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.

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.

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.

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.

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.

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.

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.

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.

[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.

Rinoseptoplastia aberta para tratamento de deformidade nasal na fissura unilateral / Open rhinoseptoplasty for the treatment of nasal deformity in the unilateral cleft lip

A correção das deformidades nasais associadas à fissura unilateral tem-se demonstrado de difícil solução cirúrgica. As características do nariz fissurado são bem conhecidas com mais de vinte alterações anatômicas. Nos últimos vinte anos, muitas técnicas e táticas foram desenvolvidas para corrigir a deformidade nasal associada à fissura unilateral. Apresentamos nossa experiência na correção da deformidade nasal em fissurados labiais unilaterais com rinoseptoplastia aberta tardia em 69 pacientes e os resultados estético e funcional.

The correction of nasal deformities in unilateral cleft lip has been demonstrated of hard surgery solution. The characteristics features of cleft lip nose are wellknown with more than 20 abnormal anatomical components. Within the last twenty years, many techniques had been developed to correct the associated nasal deformity associated with unilateral cleft lip. We present our experience in the correction of unilateral cleft lip nasal deformity with delayed open rhinoseptoplasty in 69 patients and the cosmetic and functional results.

[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.

[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.

[Upper urinary tract tumors: results of treatment and follow-up]. / Tumores del tracto urinario superior: resultados del tratamiento y seguimiento.

OBJECTIVE: To present the results of treatment and follow-up of 105 patients with tumor of the upper urinary tract. METHODS: A retrospective study was conducted on 105 patients (88 male and 17 female; mean age 68.3 years) with tumor of the upper urinary tract that had been treated from 1975 to 1997. In total 114 functional units were treated, including recurrences and bilateral tumors. The sites of involvement were: ureter (49.9%), pelvis (41.2%) and the entire upper urinary tract (8.7%). Ninety-six percent were transitional cell carcinomas: 4.8% were well differentiated (GI), 68% moderately differentiated (G2) and 26.8% poorly differentiated (G3); 58.6% were superficial, while 41.3% showed tumor invasion into or beyond the muscle layer. Ninety-two of the 105 patients were followed. The SPSS program was employed for the statistical analysis. The survival was calculated by the Kaplan-Meier method and the differences by the log rank test. Multivariance analysis was performed using the Cox regression method. TREATMENT: 58% underwent radical nephroureterectomy, 30% were treated conservatively and 11.6% underwent partial resection of the upper urinary tract. Recurrence: 8.7% of the patients showed tumor recurrence. The recurrence rate after conservative surgery was 13.6% and was as high as 80% in the remaining ureter. Metastasis: 22.8% of the patients presented metastasis to the retroperitoneal lymph nodes, bone, liver and lungs. Survival: In the univariate analysis tumor stage, age, radical and conservative surgery were found to influence survival, while stage and surgery (radical or conservative) were found to be statistically important by multivariate analysis. CONCLUSIONS: The treatment of choice for high grade and stage transitional cell carcinoma is by radical surgery, whereas for the superficial and well differentiated tumors, conservative management can achieve similar survival rates while preserving the renal unit and upper urinary tract.

[Expression of protein p53 in superficial transitional carcinoma of the bladder with differing course]. / Expresión de la proteína p53 en carcinomas transicionales vesicales superficiales con distinta evolución.

OBJECTIVE: To determine the prognostic value of p53 protein expression in relation to progression of superficial bladder cancer. METHODS: A retrospective study was conducted in which p53 protein was determined in TUR fragments of 18 patients with superficial transitional cell carcinoma of the bladder with no evidence of tumor progression in the last 6 years and in 13 patients with superficial tumors that had become invasive. DO-7 monoclonal antibody was utilized (+if stained nuclei were more than 25%). RESULTS: Expression of p53 protein was found in 9 patients (50%) with bladder tumors that had not progressed and in 6 patients (46.1%) with bladder tumors that had become invasive (p = 0.83). CONCLUSION: Determination of p53 protein was not related with cancer progression in this series.

[Leiomyosarcoma of the inferior vena cava. Apropos of a case]. / Leiomiosarcoma de cava inferior. A propósito de un caso.

Presentation of one case of inferior cava leiomyosarcoma in a 24-year old female patient, incidentally diagnosed after performance of ultrasound. The complementary examinations performed (CAT, NMR, arteriography) guided to a mass of suprarenal origin. During surgery, a tumour of the inferior cava vein was suspected and was later confirmed through the pathoanatomical study of the surgical piece. Review of the clinical and diagnostic aspects placing special emphasis on treatment.

[Prostatic rhabdomyosarcoma in adults]. / El rabdomiosarcoma de próstata en el adulto.

OBJECTIVE: To report on two adult patients with prostatic embryonal rhabdomyosarcoma. The literature is briefly reviewed and the clinical, diagnostic and therapeutic aspects of this unusual variety of prostate cancer are discussed. METHODS: Two patients, aged 27 and 34 years, with prostatic embryonal rhabdomyosarcoma are presented. Both cases showed tumor dissemination at the time of diagnosis. Both patients received chemotherapy. RESULTS: A 60% reduction in tumor volume was achieved in one patient, who subsequently underwent rescue surgery and, in spite of a recurrence, is still alive 3 years after the diagnosis. The other patient showed no response to chemotherapy. He refused rescue surgery and was lost to follow-up. CONCLUSION: Embryonal rhabdomyosarcoma of the prostate in the adult is an unusual and aggressive tumor, of rapid growth and progression. Early diagnosis and treatment without delay by radical surgery and chemotherapy are essential to improve the prognosis of this disease.

[Tumors of the upper urinary tract: epidemiology, clinical, and diagnosis]. / Tumores del tracto urinario superior: epidemiología, clínica y diagnóstico.

OBJECTIVE: To review the epidemiological, clinical and diagnostic aspects of upper urinary tract tumors (UUTT). METHODS: The clinical records of 105 patients with UUTT were reviewed. There were 114 functioning units in total. Data on distribution according to sex, age at presentation, involved side, focality, localization, association with bladder tumor, risk factors, clinical features, radiological and histological findings were analyzed. Descriptive statistical analysis was performed and the means and frequency rates were estimated. RESULTS: Of the 105 patients, 88 (83.8%) were male and 17 (16.1%) were female, accounting for a male to female ratio of 5.1:1. The mean age was 68.3 +/- 10.5 years (range 24-88). The tumor involved the left side in 52 cases (49.5%), the right side in 49 cases (46.6%) and 4 cases (3.8%) had bilateral involvement; 84 (80%) were unifocal and 21 (20%) were multifocal. The pyelocaliceal region was compromised in 41.2% (47/114) of the functioning units, the lumbar ureter in 14% (16/114), the sacral ureter in 7% (8/114), the pelvic ureter in 28.9% (33/114) and the entire upper urinary tract in 8.7% (10/114). UUTT was associated with a bladder tumor in 60.9%. The bladder tumor and UUTT presented simultaneously in 26 cases (29.8%). The bladder tumor presented before the UUTT in 35 cases (40.2%) and in 26 cases (29.8%) it presented after. Smoking was found to be the most important risk factor. Hematuria was the most common reason for consultation (67.6%), followed by flank pain (23.8%), and 13.3% were asymptomatic. The most common urographic finding was a filling defect (46.4%), followed by loss of function (36.8%) and hydronephrosis (20.1%). Loss of renal function was observed in 66% of the cases with metastasis. Histologically, 99% were transitional cell carcinoma, basically moderately differentiated (68.8% grade II) and non infiltrating (58.6% pTa-pT1). CONCLUSIONS: Our findings are largely in agreement with the data published in the literature, although we have found a very high incidence of UUTT associated with bladder tumor in our series.