Effectiveness of valproate for the treatment of manic-like behavior in X-linked adrenoleukodystrophy

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Estudi de les característiques dels tumors vesicals primaris en funció de la simptomatologia i de la demora en el tractament

L'alta incidència dels tumors vesicals primaris no infiltrants de la muscular pròpia (TNIMP) en el nostre medi fa que moltes vegades es dilati el temps entre el moment de la consulta i el de la intervenció. Volem analitzar si el motiu de consulta i la demora en el tractament influeixen en les característiques d'aquests tumor

Estudi de la recidiva a la primera cistoscòpia dels tumors vesicals superficials primaris en funció del grup de risc

Els tumors vesicals superficials presenten un alt índex de recidiva, essent la recidiva als 3 mesos un factor demostrat de progressió a tumor infiltrant. Per tal d'evitar aquesta recurrència precoç es porten a terme diferents pautes de tractament adjuvan

Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients

BACKGROUND: Management of high-grade T1 (HGT1) bladder cancer represents a major challenge. We studied a treatment strategy according to substaging by depth of lamina propria invasion. METHODS: In this prospective observational cohort study, patients received initial transurethral resection (TUR), mitomycin-C, and BCG. Subjects with shallower lamina propria invasion (HGT1a) were followed without further surgery, whereas subjects with HGT1b received a second TUR. Association of clinical and histological features with outcomes (primary: progression; secondary: recurrence and cancer-specific survival) was assessed using Cox regression. RESULTS: Median age was 71 years; 89.5% were males, with 89 (44.5%) cases T1a and 111 (55.5%) T1b. At median follow-up of 71 months, disease progression was observed in 31 (15.5%) and in univariate analysis, substaging, carcinoma in situ, tumour size, and tumour pattern predicted progression. On multivariate analysis only substaging, associated carcinoma in situ, and tumour size remained significant for progression. CONCLUSIONS: In HGT1 bladder cancer, the strategy of performing a second TUR only in T1b cases results in a global low progression rate of 15.5%. Tumours deeply invading the lamina propria (HGT1b) showed a three-fold increase in risk of progression. Substaging should be routinely evaluated, with HGT1b cases being thoroughly evaluated for cystectomy. Inclusion in the TNM system should also be carefully considered

Transcriptomic analysis of micropapillary high grade T1 urothelial bladder cancer

No consensus currently exist on the optimal treatment of patients with high-risk nonmuscle invasive (HGT1) micropapillary variant of bladder cancer (MPBC). Transcripsome analysis may allow stratification of MPBC-HGT1 enabling prediction of recurrence and guide therapeutic management for individual patients. Whole transcriptome RNA-Sequencing of tumors from 23 patients with MPBC-HGT1 and 64 conventional urothelial carcinomas (cUC) (reference set) was performed. Differentially expressed genes between MPBC-HGT1 and cUC-HGT1 were explored. Cox proportional hazard models and Kapplan-Meier methods were used to assess the relation between time to progression (TTP) and individual gene expression adjusting for clinical covariates. Over 3000 genes were differentially expressed in MPBC-HGT1 as compared with cUC-HGT1 and a 26-gene signature is characteristic of MPBC within HGT1. A set of three genes; CD36, FAPB3 and RAETE1 ; were significantly associated with TTP. High expression of FABP3 and CD36 were associated with shorter TTP (p = 0.045 and p = 0.08) as was low expression of RAET1E (p = 0.01). Our study suggest that a 26-gene signature can define MPBC-HGT1 within conventional urothelial carcinomas. A prognostic risk index of three genes (FABP3, CD36 and RAET1E) was found to be associated with shorter TTP and may help classify a group of patients with MPBC-HGT1 with high-risk of early progression. These observations might have implications in terms of radical cystectomy recommendation in MPBC patients

BRCA1 and BRCA2 mutations in central and southern Italian patients

INTRODUCTION: Germline BRCA1 and BRCA2 mutations account for most hereditary breast/ovarian cancers and are associated with male breast cancer. Furthermore, constitutional mutations in these genes may occur in breast/ovarian cancer patients that do not meet stringent criteria of autosomal-dominant predisposition. The relevance of BRCA1 and BRCA2 mutations in such patients is still debated. OBJECTIVES: We sought to determine the impact of BRCA1 and BRCA2 mutations in a population of patients from central and southern Italy. We analyzed the BRCA1 and BRCA2 coding regions in 136 unrelated probands: 117 females with breast/ovarian cancer and 19 males with breast cancer. This population of patients was mostly representative of cases who are at risk for hereditary susceptibility, but who do not meet stringent criteria of autosomal-dominant predisposition. METHODS: Probands, subclassified as follows, were consecutively recruited depending on informed consent from patients attending breast cancer clinics in Rome and Naples. Selection criteria for females were as follows: breast cancer with breast cancer family history [one to two first-/second-degree relative(s), n = 55]; breast cancer diagnosed before age 40 years (no breast/ovarian cancer family history, n = 28); bilateral breast cancer (regardless of age and family history, n =10); breast cancer associated with gastrointestinal, pancreatic or uterine cancers [synchronous/metachronous or in first-degree relative(s), n = 9]; breast or ovarian cancer with family history of breast-ovarian/ovarian cancer (at least 1 first-/ second-degree relative, n = 10); and ovarian cancer with no breast/ovarian cancer family history (n = 5). Males with breast cancer were recruited regardless of age and family history. BRCA1 exon 11 and BRCA2 exons 10 and 11 were screened by PTT. Coding BRCA1 exons 2, 3, 5-10 and 12-24 and BRCA2 exons 2-9 and 12-27 were screened by SSCP. Primers are listed in Table 1. In 27 cases, analyzed by PTT along the entire BRCA1 coding sequence, BRCA1 SSCP analysis was limited to exons 2, 5, 20 and 24. Mutations were verified by sequence analysis on two independent blood samples. RESULTS: Deleterious germline BRCA1/BRCA2 mutations were detected in 11 out of 136 cases (8%). Only three BRCA2 mutations were novel. One BRCA2 mutation recurred in two unrelated probands. Table 2 shows the mutations and data concerning carriers and their families. Table 3 shows correlations between BRCA1/BRCA2 mutations and sex, age at disease diagnosis and familial clustering of breast/ovarian cancer in the total patient population. Table 4 shows the proportions of BRCA1 and BRCA2 mutations in females with site-specific breast and breast-ovarian/ovarian cancer. Table 5 shows the frequency of BRCA1/BRCA2 mutations in males. BRCA1 and BRCA2 mutations, respectively, accounted for four out of 68 (6%) and one out of 68 (1%) cases diagnosed before age 50 years, and for one out of 68 (1%) and five out of 68 (7%) cases diagnosed after age 50 years. BRCA1 mutations were found in five out of 117 females (4%) and in none of 19 males (0%), and BRCA2 mutations were found in four out of 117 females (3%) and in two out of 19 males (10%). The proportions of BRCA1 and BRCA2 mutations coincided in site-specific female breast cancers (four out of 102; ie 4% each). BRCA1 and BRCA2 equally contributed to female breast cancers, with no familial clustering in those diagnosed before age 40 years (one out of 28; 4% each), and to female breast cancers, all ages, with familial clustering in one to two relatives (three out of 55; ie 5% each). In the latter subset of cases, BRCA1 mostly accounted for tumours diagnosed before age 40 years (two out of eight; 25%), and BRCA2 for tumours diagnosed after age 50 years (three out of 34; 9%). Regardless of family history, the respective contributions of BRCA1 and BRCA2 to site-specific female breast cancers diagnosed before age 40 years were 8% (three out of 36) and 3% (one out of 36). One BRCA1 mutation was detected among the 15 female probands from breast-ovarian/ovarian cancer families (7%). Among male breast cancers, BRCA2 mutations were identified in one out of five (20%) cases with family history and in one out of 14 (7%) apparently sporadic cases. No BRCA1 or BRCA2 mutations were found in female probands with nonfamilial bilateral breast cancer (10 cases) or in those with breast cancer associated with gastrointestinal, pancreatic or uterine cancers, synchronous/metachronous or in first-degree relative(s) (nine cases). These cases were all diagnosed after age 40 years. DISCUSSION: Our results indicate a lack of relevant founder effects for BRCA1- and BRCA2-related disease in the sample of patients studied, which is consistent with other Italian studies and with ethnical and historical data. Overall, the contribution of BRCA1 and BRCA2 to breast/ovarian cancer in Italian patients appears to be less significant than in patients from communities with founder mutations. The present study is in agreement with direct estimates on other outbred populations, indicating that 7-10% of all female breast cancers that occur in patients aged under 40 years are due to BRCA1/BRCA2. We found that BRCA1 and BRCA2 equally contributed to site-specific breast cancers who had one/two breast cancer-affected first-/second-degree relative(s) or who were diagnosed within age 40 years in the absence of family history. This is consistent with recent data that indicated that the respective frequencies of BRCA1 and BRCA2 mutations are comparable in early onset breast cancer. Considering the total population of patients analyzed here, however, BRCA1 and BRCA2 mutations were mostly found in cases with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years, and BRCA2 for tumours diagnosed after age 50 years. This is in agreement with a trend, which has been observed in other populations, for the proportion of cases with BRCA2 mutations to increase, and the proportion with mutations in BRCA1 to decrease, as the age at cancer onset increases. As in other studies, the frequency of BRCA1/BRCA2 mutations taken together was lower than the estimated frequencies at comparable ages for all susceptibility alleles derived from the Contraceptive and Steroid Hormones (CASH) study. The discrepancy between direct data deriving from BRCA1/BRCA2 mutational analysis and CASH estimates could be due to several factors, including contribution of gene(s) other than BRCA1/BRCA2, differences between populations and relative insensitivity of mutational screening. Only BRCA1 mutations were found in breast/ovarian and site-specific ovarian cancer families. BRCA2, but not BRCA1 mutations were found in the male breast cancers. The overall proportion of males with BRCA2 mutations was high when compared with data from other studies on outbred populations, but was low compared with data from populations with founder effects. The present results should be regarded as an approximation, because the following types of mutation are predicted to escape detection by the screening strategy used: mutations in noncoding regions; missense mutations within BRCA1 exon 11 and BRCA2 exons 10 and 11; large gene deletions; and mutations within the first and last 180 nucleotides of the amplicons analyzed by PTT

Wide-field dynamic astronomy in the near-infrared with Palomar Gattini-IR and DREAMS

There have been a dramatic increase in the number of optical and radio transient surveys due to astronomical transients such as gravitational waves and gamma ray bursts, however, there have been a limited number of wide-field infrared surveys due to narrow field-of-view and high cost of infrared cameras, we present two new wide-field near-infrared fully automated surveyors; Palomar Gattini-IR and the Dynamic REd All-sky Monitoring Survey (DREAMS). Palomar Gattini-IR, a 25 square degree J-band imager that begun science operations at Palomar Observatory, USA in October 2018; we report on survey strategy as well as telescope and observatory operations and will also providing initial science results. DREAMS is a 3.75 square degree wide-field imager that is planned for Siding Spring Observatory, Australia; we report on the current optical and mechanical design and plans to achieve on-sky results in 2020. DREAMS is on-track to be one of the first astronomical telescopes to use an Indium Galium Arsenide (InGaAs) detector and we report initial on-sky testing results for the selected detector package. DREAMS is also well placed to take advantage and provide near-infrared follow-up of the LSST

New steps on an old path: Novel estrogen receptor inhibitors in breast cancer

: Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in hormone receptor positive (HR+) breast cancer (BC). Thus, endocrine therapy (ET) alone or in combination with targeted agents constitutes the mainstay of the treatment for this BC subtype. Despite its efficacy, intrinsic or acquired resistance to ET occurs in a large proportion of cases, mainly due to aberrant activation of ER signaling (i.e. through ligand-independent ER activation, in the presence of estrogen receptor 1 (ESR1) gene aberration or ER protein phosphorylation) and/or the upregulation of escape pathways, such as the PI3K/AKT/mTOR pathway. Therefore, the development of new ER pathway targeting agents remains essential to delay and overcome ET resistance, enhance treatment efficacy and tolerability, and ultimately prolong patient survival and improve their quality of life. Several novel ER targeting agents are currently under investigation. Among these, the oral selective ER degraders (SERDs) represent the pharmacological class at the most advanced stage of development and promise to enrich the therapeutic armamentarium of HR+ BC in the next few years, as they showed promising results in several clinical trials, either as single ET agents or in combination with targeted therapies. In this manuscript, we aim to provide a comprehensive overview on the clinical development of novel ER targeting agents, reporting the most up-to-date evidence on oral SERDs and other compounds, including new selective ER modulators (SERMs), ER proteolysis targeting chimera (PROTACs), selective ER covalent antagonists (SERCAs), complete ER antagonists (CERANs), selective human ER partial agonists (ShERPAs). Furthermore, we discuss the potential implications of introducing these novel treatment strategies in the evolving and complex therapeutic scenario of HR+ BC

Multimodal neuroimaging approach to variability of functional connectivity in disorders of consciousness: A PET/MRI pilot study

Behavioral assessments could not suffice to provide accurate diagnostic information in individuals with disorders of consciousness (DoC). Multimodal neuroimaging markers have been developed to support clinical assessments of these patients. Here we present findings obtained by hybrid fludeoxyglucose (FDG-)PET/MR imaging in three severely brain-injured patients, one in an unresponsive wakefulness syndrome (UWS), one in a minimally conscious state (MCS), and one patient emerged from MCS (EMCS). Repeated behavioral assessment by means of Coma Recovery Scale-Revised and neurophysiological evaluation were performed in the two weeks before and after neuroimaging acquisition, to ascertain that clinical diagnosis was stable. The three patients underwent one imaging session, during which two resting-state fMRI (rs-fMRI) blocks were run with a temporal gap of about 30 min. rs-fMRI data were analyzed with a graph theory approach applied to nine independent networks. We also analyzed the benefits of concatenating the two acquisitions for each patient or to select for each network the graph strength map with a higher ratio of fitness. Finally, as for clinical assessment, we considered the best functional connectivity pattern for each network and correlated graph strength maps to FDG uptake. Functional connectivity analysis showed several differences between the two rs-fMRI acquisitions, affecting in a different way each network and with a different variability for the three patients, as assessed by ratio of fitness. Moreover, combined PET/fMRI analysis demonstrated a higher functional/metabolic correlation for patients in EMCS and MCS compared to UWS. In conclusion, we observed for the first time, through a test-retest approach, a variability in the appearance and temporal/spatial patterns of resting-state networks in severely brain-injured patients, proposing a new method to select the most informative connectivity pattern