevalent exposures which may play a role, either directly or through their influence on metabolism, in the aetiology of childhood malignant central nervous system (CNS) tumours. The hypothesis was investigated in the Epidemiological Study on childhood Cancer and Leukemia ESCALE study, a national population-based case-control study carried out in France in 2003-2004. The study included 209 incident cases of CNS tumours and 1681 population-based controls, frequency matched with the cases by age and sex. The data were collected through a standardized telephone interview of the biological mothers. No association between maternal smoking during pregnancy and CNS tumours [odds ratio (OR): 1.1 (0.8-1.6)] was observed. Paternal smoking during the year before birth was associated with CNS tumours (P for trend=0.04), particularly astrocytomas [OR: 3.1 (1.3-7.6)]. Maternal alcohol consumption during pregnancy was not associated with CNS tumours. Associations between ependymomas and the highest consumption of coffee [OR: 2.7 (0.9-8.1)] and tea [OR: 2.5 (1.1-5.9)] were observed. A strong association between CNS tumours and the highest maternal consumption of both coffee and tea during pregnancy was observed [OR: 4.4 (1.5-13)]. The results constitute additional evidence for a role of paternal smoking and suggest that maternal coffee and tea consumption during pregnancy may also increase the risk of CNS tumours. The study does not suggest an increased risk of CNS tumours related to alcohol consumption during pregnancy.

Birth characteristics and childhood malignant central nervous sytem tumors: the ESCALE study (French Society for Childhood Cancer).

BACKGROUND: Determining the role of pre- and perinatal factors in the aetiology of childhood malignant central nervous (CNS) tumors, using data from the French national case-control study, ESCALE. METHODS: ESCALE included all children in France less than 15 years old with a diagnosis of acute leukaemia, lymphoma, malignant CNS tumor, or neuroblastoma (2003-2004). In all, 209 malignant CNS tumor cases (80% of the eligible cases) and 1681 population-based controls (71%) were included using quotas ensuring frequency matching with the cases by age and gender. Case and control mothers were interviewed using a standardised telephone interview, which elicited birth characteristics, congenital malformation, maternal reproductive history, and use of assisted reproductive technologies for the index child. RESULTS: The cases and controls did not differ in terms of gestational age at birth, birth weight, birth order, breastfeeding, or parental age at birth. There was no association between assisted reproduction for the index child and malignant CNS tumor (OR=1.1 [0.6-2.2]). A positive association between a maternal history of one miscarriage and malignant CNS tumor was observed (OR=1.4 [1.0-2.0], p<0.05), especially for glial cell tumors (other glioma: OR=2.0 [1.1-3.6]). CONCLUSION: The results suggest a possible association between a maternal history of one miscarriage and the risk of malignant CNS tumor.

Successful treatment for advanced small cell carcinoma of the ovary.

Small cell carcinoma of the ovary is a rare and aggressive malignant tumour with a poor prognosis. The authors describe two females, 12 and 13 years old, who presented with advanced stage disease. They were treated with surgical resection, multiagent chemotherapy and high-dose chemotherapy followed by autologous bone marrow transplantation. They remain free of disease more than 9.5 and 14 years since the diagnosis.

[Doctor-patient relationship in oncology: how to prevent and solve some conflicts?]. / La relation médecin-malade en oncologie: comment prévenir et résoudre certains conflits ?

The inequality between doctor(s) and patient(s) is a frequent cause of ethical and relational difficulties. To know the elements of this inequality is a requirement to improve their relationship. The major elements of this inequality: the patient experiments suffering and may die; the doctor belongs to a group, has a wide knowledge, the ability to cure, is active. Some elements diminish this inequality: patients associations; new laws (the right to be informed, to give one's informed consent, to have free access to one's medical file, to refuse the treatment, etc.); relinquishing paternalism and making shared decision; improving doctor's competence in information. Equality also means solidarity and reciprocal knowledge, respect and trust. Specific objectives have to be acknowledged: the patient's and the doctor's ones can be different. Patients and doctors should have an equal exigency of rights and duties: they cannot do or demand anything. Both of them need to be recognized as competent in their own tasks, and responsible towards each other, the other patients, themselves. They equally require to preserve one's ideals, to keep one's identity, one's sense of dignity and value. Equal freedom to think and act can be hindered by the influence of others, but also by inadequate emotions, fantasies, unconscious thoughts and memories. The psycho-oncologists and the psychoanalytic experience are therefore useful to overcome these unconscious obstacles. Medical staff should also have the experience of solving the ethical difficulties that inequality can raise.

Remediation of learning difficulties in children after treatment for a cerebellar medulloblastoma: a single-case study.

In the process of establishing a methodology for individualized remediation programmes in children treated for cerebellar tumour, this study followed prospectively over 11 years a young child treated for a medulloblastoma at 18 months of age throughout the rehabilitation process. Repeated neuropsychological and academic evaluations evidenced temporary disruptive behaviour, deficient manual and visual abilities, attention and working memory difficulties, but preserved language abilities, in relation with vermian and left cerebellar damage. However, the described remediation programmes and interventions allowed the child to have fluent progression in school. Limits and benefits of rehabilitation are discussed.

Design of PETAL multipetawatt high-energy laser front end based on optical parametric chirped pulse amplification.

We report on a single shot optical parametric chirped pulse amplifier designed to seed the Petawatt Aquitaine Laser on the Laser Integration Line facility multipetawatt high-energy laser. The scheme is based on a stretched signal pulse at 1053 nm amplified with 20% conversion efficiency by a monomode pump pulse at 527 nm. The homemade pump laser is able to deliver a single shot beam with a square flat top spatial profile and programmable temporal shape. A high-stability 150 mJ, 8 nm, and 4.5 ns stretched pulse is then obtained with an excellent quality spatially shaped beam.

Family history of cancer in children with acute leukemia, Hodgkin's lymphoma or non-Hodgkin's lymphoma: the ESCALE study (SFCE).

The role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case-control study, was carried out in France over the period, 2003-2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0-2.2]) and NHL (OR = 1.8 [1.3-2.5]), but not AL (OR = 1.0 [0.9-1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0-3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3-22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL.

Multicenter randomized trial of chewing gum for preventing oral mucositis in children receiving chemotherapy.

The properties of saliva led us to hypothesize that the salivary flow increase induced by gum chewing might protect the oral mucosa from lesions due to cancer chemotherapy. We conducted a multicenter randomized trial to evaluate the efficacy of chewing gum in preventing oral mucositis in 145 children receiving chemotherapy regimens expected to induce WHO grade 3-4 oral mucositis in at least 30% of patients. Patients were allocated at random to standard oral care with or without 5 gum pieces per day. No overall reduction in severe oral mucositis occurred in the gum arm (51%) compared with the standard arm (44%). VIDE, COPADM, and multidrug intensive chemotherapy caused severe oral mucositis in 75% of patients in both arms. In patients receiving less toxic regimens, a decrease in WHO grade 1-4 oral mucositis was noted in the gum arm compared with the standard arm (49% vs. 72%, P=0.03). In the multivariate analysis, the risk of oral mucositis was related only to the type of chemotherapy regimen, suggesting that further strategies for preventing oral mucositis could be mainly based on these criteria.

Concomitant chemo-radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: a case-control study.

Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.

Radiation dose and long term risk of cardiac pathology following radiotherapy and anthracyclin for a childhood cancer.

PURPOSE: To determine the cardiac status in children 15 years (yrs) or more after a solid tumour treatment. PATIENTS AND METHODS: Of the 447 patients, 229 were fully studied and 218 were not. The following cardiac evaluation was proposed to all the 447 consecutive patients: (1) cardiac Doppler US by one of two expert cardiologists; (2) cardiac rhythm and conduction abnormalities including 24-h holter ECG; (3) (131)I-mIBG myocardial scintigraphy; (4) serum brain natriuretic peptide levels at rest; (5) an exercise test with VO(2)max measurement. The radiation dose delivered to 7 points in the heart was estimated for all patients who had received radiotherapy. RESULTS: Cardiac disorder was diagnosed in 89 evaluated patients (39%) including 24 heart failures and 65 other asymptomatic cardiac diseases. When adjusting on potential confounders, cardiac disorder and cardiac failure risks were respectively linear (ERR at 1 Gy: 26%) and linear-quadratic (ERR at 1 Gy: 19%) functions of the average radiation dose received to the heart. No interaction between cumulative dose of adriamycin and average radiation dose was evidenced for cardiac disorders, but the ERR/Gy of cardiac failure was higher for patients receiving less than 350 mg/m(2) of Adriamycin. CONCLUSION: Long term heart pathologies are probably one of the major iatrogenic risks encored by patients who survived a childhood cancer. This study strongly emphasizes the need to limit the heart irradiation during radiotherapy, particularly, for patients who also received or were susceptible to later received adriamycin.

[Refusing treatment: patient responsibility and autonomy. About a French National Consultative Ethics Committee statement(no 87, April 2005)]. / Refuser le traitement: responsabilité et autonomie du patient. A propos de l'avis no 87 (avril 2005) du Comité consultatif national d'éthique.

A recent French National Consultative Ethics Committee statement confirms that medical doctors are required by law to accept a patient's refusal of treatment, even if the consequence is the loss of chances of being cured. This refusal raises difficult clinical and ethical issues. Respecting a patient's decision is only valid when he/she is fully responsible, able to understand the proposed treatments and the consequences of his/her refusal, uninfluenced by friends and relatives, ignorance, disarray, an excessively pessimistic appraisal of the situation, a conflict with the doctors or with medicine. Doctors must avoid passively accepting a refusal without discussion but must also avoid paternalism or moral pressure. Adequate mutual knowledge of the way they think, their values and their objectives helps to maintain mutual respect and confidence in the patient-doctor relationship: the doctor is not a "supertechnician" nor is the patient a treatment consumer. Information, knowledge of the possibilities and limits of current medicine and of patients'complex, conscious and unconscious motives (which justifies the psycho-oncologist's role), recommendations of medical societies, experience of difficult ethical issues help to avoid unauthentic refusals, conflicts and staff burnout.

Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology.

PURPOSE: To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. PATIENTS AND METHODS: We compared two populations that were similar with regard to age, stage, pre-autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982-1993), whereas the CT group (n = 30) received conditioning without TBI (1985-1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver, kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. RESULTS: Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. CONCLUSION: The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma.