Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer.

BACKGROUND: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. MATERIALS AND METHODS: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. RESULTS: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). CONCLUSIONS: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

An imported case of acute pulmonary coccidioidomycosis in an Italian traveller.

Coccidioidomycosis is a fungal infection caused by the Coccidioides species, which is endemic in the deserts of the southwestern region of the United States, northern Mexico, and in some areas of Central and South America. We describe a case of pulmonary coccidioidomycosis in a 49-year-old Italian man who came to our hospital with fever and joint and muscle pain 10 days after his return to Italy from Venezuela. Computer Tomography revealed multiple bilateral pulmonary nodules with mediastinal lymphadenopathy. Pulmonary coccidioidomycosis was diagnosed by a serological test, and fluconazole was immediately started. The patient improved within 2 weeks, with complete clinical recovery after 6 months of therapy. This case appears to be part of a large serologically unconfirmed outbreak. In order to provide early diagnosis and treatment, healthcare providers should be aware of coccidioidomycosis, even in travellers returning home from short trips to endemic areas.

Prospective study on the prevalence and associated risk factors of cryptorchidism in 6246 newborn boys from Nice area, France.

To assess the incidence and risk factors of cryptorchidism in Nice area. A 3-year prospective study was conducted at two maternity wards involving neonatal screening of boys born ≥34weeks of amenorrhoea. Methodology was strict with examination at birth, 3 and 12months by the same paediatrician. Two strictly matched controls were included for each case. Information on child and parents (medical history, pregnancy, lifestyle) was recorded using medical chart and self-administered questionnaires. A total of 102 of 6246 boys were born with cryptorchidism (prevalence 1.6%, 95 included). Half of them were still cryptorchid at three and 12months with, however, 10% of secondary re-ascent (recurrent cryptorchidism) at 12months, justifying long-term follow-up. Cryptorchidism at birth was associated with instrumental delivery, inguinal hernia and urogenital malformations, particularly micropenis and paternal history of cryptorchidism. Our results suggest that maternal exposure to anti-rust or phthalates could be a risk factor, whereas eating fruits daily seemed somewhat protective. Prevalence of cryptorchidism in our area is on the lower bracket compared with other countries, and is associated with both familial and environmental risk factors.

Antibodies to a new viral citrullinated peptide, VCP2: fine specificity and correlation with anti-cyclic citrullinated peptide (CCP) and anti-VCP1 antibodies.

Anti-citrullinated protein/peptide antibodies (ACPA) are a hallmark of rheumatoid arthritis (RA) and can be measured using different citrullinated substrates. In this paper we describe a new viral citrullinated peptide - VCP2 - derived from the Epstein-Barr virus-encoded protein EBNA-2 and analyse its potential as substrate for ACPA detection. Analysing sera from 100 RA patients and 306 controls, anti-VCP2 immunoglobulin (Ig)G were found in 66% of RA sera, IgM in 46% and IgA in 39%, compared with less than 3% of control sera. Anti-VCP2 IgG was associated with erosive arthritis, the presence of rheumatoid factor and anti-VCP1 and anti-cyclic citrullinated peptide (CCP) antibodies. Anti-VCP2 antibodies were detected in 1% and anti-VCP1 antibodies in 4% of CCP-negative RA sera; conversely, 3% of the VCP-negative sera were CCP-positive. Taken together, these data suggest that VCP2 could offer a valuable tool for ACPA detection. Inhibition assays showed that two non-overlapping epitopes - a citrulline-glycine stretch shared between VCP1 and VCP2 and the N-terminal portion of the VCP2 sequence - were targeted by anti-VCP2 antibodies. Moreover, in some RA sera that tested positive in CCP and VCP2 assays, preincubation with VCP2 inhibited binding to CCP, whereas in other sera the binding was unaffected. Thus, the reactivity with more than one ACPA substrate might be due in some RA patients to antibody populations with different specificities, and in others to cross-reactive antibody populations. Finally, affinity-purified anti-VCP2 antibodies immunoprecipitated deiminated Epstein-Barr virus nuclear antigen (EBNA-2) from an EBNA-2-transfected cell line, suggesting that viral sequences may be involved in the generation of the ACPA response.

Analysis of co-receptor usage of circulating viral and proviral HIV genome quasispecies by ultra-deep pyrosequencing in patients who are candidates for CCR5 antagonist treatment.

UDPS combined with genotypic algorithms for prediction of HIV-1 co-receptor usage may provide quantitative data about the tropism of each variant present in the viral quasispecies. The aim of the present study was to assess co-receptor usage by ultra-deep pyrosequencing (UDPS), in comparison with the reference phenotypic test (Trofile), in patients who are candidates for CCR5 antagonist treatment, in both circulating and proviral HIV-1. Seventeen patients who were tested by Trofile were enrolled. UDPS of the V3 loop region was carried out on both plasma RNA and proviral DNA. Genotypic prediction of co-receptor usage was established by position-specific score matrices (PSSM) and confirmed, in discordant cases, with geno2pheno. Genetic heterogeneity of the RNA and DNA quasispecies was assessed as well. A total of 196,729 V3 sequences were considered (mean coverage per site, 6346). Concordance between phenotypic test and UDPS with PSSM was 0.82. Geno2pheno results were in line with those obtained with PSSM. Proviral quasispecies were more heterogeneous than those found in circulating HIV. In most patients eligible for CCR5 antagonist treatment, X4 variants were detected in proviral DNA, ranging from 1.0% to 52.7%. UDPS combined with genotypic algorithms for co-receptor usage prediction highlighted the presence of minority variants, with a discordant tropism with respect to the predominant population, in both circulating viral and proviral HIV. In most patients treated with Maraviroc the virological response was independent of the presence of X4 in proviral DNA. The clinical impact of minority X4 variants present in patients who are candidates for anti-CCR5 antagonists remains a crucial point to be addressed.

Switching of inferred tropism caused by HIV during interruption of antiretroviral therapy.

After interruption of highly active antiretroviral therapy, 15 out of 53 patients with the X4 HIV strain had a significantly larger decrease in CD4(+) T cell count (P = 0.001) and shorter length of treatment interruption (P = 0.02) than patients with the R5 strain. At treatment resumption, HIV inferred tropism switched from the X4 strain to the R5 variant in 9 patients (60%). These patients had a prolonged length of treatment interruption compared to that of those who still carried the X4 strain.

Comparison of real-time PCR methods for measurement of HIV-1 proviral DNA.

The use of HIV-1 DNA quantitation in cellular reservoirs to predict disease progression and treatment outcome in infected patients is hampered by the lack of standardization among the available methods. In the present study, real-time PCR methods used commonly for HIV-1 proviral DNA evaluation were compared, showing strong differences in the results, probably as a consequence of genome variability in the target regions. Standardization of HIV-1 proviral DNA quantitation assays is needed for use in clinical management of patients with HIV-1.

Prognostic factors of long-term CD4+count-guided interruption of antiretroviral treatment.

Aim of the study was to determine predictors of the duration of antiretroviral treatment interruption in patients infected with HIV. This pilot prospective, open-label, multicenter trial comprised 62 HIV-seropositive subjects who decided voluntarily to interrupt therapy after two or more years of successful HAART. The primary end-point was the time to patients being free of therapy before reaching a CD4+ cell count < or =350/microl. Fifteen of 62 patients remained in treatment interruption for more than 180 days. Patients restarting therapy had higher HIV-DNA levels (P = 0.05), were treated more frequently with NNRTI-drugs (P = 0.02), had a shorter period of HAART (P = 0.046), and lower CD4+ cell counts after day 14 of interruption of treatment (P = 0.04). Multivariate regression analysis showed that less than 323 baseline proviral HIV-DNA cp/10(6) PBMCs and more than 564 CD4 cells/microl at day 14 after interruption were associated independently with a reduced risk of restarting treatment (P = 0.041 and P = 0.012, respectively). A score based on CD4+ cell counts at nadir, at baseline, at week 2 of treatment interruption, and on baseline HIV-DNA values can identify patients with a prolonged period free safely of treatment.

[Environmental pollutants in maternal milk and cryptorchidism]. / Polluants environnementaux dans le lait maternel et cryptorchidie.

OBJECTIVE: Numerous maternal lipophilic compounds are eliminated into milk during lactation, their concentrations reflecting fetal in utero exposure. Some of them are endocrine disruptors. Their role in the occurrence of genital malformation, dysfunction or cancer has been suggested. We wanted to study the exposure of our population and its potential association with cryptorchidism, as few clinical studies are available. PATIENTS AND METHODS: Over three years, we screened for cryptorchidism all boys born alive at or above 34 weeks of gestational age, in two maternity wards (CHU Nice, CHG Grasse). Cryptorchid boys were matched with two controls. Nursing mothers provided a colostrum sample that was screened for 15 compounds known for their antiandrogenic and/or anti estrogenic properties, including dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), dibutylphthalate (DBP) (& metabolite monobutylphthalate-mBP) and hexachlorobenzene (HCB). RESULTS: Out of 6246 boys, 102 were cryptorchid (1.6%). All available colostrums (56 for cryptorchid and 69 for controls) were contaminated. Median concentrations of DDE, PCBs, HCB and phthalates were higher though not significantly in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups for DDE and SigmaPCBs, with a trend for mBP. Odds ratio (OR) for cryptorchidism was increased for the highest score of SigmaPCB, with a trend only for DDE versus the lowest score of those components. Our results are similar to those of a Scandinavian study with comparable design. DISCUSSION AND CONCLUSIONS: Our results show the universal contamination of milk with endocrine disruptors in our area, and support the association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE, alone or in association with other chemicals.

Evolution of a prolactin-secreting pituitary microadenoma into a fatal carcinoma: a case report.

Pituitary carcinomas are very rare tumors, nearly always presenting as widely invasive masses, although the hallmark of these lesions is the finding of distant metastases. One third of reported cases are prolactin (PRL)-secreting tumors. We report the case of a fatal pituitary carcinoma evolving within 4 years from a PRL-secreting microadenoma. A 22-year-old woman presented because of galactorrhea. Evaluation of the patient disclosed slight hyperprolactinemia and magnetic resonance imaging (MRI) showed a 7-mm intrapituitary lesion, which responded to treatment with cabergoline. About 4 years after the first evaluation she developed sudden headache, ptosis, and diplopia in the right eye. MRI disclosed the growth of a large pituitary mass, invading the right cavernous sinus. Despite two trans-sphenoidal surgical procedures followed by gamma-knife radiosurgery, the patient showed rapid local progression of the tumor and the occurrence of new lung lesions, probably of metastatic nature. The patient died 7 months after the development of her first neurological symptoms because of tumor apoplexy and subsequent subarachnoid hemorrhage. This case represents the first documented rapid evolution from a microprolactinoma initially responding to dopamine agonists to a fatal pituitary carcinoma.

Unilateral corneal endothelial dystrophy and anterior keratoconus.

PURPOSE: To describe a case of keratoconus and Fuchs' corneal endothelial dystrophy in the left eye with no corneal disease in the right eye. METHODS: A 64-year-old woman presented with visual impairment in her left eye; computer-assisted topographic analysis and specular microscopy were performed in both eyes and left cornea was histopathologically examined. RESULTS: Keratoconus was diagnosed by slit-lamp examination, keratometry, and computer-assisted topographic analysis. Corneal endothelial dystrophy was diagnosed on the basis of clinical examination and specular microscopy. Histopathologic examination revealed a stromal degeneration typical of keratoconus and a non-guttae form of endothelial dystrophy. CONCLUSIONS: This is a rare case of unilateral corneal endothelial dystrophy and keratoconus.

PADI4 gene in multiple sclerosis: a family-based association study.

In multiple sclerosis (MS) MBP is heavily citrullinated by peptidylarginine deiminase (PAD). This post-translational modification may be crucial for its pathogenesis. PADI4 is the isoform expressed in inflammatory infiltrates. The aim of this study was to analyse the role of PADI4 gene in conferring susceptibility to MS, by means of a family-based association study, testing three SNPs by RFLP. No association was found either with single SNPs or haplotypes. Similarly no significant association was detected partitioning the patients according to DRB1*15 positivity or disease severity. These results do not support a major role of the PADI4 gene, but further studies may contribute to clarify the genetic factors that regulate deimination.

Primary intramedullary primitive neuroectodermal tumor (PNET)--case report and review of the literature.

Spinal primitive neuroectodermal tumors (PNET) are very rare tumors, and intramedullary localization is even less common. Indeed, amongst the 23 cases of the spinal PNET described in the literature, only eight cases had an intramedullary localization. Following the WHO 2000 classification, PNETs have been considered embryonal tumors composed of undifferentiated neuroepithelial cells with a capacity of differentiation into different cellular lines, such as astrocytic, ependymal, melanotic and muscular. They have been considered to arise from a neoplastic transformation of primitive neuroepithelial cells, thereby making their presence possible in any part of the central nervous system. The optimal treatment for these malignant tumors is not yet clear, although, over the years, radiotherapy has been considered the best treatment for spinal PNETs. The described case is that of a 38-year-old man with a primary intra-extramedullary PNET, treated by laminectomy, open biopsy and chemotherapy. The patient, 18 months after the onset of his symptomatology, died without cerebral tumor involvement.

The immune response to citrullinated antigens in autoimmune diseases.

Post-translational modifications of proteins occur very frequently. One of these modifications, citrullination, is the result of arginine deimination operated by an enzyme, peptidylarginine deiminase (PAD), whose activity is under strict genetic control. Serum antibodies reactive with citrullinated proteins/peptides are a very sensitive and specific marker for rheumatoid arthritis. Genes encoding for PAD enzymes have been investigated in RA: the PADI4 gene confers susceptibility to RA in Japanese patients, but not in Caucasians.

[Cystic papillary tumor of the pancreas: a rare etiology of abdominal mass in children]. / Tumeur kystique et papillaire du pancréas: une cause rare de masse abdominale.

BACKGROUND: Malignant pancreatic tumors are very uncommon in childhood. CASE REPORT: A 13-year-old girl was admitted for investigation of an abdominal mass with fever. Ten months earlier, clinical examination performed for similar symptoms found an epigastric mass which resolved spontaneously. Radiological investigations showed a well-encapsulated cystic tumor in the pancreas. Excision revealed a papillary cystic tumor of the pancreas. CONCLUSION: Papillary cystic tumor of the pancreas is an unfrequent cause of abdominal mass in children. Its excellent prognosis after complete excision is quite different from that of other malignant pancreatic tumors.

[Childhood visceral leishmaniasis in the Alpes-Maritimes from 1985 to 1992]. / La leishmaniose viscérale infantile dans les alpes-maritimes de 1985 a 1992.

Here, we present an analysis of clinical and biological data from 15 infantile visceral leishmaniasis recorded between 1985 and 1992 in the French department of Alpes-Maritimes. The association of fever, splenomegalia, tricytopenia remains the most constant and predictive of diagnosis (90% of cases). Bone marrow smear affirms diagnosis in 93% of cases. Leishmania infantum MON-1 is the causative agent. Except for one case of advanced stade with severe hepatic lesions and one case of clinical resistance to Glucantime, prognosis is favourable under treatment with antimony derivatives. The long term results for children considered cured after initial treatment is satisfactory. In the department, the number of cases of combined ages has increased regularly since 1985. The number of infantile forms has increased but now represents nevertheless no more than 28% of total cases. On the other hand, cases are increasing in adults and 40% of those adult cases are in HIV positive patients.

[Congenital toxoplasmosis in the Alpes-Maritimes region. Apropos of 26 cases observed between 1984 and 1990]. / La toxoplasmose congénitale dans les Alpes-Maritimes. A propos de 26 cas observés entre 1984 et 1990.

Twenty-six cases of congenital toxoplasmosis observed in the department of Alpes Maritimes (Chief Town: Nice) between 1984 and 1990 are reported. All affected children were treated by pyrimethamine and sulfonamide as soon as the diagnosis was established. None of them exhibited serious sequellae. In most cases (58%) there were no clinical manifestations in agreement with other reports. Benign manifestations were observed in 10 cases (38%): 4 chorioretinitis; 4 intracranial calcifications: 1 febrile seizure; 7 hyperproteinorachias: 3 isolated and 4 associated with other signs. In 3 cases, secondary lesions appeared during the treatment period. This confirms the need for active therapeutic research in order to decrease the risk of late ocular complication which is the major problem of the disease.