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von Hippel-Lindau disease is an inherited multisystemic familial cancer syndrome caused by mutations of the VHL gene. The spectrum of clinical manifestations is broad and includes central nervous system hemangioblastomas and visual benign and malignant tumors. The various manifestations can be demonstrated by means of different imaging techniques such as magnetic resonance imaging, computed tomography, and fluorescein retinal hemangiography. A systematic approach must be followed for repeated screening in patients at risk, since many lesions in VHL disease are treatable.

Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.

Identify the bacteria responsible for cutaneous infections observed in private practice and test their sensitivity to currently used antibiotics.The patients were examined by dermatologists. A bacteriological sample was taken and sent to a central laboratory for identification of the germ and antibiograms were performed and the minimal inhibiting concentrations (MIC) determined.Folliculitis, impetigo and furuncles were the three most frequent primary infections. Four hundred and forty-three patients were included and 442 samples were placed in culture. Cultures were positive in 265 cases (a single bacterial strain in 231 cases). Staphylococcus aureus was isolated in 208 cases, streptococci in 11 and enterobacteria in 3; occasionally several germs were present. Eight strains of staphylococci were meti-R (4 p. 100). All the strains were sensitive to pristinamycin and mupirocin and 90 p. 100 were sensitive to fusidic acid.The occurrence and diffusion of resistant strains is a daily concern in hospitals. In general practice, although care must be taken, the problem rarely occurs and the antibiotics used remain effective.

Pourfour du Petit syndrome, rarely reported, is the opposite of Claude Bernard-Horner syndrome.A 67 years old female is hospitalised for dysphagia, allowing the discovery of oesophagus carcinoma with mediastinal, pleural and costal extension. The discovery of left unilateral mydriasis associated with exophthalmos and eyelid retraction suggest Pourfour du Petit syndrome; this diagnosis is confirmed by CT-scan, finding pedicular lysis of high dorsal vertebras and intra-canalar tumoral extension.Pourfour du Petit syndrome has the same localisation value and the same aetiologies as Claude Bernard-Horner syndrome, but its mechanism proceeds byan exciting lesion of cervical sympathetic nervous system. The recognition of this entity can allow the diagnosis of pathologies that need emergency treatment.

In a BRCA1 screening in familial breast cancer carried out in different centres in Spain, France, and United Kingdom, a missense mutation 330AG which results in a Arg to Gly change at codon 71 (R71G) was independently identified in 6 families, all of them with Spanish ancestors. This residue coincides with the -2 position of the exon 5 donor splice site. We further investigated the effect of this base substitution on the splicing of BRCA1 mRNA. The sequence analysis of the cDNA indicated that 22 bp of exon 5 were deleted, creating with the first bases of exon 6 a termination codon at position 64, which results in a truncated protein. The BRCA1 haplotype of the R71G carrier patients and Spanish controls was analysed by use of six microsatellites located within or near BRCA1. Our results are consistent with the possibility that these families shared a common ancestry with BRCA1 R71G being a founder mutation of Spanish origin.

In France, immediate breast reconstruction (IBR) for infiltrating carcinoma remains controversial. Many teams advocate the possible event of a post mastectomy radiotherapy and its negative effect on IBR. In our Institute we do not exclude infiltrating breast cancer patient from IBR. In the poor prognostic patients who wish IBR, we recommend autologous IBR to obtain the best aesthetic result with minimum revision procedures and best tolerance to adjuvant radiotherapy. From January 1993 to December 1997, we performed 687 IBR with myocutaneous flap for infiltrating carcinomas. In this group only 68 patients needed postoperative chest wall radiotherapy (45 Gy): 27 TRAM flap, 41 latissimus flap. Only one of the TRAM but 39 of latissimus flaps were associated with a prosthesis. The mean follow-up was 24 months. Fourteen patients developed metastatic disease, and ten were dead at the time of the chart revue. The autogenous TRAM flap tolerate radiation quite well and remain soft and mobile. The latissimus flap associated with a prosthesis developed capsular contracture (BAKER II or III) in 71% of cases. In all cases the cosmetic impairment was not important and the result after capsulectomy remained soft. We concluded that IBR could be offered to motivated patients in all stages of the disease regardless of the subsequent chest wall radiotherapy, and we recommend its use for possible autologous reconstruction.

The genotype-phenotype relationship of Lynch syndrome displays many enigmatic features which cannot be explained satisfactorily by the prevailing concepts of carcinogenesis and genetic predisposition to cancer. We propose here a new model of carcinogenesis divided into two and only two evolutive phases: a) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated ageing process; b) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the non-transformed RER+ clones, eventually rescue one mismatch repair-deficient cell that gives rise to the malignant clone. Carcinogenesis is proposed here to progress irreversibly and very rapidly once initiated. We shall show how this model provides a meaningful etiologic and pathogenic interpretation of all the curious features of Lynch syndrome.

Lynch syndrome is a hereditary predisposition to colorectal cancer (CRC) and other cancers caused by germline mutations in mismatch repair (MMR) genes. Almost all the cancers diagnosed in Lynch syndrome have an acquired MMR deficiency, a replication error (RER) mutator phenotype that is also found in a minority of sporadic cancers developed in the target organs of Lynch syndrome. Lynch syndrome displays many curious features that cannot be accounted for by the prevailing concepts of carcinogenesis and genetics: (1) CRCs occur preferentially in the right side of the colon, whereas the majority of sporadic cases develop in the left colon; (2) the increased risk of CRC is not associated with an increased incidence of adenomatous polyps, which are necessary precancerous lesions in the development of common CRCs; (3) the tumor spectrum in Lynch syndrome is restricted to the colon and some extracolonic sites, whereas the responsible MMR genes are ubiquitously expressed; (4) the tumor risk, which is negligible during childhood, becomes significant during adulthood at the age of 25 and thereafter remains essentially constant throughout the ages. (5) Finally, the sporadic counterparts to the CRCs diagnosed in the setting of Lynch syndrome very curiously develop almost exclusively in the right colon, whereas this right-sidedness is much less pronounced in Lynch syndrome. To explain these anomalies, we propose a model of RER+ carcinogenesis based on the simple idea that the RER mutator phenotype has only short-term viability in normal cells. The proposed model states that the RER+ carcinogenesis is divided into two clearly distinct evolutive phases: (1) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated aging process; (2) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the nontransformed RER+ clones, eventually rescue one RER+ cell that gives rise to the malignant clone. It will be shown that this theoretical framework with its heterodox initiation process not only possesses the virtue of allowing an understanding of Lynch syndrome, but may also have broader applications to all research fields dealing with carcinogenesis.

In the last twenty years, our understanding of carcinogenesis has evolved from a description of the natural history of cancer development, a conception inherited from Darwin, to the dissection of the underlying molecular mechanisms leading to phenotypic changes in cells, a neodarwinian interpretation. Most scientists agree that random germ cell mutations enhancing cell survival and reproduction capacities play a major role in the evolution of species and that carcinogenesis progresses from acquisition of genetic anomalies which alter the normal function of oncogens or antioncogens. Since the discovery of src, the first oncogen to be identified twenty years ago, and more recently the discovery of antioncogens such as p53, hopes and expectations have grown steadily, and passionately, often far beyond reason dietated by the real world of clinical medicine. Yet curiously, many clinicians hesitate to express one essential point: advances in science and technology, is not equivalent to advances in medicine. It is our responsibility to resist the illusion of progress, for this illusion turns out to have a negative impact in our patients. To paraphrase the French philosopher André Comte-Sponville, the power conferred by the exercise of medicine is not based solely on scientific knowledge, but also on human compassion.

Serum antibodies reacting with the tumor suppressor protein p53 have been detected previously in cancer patients with a variety of neoplasms. Two initial (although insufficient) prerequisites for a B-cell response to occur have been proposed: p53 protein accumulation in the tumor or a mutant p53 gene, or both. We have examined 65 esophageal cancer cases (42 from Guangzhou and Shenyang, People's Republic of China, and 23 from Paris, France) to obtain a prevalence estimate of anti-p53 antibodies for this type of cancer and to define the relationship of p53 tumor status to B-cell immune response. Sera were analyzed in a triplicate assay (enzyme-linked immunoassay, immunoprecipitation, and immunoblot) for anti-p53 antibodies. Tumor DNA was screened for mutations in exons 5-8, and tumor tissue was examined by immunohistochemistry for abnormal p53 protein accumulation. p53 mutations were found in 36 (58%) of 62 cases analyzed. Sixteen patients (25%) had circulating antibodies to the tumor suppressor protein. All but two (88%) of the tumors from seropositive cases had a mutation in the DNA binding region of the p53 gene, and with one exception, these tumors also showed nuclear accumulation of the p53 protein. In contrast, tumor mutations were found in just 22 (46%) of the 48 individuals in whom we did not detect anti-p53 antibodies. Among the 22 seronegative cases for which we found no tumor mutations, 11 revealed p53 protein accumulation by immunohistochemical analysis. Thus, circulating anti-p53 antibodies may be present in one-fourth of esophageal cancer patients, most of whom also would be expected to have a p53 gene mutation in their tumors. Patients without such mutations appear considerably less likely to mount a B-cell response to the p53 tumor suppressor protein than those that do (P0.01).

Ataxia telangiectasia (AT) is a recessive genetic disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation hypersensitivity, and increased predisposition to cancer. Reduced or delayed induction of the tumor suppressor protein p53 after gamma -irradiation was reported. These characteristics may be compatible with an inability to correctly regulate apoptosis. We show here that AT lymphocytes and EBV-transformed lymphoblasts demonstrate a significantly higher level of spontaneous apoptosis, whereas ionizing radiation-induced apoptosis is reduced compared to normal cells. However, neither AT nor normal primary fibroblasts undergo apoptosis after irradiation. Consequently, we conclude that the radiosensitivity of the AT cells is not related to an increased apoptotic response. Finally, we show that SV40-transformed AT fibroblasts undergo gamma- ray-induced apoptosis, while SV40-transformed normal cells do not. This result raises the question of the physiological relevance of the latter cellular model with respect to the AT phenotype.

This review focuses on the genetics of inborn predisposition to the development of cancer. The gene defects responsible for the majority of the most common syndromes of inherited predisposition to cancer have been deciphered during the last five years. These discoveries have shown that the genetics of most of these inherited forms of cancer is remarkably simple: the mechanism underlying the risk of cancer is precisely the one proposed by Knudson to explain the inherited forms of retinoblastoma. Only a small minority of the cancers are imputable to inherited mutations causing a very high risk of cancer. However, low penetrance susceptibility genes, mainly acting as environmental risk modifiers, are probably involved in the development of the majority of cancers. As much as possible, we will consider the immediate and long term possible repercussions on everyday medical practice of these advances in basic understanding of genetic cancer risks.

Cancers are the most frequent and at the same time the most complicated of somatic genetic diseases. Technical progress in the last fifteen years has enabled to analyse the acquired genetic abnormalities found in the vast majority of cancers. This molecular dissection of cancer has led to an understanding of this disease that can basically be viewed as a rupture of the balance between two class of genes, the oncogenes and the antioncogenes. This article defines the properties of these cancer genes and gives through a few examples an insight into the various mechanisms of cancerogenesis.

p53 antibodies have been found in sera of patients with breast and lung carcinomas and in children with B-lymphomas. We report here the presence of p53 antibodies in sera of patients with 11 different types of cancer. The frequency of seropositives for p53 varied among the different types of cancer, but a correlation with the frequency of p53 gene alteration was established. Using a powerful peptide enzyme-linked immunosorbent assay, we demonstrated that the immune response of patients with p53 antibodies was restricted to a small subset of peptides localized in the amino and carboxy termini of p53, whatever the type of cancer. Given the similarities of the patterns of immune responses in patients with p53 antibodies and animals hyperimmunized with human p53, we propose that the p53 humoral response is the result of a self-immunization process which is itself the consequence of p53 protein accumulation in tumor cells.

This report describes a new polymorphism, in intron 3 of the p53 gene, which consists of a single repeat of 16 nucleotides, absent in the published wild-type p53 gene sequence. In the Caucasian population tested (n = 82), 28% of individuals were heterozygotes for this polymorphism. Using PCR-based analysis, we were able to demonstrate p53 allelic losses in three of six breast tumors from heterozygote patients tested.

A 15 years old boy was admitted to the hospital for high fever, and a four month history of abdominal pain and weight loss. Clinical examination showed painful swelling of the left lumbar region. A retro peritoneal mass was revealed by tomodensitometry. There was a marked biological inflammatory syndrome without bacteriological evidence of infectious disease. Final diagnosis was performed by surgery showing a big abscess. Bacteriological culture of pus was positive for a Haemophilus actinomycetemcomitans.

Thirty-one infants and children aged 1 month to 15 years 3 months were treated with ceftriaxone once a day for the treatment of a meningitis related to Neisseria meningitidis (19 cases), haemophilus influenzae (7 cases), streptococcus pneumoniae (1 case), not identified bacteria (4 cases). All identified bacteria were sensitive to ceftriaxone. Twenty children were treated with 100 mg/kg/day, 11 with 50 mg/kg/day. CSF was sterile at the first control-generally performed 30 h after the onset of treatment-in all cases. Despite a great number of severe forms (fulminans purpura and septic shock; 11 cases; severe neurologic disturbances: 6 cases), all patients survived and recovered after a treatment of 9 to 22 days. Two infants exhibited neurologic sequelae: deafness, delayed development and hydrocephalus. Tolerance to ceftriaxone appeared to be good. With a 100 mg/kg/day dosage, mean CSF level at 6 h was 3.3 mg/l (0.8-7.7), on the first day of treatment. At the end of treatment, mean CSF level at 24h was 0.47 (0.15-2.5). With a 50 mg/kg/day dosage, mean CSF level at 6 h was 2,1 mg/l (1.1-3.9) in the first day of treatment. At the end of the treatment, mean CSF level at 24h was 0.22 mg/l (0.08-0.5). Once a day administration of ceftriaxone is adequate for the treatment of meningitis in infants and children. Though a 50 mg/kg/day dosage is probably sufficient in most cases, it seems to be more secure to use a 100 mg/kg/day dosage.

Pefloxacin, a new fluoroquinolone, was given to 10 volunteers in single 400-mg oral doses repeated at 12-h intervals during 7 days. Serum, saliva, and feces samples were collected before and at appropriate intervals after the initiation of treatment. Drug concentrations were determined by bioassay. Qualitative and quantitative analyses of the saliva and fecal floras were performed. Mean concentrations in saliva (3.46 micrograms/ml on day 1 and 7.54 micrograms/ml on day 7) were closely related to levels in serum. High concentrations of pefloxacin were found in the feces (645 micrograms/g on day 8). No modification of oral flora was observed. In the fecal flora, members of the family Enterobacteriaceae were eliminated between days 2 and 8. The alterations in streptococci and anaerobic flora were not significant; Bacteroides fragilis was more resistant to pefloxacin after treatment. Clostridium difficile was not detected, and there was no overgrowth by yeasts. No side effects were observed.

The prevalence of antibodies to 13 Legionella antigens was compared in three populations: 583 blood donors, 140 tuberculosis patients and 66 patients with acute non-legionellosis pneumonia. Antibody levels were determined by indirect immunofluorescence (IFA) using formalin-fixed antigens prepared from bacteria developed in embryonated hen yolk sac. The very weak prevalence of anti-L. pneumophila antibodies in a healthy population [almost 0 for serogroups (SG) 2, 3, 4 and 5; 1.5% for SG 6 and a maximum of 2.5% for SG 1 at a titer of 1: 16] confirms the criteria that have been recommended by the Centers for Disease control, USA. For the other legionellae studied, these criteria cannot be applied due to a higher prevalence in healthy populations (14.5% with levels of 1: 16-32 and 1% with levels of 1: 64-128 for L. bozemanii and progressively decreasing by as much as 2% for the other species: L. micdadei, L. longbeachae, L. gormanii, L. dumoffii and L. jordanis), in tuberculosis patients (12.1% with a level at 1: 64-128 for L. bozemanii, and for the same titer, 9.2% for L. gormanii, 5.7% for L. micdadei, 5% for L. longbeachae 2), and also in acute pneumonia (2 to 3.3% with levels of 1: 64-128 for L. longbeachae 1 and 2, L. jordanis, L. dumoffii, L. micdadei and L. bozemanii). Although the significance of these prevalences remains to be discussed, with formalin-fixed antigens, it seems reasonable for these species to assign a threshold of 1: 256 for the presumptive serodiagnosis following seroconversion.