Axillary Lymph Node Dissection for Sentinel Lymph Node Micrometastases May Be Safely Omitted in Early-Stage Breast Cancer Patients: Long-Term Outcomes of a Prospective Study.

OBJECTIVES: To evaluate the long-term disease-free and overall survival of patients with sentinel lymph node (SLN) micrometastases, in whom a completion axillary lymph node dissection (ALND) was systematically omitted. BACKGROUND: The use of step sectioning and immunohistochemistry for SLN analysis results in a more accurate histopathologic examination and a higher detection rate of micrometastases. However, the clinical relevance and therapeutic implications of SLN micrometastases remain a matter of debate. METHODS: In this prospective study, 236 SLN biopsies were performed in 234 consecutive early-stage breast cancer patients (T1, T2 </= 3 cm, cN0 M0) between 1998 and 2002. The SLN were examined by step sectioning and stained with hematoxylin and eosin and immunohistochemistry. None of the patients with negative SLN or SLN micrometastases (International Union Against Cancer classification, >.2 mm to </=2 mm) underwent a completion ALND or radiation to the axilla. Long-term overall and disease-free survivals were compared between patients with negative SLN and those with SLN micrometastases by log rank tests. RESULTS: The SLN was negative in 55% of patients (123 of 224). SLN micrometastases were detected in 27 patients (27 of 224, 12%). After a median follow-up of 77 months (range, 24-106 months), neither locoregional recurrences nor distant metastases occurred in any of the 27 patients with SLN micrometastases. There were no statistically significant differences for overall (P = .656), locoregional (P = .174), and axillary and distant disease-free survival (P = .15) between patients with negative SLN and SLN micrometastases. CONCLUSIONS: This analysis of unselected patients provides evidence that a completion level I and II ALND may be safely omitted in early-stage breast cancer patients with SLN micrometastases.

Recovering the Elliott invariant from the Cuntz semigroup

Let A be a simple, separable C*-algebra of stable rank one. We prove that the Cuntz semigroup of C (T, A) is determined by its Murray-von Neumann semigroup of projections and a certain semigroup of lower semicontinuous functions (with values in the Cuntz semigroup of A). This result has two consequences. First, specializing to the case that A is simple, finite, separable and Z-stable, this yields a description of the Cuntz semigroup of C (T, A) in terms of the Elliott invariant of A. Second, suitably interpreted, it shows that the Elliott functor and the functor defined by the Cuntz semigroup of the tensor product with the algebra of continuous functions on the circle are naturally equivalent.

Avaluació de la teratogènia in vitro mitjançant el cultiu d’embrions sencers (WEC)

Projecte de recerca elaborat a partir d’una estada a la Charité - Universitätsmedizin Berlin, Alemanya, entre novembre i desembre del 2007. En aquest treball es presenta el protocol a seguir per a dur a terme el cultiu d’embrions sencers in vitro (Whole Embryo Culture, WEC). Amb aquest protocol es pretén implementar la tècnica del WEC en el laboratori de la Unitat de Toxicologia de la Facultat de Farmàca (UB), seguint la metodologia apresa durant l’estada i deixant per escrit tots els passos seguits i el material i la metodologia concreta de cadascun d’ells. En el WEC es cultiven embrions de rata de 9.5 dies durant 48h en ampolles rotatòries en un medi líquid i amb una fase gasosa controlats. Durant el cultiu, tenen lloc dos processos principals: el plegament de l’embrió i l’organogènesi. Els embrions durant els dos dies que dura el cultiu es pleguen en els plans transversal i sagital, passant d’un embrió pla a un altre de cilíndric en forma de “C”. En aquest període, a més, es produeixen importants processos d’organogènesi com la neurulació, la formació de la cresta neural, dels somites, dels vasos sanguinis - el cor inclòs- i de la sang. Es comencen a formar la placoda nasal, la vesícula oftàlmica, la vesícula òtica, les extremitats superiors i inferiors i la cua. En la memòria adjunta es descriuen amb detall els processos d'aparellament dels animals, preparació del material i del medi de cultiu, el procés d'aïllament del embrions en el dia 9.5, les condicions de cultiu i l'avaluació dels embrions en el dia 11.5. Finalment es presenten resultats d'embrions en situació control amb un correcte desenvolupament i es mostra com, al final de l'estada, es va aconseguir el cultiu d’embrions control amb un desenvolupament correcte i estadísticament sense diferències respecte als diferents paràmetres mesurats en comparació amb els embrions control de la Charité-Universitätsmedizin de Berlin.

Cerebellar transcranial direct current stimulation modulates verbal working memory.

BACKGROUND: Neuroimaging studies show cerebellar activations in a wide range of cognitive tasks and patients with cerebellar lesions often present cognitive deficits suggesting a cerebellar role in higher-order cognition. OBJECTIVE: We used cathodal transcranial direct current stimulation (tDCS), known to inhibit neuronal excitability, over the cerebellum to investigate if cathodal tDCS impairs verbal working memory, an important higher-order cognitive faculty. METHOD: We tested verbal working memory as measured by forward and backward digit spans in 40 healthy young participants before and after applying cathodal tDCS (2 mA, stimulation duration 25 min) to the right cerebellum using a randomized, sham-controlled, double-blind, cross-over design. In addition, we tested the effect of cerebellar tDCS on word reading, finger tapping and a visually cued sensorimotor task. RESULTS: In line with lower digit spans in patients with cerebellar lesions, cerebellar tDCS reduced forward digit spans and blocked the practice dependent increase in backward digit spans. No effects of tDCS on word reading, finger tapping or the visually cued sensorimotor task were found. CONCLUSION: Our results support the view that the cerebellum contributes to verbal working memory as measured by forward and backward digit spans. Moreover, the induction of reversible "virtual cerebellar lesions" in healthy individuals by means of tDCS may improve our understanding of the mechanistic basis of verbal working memory deficits in patients with cerebellar lesions.

Eptingiacea and Saturnaliacea (Radiolaria) from the middle Carnian of Turkey and some late Ladinian to early Norian samples from Oman and Alaska

This article is a taxonomic study of the radiolarian species of the superfamilies Eptingiacea and Saturnaliacea occurring in the middle Carnian fauna from the Koseyahya section, near the town of Elbistan, southeastern Turkey. This fauna is characteristic of the Tetraporobrachia haeckeli Radiolarian Zone as defined in Austria and later found also in Turkey and Oman. It comes from an 8 m thick succession of clayey/cherty limestones from the lower part of the section. In addition, a few species from the late Ladinian and Carnian from Oman and the early Norian from Alaska have also been included in this study, in order to improve some generic diagnoses and to show the diversity and evolutionary trends of some genera. 32 radiolarian species of which 22 are new are described and illustrated, and assigned to 16 genera of which three are new (Capnuchospyris, Veleptingium, and Triassolaguncula). The diagnoses of some species, genera, subfamilies and families have been revised, and the family Eptingiidae has been raised to the rank of superfamily.

Serum anticholinergic activity and postoperative cognitive dysfunction in elderly patients.

BACKGROUND: Cerebral cholinergic transmission plays a key role in cognitive function, and anticholinergic drugs administered during the perioperative phase are a hypothetical cause of postoperative cognitive dysfunction (POCD). We hypothesized that a perioperative increase in serum anticholinergic activity (SAA) is associated with POCD in elderly patients. METHODS: Seventy-nine patients aged >65 years undergoing elective major surgery under standardized general anesthesia (thiopental, sevoflurane, fentanyl, and atracurium) were investigated. Cognitive functions were assessed preoperatively and 7 days postoperatively using the extended version of the CERAD-Neuropsychological Assessment Battery. POCD was defined as a postoperative decline >1 z-score in at least 2 test variables. SAA was measured preoperatively and 7 days postoperatively at the time of cognitive testing. Hodges-Lehmann median differences and their 95% confidence intervals were calculated for between-group comparisons. RESULTS: Of the patients who completed the study, 46% developed POCD. Patients with POCD were slightly older and less educated than patients without POCD. There were no relevant differences between patients with and without POCD regarding gender, demographically corrected baseline cognitive functions, and duration of anesthesia. There were no large differences between patients with and without POCD regarding SAA preoperatively (pmol/mL, median [interquartile range]/median difference [95% CI], P; 1.14 [0.72, 2.37] vs 1.13 [0.68, 1.68]/0.12 [-0.31, 0.57], P = 0.56), SAA 7 days postoperatively (1.32 [0.68, 2.59] vs 0.97 [0.65, 1.83]/0.25 [-0.26, 0.81], P = 0.37), or changes in SAA (0.08 [-0.50, 0.70] vs -0.02 [-0.53, 0.41]/0.1 [-0.31, 0.52], P = 0.62). There was no significant relationship between changes in SAA and changes in cognitive function (Spearman rank correlation coefficient preoperatively of 0.03 [95% CI, -0.21, 0.26] and postoperatively of -0.002 [95% CI, -0.24, 0.23]). CONCLUSIONS: In this panel of patients with low baseline SAA and clinically insignificant perioperative anticholinergic burden, although a relationship cannot be excluded in some patients, our analysis suggests that POCD is probably not a substantial consequence of anticholinergic medications administered perioperatively but rather due to other mechanisms.

Anàlisi i proposta de renovació de la web dels Estudis d'Humanitats i Filologia de la UOC

Aquest treball té com a finalitat, d'una banda, col·laborar a determinar les mancances, tant de disseny com de contingut, que té actualment el web dels Estudis d'Humanitats i Filologia de la UOC i, de l'altra, fer una proposta d'un nou disseny, que inclogui la reestructuració dels continguts.

Die Säuglingssterblichkeit in der Schweiz: multivariate Betrachtung. [Perinatal mortality in Switzerland: a multivariate analysis]

A regression analysis using a linked file of all Swiss births und perinatal deaths 1979-1981 showed a significant relation between birthweight and canton. Sex of infant and multiplicity of birth were significant, too. For live births, marital and socio-economic status of mother and father relate to birthweight. Logistic regressions brought out relationships between the risk of stillbirth and occupation of father, nationality and marital status of mother, apart from birthweight. For live births, only sex and (weakly) marital status and rank of the child were influencial after correction for birthweight.

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. METHODS: Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. RESULTS: Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). CONCLUSIONS: Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

Trends in self-reported prevalence and management of hypertension, dyslipidaemia and diabetes in adults in Switzerland, 1992-2007

Purpose: to assess the trends of self-reported prevalence of cardiovascular risk factors (CV RFs: hypertension, dyslipidaemia, diabetes) and their management for period 1992 to 2007 in the Swiss population. Methods: four National health interview surveys conducted between 1992 and 2007 in representative samples of the Swiss population (63,782 subjects overall). Self-reported CV RFs prevalence, treatment and controllevels were computed after weighting. Weights were calculated by raking ratio such that the marginal distribution of the weighted totals conforms to the marginal distribution of the targeted population. Multivariate analysis adjusted on age, sex, education, nationality and SMI was conducted using logistic regression. Results: prevalence of ail CV RFs increased between 1992 and 2007, see table. Although the self-reported prevalence of treatment among subjects with CV RFs increased, and this was confirmed by multivariate analysis: OR for hypocholesterolaemic treatment relative to 1992: 0.64 [0.52-0.78]; 1.39 [1.18-1.65] and 2.00 [1.69-2.36] for 1997, 2002 and 2007, respectively. Still, in 2007, circa 40% of hypertensive, 60% of dyslipidaemic and 50% of diabetic subjects weren't treated. Conversely, an adequate control of CV RFs was reported by treated subjects, with an increase during the study period. This increase was confirmed by multivariate analysis (not shown). Conclusion: the self-reported prevalence of hypertension, dyslipidaemia and diabetes increased between 1992 and 2007 in the Swiss population. Despite a good control of treated subjects, still a significant percentage of subjects with CV RFs are not treated.

Selecting control genes for RT-QPCR using public microarray data.

Background: Gene expression analysis has emerged as a major biological research area, with real-time quantitative reverse transcription PCR (RT-QPCR) being one of the most accurate and widely used techniques for expression profiling of selected genes. In order to obtain results that are comparable across assays, a stable normalization strategy is required. In general, the normalization of PCR measurements between different samples uses one to several control genes (e. g. housekeeping genes), from which a baseline reference level is constructed. Thus, the choice of the control genes is of utmost importance, yet there is not a generally accepted standard technique for screening a large number of candidates and identifying the best ones. Results: We propose a novel approach for scoring and ranking candidate genes for their suitability as control genes. Our approach relies on publicly available microarray data and allows the combination of multiple data sets originating from different platforms and/or representing different pathologies. The use of microarray data allows the screening of tens of thousands of genes, producing very comprehensive lists of candidates. We also provide two lists of candidate control genes: one which is breast cancer-specific and one with more general applicability. Two genes from the breast cancer list which had not been previously used as control genes are identified and validated by RT-QPCR. Open source R functions are available at http://www.isrec.isb-sib.ch/similar to vpopovic/research/ Conclusion: We proposed a new method for identifying candidate control genes for RT-QPCR which was able to rank thousands of genes according to some predefined suitability criteria and we applied it to the case of breast cancer. We also empirically showed that translating the results from microarray to PCR platform was achievable.

Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS), can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T), another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS - but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrolment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02). Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.

Severity of endoscopically detected esophageal inflammatory and fibrostenotic features correlates with degree of esophageal eosinophilia in adults with eosinophilic esophagitis

Background: Eosinophilic esophagitis (EoE) has emerged as a leading cause of dysphagia in adults. Characteristic esophageal features on endoscopy include structural/fibrostenotic (rings, narrow caliber, strictures) and inflammatory manifestations (longitudinal furrows, exudates, edema). Aim: The purpose of this study was to correlate the clinical, endoscopic and histopathologic features in adult EoE patients. Methods: A total of 106 encounters of 81 patients with EoE were analyzed. Data included an EoE-directed symptom-severity patient questionnaire evaluating symptoms of dysphagia (frequency, intensity, duration), meal duration, chest pain, and overall symptom severity. Video recordings of endoscopies were reviewed in a blinded manner using a classification and grading scheme for the esophageal features of EoE. Histopathology was reviewed for peak eosinophil count/high power field by pathologists blinded to the patients' clinical status. Associations between endoscopic features, histology and symptoms were evaluated using the Spearman rank correlation analysis. Results: The endoscopic severity of both structural and inflammatory esophageal features of EoE, including rings, exudates, longitudinal furrows, and edema, correlated significantly with peak eosinophil counts (see Table 1). Presence of "crepe paper mucosa" did not demonstrate significant association with peak eosinophil counts. Both structural (rings, narrow-caliber esophagus and strictures) and inflammatory (furrows, exudates and edema) composite endoscopic scores demonstrated a strong correlation with peak eosinophil counts. The strongest association with the degree of esophageal eosinophilia was found with a combination of both structural and inflammatory findings (p < 0.0001). The esophageal diameter (in mm) was negatively correlated with overall symptom severity (Spearman's rho = -0.4883, P = 0.0339). None of the individual or combined patient reported symptoms correlated significantly with either endoscopic or histopathologic findings. Conclusion: The severity of both structural and inflammatory endoscopic features associated with EoE is significantly associated with the degree of esophageal eosinophilia. Patient reported symptom severity was not associated with the degree of esophageal eosinophilia. Esophageal stricture diameter was inversely correlated with EoE symptom severity. The prognostic and therapeutic implications of these observations need to be determined.

Autologous Stem Cell Transplantation (ASCT) for Enteropathy-Associated T-Cell Lymphoma (EATL): Final Analysis of a Retrospective Study On the Behalf of Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT).

Background: EATL is a rare subtype of peripheral T-cell lymphomas characterized by primarily intestinal localization and a frequent association with celiac disease. The prognosis is considered to be poor with conventional chemotherapy. Limited data is available on the efficacy of ASCT in this lymphoma subtype. Primary objective: was to study the outcome of ASCT as a consolidation or salvage strategy for EATL. The primary endpoint was overall survival (OS) and progression-free survival (PFS). Eligible patients were > 18 years who had received ASCT between 2000-2010 for EATL that was confirmed by review of written histopathology reports, and had sufficient information on disease history and follow-up available. The search strategy used the EBMT database to identify patients potentially fulfilling the eligibility criteria. An additional questionnaire was sent to individual transplant centres to confirm histological diagnosis (histopathology report or pathology review) as well as updated follow-up data. Patients and transplant characteristics were compared between groups using X2 test or Fisher's exact test for categorical variables and t-test or Mann-Whiney U-test for continuous variables. OS and PFS were estimated using the Kaplan-Meier product-limit estimate and compared by the log-rank test. Estimates for non-relapse mortality (NRM) and relapse or progression were calculated using cumulative incidence rates to accommodate competing risk and compared to Gray's test. Results: Altogether 138 patients were identified. Updated follow-up data was received from 74 patients (54 %) and histology report from 54 patients (39 %). In ten patients the diagnosis of EATL could not be adequately verified. Thus the final analysis included 44. There were 24 males and 20 females with a median age of 56 (35-72) years at the time of transplant. Twenty-five patients (57 %) had a history of celiac disease. Disease stage was I in nine patients (21 %), II in 14 patients (33 %) and IV in 19 patients (45 %). Twenty-four patients (55 %) were in the first CR or PR at the time of transplant. BEAM was used as a high-dose regimen in 36 patients (82 %) and all patients received peripheral blood grafts. The median follow-up for survivors was 46 (2-108) months from ASCT. Three patients died early from transplant-related reasons translating into a 2-year non-relapse mortality of 7 %. Relapse incidence at 4 years after ASCT was 39 %, with no events occurring beyond 2.5 years after ASCT. PFS and OS were 54 % and 59 % at four years, respectively. There was a trend for better OS in patients transplanted in the first CR or PR compared to more advanced disease status (70 % vs. 43 %, p=0.053). Of note, patients with a history of celiac disease had superior PFS (70 % vs. 35 %, p=0.02) and OS (70 % vs. 45 %, p=0.052) whilst age, gender, disease stage, B-symptoms at diagnosis or high-dose regimen were not associated with OS or PFS. Conclusions: This study shows for the first time in a larger patient sample that ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. Patients transplanted in first CR or PR appear to do better than those transplanted later. ASCT should be considered in EATL patients responding to initial therapy.