FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.

FGFR3 and Tp53 mutations have been proposed as defining two alternative pathways in the pathogenesis of transitional bladder cancer. FGFR3 mutations are associated with low-grade tumors and a favorable prognosis. Tp53 alterations are associated with advanced tumors and, possibly, with a poor prognosis. We focus here on the subgroup of T1G3 superficial tumors because they are a major clinical challenge. Patients (n = 119) were identified from a prospective study of 1,356 cases. Mutations in FGFR3 (exons 7, 10, and 15) and Tp53 (exons 4-9) were analyzed using PCR and direct sequencing. All cases were followed for recurrence and death. Survival was analyzed using Kaplan-Meier curves and multivariable Cox regression. FGFR3 mutations were detected in 20 (16.8%) tumors; 100 mutations in Tp53 were found in tumors from 78 (65.5%) cases. Multiple alterations in Tp53 were present in 19 tumors (16%). Inactivating mutations were present in 58% of tumors. The combined mutation distribution (FGFR3/Tp53) was: wt/wt (34.5%), mut/wt (7.6%), wt/mut (48.7%), and mut/mut (9.2%), indicating that the presence of either mutation did not depend on the other (P value = 0.767). FGFR3 and Tp53 mutations were not associated with clinicopathologic characteristics of patients and did not predict, alone or in combination, recurrence or survival. Taking the risk of the wt/wt group as reference, the mutation-associated risks of cancer-specific mortality were: mut/wt 1.42 (0.15-13.75), wt/mut 0.67 (0.19-2.31), mut/mut 1.62 (0.27-9.59). These molecular features support the notion that T1G3 tumors are at the crossroads of the two main molecular pathways proposed for bladder cancer development and progression.     

The pattern of attentional deficits in Parkinson's disease

BackgroundCognitive impairment without dementia is frequent in Parkinson's disease. It often presents as a dysexecutive syndrome with deficient attentional resource allocation. The nature of attention deficits in Parkinson's disease has rarely been investigated with robust, theory-based tasks. The main objective of the present study was to investigate attention disorders in Parkinson's disease patients by applying a paradigm based on a model of attention. We also sought to identify the main demographic and clinical characteristics associated with attention deficits in Parkinson's disease.MethodsEighty non-demented Parkinson's disease patients and 60 healthy controls participated in the study. Attention was assessed in a computer-controlled reaction time paradigm. The test session comprised a simple reaction time task and four choice reaction time tasks: a go/no-go task, a one-dimension, focused-attention task, a two-dimension, divided-attention task and an alternating task. Performance was assessed by composite measures: (i) cognitive reaction time, corresponding to the difference between the simple reaction time and the choice reaction time in the given condition, and (ii) reaction time variability, corresponding to the sum of the coefficients of variance of the reaction times. Accuracy was also considered.ResultsApart from an overall slowing and greater reaction time variability, Parkinson's disease patients were only significantly impaired in the alternating condition. This set-shifting impairment was associated with their performance in the go/no-go and divided-attention conditions.ConclusionOur systematic assessment of the different attentional subcomponents revealed that mental flexibility is particularly impaired in non-demented Parkinson's disease patients.     

Exposure to second-hand smoke and reproductive outcomes depending on maternal asthma

Tobacco consumption and exposure to second-hand smoke (SHS) are associated with reduced birth weight. One issue that has not been clarified previously is that of the potential higher risk of this outcome in mothers with asthma. We assessed the role of prenatal maternal tobacco use and SHS on reproductive outcomes and assessed the interaction with maternal history of asthma. Data was collected from the INMA study, a maternal birth cohort selected from the general population established in Spain in 2002. We measured cotinine at the 32nd week of pregnancy in 2,219 females. Diagnosed maternal asthma was self-reported during pregnancy. 35% of mothers reported not being exposed to smoking or SHS during pregnancy. Active smoking (i.e. self-reported or cotinine >50 ng·mL(-1)) was related to a 134 g decrease in birth weight and a relative risk of 1.8 for small for gestational age and fetal growth restriction. These results were not modified by maternal asthma. Maternal asthma had a similar frequency in all exposure groups. Non SHS-exposed females had the lowest prevalence of asthma. SHS (i.e. cotinine 20-50 ng·mL(-1)) decreased birth weight by 32 g among those without maternal asthma, but these differences were not statistically significant (95% CI -88.76-24.76). Maternal asthma did not promote these effects. Maternal history of asthma did not modify the effects of smoking on reproductive outcomes in a cohort sampled from the general population.     

Cytological Diagnosis of Bilateral Breast Implant‐Associated Lymphoma of the ALK‐Negative Anaplastic Large‐Cell Type. Clinical Implications of Peri‐Implant Breast Seroma Cytological Reporting

The cytological examination of peri‐prosthetic breast effusions allowed the diagnosis of bilateral breast‐implant ALK‐negative anaplastic large cell lymphoma (BI‐ALCL) in the case reported. Ten years after reconstructive surgery with bilateral breast implants, a large unilateral seroma developed and was cytologically analyzed. The presence of CD30 and CD4‐positive large‐sized atypical lymphoid cells exhibiting horseshoe‐shaped nuclei and a brisk mitotic activity rendered the diagnosis of BI‐ALCL. Similar cells were seen in the peri‐prosthetic fluid intraoperatively collected from the contralateral breast. Although initial histological analysis of the capsulectomy specimens showed unilateral tumor, the cytological findings prompted a more thorough tissue sampling, resulting in the diagnosis of bilateral disease. BI‐ALCL usually follows an indolent clinical course; however, there are reported cases with an aggressive behavior. While the presence of bilateral disease is a putative risk factor for a bad prognosis, the small number of cases reported precludes a definitive assessment of this risk. Since most BI‐ALCL present with late seromas, cytologic analysis of these effusions in women with breast implants should be mandatory. Cytology is a safe tool for diagnosis and follow‐up of patients with breast implant‐related late seromas, sometimes proven more sensitive than histological analysis. Complete bilateral capsulectomy and a detailed histological analysis should follow a cytological diagnosis of BI‐ALCL in a breast effusion in order to avoid false negative diagnoses. Our case constitutes the first published report of a bilateral BI‐ALCL diagnosed by cytology. Diagn. Cytopathol. 2016;44:623–627. © 2016 Wiley Periodicals, Inc.     

Small cell carcinoma of the prostate presenting with Cushing Syndrome. A narrative review of an uncommon condition

Small cell carcinoma (SCC) of the prostate is an uncommon condition; there are very few cases in which presenting symptoms are consistent with Cushing Syndrome (CS). We report a new case in which CS triggers the suspicion of an SCC of the prostate and a review of the published cases of SCC of the prostate presenting with CS. The origin of these neoplasms is still unclear. It may be suspected when laboratory features appear in patients diagnosed with prostatic adenocarcinoma which becomes resistant to specific therapy. SCC usually occurs after the 6th decade. Patients suffering SCC of the prostate presenting with CS usually present symptoms such as hypertension, hyperglycemia, alkalosis or hypokalemia; cushingoid phenotype is less frequent. Cortisol and ACTH levels are often high. Prostatic-specific antigen levels are usually normal. CT scan is the preferred imaging test to localize the lesion, but its performance may be improved by adding other tests, such as FDG-PET scan. All patients have metastatic disease at the time of diagnosis. Lymph nodes, liver and bone are the most frequent metastases sites. Surgery and Ketokonazole are the preferred treatments for CS. The prognosis is very poor: 2- and 5-year survival rates are 27.5 and 14.3%, respectively.

• Key messages

• When a patient presents with ectopic Cushing Syndrome but lungs are normal, an atypical localization should be suspected.

• We should suspect a prostatic origin if Cushing Syndrome is accompanied by obstructive inferior urinary tract symptoms or in the setting of a prostatic adenocarcinoma with rapid clinical and radiological progression with relatively low PSA levels.

• Although no imaging test is preferred to localize these tumors, FDG-PET-TC can be very useful. Hormone marker scintigraphy (e.g. somatostatin) could be used too.

• As Cushing Syndrome is a paraneoplastic phenomenon, treatment of the underlying disease may help control hypercortisolism manifestations.

• These tumors are usually metastatic by the time of diagnosis. They have very poor prognosis.

     

Social Factors Associated with Non-initiation and Cessation of Predominant Breastfeeding in a Mother–Child Cohort in Spain

Objective The aim of the study was to identify factors associated with non-initiation and cessation of predominant breastfeeding (PBF) in a mother–child cohort from Spain. Materials and Methods The analysis included 2195 mother-infant from birth to 14 months post- delivery recruited between 2004 and 2008. Maternal characteristics were collected during the pregnancy. Lactation data were obtained at 6 and 14 months after delivery. PBF was defined as intake of breast milk plus liquids like juices or water. The PBF cessation was calculated using the date that women started PBF and the date that she reported to start giving infant formula and/or food. The relationship between maternal variables and PBF initiation and cessation was modeled using logistic and Cox proportional hazards regression analysis. Results The prevalence of PBF at hospital discharge was 85.3, 53.4% at 3 months, 46.1% at 4 months and 7.2% at 6 month. Only two women continued PBF at 12 months and none at 14 months. The initiating of PBF was associated with higher levels of maternal education, being a first-time mother and worked in a non-manual occupation. Higher level of physical activity, not smoking and having a healthy BMI, were also positively associated with PBF initiation. PBF cessation was higher in young, obese women, who had had complications during the pregnancy, and who had lower levels of education and smoked. The employment status of women, in week 32 of pregnancy and also in month 14 post-delivery, determined likelihood of PBF cessation. Conclusions Healthier habits and education positively influenced PBF initiation and duration. Decrease in PBF duration rates in Spain can be interpreted in part as a consequence of women returning to work.     

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

Calcium (Ca²⁺) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca²⁺ entry, storage, and release. Store‐operated Ca²⁺ entry (SOCE) is a major mechanism controlling extracellular Ca²⁺ entry, and mainly relies on the accurate interplay between the Ca²⁺ sensor STIM1 and the Ca²⁺ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca²⁺ homeostasis and are associated with severe human disorders. Recessive loss‐of‐function mutations impair SOCE and cause combined immunodeficiency, while dominant gain‐of‐function mutations induce excessive extracellular Ca²⁺ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.     

Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain

Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child’s neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children’s Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: −22.95, −0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.     

Analysis of autonomic outcomes in APOLLO,a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.