Implementation of a molecular tumor board at a regional level to improve access to targeted therapy.

BACKGROUND: With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. MATERIAL AND METHODS: Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. RESULTS: In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). CONCLUSIONS: In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Prognostic and Predictive Factors of Ebola Virus Disease Outcome in Elderly People during the 2014 Outbreak in Guinea.

Elderly people occupy a prominent position in African societies; however, their potential linkage to high case fatality rate (CFR) in Ebola virus disease (EVD) was often overlooked. We describe the predictive factors for EVD lethality in the elderly. A total of 2,004 adults and 309 elderly patients with confirmed EVD were included in the analysis. The median age (interquartile range) was 35 years (23-44) in adults and 65 years (60-70) in the elderly. The proportion of funeral participation was significantly higher in the elderly group than in the adult group. Duration (in days) between the onset of symptoms and admission was significantly longer in elderly. CFR in the elderly people was also significantly higher (80.6%) than in the adult group (66.2%). Funeral participation constituted a risk factor for the transmission of EVD in elderly people.

Ebola virus disease in children during the 2014-2015 epidemic in Guinea: a nationwide cohort study.

The most recent epidemic of Ebola virus disease (EVD) has resulted in more than 11,000 deaths in West Africa. It has threatened child health in the affected countries, including Guinea. This nationwide retrospective cohort study included all children under 20 years of age with laboratory-confirmed EVD in Guinea during the 2014-2015 Ebola outbreak for analysis. Of 8,448 children with probable or suspected EVD, 695 cases were laboratory-confirmed EVD. The overall case fatality rate (CFR) was 62.9%. Pediatric patients with younger age had a significantly higher rate of death (adjusted OR = 0.995; 95%CI = 0.990-1.000; p = 0.046), with the highest CFR of 82.9% in children aged less than 5 years. Fever (91%), fatigue (87%), and gastrointestinal signs and symptoms (70%) were common clinical features on admission of the pediatric patients, while bleeding signs were not occurring often (24%). None of clinical features and epidemiologic risk factors for Ebola were associated with mortality outcome in our cohort study. CONCLUSION: EVD is a major threat to child health, especially among children under 5 years of age. To date, none of demographic and clinical features, except younger age, have been consistently shown to affect mortality outcome in children infected with Ebola virus. What is Known: • The 2014-2015 West Africa Ebola epidemic is the largest and most widespread outbreak of Ebola virus disease (EVD) in history, with more than 11,000 deaths in Guinea, Liberia, and Sierra Leone. • During ongoing outbreak investigations, it is suggested that young children aged less than 5 years are particularly vulnerable and highly susceptible to death. What is New: • Demographic and clinical characteristics of the nationwide cohort of pediatric patients with laboratory-confirmed EVD in Guinea are reported. • The results confirm the high rate of death among EVD children under 5 years of age, while none of demographic and clinical features, except younger age, could serve as a predictor of mortality outcome in pediatric patients with EVD.

Factors associated with treatment lag in infantile spasms.

AIM: the aim of this study was to evaluate the conditions in which infantile spasms are diagnosed and their possible impact on the course of the disease. METHOD: we carried out a retrospective study of the reasons for delayed treatment of infantile spasms (treatment lag) in western France over the period 1990-2003. A total of 156 infants, 87 male (55%) and 69 female (45%), with infantile spasms were identified, in 45 (29%) of whom the spasms were symptomatic. They were aged 1 week to 24 months (median 20wks, mean 22.4, SD 13.3) at first symptoms. To be included in the study, participants had to exhibit a combination of clusters of spasms, altered psychomotor development, and paroxysmal electroencephalographic (EEG) activity, as defined by the International League Against Epilepsy. We did not restrict onset to the first year of life as infantile spasms may begin after the age of 1 year. RESULTS: the mean time from appearance of first symptom to first visit to a medical practitioner was 4 weeks. In 14% of cases, the reason for the visit was non-neurological, the parents having noticed no neurological symptoms before the visit. The diagnosis was missed at first visit in 38% of the cases examined, with the incorrect diagnosis mostly commonly being gastro-oesophageal reflux or no abnormality. This increased to 74% after a second visit, in all cases based on an abnormal EEG. However, in 5% the time between first presentation and diagnosis was over 2 months and up to 10 visits were required. The time lag between first presentation and diagnosis was significantly longer for individuals presenting to general practitioners than to paediatricians (p=0.03). Response to treatment was poorer in those in whom diagnosis was delayed. INTERPRETATION: various steps could be taken to reduce treatment lag such as training general practitioners, informing the parents of individuals at risk about the possibility of infantile spasms, and recommending that EEG is performed before brain imaging in children with unexplained psychomotor delay.

Impact of age, leukocyte count and day 21-bone marrow response to chemotherapy on the long-term outcome of children with philadelphia chromosome-positive acute lymphoblastic leukemia in the pre-imatinib era: results of the FRALLE 93 study.

BACKGROUND: We explored the heterogeneity of philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL) in a study of the effect of early features on prognosis in children. Here we report the long-term results of the FRALLE 93 study conducted in the era before the use of tyrosine kinase inhibitors. METHODS: Between 1993 and 1999, 36 children with Ph1-ALL were enrolled into the FRALLE 93 protocol. After conventional four-drug induction, children were stratified by availability of an HLA-matched sibling. RESULTS: Complete remission (CR) was observed in 26 children (72%), of which 13 underwent allogeneic bone marrow transplantation (BMT). Thirty-one children were good responders to prednisone, defined on day 8, and 21 were good responders to chemotherapy, defined by day-21 bone marrow (M1). Overall five-year disease-free survival (DFS) was 42 +/- 9.7%. Based on multivariate analysis, two groups showed marked differences in five-year outcome: children with age<10, leukocyte count <100,000/mm3 and day-21 M1 marrow had a more favorable prognosis (14 pts: 100% CR, event free survival [EFS]: 57%, overall survival [OS]: 79%), than the high-risk group (22 patients: 55% CR, EFS: 18%, OS: 27%) (p < 0.005). We also observed a non statistically significant difference (p = 0.14) in outcome between these groups for transplanted patients (5-year DFS: 83 +/- 14% and 33 +/- 15%, respectively). CONCLUSION: Age, leukocyte count and early response to treatment defined by the D21 bone marrow response provide an accurate model for outcome prediction. The combination of available tools such as minimal residual disease assessment with determination of these simple factors could be useful for refining indications for BMT in the current era of tyrosine-kinase inhibitor-based therapy.

Childhood cancer survival in France, 1990-1999.

The aim of this study was to describe the overall survival after childhood cancer in France using follow-up data from regional population-based registries. The survival of children (aged under 15 years) diagnosed with a cancer during 1990-1999 was analysed. For all cancers, the survivals were, respectively, 90.3% [89.4-91.3] at 1-year, 75.2% [73.8-76.6] at 5 years and 72.2% [70.7-73.7] at 10 years. During the 1990s, the average improvement in the 5-year survival was +1.2% per year. Adjusted for gender, age, area of residence and stage, children with cancer diagnosed between 1995 and 1999 had a 0.80 reduced risk of dying compared with those whose cancer had been diagnosed between 1990 and 1994. The increase of survival at the population level reflects a global improvement in childhood cancer care. The Paediatric Registries, in association with the French Society of Childhood Cancer, are now collecting data to quantify on a national basis the other events, at least relapse and second cancers.

Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia.

BACKGROUND: The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR. RESULTS: We compared the leukemia cell gene expression profiles of 16 TEL/AML1-positive ALL patients to those of 44 TEL/AML1-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -RUNX1, TCFL5, TNFRSF7, CBFA2T3, CD9, SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7, SEMA6A, CTGF, LSP1, TFPI - highlighting the biology of the TEL/AML1 sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of RUNX1 (AML1) was further investigated and in one third of the patients correlated with cytogenetic findings. CONCLUSION: Gene expression analyses of leukemia cells from 60 children with TEL/AML1-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the TEL/AML1-positive ALL sub-group.

Particular cutaneous side effects with etoposide-containing courses: is VP16 or etoposide phosphate responsible?

PURPOSE: Etoposide is commercially available in France in two different pharmaceutical forms: VP16 and its phosphate ester (etoposide phosphate, EP). EP shows better chemical and physical properties, is said to be less toxic but is five times more expensive than VP16. Some criteria were defined for the use of each form in the Paediatric Oncohaematology Department in Hopital Sud in Rennes. As some particular cutaneous side effects were observed during treatment with etoposide-based course in this department, a retrospective study was initiated. The aims of this work were to determine the side effects (especially cutaneous toxicity), whether the pharmaceutical formulation of etoposide had any influence on the toxicity of the drug, and whether the observed side effects resulted from etoposide alone or from particular antineoplastic drug associations. METHODS: Five types of etoposide-containing protocols were chosen: NB 97 and NB 99 (neuroblastoma), FRALLE 93 (acute lymphoid leukaemia), LAME 91 (acute myeloid leukaemia), OS 94 (osteosarcoma), Ewing 97 and Euro-Ewing 99 (Ewing sarcoma). The medical files of 36 children (88 EP courses, 25 VP16 courses) included in these protocols were analysed on the basis that if a child showed a side effect during a course, the child had to have recovered from that side effect before the beginning of the next course. RESULTS: Apart from classical side effects (haematological and digestive toxicities etc.), two particular cutaneous side effects were observed: (1) palmar-plantar eruptions and nail inflammations, and (2) irritation of the anal area and anal fissures. Those side effects were observed with three of the studied protocols: NB 97, OS 94 and Ewing sarcoma treatments. CONCLUSIONS: No striking differences in toxicity appeared between the two etoposide formulations, but this retrospective study seemed to confirm the appearance of particular cutaneous and anal side effects especially with two associations: (1) etoposide-ifosfamide (OS 94 and Ewing 97), and (2) etoposide-ifosfamide-Adriamycin-vincristine (VIDE course of the Euro-Ewing 99 protocol).

Cancer incidence among children in France, 1990-1999.

BACKGROUND: Cancer is the second most important cause of death for children aged less than 15 years in France, unintentional injuries being the leading cause. The aim of the present study was to estimate the incidence of childhood cancer from six Childhood Cancer Registries covering 32% of France. PROCEDURE: Incident cancer cases diagnosed between 1990 and 1999 in children (0-14 years) resident in the administrative areas covered by each Registry were included. Annual age-standardized rates (ASRs) were adjusted by the world population. The estimated annual percent change (EAPC) was used to measure trend towards changes in the annual age-standardized incidence rate. RESULTS: With 4234 registered cases, the ASRs per million children were 137.5 for all cancers combined, 42.3 for leukemia, 29.1 for central-nervous-system tumors, 15.6 for lymphomas, 14.1 for sympathetic-nervous-system tumors, and 9.1 for renal tumors. The ASR of all cancers combined was slightly higher in males (145.8 per million children) than in females (128.7 per million children) with an M/F ratio of 1.2. No significant incidence trend was observed, with an EAPC of +0.2% [IC 95% (-2.5; +3.0); P = 0.89]. CONCLUSIONS: The estimated incidence rates are similar to those reported in previous studies in European and North American countries. These results will contribute to the development of National Registration of Childhood Cancer in France and support the national research program on childhood cancer.

Impact of Topoisomerase II alpha and spermine on the clinical outcome of children with acute lymphoblastic leukemia.

It has been reported in the literature that a leukemic cell may be (or become) resistant to anti-cancer treatment because many mechanisms, such as efflux membrane pump (multi-drug resistance, MDR-P170), intracellular transport (LRP, MRP), or different detoxification systems (glutathione transferases, methallothioneines) may be implicated. Topoisomerase II alpha (TopoII) are also reported as responsible for resistance since their main action is to repair DNA breakage. Polyamines are described as having a protective DNA action by stabilizing the double stranded DNA helix. For these reasons we investigated 65 children with acute lymphoblastic leukemia using an immunocytochemical method to elucidate the potential role of Topoisomerase and polyamines in drug resistance. Most children (60/65) were treated with the French (acute lymphoblastic leukemia, ALL) protocol (FRALLE-93) in which B and C arms include (at least) VP16. Children with cytoplasmic TopoII positivity (18 cases) were more resistant since their overall survival was 34 months compared to more than 110 months for negative cases ( P = 0.0003). Polyamines may be associated with drug resistance since the overall survivals were 51 months and 92 months for positive and negative patients, respectively, but the P-value is only 0.13. We conclude that Topoisomerase and polyamines must be tested at diagnosis as new possible markers for chemo-resistance. Larger series are needed to confirm these preliminary results and to verify if the use of anti epipodophillotoxin agents (as it is the case for FRALLE B or C) should be excluded for positive cases.

Central neurotoxicity of cyclosporine in two children with nephrotic syndrome.

The central neurotoxicity of cyclosporin A (CsA) has been abundantly documented in pediatric and adult recipients of bone marrow or organ transplants, with variations in the rate of occurrence from 0.5% to 35%. We report two cases of central neurotoxicity ascribable to CsA in children with nephrotic syndrome due to lipoid nephrosis. The manifestations of CsA-related central neurotoxicity include confusion, aphasia, dystonias, akinetic mutism, parkinsonism, palsies, seizures, catatonia, coma, brain hemorrhage, and cortical blindness. Decreased density of the cerebral white matter is visible by computed tomography (CT) in 50% of cases, with the most commonly involved sites being the occipital cortex, the cerebellum, the periventricular substance, and the brainstem. Magnetic resonance imaging is more sensitive and more specific than CT for investigating the white matter. High-signal lesions are seen on T2-weighted sequences in the areas that are abnormal by CT. Many risk factors have been reported, including hypomagnesemia, hypocholesterolemia, high-dose glucocorticoid therapy, arterial hypertension, and infections. We present two patients with central neurotoxicity both of whom have elevated cholesterol levels.