The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

Links between gender norms and the intergenerational transmission of health information in parents carrying BRCA1/2 pathogenic variants.

Understanding how gender norms affect parents' communication of genetic and cancer risk information to their children can enable healthcare professionals to better facilitate cascade genetic testing. We conducted a qualitative study with semi-structured interviews to determine social factors associated with parents carrying the BRCA1/2 pathogenic variants who communicated cancer prevention practices to their children. Thirty adult carriers (23 women, 7 men) participated in the interviews. All had at least one child aged over 8 years old. Interview topics included their discovery of the variants, their relationship to their body and to the risk of cancer, as well as disclosure to and subsequent communication with their children after testing positive for BRCA1/2. The interviews were analyzed qualitatively, and the major themes identified were identified and compared. We described the roles played by the BRCA1/2 carriers and their partners in communicating cancer prevention practices to their children, from how they managed their own risk of cancer after testing positive, to how they disclosed the risks linked to these pathogenic variants to their children. We also described their involvement in the process of their children going for professional genetic consultation. Gender norms lead women to be more attentive than men to their own health and that of their loved ones. In the context of the transmission of genetic information to children, gender differences in behavior are reinforced by perceptions of the risks of BRCA1/2 variants and women's related health management practices. Cancer prevention is shaped by complex links between gender norms and health management practices.

Gender gaps in preschool age: A study of behavior, neurodevelopment and pre-academic skills.

Background: Female educational advantage is evident from elementary school and throughout the education system. Understanding the gender differences that precede school entry might provide important insight as to why girls outperform boys later in their educational careers. Aims: The aim of this study was to explore gender differences in early literacy and numeracy skills, as well as a range of neurodevelopmental and behavioral domains between the age of five and six years. Methods: We used questionnaire data from preschool teachers in the Norwegian Mother, Father and Child Cohort Study reported for 7467 children attending the final year in preschool, to explore gender differences and age patterns by fitting flexible regression models predicting pre-academic, behavioral and neurodevelopmental outcomes. Results: We found gender differences favoring girls for all outcomes except internalizing behavior. For neurodevelopment and behavior, differences in adjusted standardized scores ranged from 46% of a standard deviation (95% confidence interval (CI) 0.41, 0.50) in overall school readiness to 31% of a standard deviation difference in externalizing behavior problems (CI 0.21, 0.41). We found gender differences for all literacy skills in favor of girls. The gender gap in naming and adding numbers was small, but in favor of girls. Increasing age was associated with improved pre-academic skills and school readiness, as well as reduction of attention problems and language difficulties, the latter especially for boys. Conclusions: We conclude that gender differences favoring girls exist prior to school entry for a broad range of pre-academic, behavioral and neurodevelopmental skills relevant to school functioning.

The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.

Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma.

BACKGROUND: Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. PATIENTS AND METHODS: Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. RESULTS: Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. CONCLUSIONS: Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. CLINICALTRIALSGOV: NCT01111903.

Prognostic factors in 401 elderly women with metastatic breast cancer.

BACKGROUND: Elderly patients with metastatic breast cancer have a prognosis and outcome that may be dependent on a host of factors. PATIENTS AND METHODS: We retrospectively analyzed 401 female breast cancer patients who developed metastatic disease after the age of 70 years in order to define potential prognostic factors for specific survival at the time of first recurrence. RESULTS: With a median follow-up of 60 months from the time of recurrence, the median specific survival was 21.0 months (95% CI 17.0-23.0). In multivariate analysis we demonstrated that negative hormonal receptor status (p = 0.002), presence of positive lymph nodes at initial cancer diagnosis (hazard ratio, HR = 1.37; 95% CI 1.07-1.75; p = 0.01), site of metastasis (p < 10(-4)) and metastasis-free interval (HR = 0.99; 95% CI 0.95-0.99; p = 0.008) constituted unfavorable independent prognostic factors able to predict specific survival from the time of metastatic occurrence. Age at initial diagnosis, Scarff-Bloom Richardson grade and adjuvant treatments were significant only in univariate analysis. CONCLUSION: These survival prognostic factors associated with the use of a specific geriatric questionnaire to assess frailty may assist physicians in evaluating the patient's survival potential and choose a tailored treatment to this cancer population.

Phase I trial of gemcitabine combined with capecitabine and erlotinib in advanced pancreatic cancer: a clinical and pharmacological study.

BACKGROUND: The aim of this phase I trial was to define the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of erlotinib combined with capecitabine and gemcitabine in the treatment of advanced pancreatic cancer (APC). METHODS: Gemcitabine was administered intravenously at 1,000 mg/m(2)/week (days 1, 8 and 15) and oral capecitabine from day 1 to day 21 at 1,660 mg/m(2)/day. Oral erlotinib was administered daily continuously at escalating doses (28-day cycle). Dose levels (DLs) 1, 2, 3 and 4 were 50, 75, 100 and 125 mg/day, respectively. Pharmacokinetic analysis of the three drugs was performed in the first cycle. RESULTS: Nineteen patients were enrolled. At the MTD (DL4; 125 mg/day erlotinib), 100% of patients developed DLT consisting of grade 4 febrile neutropenia and nonhematological grade 3 events (vomiting, diarrhea, stomatitis, rash). The most common toxicities, regardless of grade, were neutropenia, anemia, rash and diarrhea. Erlotinib systemic exposure was significantly related to the administered dose. Of note, toxicity was significantly associated with elevated systemic exposure of capecitabine anabolites. CONCLUSION: When combined concurrently with 1,000 mg/m(2)/week gemcitabine and 1,660 mg/m(2)/day capecitabine, erlotinib can be administered safely at a daily dose of 100 mg in APC patients.

A phase I study of UFT-oral vinorelbine in metastatic breast cancer.

BACKGROUND: Despite current treatment options, metastatic breast cancer (MBC) remains essentially incurable, requiring research on new drugs or combinations to improve survival and quality of life. PATIENTS AND METHODS: This phase I study was designed to define the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose of all-oral tegafur-uracil (UFT)/folinic acid combined with vinorelbine as chemotherapy for MBC. Starting doses were 40 mg/m(2)/week of oral vinorelbine administered continuously and 250 mg/m(2)/day of UFT plus 90 mg/day of folinic acid from day 1 to day 28, followed by a 1-week rest period. RESULTS: Ten patients were included. Eight were evaluable for toxicity and antitumor response. The second dose level was shown to be the MTD. At this dose, 2 out of 5 patients receiving oral vinorelbine at 40 mg/m(2)/week and UFT at 300 mg/m(2)/day developed DLT consisting of grade 3 asthenia and grade 3 nausea despite standard prophylaxis. Other toxicities were grade 1 diarrhea and anemia. There were no treatment-related deaths. CONCLUSIONS: The recommended dose for this combination seems to be the first dose level. A stable response was observed for 6 patients (average 33 weeks). This combination appears to be well-tolerated and offers an alternative to intravenous chemotherapy.

Mutation analysis of the spike protein in Italian feline infectious peritonitis virus and feline enteric coronavirus sequences.

Feline coronavirus (FCoV) exists as two different genotypes, FCoV type I and II, each including two biotypes, feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), the latter being a virulent variant originating from the former virus. Recently, two amino acid substitutions, M1058L and S1060A, within the spike protein have been associated to the FECV/FIPV virulence change. In this study, we have analysed the frequency of detection of such mutations in FIPV and FECV strains circulating in Italian cats and obtained information about their evolutionary relationships with reference isolates. A total of 40 FCoV strains, including 19 strains from effusions or tissue samples of FIP cats and 21 strains from faecal samples of non-FIP cats, were analysed. Mutation M1058L was detected in 16/18 FCoV-I and 1/1 FCoV-II strains associated with FIP, while change S1060A was presented by two FIPV strains. By phylogenetic analysis, FCoV sequences clustered according to the genotype but not according to the biotype, with FECV/FIPV strains recovered from the same animal being closely related. Further studies are needed to better define the genetic signatures associated with the FECV/FIPV virulence shift.

Prognostic factors in 1,038 women with metastatic breast cancer.

BACKGROUND: Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. PATIENTS AND METHODS: From 1975 to 2005, a total of 1,038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. RESULTS: It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. CONCLUSION: These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.

Do mothers also "manipulate" grandparental care?

Paternity uncertainty has proven to be a robust ultimate hypothesis for predicting the higher investment in grandchildren observed among maternal grandparents compared to that of the paternal grandparents. Yet the proximate mechanisms for generating such preferred biases in grandparental investment remain unclear. Here we address two different questions for better understanding the proximate mechanisms leading to the observed bias in grandparental investments: (i) is there a larger emphasis on resemblance descriptions (between grandchildren and grandparent) among daughters than among sons, and (ii) do mothers really believe that their offspring more resemble their parents, that is, the children's grandparents, than fathers do? From questioning grandparents, we find that daughters more often and more intensely than sons express opinions about grandchild-grandparent resemblance. Moreover, daughters also seem to believe that their children more resemble their grandmother than sons do. The latter is, however, not the case for beliefs about children's resemblance to grandfathers. In sum, our results suggest that even in a population of Norwegians, strongly influenced by ideas concerning gender equality, there exist a sexual bias among parents in opinions and descriptions about grandchild-grandparent resemblance. This resemblance bias, which echoes that of mothers biasing resemblance descriptions of newborns to putative fathers, does not seem to represent a conscious manipulation. Yet it could be instrumental for influencing grandparental investments. We believe that a "manipulative mother hypothesis" might parsimoniously account for many of the results relating to biased alloparenting hitherto not entirely explained by "the paternity uncertainty hypothesis."

Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa lung infection is a main cause of disability and mortality worldwide. Acute inflammation and its timely resolution are crucial for ensuring bacterial clearance and limiting tissue damage. Here, we investigated protective actions of resolvin (Rv) D1 in lung infection induced by the RP73 clinical strain of P. aeruginosa. RvD1 significantly diminished bacterial growth and neutrophil infiltration during acute pneumonia caused by RP73. Inoculum of RP73, immobilized in agar beads, resulted in persistent lung infection up to 21 days, leading to a non resolving inflammation reminiscent of human pathology. RvD1 significantly reduced bacterial titer, leukocyte infiltration, and lung tissue damage. In murine lung macrophages sorted during P. aeruginosa chronic infection, RvD1 regulated the expression of Toll-like receptors, downstream genes, and microRNA (miR)-21 and 155, resulting in reduced inflammatory signaling. In vitro, RvD1 enhanced phagocytosis of P. aeruginosa by neutrophils and macrophages, recapitulating its in vivo actions. These results unveil protective functions and mechanisms of action of RvD1 in acute and chronic P. aeruginosa pneumonia, providing evidence for its potent pro-resolution and tissue protective properties on airway mucosal tissue during infection.

Haematological evaluation of weekly therapy with topotecan for the treatment of recurrent ovarian cancer resistant to platinum-based therapy.

Topotecan is indicated in the treatment of advanced-stage ovarian cancers refractory to prior platinum-based regimen. The aim of this study was to compare the standard therapeutic strategy with a novel strategy of weekly administration of topotecan. The primary endpoints were dose density and overall tolerance. This retrospective cohort study included patients with ovarian cancer in relapse. During a first period (1998-2001), 24 patients received the standard topotecan dose of 1.5 mg/m(2)/day for 5 consecutive days with a 3-week interval between each treatment course. During a second period (2003-2006), 21 patients received a weekly topotecan dose of 4 mg/m(2) for 3 weeks out of every 4. Grades III and IV haematological toxicities were more frequent with the standard strategy (p < 0.05), even after adjustment of the prescription of erythropoietin and G-CSF. With the weekly strategy, an increase in dose density and a reduction in the number of delayed doses were observed. No significant difference between the 2 strategies was found in terms of response to the treatment and specific survival. This study suggests that the weekly administration of topotecan 4 mg/m(2), for 3 weeks out of every 4, results in a better maintenance of dose density and a reduction in haematological toxicity.

Detection and quantification of Anaplasma marginale DNA in blood samples of cattle by real-time PCR.

A TaqMan-based real-time PCR assay was developed for the diagnosis of Anaplasma marginale infection of cattle. The established assay was proven to be highly specific, since no cross-reactions were observed with other Anaplasma species of ruminants, including the closely related Anaplasma centrale, or other haemoparasites of ruminants (Anaplasma bovis, Anaplasma ovis, Anaplasma phagocytophilum, Babesia bovis, Babesia bigemina, Theileria annulata and Theileria buffeli). The detection limit was equal to that of nested (n)PCR (10(1) copies of standard DNA and 3 x 10(1) infected erythrocytes ml(-1) of blood). The assay was also reproducible, as shown by satisfactory low intra-assay and inter-assay coefficients of variation. Fifty-four blood samples of ruminants (cattle, n = 51; sheep, n = 2; goats, n = 1), that had been tested previously by reverse line blot (RLB) hybridisation, were subjected to an nPCR assay and the newly established real-time PCR assay. By using real-time PCR, A. marginale DNA was detected in 39/51 bovine samples, with DNA titres ranging from 3.60 x 10(3) to 5.70 x 10(8) copies ml(-1) of blood, whereas sheep and goat samples tested negative. The concordance with nPCR was 100%, whereas a unique sample that had tested negative by RLB gave positive results by nPCR and real-time PCR. The established assay could overcome the limitations of existing diagnostic methods, allowing for simultaneous detection and quantification of the A. marginale DNA in bovine blood, that is essential to support the clinical diagnosis, to assess the carrier status of the animals and to evaluate the efficacy of vaccines and antirickettsial drugs.

Infectious canine hepatitis: an "old" disease reemerging in Italy.

Four outbreaks of infectious canine hepatitis (ICH) occurring in Italy between 2001 and 2006 are reported. Three outbreaks were observed in animal shelters of southern Italy, whereas a fourth outbreak involved two purebred pups imported from Hungary few days before the onset of clinical symptoms. In all outbreaks canine adenovirus type 1 (CAV-1) was identified by virus isolation and PCR. In three outbreaks, other canine viral pathogens were detected, including canine distemper virus, canine parvovirus or canine coronavirus. The present study shows that CAV-1 is currently circulating in the Italian dog population and that vaccination is still required.

Familial hematological malignancies: ASXL1 gene investigation.

PURPOSE: Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological malignancies have been reported until now due to the low occurrence. We have described in previous study PRF1 and CEBPA variants that might contribute to the background of genetic factors, which encourage us to extend our investigations to other cooperating genes. The aim of this study is to determine whether germline additional sex combs-like 1 (ASXL1) gene mutations may be involved? METHODS/PATIENTS: In this study, we investigated the candidate gene ASXL1 by direct sequencing in 88 unrelated Tunisian and French families with aggregated hematological malignancies. RESULTS: We report a new p.Arg402Gln germline missense substitution in two related Tunisian patients which has not been previously described. We identified here this variant for the first time in non-Hodgkin lymphoma. The p.Arg402Gln variant was not found in 200 control chromosomes. In silico analysis has predicted potential deleterious effect on ASXL1 protein. CONCLUSIONS: From an extended candidate genes analyzed in the field of familial hematological malignancies, ASXL1 might be involved. This variant should be considered since a potential damaging effect was predicted by in silico analysis, with a view to develop functional assay in order to investigate the biological assessment.

[Incomplete urethral duplication in a male. A case report]. / Duplicidad uretral incompleta en un varón. Aportación de un nuevo caso.

Urethral duplication is a rare congenital anomaly affecting mainly males and being usually diagnosed during paedriatric age. We report a 20 year old male complaining of double urethral meatus with double urinary stream. Physical examination confirmed and additional hypospadic meatus below a normally placed urethral meatus. Retrograde urethro-cystography and voiding cysto-urethrograms showed two distinct urethras originating from a common bladder neck and the diagnosis of Effmann type IIA2 incomplete urethral duplication was made. No treatment was felt to be applied after associated anomalies were ruled out.

Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly.

The human sirtuin 3 (SIRT3) gene encodes a putative mitochondrial NAD-dependent deacetylase (SIRT3) which belongs to the evolutionary conserved family of sirtuin 2 proteins. Studies in model organisms have demonstrated that SIR2 genes control lifespan, while no data are available regarding a possible role of SIRT3 in human longevity. By analysing the genotype-specific survival function relevant to the G477T marker of SIRT3, we found that in males the TT genotype increases (p=0.0272), while the GT genotype decreases (p=0.0391) survival in the elderly. Since SIRT3 lies in a chromosomal region (11p15.5) where four genes potentially associated with longevity are located (HRAS1, Insulin-like Growth Factor 2, Proinsulin, and Tyrosine Hydroxylase) we tested for linkage-disequilibrium between G477T alleles and alleles of the above genes. The disequilibrium was not significant in any case, thus suggesting that SIRT3 itself, or a gene strictly linked to SIRT3, may have a role in human longevity.

[Etiopathogenesis and management of paraneoplastic fever and Stauffer syndrome in renal carcinoma]. / Etiopatogenia y manejo de la fiebre paraneoplásica y del síndrome de Stauffer en el carcinoma renal.

Some paraneoplastic syndromes as fever, cachexia, loss of weight or hepatic dysfunction, are relatively frequent in patients affected by a renal cell carcinoma (RCC). However their pathogeny has been unknown until a short time ago. The advances in immunology have permitted to identify the interleukin-6 as the responsible for these changes. In spite of our better knowledge, the treatment of these paraneoplastic syndromes, when persist after the removal of the tumor, continues being a challenge. We present the case of a patient with a renal cell carcinoma that began as a feverish syndrome, developing thereinafter a hepatic dysfunction or Stauffer's syndrome. The paraneoplastic symptoms persisted after removal of the tumor. No response to the administered treatment has been observed. The patient died two months after the surgery.

[Bilateral germ tumors of the testis. Report of 5 cases and review of the literature]. / Tumores germinales bilaterales de testículo. Aportación de cinco casos y revisión de la literatura.

OBJECTIVE: To know the prevalence of the bilateral germ cell tumours of testis diagnosed in our Department and to review the literature. MATERIAL AND METHODS: 64 patients diagnosed of a germ cell tumour of the testis were followed during an average period of 51.4 months (1-168 months). RESULTS: 5 (7.8%) patients developed a second germ cell testicular tumour. In one patient the tumours were synchronous while in the remaining four were metachronous, occurring in an average interval of 59 months. One patient with a metachronous tumour died as consequence of the second tumour. In two of the five patients risk factors were identified, one presented testicular atrophy and the second referred history of undescended testis. DISCUSSION: The probability of developing a germinal testis tumour between the patients with history of a previous germ cell tumour of the testis is sensibly greater than between the general population. The prevalence of the bilateral tumours of the testis oscillates between 1-5% and approximately 75% will be metachronous. The principal factor that can predict the appearance of a second testicular tumour is the presence of the carcinoma in situ (Cis) in the contralateral testicular biopsy. Except in cases of testicular atrophy or previous history of undescended testis we do not recommend routine biopsy of the other testis.