Traumatic spinal epidural hematoma in a 1-year-old boy.

Traumatic spinal epidural hematoma is uncommon in children, making rapid diagnosis difficult. In this report, we present a case of traumatic cervical epidural hematoma in a 1-year-old boy, diagnosed with computed tomography scanning and magnetic resonance imaging (MRI). Management was conservative and the lesion regressed spontaneously. The presentation in childhood is often nonspecific. MRI is the imaging modality of choice for diagnosing these lesions. Conservative treatment has to be considered in cases with a benign clinical course and provided that the patient is followed up neurologically with repeated MRI.

[Dermo-hypodermitis caused by group B Streptococcus in infants under 3 months of age: A retrospective study in two hospitals]. / Dermo-hypodermites à streptocoque du groupe B chez les nourrissons de moins de 3 mois : étude rétrospective dans deux centres hospitaliers.

BACKGROUND: Very few studies describe group B streptococcal dermo-hypodermitis in newborns. OBJECTIVES: To describe the incidence, clinical characteristics, and course of group B streptococcal dermo-hypodermitis in infants less than 3 months old. PATIENTS AND METHODS: Infants under 3 months of age, hospitalized for group B streptococcal dermo-hypodermitis at Robert Debré University Hospital, Paris, France, and at Orsay Hospital, Orsay, France, between January 2002 and August 2013, were included in a retrospective study. RESULTS: Five infants were included in this study. All the infections occurred late. Dermo-hypodermitis accounted for 7% of the overall late-onset group B streptococcal infections during the same period. Four patients were male and had a risk factor of maternal-fetal infection (prematurity/hypotrophy). Four patients had specific clinical signs of dermo-hypodermitis with septic shock features on admission. One patient had meningitis and associated parotitis. Group B Streptococcus was isolated from blood culture of all patients. Serotype III Streptococcus was identified in four cases. The duration of intravenous antibiotic therapy varied from 7 to 23 days and the total duration of antibiotic therapy was between 14 and 44 days. The progression was favorable for all the infants, with no recurrence. CONCLUSION: Dermo-hypodermitis in infants under 3 months of age is rare but could be an early indicator of group B streptococcal bacteremia and/or sepsis. Early diagnosis of this severe complication and appropriate antibiotic therapy are critical.

Rare germline large rearrangements in the BRCA1/2 genes and eight candidate genes in 472 patients with breast cancer predisposition.

Hereditary breast cancers account for up to 5-10 % of breast cancers and a majority are related to the BRCA1 and BRCA2 genes. However, many families with breast cancer predisposition do not carry any known mutations for BRCA1 and BRCA2 genes. We explored the incidence of rare large rearrangements in the coding, noncoding and flanking regions of BRCA1/2 and in eight other candidate genes--CHEK2, BARD1, ATM, RAD50, RAD51, BRIP1, RAP80 and PALB2. A dedicated zoom-in CGH-array was applied to screen for rearrangements in 472 unrelated French individuals from breast-ovarian cancer families that were being followed in eight French oncogenetic laboratories. No new rearrangement was found neither in the genomic regions of BRCA1/2 nor in candidate genes, except for the CHEK2 and BARD1 genes. Three heterozygous deletions were detected in the 5' and 3' flanking regions of BRCA1. One large deletion introducing a frameshift was identified in the CHEK2 gene in two families and one heterozygous deletion was detected within an intron of BARD1. The study demonstrates the usefulness of CGH-array in routine genetic analysis and, aside from the CHEK2 rearrangements, indicates there is a very low incidence of large rearrangements in BRCA1/2 and in the other eight candidate genes in families already explored for BRCA1/2 mutations. Finally, next-generation sequencing should bring new information about point mutations in intronic and flanking regions and also medium size rearrangements.

Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.

BACKGROUND: Many unclassified variants (UV) of BRCA1 or BRCA2 may have an effect on pre-mRNA splicing. Patient blood samples suitable for RNA extraction are not always available for testing UVs at the RNA level. METHODS: Analyses of RNA from patient peripheral blood were performed, using a one-step reverse transcriptase-PCR (RT-PCR) protocol, and were compared with an ex vivo splicing assay based on PCR-amplified patient DNA inserted into a splicing reporter minigene. Using both methods 20 variants found in 17 patients were examined. RESULTS: Data from patient RNA and from the minigene assay were fully concordant, but the ex vivo splicing assay, which is monoallelic, clarified several ambiguities in the patient RNA data. Two intronic variants induced strong splicing defects: BRCA1 c.4987-5T-->A (IVS16-5T-->A) induced exon 17 skipping and BRCA2 c.316+5G-->C (IVS3+5G-->C) induced complete skipping of exon 3. Of the exonic variants, BRCA2 c.7805G-->C (p.Arg2602Thr), at the last base of exon 16, induced both exon skipping and activation of a cryptic exonic donor site, and BRCA2 c.8023A-->G (p.Ile2675Val) generated a strong donor site within exon 18. These four variants were thus classified as pathogenic, because of the total absence of a normal transcript from the corresponding allele. Variant BRCA2 c.9501+3A-->T (IVS25+3A-->T) induced incomplete skipping of exon 25, suggesting a mutation with incomplete penetrance, and BRCA2 c.8257_8259del (p.Leu2753del) modified the alternative splicing of exons 17 and 18. CONCLUSIONS: We show that functional analysis using a splicing reporter minigene is sensitive and specific, and should be used for initial screening of potential splicing defects, especially when patient RNA is not readily available.

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

No BCL-2 protein over expression but BCL-2/IgH rearrangements in B cells of patients with persistent polyclonal B-cell lymphocytosis.

INTRODUCTION: Persistent polyclonal B-cell lymphocytosis is a rare hematological disorder, characterized by a chronic, stable and absolute polyclonal lymphocytosis, the presence of binucleated lymphocytes, a polyclonal increase in serum IgM immunoglobulin and clonal cytogenetic abnormalities involving chromosome 3. For explaining the expansion of B-lymphocytes pool in PPBL, an association with cigarette smoking and/or chronic Epstein-Barr virus infection have been suggested but both hypotheses have been ruled out. MATERIALS AND METHODS: We studied the presence of BCL-2/IgH rearrangements in a series of eight PPBL patients (seven females and one male) by a nested polymerase chain reaction (PCR), targeting the Major Breakpoint Region in BCL-2 locus and we explored the BCL-2 protein expression by Western blot. RESULTS: We demonstrated: (a) the constant presence of BCL-2/IgH rearrangements in eight out of eight DNA samples, (b) multiple rearrangements in three out of eight cases and, (c) normal BCL-2 protein expression, as compared to BCL-2 level in B-lymphocytes from healthy population. CONCLUSION: Despite the presence of BCL-2/IgH rearrangements, the accumulation of B lymphocytes in PPBL is not related to an overexpression of BCL-2 protein.

[Mutation by deletion-insertion in BRCA-1 gene in three unrelated French breast/ovarian cancer families: possible implication of a mobile element]. / Mutation par délétion-insertion dans le géne BRCA-1 dans trois families françaises non apparentées de cancers du sein et/ou de l'ovaire: possible implication d'un elément mobile.

A new type of mutation by deletion-insertion in BRCA-1 gene is found in three unrelated French breast/ovarian cancer families. Surprisingly, deletion and insertion occurred at the same nucleotide position at the end of exon 11 (3958del5ins4), thus generating a truncated protein. This original mutation consists in a deletion of 5 bp (CTCAG) and in an insertion of 4 different bp (AGGC). Here, we proposed two hypothesis to explain this phenomenom. The first hypothesis is the formation of a hairpin stem-loop structure comprising the mutational site and the sequence corresponding to the duplication insertion 2 nucleotides before the mutation. The second hypothesis, more speculative, consists in an abortive integration of a human mobile element as a human transposon (tigger 1) which involved a deletion of 5 bp during its excision and an insertion of 4 bases corresponding to the 5' extremity of the transposon.

Systematic sequencing of the BRCA-1 coding region for germ-line mutation detection in 70 French high-risk families.

Seventy French high-risk families were screened for germ-line BRCA-1 mutations. The BRCA-1 coding region and the exon-intron boundaries were sequenced, except when pre-screening by PTT revealed a truncated protein in exon 11. Germ-line BRCA-1 mutations were detected in 24% of families. The number of breast and ovarian cancers per family, a relative young age at ovarian cancer diagnosis, and the occurrence of breast and ovarian cancer in the same patient significantly predicted the presence of a BRCA-1 mutation. The low BRCA-1 mutation frequency suggested that some alterations were not detected and some families were probably BRCA-2 or BRCAx carriers.

New mechanism of BRCA-1 mutation by deletion/insertion at the same nucleotide position in three unrelated French breast/ovarian cancer families.

A novel complex mutation consisting of a small deletion/insertion (3958del5ins4) was found in the breast cancer-1 gene (BRCA-1) in three unrelated French breast and/or ovarian cancer families. These mutations occurred at the same nucleotide position of the 3' end of exon 11. The wild-type sequence, CTCAG, was deleted and replaced by AGGC in the three families. The consequence is the generation of a stop codon, TAG, resulting in a truncated protein. We propose two different mechanisms to explain the generation of this complex mutation: (i) the simultaneous occurrence of a deletion and an insertion in a stem-loop structure and (ii) the abortive integration of a human transposable element (Tigger 1) that deleted 5 nucleotides and inserted a 4-nucleotide "scar", corresponding to the 5' extremity of the transposon.

Clinical impact of pharmacokinetically-guided dose adaptation of 5-fluorouracil: results from a multicentric randomized trial in patients with locally advanced head and neck carcinomas.

A significant link between 5-fluorouracil (5FU) plasma concentration and its therapeutic activity has been demonstrated in colon and head and neck cancer patients for 5FU used as a continuous infusion. Dose adjustment based on pharmacokinetic follow-up has been proposed to decrease hematological and digestive toxicities, but the clinical impact of this approach has not yet been demonstrated. A randomized multicentric study was conducted to evaluate the clinical interest of 5FU dose adaptation guided by pharmacokinetics. One hundred twenty-two head and neck cancer patients were randomly assigned to receive induction chemotherapy with cisplatin (100 mg/m2, day 1) and 5FU (96-h continuous infusion), either at standard dose (St-arm; 4 g/m2) or at a dose adjusted according to the 5FU area under the curve (AUC0-48h; PK-arm). In total, 106 patients were evaluable for toxicity and response. In the PK-arm (n = 49), 5FU doses and area under the curve were significantly reduced during cycle 2 and cycle 3 (P < 0.001) as compared with the St-arm (n = 57). Grade 3-4 neutropenia and thrombopenia were significantly more frequent in the St-arm as compared with the PK-arm (17.5% versus 7.6%, respectively; P = 0.013). No grade 3-4 mucositis occurred in the PK-arm, whereas 5.1% was observed in the St-arm (P < 0.01). The objective response rate was comparable in the two treatment arms: 77.2% in the St-arm versus 81.7% in the PK-arm. The present study is the first to demonstrate, in a randomized design, the clinical interest of an individual 5FU dose adaptation based on pharmacokinetic survey, in terms of therapeutic index improvement.

Clinical randomized study of 5FU monitoring versus standard dose in patients with head and neck cancer: preliminary results.

Prospective studies of dose adaptation of continuous 5FU infusion combined with cisplatin have shown that pharmacologically guided dosing was feasible in the treatment of head and neck carcinomas. Adaptative dosing results in reduced haematological toxicity, but few data are available for clinical response rate. Preliminary results (38 patients) of a randomized trial comparing standard dose of 5FU (20 patients) and monitoring of 5FU based on pharmacokinetic information (half-cycle area under the curve, 18 patients) indicate that haematological tolerance and complete response rate were improved. Severe (GIII-GIV) thrombocytopenia and neutropenia were significantly reduced during cycle 2 (0% versus 11.1% and 5.5% versus 27.7% respectively, p < 0.01) and cycle 3 (0% versus 27.7% and 6.6% versus 33.3% respectively, p < 0.001). The complete response rate was increased in the group with monitoring of 5FU doses (55.5% versus 40.0%, p < 0.001). These interesting results will be confirmed at the end of the trial, which is expected to include 126 patients.

[Hereditary predisposition for cancer of the breast and the ovary]. / Prédisposition héréditaire aux cancers du sein et de l'ovaire.

Familial breast cancers represent about 10% of all cases of breast cancers. A predisposition locus has been located in the 17q21 chromosomal region. Nineteen French breast and breast-ovarian cancer families were tested for linkage with five highly polymorphic 17q markers. The five breast-ovarian cancer families as a group give positive evidence for linkage, whereas the 14 breast cancer families do not. Heterogeneity of linkage of familial breast cancer is significant in France and supports the existence of more than one susceptibility gene.

[Renal toxicity of 9-hydroxy-2-methyl-ellipticinium]. / Toxicité rénale du 9-hydroxy-2-méthylellipticinium.

9-hydroxy-2-methyl-ellipticinium (HME) is an intercaling agent mainly potent in metastatic breast cancer. Its almost complete lack of bone marrow toxicity is of greatest value. However, among 385 patients 20 cases of renal failure were observed: renal failure is gradual, non reversible except in four cases with acute renal failure. Histological and ultrastructural studies, performed in 8 cases, showed exclusively proximal tubular lesions, without glomerular or interstitial lesions. We have evidence that there is a relation between the cumulative dose and the severity of the lesions. A prospective study was done in 30 patients. An increase in enzymuria, proteinuria and glycosuria was observed in most patients after HME infusion. HME is an efficient drug in the treatment of bone metastases of breast cancer. Renal function should be carefully monitored during HME administration.