Acquired gene alterations in patients treated with ribociclib plus endocrine therapy or endocrine therapy alone using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials.

BACKGROUND: A prior pooled analysis of the MONALEESA-2, -3, and -7 trials identified baseline markers predictive of sensitivity or resistance to ribociclib plus endocrine therapy (ET). We report the results of an analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples across the MONALEESA trials. PATIENTS AND METHODS: Paired baseline and EOT ctDNA samples from MONALEESA-2, -3, and -7 were sequenced using a targeted next-generation sequencing panel. Genes with an EOT alteration prevalence of >5% were included. A McNemar test was performed on paired samples and adjusted for multiple testing to control the false discovery rate. A Bayesian mixed-effects model was used to adjust for ctDNA fraction at both time points and for study differences. RESULTS: The analysis included 523 paired samples. At EOT, 21 genes had a >5% alteration prevalence. A trend for higher ctDNA fraction at EOT vs baseline (P=0.08) was observed. Prevalence of alterations was higher at EOT vs baseline in RB1, SPEN, TPR, PCDH15, and FGFR2 in the ribociclib arm; PBRM1 in the placebo arm; and ESR1 in both arms. The mixed-effects model demonstrated that the same trends for increased prevalence of these alterations at EOT were observed after adjusting for ctDNA fraction and that the increased rate of RB1 and SPEN alterations at EOT were specific to ribociclib plus ET. Analysis of ESR1 indicated a similar increase at EOT in both arms. The most common acquired ESR1 mutations at EOT included Y537C/N/S/D, D538G, E380Q, and L536H/R/P/LC. The prevalence of PIK3CA hotspot mutations at baseline and EOT was similar. CONCLUSIONS: This analysis identified acquired gene alterations in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus ET or placebo plus ET. These data may support further studies on acquired resistance mechanisms and inform future systemic interventions in the post-CDK4/6 inhibitor setting.

Pooled ctDNA analysis of MONALEESA phase III advanced breast cancer trials.

BACKGROUND: The phase III MONALEESA trials tested the efficacy and safety of the cyclin-dependent kinase (CDK)4/6 inhibitor ribociclib with different endocrine therapy partners as first- or second-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Using the largest pooled biomarker dataset of the CDK4/6 inhibitor ribociclib in ABC to date, we identified potential biomarkers of response to ribociclib. PATIENTS AND METHODS: Baseline circulating tumour DNA from patients in the MONALEESA trials was assessed using next-generation sequencing. An analysis of correlation between gene alteration status and progression-free survival (PFS) was carried out to identify potential biomarkers of response to ribociclib. RESULTS: Multiple frequently altered genes were identified. Alterations in ERBB2, FAT3, FRS2, MDM2, SFRP1, and ZNF217 were associated with a greater PFS benefit with ribociclib versus placebo. Patients with high tumour mutational burden (TMB) and with ANO1, CDKN2A/2B/2C, and RB1 alterations exhibited decreased sensitivity to ribociclib versus placebo. CONCLUSIONS: Although exploratory, these results provide insight into alterations associated with the improved response to ribociclib treatment and may inform treatment sequencing in patients with actionable alterations following progression on CDK4/6 inhibitors. Validation of potential biomarkers identified here and development of prospective trials testing their clinical utility are warranted. GOV IDENTIFIERS: NCT01958021, NCT02422615, NCT02278120.

Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.

BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q.

BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.

Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457-0.704; log-rank P = 9.63 × 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. Clinical trials number: NCT01958021.

Mite species identification in the production of allergenic extracts for clinical use and in environmental samples by ribosomal DNA amplification.

The identification of allergy-causing mites is conventionally based on morphological characters. However, molecular taxonomy using ribosomal DNA (rDNA) may be particularly useful in the analysis of mite cultures and purified mite fractions in the production of allergenic extracts. Full-length internal transcribed spacers (ITS1 and ITS2) were obtained from Dermatophagoides farinae, Dermatophagoides pteronyssinus, Dermatophagoides microceras and Euroglyphus maynei (Astigmata: Pyroglyphidae), Glycyphagus domesticus and Lepidoglyphus destructor (Astigmata: Glycyphagidae), Tyrophagus fanetzhangorum, Tyrophagus putrescentiae, Tyrophagus longior, Tyrophagus neiswanderi, Acarus farris and Acarus siro (Astigmata: Acaridae), and Blomia tropicalis (Astigmata: Echymopodidae), using mite-specific primers. Polymerase chain reaction (PCR) products were digested with HpaII and RsaI restriction enzymes in order to produce species-specific PCR restricted fragment length polymorphism (RFLP) profiles. A semi-nested re-amplification step was introduced before the RFLP in order to apply the method to environmental samples. Results demonstrate that rDNA sequences can be used for the unambiguous identification of mite species. The PCR-RFLP system allows the identification of species in purified mite fractions when the availability of intact adult mite bodies for morphological identification is limited. This reliable and straightforward PCR-RFLP system and the rDNA sequences obtained can be of use in the identification of allergy-causing mite species.

Growth retardation and tumour inhibition by BRCA1.

Inherited mutations in BRCA1 predispose to breast and ovarian cancer, but the role of BRCA1 in sporadic breast and ovarian cancer has previously been elusive. Here, we show that retroviral transfer of the wild-type BRCA1 gene inhibits growth in vitro of all breast and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1 has no effect on growth of breast cancer cells; ovarian cancer cell growth is not affected by BRCA1 mutations in the 5' portion of the gene, but is inhibited by 3' BRCA1 mutations. Development of MCF-7 tumours in nude mice is inhibited when MCF-7 cells are transfected with wild-type, but not mutant, BRCA1. Most importantly, among mice with established MCF-7 tumours, peritoneal treatment with a retroviral vector expressing wild-type BRCA1 significantly inhibits tumour growth and increased survival.

Embolic stroke of undetermined source: beyond atrial fibrillation.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) accounts for 25% of all cerebral infarcts; only 30% are associated with paroxysmal atrial fibrillation (AF). Various biochemical, electrocardiographic, and echocardiographic findings may suggest left atrial damage and increased risk of embolism in the absence of clinically documented AF or atrial flutter. In this review, we analyse the available evidence on atrial cardiopathy or atrial disease, its involvement in ESUS, and its identification through electrocardiographic, echocardiographic, and serum markers and its possible therapeutic implications. DEVELOPMENT: A systematic search was conducted on MEDLINE (PubMed) using the following MeSH terms: MeSH [ESUS]+[atrial cardiopathy]+[atrial fibrillation]+[interatrial block]+[treatment]. We selected what we considered to be the most useful original prospective or retrospective studies and systematic reviews. We then read the full texts of the articles and checked the references cited in each article. We analyse epidemiological and demographic variables of patients with ESUS, as well as recent evidence related to presentation and prognosis and factors associated with recurrence and mortality. We review the contribution of atrial cardiopathy diagnosis prior to the detection of AF and the clinical, electrocardiographic, and echocardiographic variables and the biochemical markers associated with its development and its potential contribution to cerebral embolism. CONCLUSIONS: The systematic search of biochemical and electrocardiographic, and echocardiographic alterations can be useful to identify ESUS patients at higher risk of recurrence.

Clinical characteristics of patients with epilepsy attending primary health care. / Características clínicas de pacientes con epilepsia atendidos en la atención primaria.

OBJECTIVE: This study aimed to fill the current knowledge gap in the literature by identifying the demographic and clinical characteristics of patients with epilepsy attending primary health care (PHC). PATIENTS AND METHODS: This was a cross-sectional study involving adults (= 18 years of age) with epilepsy attending PHC from a developing country between 2015 and 2019. Demographic information and epilepsy-related data were collected. RESULTS: A total of 140 patients (51.4% male; mean [± SD] age 44.9 ± 17.8 years) were evaluated. The mean age at onset of seizures was 29.9 ± 22.9 years, with a mean evolution of 14.3±15.4 years. Focal seizures accounted for 88.57% of cases and evolved into bilateral tonic-clonic attack (45.16%). Of those that were generalized, motor seizures accounted for 81.82%, absence 9.09%, and motor + absence 9.09%. Among generalized onset motor seizures, tonic-clonic was predominant, accounting for 55.56%. Among types, focal epilepsy predominated (88.57%). The primary etiologies were unknown (62.14%), structural causes (27.85%) and infectious (9.28%). Patients undergoing monotherapy accounted for 66.1%, with epilepsy control in 92.4%. The most commonly used antiepileptic drugs were carbamazepine (33.1%), valproic acid (28.2%), and phenobarbital (10.4%). CONCLUSIONS: Male sex, seizures, and focal epilepsy were prevalent. Magnetic resonance imaging was more useful than computed tomography. Most etiologies were unknown; however, mesial temporal sclerosis and neurocysticercosis were the most prevalent known causes. Most patients were controlled using a monotherapy regimen. The implementation of International League Against Epilepsy classifications and definitions was feasible and useful.

TITLE: Características clínicas de pacientes con epilepsia atendidos en la atención primaria.Objetivo. Este estudio tuvo como objetivo llenar el vacío de conocimiento actual en la bibliografía mediante la identificación de las características demográficas y clínicas de los pacientes con epilepsia que asisten a la atención primaria de salud. Pacientes y métodos. Éste fue un estudio transversal que involucró a adultos (18 años o mayores) con epilepsia que asistieron a atención primaria de salud de un país en desarrollo entre 2015 y 2019. Se recopilaron información demográfica y datos relacionados con la epilepsia. Resultados. Se evaluó a un total de 140 pacientes ­51,4%, varones; edad media (± desviación estándar), 44,9 ± 17,8 años­. La edad media de inicio de las crisis fue de 29,9 ± 22,9 años, con una evolución media de 14,3 ± 15,4 años. Las crisis focales presentes en el 88,57% de los casos y evolucionaron a crisis tonicoclónicas bilaterales (45,16%). De las generalizadas, las crisis motoras predominaron con el 81,82%; las ausencias, el 9,09%; y las motoras + ausencias, el 9,09%. Entre las crisis motoras de inicio generalizado, predominó la tonicoclónica, con un 55,56%. Entre los tipos, predominó la epilepsia focal (88,57%). Las etiologías primarias fueron desconocidas (62,14%), causas estructurales (27,85%) e infecciosas (9,28%). Los pacientes en monoterapia representaron el 66,1%, con control de la epilepsia en el 92,4%. Los fármacos antiepilépticos más utilizados fueron la carbamacepina (33,1%), el ácido valproico (28,2%) y el fenobarbital (10,4%). Conclusiones. Predominaron el sexo masculino, las convulsiones y la epilepsia focal. La resonancia magnética fue más útil que la tomografía computarizada. La mayoría de las etiologías se desconocían; sin embargo, la esclerosis temporal mesial y la neurocisticercosis fueron las causas conocidas más prevalentes. La mayoría de los pacientes se controlaron con un régimen de monoterapia. La implementación de las clasificaciones y definiciones de la Liga Internacional contra la Epilepsia fue factible y útil.

Crizotinib in patients with tumors harboring ALK or ROS1 rearrangements in the NCI-MATCH trial.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Detection of fully refocused polyamine spins in prostate cancer at 7 T.

(1)H MRSI is often used at 1.5 or 3 T to study prostate cancer, where the ratio of choline + creatine to citrate is taken as a marker for tumour presence. Recently, the level of polyamines (mainly spermine) has been shown to improve specificity even further. However, the in vivo detection of these polyamines (at 3.1 ppm) is hampered by signal cancellation as a result of J-coupling effects and signal overlap with choline (3.2 ppm) and creatine (3.0 ppm) resonances. At higher magnetic field strengths, the chemical shift dispersion will increase, which allows the use of very selective radiofrequency pulses to refocus J-coupled spins. In this work, we added selective refocusing pulses to a semi-LASER (localisation based on adiabatic selective refocusing) sequence at 7 T, and optimised the inter-pulse timings of the sequence for fully refocused detection of spermine spins, whilst maintaining optimised detection of choline, creatine and the strongly coupled spin system of citrate.

Peficitinib hydrobromide to treat rheumatoid arthritis.

Peficitinib hydrobromide is a small Janus kinase inhibitor (JAK1, JAK2, JAK3 and TYK2) molecule for the treatment of rheumatoid arthritis (RA). Phase II and phase III clinical trials and extension studies with different doses have been conducted to assess the drug's efficacy and safety with substantially improved outcomes observed in RA. This JAK inhibitor oral drug demonstrated clinical response as once-daily monotherapy in patients with moderate to severe RA, also in combination with methotrexate (MTX), who had an inadequate response to MTX. The findings from studies of this new JAK inhibitor have shown that, both in monotherapy as well as in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), it has efficacy, safety and tolerability in RA patients.

Impact of organ confined prostate cancer treatment on quality of life. / Impacto en la calidad de vida del tratamiento del cáncer de próstata organoconfinado.

INTRODUCTION: Prostate cancer (PCa) is the second most common male cancer in the world. Its incidence is estimated to grow to 1.7 million new cases and 499,000 new deaths by 2030. Treatment of OCPC can affect patients physically and mentally, as well as their close relationships and their job or career, which conditions health-related quality of life (QoL). OBJECTIVE: Evaluate the impact on QoL attributable to the treatment for Organ Confined Prostate Cancer (OCPC). MATERIALS AND METHODS: Prospective multicenter observational study of 406 patients with OCPC treated from January 2015 to June 2018. The sample was divided into four study groups, according to the type of treatment: radical prostatectomy (RP) (GA), external radiotherapy (ERT) (GB), brachytherapy (BT) (GC) and other treatments different from monotherapy with RP, ERT or BT (GD). RESULTS: The age in GC was lower, the mean Prostate Specific Antigen (PSA) of all patients was 8.13 ng/ml, the group with the highest mean PSA was GB with a mean of 10.43 ng/dL, the mean Tumor Stage (TNM) was 3.82, and GD had the lowest post treatment quality of life. CONCLUSION: OCPC treatment affects QoL. Curative monotherapies, specifically RP and BT, have less effect on QoL than external radiotherapy or other therapeutic alternatives. Urinary incontinence and fistulas secondary to OCPC have the highest impact on QOL impairment. The internationally validated SF 36 questionnaire is a useful cross-sectional measure of QOL to compare the impact of OCPC treatment modalities.

Cyclin-dependent kinase inhibitor p27(Kip1) is required for mouse mammary gland morphogenesis and function.

We have studied the role of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) in postnatal mammary gland morphogenesis. Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation. However, recent evidence about the stabilizing effect of p27 on cyclin D1-Cdk4 complexes suggests that p27 deficiency might recapitulate the hypoplastic mammary phenotype of cyclin D1-deficient animals. These hypotheses were investigated in postnatal p27-deficient (p27(-/-)), hemizygous (p27(+/)-), or wild-type (p27(+/+)) mammary glands. Mammary glands from p27(+/)- mice displayed increased ductal branching and proliferation with delayed postlactational involution. In contrast, p27(-/-) mammary glands or wild-type mammary fat pads reconstituted with p27(-/-) epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate. The association of cyclin D1 with Cdk4, the kinase activity of Cdk4 against pRb in vitro, the nuclear localization of cyclin D1, and the stability of cyclin D1 were all severely impaired in p27(-/-) mammary epithelial cells compared with p27(+/+) and p27(+/-) mammary epithelial cells. Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D-Cdk4 function in the mammary gland.

Embolic stroke of undetermined source: Beyond atrial fibrillation. / Infarto cerebral embólico de origen no determinado: más allá de la fibrilación auricular.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) accounts for 25% of all cerebral infarcts; only 30% are associated with paroxysmal atrial fibrillation (AF). Various biochemical, electrocardiographic, and echocardiographic findings may suggest left atrial damage and increased risk of embolism in the absence of clinically documented AF or atrial flutter. In this review, we analyse the available evidence on atrial cardiopathy or atrial disease, its involvement in ESUS, and its identification through electrocardiographic, echocardiographic, and serum markers and its possible therapeutic implications. DEVELOPMENT: A systematic search was conducted on MEDLINE (PubMed) using the following MeSH terms: MeSH [ESUS]+[atrial cardiopathy]+[atrial fibrillation]+[interatrial block]+[treatment]. We selected what we considered to be the most useful original prospective or retrospective studies and systematic reviews. We then read the full texts of the articles and checked the references cited in each article. We analyse epidemiological and demographic variables of patients with ESUS, as well as recent evidence related to presentation and prognosis and factors associated with recurrence and mortality. We review the contribution of atrial cardiopathy diagnosis prior to the detection of AF and the clinical, electrocardiographic, and echocardiographic variables and the biochemical markers associated with its development and its potential contribution to cerebral embolism. CONCLUSIONS: The systematic search of biochemical and electrocardiographic, and echocardiographic alterations can be useful to identify ESUS patients at higher risk of recurrence.

Cognitive function assessment in elderly patients with overactive bladder treated with transdermal oxybutynin. / Evaluación de la función cognitiva en pacientes de edad avanzada con vejiga hiperactiva tratados con oxibutinina transdémica.

INTRODUCTION AND OBJECTIVES: Older patients with overactive bladder under antimuscarinic treatment are especially susceptible to cognitive impairment. The aim was to assess short term changes in cognitive function in elderly patients with overactive bladder treated with transdermal oxybutynin. MATERIALS AND METHODS: Observational, retrospective, multicentre study in patients with overactive bladder aged 65-80 years undergoing treatment with transdermal oxybutynin. Before and after one month of treatment, cognitive function using the Memory Alteration Test and Clock-Drawing Test, changes in symptoms with validated questionnaires, patient perception of treatment response using Treatment Benefit Scale and treatment adherence with the modified Morisky-Green test, were assessed. RESULTS: From 85 eligible patients, 70 completed the assessment (mean age: 71.4±4.5; BMI: 28.7±3.1kg/m2). No cognitive impairment was observed after one month with transdermal oxybutynin: Memory Alteration Test (+1 point; 95%CI: 0.0-1.5), Clock-Drawing Test (0 points; 95%CI: 0.0-0.0). A statistically significant improvement (P<.001) was observed in all urinary storage symptoms, except stress urinary incontinence. There was an improvement in the Bladder Control Self-Assessment Questionnaire (symptom score: -2.27; 95%CI: -2.8, -1.7; P<.001; bother score: -2.73; 95%CI: -3.3, -2.1; P<.001). 70% of patients reported either a stable or improved bladder condition according to the Patient Perception of Bladder Condition questionnaire. 72.8% of patients reported that their urinary problems had improved or greatly improved with an 84.3% treatment adherence. CONCLUSIONS: No cognitive impairment was observed in elderly patients after one month of treatment with transdermal oxybutynin; urinary urgency symptoms improved and there was adequate treatment adherence.

[Malignant fibrous histiocytoma of the spermatic cord. Presentation of one case and literature revision]. / Histiocitoma fibroso maligno de cordón espermático. Presentación de un caso y revisión de la literatura.

We present a case of malignant fibrous histiocytoma (MFH) of the spermatic cord. An 80-years-old man was admitted to the hospital with a left scrotal mass, related to a genital traumatism several months ago. Under the suspicion of a testicular tumor, left radical orchiectomy was performed. Histological examination of the tumoral mass revealed a malignant fibrous histiocytoma. The tumor was firmly adhered to the spermatic cord. MFH is an extremely rare, highly malignant connective tissue tumor, which may, occasionally, affect the male genital tract. There are no agreed treatment principles. The overall prognosis is poor.

Endoscopic endonasal surgery complication: new methods of intracavernous internal carotid artery injury treatment.

OBJECTIVES: To present new interventional neuroradiology methods of management of an ICA injury during functional endoscopic sinus surgery (FESS). CASE: The authors report the case of a patient who presented an ICA injury during a FESS and who could undergo an embolization. This embolization stopped the epistaxis and saved the patient from a lethal issue without any aftereffect. DISCUSSION: After a review of the literature the authors describe the circumstances of occurrence, the urgent management and the modern treatment of an ICA injury. Along with the progress in neuroradiology, the embolization represents a top grade treatment of this complication. Embolization with stent keeps permeable the ICA axis which represents a major progress in the management. CONCLUSION: The success of the management of an ICA injury relies on the close collaboration between anesthesist, otorhinolaryngologist surgeon and interventional neuroradiologist. Since 2004, modern techniques of interventional neuroradiology using new stents allow to keep permeable the ICA axis.