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Follicular dendritic cell sarcomas (FDCS) are classified as histiocytic and dendritic cell neoplasms in the WHO 2017 classification of hematopoietic and lymphoid tissue tumors [1]. It is an extremely rare malignant tumor with morphological and phenotypic characteristics of follicular dendritic cells (FDC) [2]. These are derived from the mesenchymal stromal cells of the lymphoid follicles. They are an indispensable link between innate and adaptive immune responses. In this study, we raise through two observations the positive and differential diagnostic difficulties of this entity and we recall its morphological, immunohistochemical and evolutionary characteristics. Only 400 cases of FDCS are described in the literature. Our observation raises the problems of differential diagnosis frequently posed by follicular dendritic cell sarcoma. The main differential diagnosis is with metastasis of undifferentiated carcinoma. The positivity of the dendritic follicular markers (CXCL13, CD21, CD35, FDCSP and SRGN) makes it possible to affirm the diagnosis. Surgery is the treatment of reference. Dendritic follicular cell sarcomas are a nosological entity that is still under debate. Given their diagnostic difficulties, the demand for histological proof reading within the frame work of a specialized network is of great interest.

The solitary fibrous tumor (TFS) is a rare mesenchymal tumor, described initially in the pleura, but can sit in any anatomical site. Subcutaneous localization in the lumbar region is rarely described. We report through this work the main super pleural localizations currently described, as well as the most characteristic elements of the diagnosis in terms of histological and immunohistochemical analysis likely to improve their recognition. This is a 36-year-old woman who was seen for subcutaneous parietal mass in the lumbar region. The histological aspect and the immunohistochemical profile made it possible to evoke the diagnosis of solitary fibrous tumor. The TFS has the same anatomo-clinical characteristics regardless of its seat. It occurs in adults between 26 and 82 years, with no predominance of sex. It is most often asymptomatic. The radiological aspect is not specific. This unusual superficial presentation in the lumbar region may pose a diagnostic challenge, given the importance of the morphological and immunophenotypic spectrum and the overlap of SFT with other neoplasms. A fusion of the two NAB2-STAT6 genes by intrachromosomal inversion on chromosome 12 (q13q13) is found in 70 to 90% of cases. Postoperative monitoring is necessary given the risk of local recurrence in the absence of predictive criteria for the evolution.

Epstein Barr virus; Prognosis; Response to treatment Virus de Epstein Barr; Pronóstico; Respuesta al tratamiento Virus d'Epstein Barr; Pronòstic; Resposta al tractament The treatment of head and neck and salivary gland tumours is complicated and evolves constantly. Prognostic and predictive indicators of response to treatment are enormously valuable for designing individualized therapies, which justifies their research and validation. Some biomarkers, such as p16, Epstein–Barr virus, PD-L1, androgen receptors and HER-2, are already used routinely in clinical practice. These biomarkers, along with other markers that are currently under development, and the massively parallel sequencing of genes, ensure future advances in the treatment of these neoplasms. In this consensus, a group of experts in the diagnosis and treatment of tumours of the head and neck and salivary glands were selected by the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica—SEAP) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica—SEOM) to evaluate the currently available information and propose a series of recommendations to optimize the determination and daily clinical use of biomarkers. SEOM and SEAP acknowledge the financial support for this project in the form of unrestricted collaboration in the logistics from AstraZeneca.

Background & Aims Inflammatory bowel diseases (IBDs) that encompass both ulcerative colitis and Crohn’s disease are a major public health problem with an etiology that has not been fully elucidated. There is a need to improve disease outcomes and preventive measures by developing new effective and lasting treatments. Although polyunsaturated fatty acid metabolites play an important role in the pathogenesis of several disorders, their contribution to IBD is yet to be understood. Methods Polyunsaturated fatty acids metabolite profiles were established from biopsy samples obtained from Crohn’s disease, ulcerative colitis, or control patients. The impact of a prostaglandin I2 (PGI2) analog on intestinal epithelial permeability was tested in vitro using Caco-2 cells and ex vivo using human or mouse explants. In addition, mice were treated with PGI2 to observe dextran sulfate sodium (DSS)-induced colitis. Tight junction protein expression, subcellular location, and apoptosis were measured in the different models by immunohistochemistry and Western blotting. Results A significant reduction of PGI2 in IBD patient biopsies was identified. PGI2 treatment reduced colonic inflammation, increased occludin expression, decreased caspase-3 cleavage and intestinal permeability, and prevented colitis development in DSS-induced mice. Using colonic explants from mouse and human control subjects, the staurosporine-induced increase in paracellular permeability was prevented by PGI2. PGI2 also induced the membrane location of occludin and reduced the permeability observed in colonic biopsies from IBD patients. Conclusions The present study identified a PGI2 defect in the intestinal mucosa of IBD patients and demonstrated its protective role during colitis., Graphical abstract

Aims Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA‐34a (miR‐34a) among the most upregulated miRs in tubers. Here, we characterised miR‐34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR‐34a. Methods We analysed the expression of miR‐34a in resected cortical tubers (n = 37) compared with autopsy‐derived control tissue (n = 27). The effect of miR‐34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH‐SY5Y cells following miR‐34a transfection. Results The peak of miR‐34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR‐34a was also strongly expressed in foetal TSC cortex. Overexpression of miR‐34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR‐34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. Conclusions MicroRNA‐34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR‐34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC., MicroRNA‐34a (MiR‐34a) is overexpressed in cortical tubers from children with tuberous sclerosis complex with a peak during infancy. MiR‐34a negatively regulates constitutively activated mechanistic target of rapamycin complex 1 in human astrocytes. MiR‐34a overexpression impairs corticogenesis in the embryonic mouse brain, potentially through targeting genes involved in neuronal migration.

Aim: To develop a microsimulation model to assess the potential health economic impact of software-assisted MRI in detecting disease activity or progression in relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We develop a simulated decision analytical model based on a hypothetical cohort of RRMS patients to compare a baseline decision-making strategy in which only clinical evolution (relapses and disability progression) factors are used for therapy decisions in MS follow-up, with decision-making strategies involving MRI. In this context, we include comparisons with a visual radiologic assessment of lesion evolution, software-assisted lesion detection, and software-assisted brain volume loss estimation. The model simulates clinical (EDSS transitions, number of relapses) and subclinical (new lesions and brain volume loss) disease progression and activity, modulated by the efficacy profiles of different disease-modifying therapies (DMTs). The simulated decision-making process includes the possibility to escalate from a low efficacy DMT to a high efficacy DMT or to switch between high efficacy DMTs when disease activity is detected. We also consider potential error factors that may occur during decision making, such as incomplete detection of new lesions, or inexact computation of brain volume loss. Finally, differences between strategies in terms of the time spent on treatment while having undetected disease progression/activity, the impact on the patient’s quality of life, and costs associated with health status from a US perspective, are reported. Results: The average time with undetected disease progression while on low efficacy treatment is shortened significantly when using MRI, from around 3 years based on clinical criteria alone, to 2 when adding visual examination of MRI, and down to only 1 year with assistive software. Hence, faster escalation to a high efficacy DMT can be performed when MRI software is added to the radiological reading, which has positive effects in terms of health outcomes. The incremental utility shows average gains of 0.23 to 0.37 QALYs over 10 and 15 years, respectively, when using software-assisted MRI compared to clinical parameters only. Due to long-term health benefits, the average annual costs associated with health status are lower by $1500–$2200 per patient when employing MRI and assistive software. Conclusions: The health economic burden of MS is high. Using assistive MRI software to detect and quantify lesions and/or brain atrophy has a significant impact on the detection of disease activity, treatment decisions, health outcomes, utilities, and costs in patients with MS.

Glomerulonefritis creixent; Implants mamaris de silici; Esclerosi sistèmica Crescentic glomerulonephritis; Silicon breast implants; Systemic sclerosis Glomerulonefritis creciente; Implantes mamarios de silicio; Esclerosis sistémica The relationship between silicon breast implants (SBIs) and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) has been extensively analysed, with discordant results. We present a 45-year-old woman with confirmed systemic exposure to SBI who developed systemic sclerosis (SSc) followed by anti-neutrophil cytoplasmic antibody anti-myeloperoxidase vasculitis with renopulmonary syndrome. The novelty of our case is, first, confirmation of systemic exposure to SBI and, second, chronologic development of not one, but two severe autoimmune diseases. Controversy may still remain regarding SBIs and ASIA because it is unclear that previous studies confirmed systemic exposure to silicon in their cohort of patients. Grant number: PI18/00356 - Instituto de Salud Carlos III - FEDER "Una manera de hacer Europa" - CERCA Programme/Generalitat de Catalunya - IRBLleida - Fundació Dr. Pifarré

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment., Instituto de Salud Carlos III PI17/00989, European Regional Development Fund "A way to build Europe", Ramon y Cajal - Ministry of Economy and Competitiveness RYC-2015-18382, Ministry of Education, Culture and Sport FPU14/05461, University of Granada

The influence of energy restriction (ER) on muscle is controversial, and the mechanisms are not well understood. To study the effect of ER on skeletal muscle phenotype and the influence of vitamin D, rats (n = 34) were fed a control diet or an ER diet. Muscle mass, muscle somatic index (MSI), fiber-type composition, fiber size, and metabolic activity were studied in tibialis cranialis (TC) and soleus (SOL) muscles. Plasma vitamin D metabolites and renal expression of enzymes involved in vitamin D metabolism were measured. In the ER group, muscle weight was unchanged in TC and decreased by 12% in SOL, but MSI increased in both muscles (p &lt, 0.0001) by 55% and 36%, respectively. Histomorphometric studies showed 14% increase in the percentage of type IIA fibers and 13% reduction in type IIX fibers in TC of ER rats. Decreased size of type I fibers and reduced oxidative activity was identified in SOL of ER rats. An increase in plasma 1,25(OH)2-vitamin D (169.7 ± 6.8 vs. 85.4 ± 11.5 pg/mL, p &lt, 0.0001) with kidney up-regulation of CYP27b1 and down-regulation of CYP24a1 was observed in ER rats. Plasma vitamin D correlated with MSI in both muscles (p &lt, 0.001), with the percentages of type IIA and type IIX fibers in TC and with the oxidative profile in SOL. In conclusion, ER preserves skeletal muscle mass, improves contractile phenotype in phasic muscles (TC), and reduces energy expenditure in antigravity muscles (SOL). These beneficial effects are closely related to the increases in vitamin D secondary to ER.

Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations. Yes

The present study used receiver operating characteristic (ROC) curve analysis to investigate the accuracy of body composition and raw bioelectrical impedance analysis (BIA) in correctly classifying disordered eating attitudes (DEA) in dance students. Participants were 81 female dancers assigned in two groups: beginner training (BT, age (mean &plusmn, SD) = 10.09 &plusmn, 1.2 years, n = 32) and advanced training (AT, age = 15.37 &plusmn, 2.1 years, n = 49). Fat mass (FM) was estimated by Slaughter&rsquo, s equation and skeletal muscle with Poortman&rsquo, s equation. Impedance (Z), resistance (R), reactance (Xc) and phase angle (PhA) were obtained through multifrequency BIA at a frequency of 50 kHz. Fat-free mass (FFM) was assessed using Sun&rsquo, s equation. For evaluation of DEA, the Eating Attitudes Test-26 (EAT-26) questionnaire was performed. We defined an EAT-26 score &ge, 20 as positive for DEA. Comparisons between groups were performed by a one-way ANOVA test or Kruskall-Wallis test. Spearman&rsquo, s rank correlation coefficients were performed to assess associations between variables. ROC curve analysis was utilized to test the accuracy of body composition and BIA variables in predicting DEA. In the BT group, Xc and PhA demonstrated high accuracy in predicting DEA with an area under the curve (AUC) of 0.976 (95% confidence interval (CI): 0.85&ndash, 1.00) and 0.957 (95% CI: 0.82&ndash, 0.99), respectively, (both p &lt, 0.0001). FFM Sun had an AUC of 0.836 (95% CI: 0.66&ndash, 0.94) (p &lt, 0.0001) in the BT group and FFM Slaughter was 0.797 (95% CI: 0.66&ndash, 0.90) (p &lt, 0.001) in the AT group. Reactance and Phase angle were excellent and useful predictors of DEA in the BT group.

As human Tau undergoes pathologically relevant post-translational modifications when expressed in yeast, the use of humanized yeast models for the generation of novel Tau monoclonal antibodies has previously been proven to be successful. In this study, human Tau2N4R-ΔK280 purified from yeast was used for the immunization of mice and subsequent selection of high affinity Tau-specific monoclonal antibodies. The characterization of four novel antibodies in different Tau model systems yielded a phosphorylation-dependent antibody (15A10), an antibody directed to the first microtubule-binding repeat domain (16B12), a carboxy-terminal antibody (20G10) and an antibody targeting an epitope on the hinge of the first and second amino-terminal insert (18F12). The latter was found to be conformation-dependent, suggesting structural differences between the Tau splicing isoforms and allowing insight in the roles played by the amino-terminal inserts. As this monoclonal antibody also has the capacity to detect tangle-like structures in different transgenic Tau mice and neurofibrillary tangles in brain sections of patients diagnosed with Alzheimer's disease, we also tested the diagnostic potential of 18F12 in a pilot study and found this monoclonal antibody to have the ability to discriminate Alzheimer's disease patients from control individuals based on increased Tau levels in the cerebrospinal fluid. ispartof: Frontiers In Molecular Biosciences vol:7 ispartof: location:Switzerland status: Published online

Recombinant follicle-stimulating hormone (FSH) (follitropin alfa) and biosimilar preparations are available for clinical use. They have specific FSH activity and a unique glycosylation profile dependent on source cells. The aim of the study is to compare the originator (reference) follitropin alfa (Gonal-f (R))- with biosimilar preparations (Bemfola (R) and Ovaleap (R))-induced cellular responses in vitro. Gonadotropin N-glycosylation profiles were analyzed by ELISA lectin assay, revealing preparation specific-patterns of glycan species (Kruskal-Wallis test; p < 0.05, n = 6) and by glycotope mapping. Increasing concentrations of Gonal-f (R) or biosimilar (1 x 10(-3) -1 x 10(3) ng/ml) were used for treating human primary granulosa lutein cells (hGLC) and FSH receptor (FSHR)-transfected HEK293 cells in vitro. Intracellular cAMP production, Ca2+ increase and beta-arrestin 2 recruitment were evaluated by BRET, CREB, and ERK1/2 phosphorylation by Western blotting. 12-h gene expression, and 8- and 24-h progesterone and estradiol synthesis were measured by real-time PCR and immunoassay, respectively. We found preparation-specific glycosylation patterns by lectin assay (Kruskal-Wallis test; p < 0.001; n = 6), and similar cAMP production and beta-arrestin 2 recruitment in FSHR-transfected HEK293 cells (cAMP EC50 range = 12 +/- 0.9-24 +/- 1.7 ng/ml; beta-arrestin 2 EC50 range = 140 +/- 14.1-313 +/- 18.7 ng/ml; Kruskal-Wallis test; p >= 0.05; n = 4). Kinetics analysis revealed that intracellular Ca2+ increased upon cell treatment by 4 mu g/ml Gonal-f (R), while equal concentrations of biosimilars failed to induced a response (Kruskal-Wallis test; p < 0.05; n = 3). All preparations induced both 8 and 24 h-progesterone and estradiol synthesis in hGLC, while no different EC(50)s were demonstrated (Kruskal -Wallis test; p > 0.05; n = 5). Apart from preparation-specific intracellular Ca2+ increases achieved at supra-physiological hormone doses, all compounds induced similar intracellular responses and steroidogenesis, reflecting similar bioactivity, and overall structural homogeneity.

Made available in DSpace on 2019-10-06T16:32:41Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-05-01 Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC2 and p

[Background] TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the ‘myopathic form’ of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity., [Methods] We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12., [Results] The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients., [Conclusions] The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency., This work was supported by research grants of Plan Nacional de I + D + I and Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación y Fomento de la Investigación Sanitaria”, project PI16–01843 (CP), PI16/00579 and CP09/00011 for CJM and the European Regional Development Fund (FEDER a way to achieve Europe). MAM has received funding from the Spanish ISCIII (grant PI 15/00431). A multicentric grant funded by the ISCIII (PMP15/00025 to MAM, RM, MO, CP).

Pregnancy in placental mammals places unique demands on the insulin-producing β-cells in the pancreatic islets of Langerhans. The pancreas anticipates the increase in insulin resistance that occurs late in pregnancy by increasing β-cell numbers and function earlier in pregnancy. In rodents, this β-cell expansion depends on secreted placental lactogens that signal through to the prolactin receptor. Then at the end of pregnancy, the β-cell population contracts back to its pre-pregnancy size. In the current review we focus on how glucose metabolism changes during pregnancy, how β-cells anticipate these changes through their response to lactogens, and what molecular mechanisms guide the adaptive compensation. In addition, we summarize current knowledge of β-cell adaptation during human pregnancy and what happens when adaptation fails and gestational diabetes ensues. A better understanding of human β-cell adaptation to pregnancy would benefit efforts to predict, prevent and treat gestational diabetes.

Introduction The paced serial addition test (PSAT) is regularly used to assess cognitive deficits in various neuropsychiatric conditions. Being a complex test, it reflects the status of multiple cognitive domains such as working memory, information processing speed and executive functioning. Two versions of the PSAT exist. One uses auditory stimuli through spoken numbers and is known as the PASAT, while the other one presents patients with visual stimuli and is called PVSAT. The PASAT is considered more frustrating by patients, and hence the visual version is usually preferred. Research has suggested that an interference might exist between patients' verbal answers and the auditory presentation of stimuli. We therefore removed the verbal response in this study, and aimed to investigate differences in functional brain activity through functional magnetic resonance imaging. Methods Fifteen healthy controls performed the two test versions inside an MRI scanner-switching between stimulus modality (auditory vs. visual) as well as inter-stimulus frequency (3s vs. 2s). We extracted 11 independent components from the data: attentional, visual, auditory, sensorimotor and default mode networks. We then performed statistical analyses of mean network activity within each component, as well as inter-network connectivity of each component pair during the different task types. Results Unsurprisingly, we noted an effect of modality on activity in the visual and auditory components. However, we also describe bilateral frontoparietal, anterior cingulate and insular attentional network activity. An effect of frequency was noted only in the sensorimotor network. Effects were found on edges linking visual and auditory regions. Task modality influenced an attentional-sensorimotor connection, while stimulus frequency had an influence on sensorimotor-default mode connections. Conclusions Scanner noise during functional MRI may interfere with brain activation-especially during tasks involving auditory pathways. The question whether to use PVSAT or PASAT for an fMRI study is, therefore, an important one. Specific effects of both modalities should be known to study designers. We conclude that both tests should not be considered interchangeable, as significant changes were brought to light during test performance in different modalities.

Insulin production by the pancreatic β-cell is required for normal glucose homeostasis. While key transcription factors that bind to the insulin promoter are known, relatively little is known about the upstream regulators of insulin transcription. Using a whole-genome RNA interference screen, we uncovered 26 novel regulators of insulin transcription that regulate diverse processes including oxidative phosphorylation, vesicle traffic, and the unfolded protein response (UPR). We focused on Spry2—a gene implicated in human type 2 diabetes by genome-wide association studies but without a clear connection to glucose homeostasis. We showed that Spry2 is a novel UPR target and its upregulation is dependent on PERK. Knockdown of Spry2 resulted in reduced expression of Serca2, reduced endoplasmic reticulum calcium levels, and induction of the UPR. Spry2 deletion in the adult mouse β-cell caused hyperglycemia and hypoinsulinemia. Our study greatly expands the compendium of insulin promoter regulators and demonstrates a novel β-cell link between Spry2 and human diabetes.

Once penetrated into the lungs of exposed people, asbestos induces an in vivo biomineralisation process that leads to the formation of a ferruginous coating embedding the fibres. The ensemble of the fibre and the coating is referred to as asbestos body and is believed to be responsible for the high toxicological outcome of asbestos. Lung tissue of two individuals subjected to prolonged occupational exposure to crocidolite asbestos was investigated using synchrotron radiation micro-probe tools. The distribution of K and of elements heavier than Fe (Zn, Cu, As, and Ba) in the asbestos bodies was observed for the first time. Elemental quantification, also reported for the first time, confirmed that the coating is highly enriched in Fe (~20% w/w), and x-ray absorption spectroscopy indicated that Fe is in the 3+ oxidation state and that it is present in the form of ferritin or hemosiderin. Comparison of the results obtained studying the asbestos bodies upon removing the biological tissue by chemical digestion and those embedded in histological sections, allowed unambiguously distinguishing the composition of the asbestos bodies, and understanding to what extent the digestion procedure altered their chemical composition. A speculative model is proposed to explain the observed distribution of Fe.

Avolition is a core feature of schizophrenia and may arise from altered brain connectivity. Here we used diffusion kurtosis imaging (DKI) to investigate the association between white matter (WM) microstructure and volitional motor activity. Multi-shell diffusion MRI and 24-h actigraphy data were obtained from 20 right-handed patients with schizophrenia and 16 right-handed age and gender matched healthy controls. We examined correlations between fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and motor activity level, as well as group differences in these measures. In the patient group, increasing motor activity level was positively correlated with MK in the inferior, medial and superior longitudinal fasciculus, the corpus callosum, the posterior fronto-occipital fasciculus and the posterior cingulum. This association was not found in control subjects or in DTI measures. These results show that a lack of volitional motor activity in schizophrenia is associated with potentially altered WM microstructure in posterior brain regions associated with cognitive function and motivation. This could reflect both illness related dysconnectivity which through altered cognition, manifests as reduced volitional motor activity, and/or the effects of reduced physical activity on brain WM.

Objective: Approximately 97% of the right-handers has left hemisphere language dominance. Within the language dominant hemisphere Broca's area is of crucial importance for a variety of linguistic functions. As a result, tumour resection in and around Broca's area is controversial. However, studies showed that by means of Direct Electrical Stimulation (DES) tumour resection in this region can be safely performed. We report unexpected anatomoclinical findings in a right-handed patient who underwent tumour resection in the left prefrontal lobe. Methods: Language functions in this right-handed patient were extensively examined in the pre-, intra, and postoperative phase by means of a standardised battery of neurolinguistic and neurocognitive tests. Results obtained in the pre- and postoperative phase are compared. In addition, intraoperative DES findings and postoperative functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI) results are reported. Results: Tumour resection near Broca's area was safely performed since no positive language sites were found during intraoperative DES. Since no linguistic deficits occurred in the pre-, intra-, or postoperative phase, atypical language dominance was suspected. Neuropsychological investigations, however, disclosed permanent executive dysfunction. Postoperative fMRI and DTI confirmed right cerebral language dominance as well as a crossed cerebro-cerebellar functional link with the left cerebellar hemisphere. Discussion: Atypical right hemisphere language dominance in this right-handed patient is reflected by: (1) the total absence of language problems in the pre-, intra- and postoperative phase, (2) absence of positive stimulation sites during DES, (3) a clearly more pronounced arcuate fasciculus in the right cerebral hemisphere (DTI), (4) a crossed functional connection between the right cerebrum and the left cerebellum (fMRI). Two hypothetical explanations for the pattern of crossed cerebral language dominance are put forward: (1) preoperative brain plasticity mechanisms inducing a shift of language functions to the right hemisphere or (2) right hemisphere language dominance as a maturational variant. This case with atypical cerebral language dominance shows that although DES is the 'gold standard' to identify eloquent language regions and their pathways, fMRI and DTI are important adjuncts to guide surgery, to identify language lateralisation and to study anatomoclinical correlations. (C) 2013 Elsevier B.V. All rights reserved.

Islet intraportal transplantation is since long considered as therapy for type 1 diabetes (1). Clinical proof-of-concept has been provided since the early 1980s and initiated clinical trials worldwide (2–4). In most trials with human donor islets, the liver is still used as implant site, although there is growing awareness that this site is not optimal (5). It has been shown that several of its immunologic, anatomic, and physiologic features contribute to a significant early graft loss and β-cell dysfunction. Moreover, because this implant site is inaccessible, it can also not be considered when it comes to the use of alternative β-cell sources, such as stem cell–derived β cells or the use of xenografts (6–8). Several alternative sites have been tested in animal models to improve engraftment and long-term survival and to minimize surgical complications (6, 8). Few of these alternative sites hold the potential to be translated into clinical trials, and in general, evidence of posttransplantation functions better than those reached after intraportal infusion are lacking. The present study further assesses the omentum as implant site. This site was previously shown successful for rat islet isografts, which is in itself not particular because these preparations have functioned well in many sites (9, 10). When testing human islet cell grafts in diabetic immunodeficient rats, we found a better survival in the omentum than in the liver: omental implants exhibited little infiltration and were capable to correct hyperglycemia, whereas intraportal implants lost function after a heavy inflammatory infiltration (11). We now assess whether the omental site would also provide an adequate environment for growth of the β-cell mass as is known to occur in implants of immature pancreatic cell preparations (12–14). In a previous study, we have shown the growth potential of perinatal porcine β-cell grafts implanted under the kidney capsule of nude mice (15). The implants became structurally organized as homogenous endocrine clusters with predominantly insulin-positive cells and few other endocrine cells in the periphery; the increase in β-cell mass generated the potency to normalize diabetes (15, 16). Efficient revascularization is considered to be a prerequisite for this process (17). Within 2 days after implantation, we recognized the first endothelial cells and small blood vessels in the proximity of the implants; the revascularization process, however, proceeded beyond the 20-week study period (15, 18). It is conceivable that the rapidity and extent of this process determines initial engraftment as well as subsequent adaptive growth. Because the omentum is well vascularized and has been described as a rich source of angiogenic and neurogenic factors (19–21), we wanted to compare the growth of immature porcine β-cell grafts in omentum and kidney and relate it to the vessel density that has developed in both implants. Implants in the omentum reached vessel densities comparable with those in endogenous adult porcine islets within 10 weeks after implantation, which was not the case in the kidney subcapsular space. In parallel, implant volumes were increased reflecting a beneficial effect on β-cell proliferation and numbers as well as on cellular insulin content. Our data elaborate our prior findings with human islets implants and add further support on the potential use of the omentum as an alternative site for islet transplantation. Whether the omentum could offer an alternative to intraportal transplantation in humans remains to be evaluated.

We present two cases of desmoid tumour of the anterior abdominal wall in young women in whom the defect after radical excision could not be closed without using prosthesis. The first case warranted the use of a composite mesh, the second a polypropylene prosthesis. In both cases primary closure of the skin was possible. Both women are doing fine with no sign of relapse or incisional hernia.

Radiation-induced breast angiosarcoma is a severe but rare late complication in the breast-preserving management of breast cancer through surgery and radiotherapy [1]. Often the initial diagnosis of this entity is complex given its relatively anodyne nature and usually being present in the form of typically multifocal reddish-purple papular skin lesions [2]. Because of the low incidence of this tumour, there is a limited number of studies regarding its optimal therapeutic management [3]. The preferred treatment is aggressive surgical removal and the prognosis is poor with an overall survival rate of 12-20% at five years [4]. Yes

We here report a patient with histologically proven sarcoidosis of the knee, a rare localization of sarcoidosis, which usually presents itself as a pulmonary disease. Case reports of radiological images that suggest osseous sarcoidosis of the appendicular skeleton are not so rare, however few are histologically proven. Since in our patient MRI could not distinguish between sarcoidosis and another (possibly malignant) disease, histological proof was obtained through a CT-guided biopsy. Imaging and treatment guidelines for extrapulmonary sarcoidosis are inexistent, due to lack of randomized trials.

Creating an abundant source of β(-like)-cells has been a major goal in diabetes research for many decades. The concept of cell plasticity has inspired many strategies towards regenerative medicine, but its successes have been limited until very recently. Today, most cell types in the pancreas are considered candidates for the generation of β(-like)-cells through transdifferentiation. While β(-like)-cells that are in vitro differentiated from human embryonic stem cells are already being grafted in patients, β(-like)-cells generated by transdifferentiation are not yet ready for clinical application. These cells would however offer several advantages over the current β(-like)-cells generated by directed differentiation, especially concerning safety issues. In addition, perfect control of the transdifferentiation efficiency would through targeted drug delivery support a non-invasive cell therapy for diabetes. Lastly, focusing on the exocrine pancreas as prime candidate makes sense in view of their abundance and high plasticity. Keeping these hopeful perspectives in mind, it is worth to continue focused research on the mechanisms that control transdifferentiation from pancreas exocrine to β-cells.

Introduction As neurodegeneration is recognized as a major contributor to disability in multiple sclerosis (MS), brain atrophy quantification could have a high added value in clinical practice to assess treatment efficacy and disease progression, provided that it has a sufficiently low measurement error to draw meaningful conclusions for an individual patient. Method In this paper, we present an automated longitudinal method based on Jacobian integration for measuring whole-brain and gray matter atrophy based on anatomical magnetic resonance images (MRI), named MSmetrix. MSmetrix is specifically designed to measure atrophy in patients with MS, by including iterative lesion segmentation and lesion filling based on FLAIR and T1-weighted MRI scans. Results MSmetrix is compared with SIENA with respect to test–retest error and consistency, resulting in an average test–retest error on an MS data set of 0.13% (MSmetrix) and 0.17% (SIENA) and a consistency error of 0.07% (MSmetrix) and 0.05% (SIENA). On a healthy subject data set including physiological variability the test–retest is 0.19% (MSmetrix) and 0.31% (SIENA). Conclusion Therefore, we can conclude that MSmetrix could be of added value in clinical practice for the follow-up of treatment and disease progression in MS patients.

The generation of beta(-like) cells to compensate for their absolute or relative shortage in type 1 and type 2 diabetes is an obvious therapeutic strategy. Patients first received grafts of donor islet cells over 25 years ago, but this procedure has not become routine in clinical practice because of a donor cell shortage and (auto)immune problems. Transplantation of differentiated embryonic and induced pluripotent stem cells may overcome some but not all the current limitations. Reprogramming exocrine cells towards functional beta(-like) cells would offer an alternative abundant and autologous source of beta(-like) cells. This review focuses on work by our research group towards achieving such a source of cells. It summarises a presentation given at the 'Can we make a better beta cell?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Amin Ardestani and Kathrin Maedler, DOI: 10.1007/s00125-016-3892-9 , and by Heiko Lickert and colleagues, DOI: 10.1007/s00125-016-3949-9 ) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2 ).

To test the hypothesis of crossed cerebro-cerebellar language dominance (Marien, Engelborghs, Fabbro, & De Deyn, 2001) in atypical populations, the pattern of cerebral and cerebellar language organization in a right-handed woman with a large porencephalic cyst in the left temporal lobe with no secondary clinical neurological symptoms was studied by means of an fMRI-language paradigm. Extensive neuropsychological examinations were performed to formally rule out cognitive dysfunctions. The fMRI task, consisting of a covert controlled oral word generation task, disclosed a pattern of bilateral activity in the frontal language areas, slightly more pronounced in the left hemisphere, and unilateral activation of the left inferior and superior temporal and supramarginal gyrus. This pattern of supratentorial activations was reflected at the infratentorial level by bilateral activations in the posterior lobe of the cerebellum with slightly more activity located in the right cerebellar hemisphere. This pattern of bilateral cerebral and cerebellar activation seems to confirm that the distribution of supratentorial language dominance is intrinsically reflected at the level of the cerebellum. Bilateral frontal language representation might be the consequence of neurofunctional compensation for the structural anomaly affecting eloquent brain regions resulting in an operational inefficiency of the neural network subserving language in the left hemisphere. (C) 2015 Elsevier Ltd. All rights reserved.

Equine viral arteritis (EVA) may have serious economic impact on the equine industry. For this reason, it is monitored in many countries, especially in breeding stock, to avoid its spread during breeding activities. In France, surveillance is mainly based on serological tests, since mares are not vaccinated, but difficulties in interpreting certain series of results may impair the estimation of the number of outbreaks. In this study, we propose specific rules for identifying seroconversion in order to estimate the number of outbreaks that were detected by the breeding stock surveillance component (BSSC) in France between 2006 and 2013. A consensus among multidisciplinary experts was reached to consider seroconversion as a change in antibody titer from negative to at least 32, or as an eight-fold or greater increase in antibody level. Using these rules, 239 cases and 177 outbreaks were identified. Subsequently, we calculated the BSSC's sensitivity as the ratio of the number of detected outbreaks to the total number of outbreaks that occurred in breeding stock (including unreported outbreaks) estimated using a capture-recapture model. The total number of outbreaks was estimated at 215 (95% credible interval 195-249) and the surveillance sensitivity at 82% (CrI95% 71-91). Our results confirm EVA circulation in French breeding stock, show that neutralizing antibodies can persist up to eight years in naturally infected mares and suggest that certain mares have been reinfected. This study shows that the sensitivity of the BSSC is relatively high and supports its relevance to prevent the disease spreading through mating.

The detection of autochthonous aquatic bacteria in tissue samples from drowning cases is increasingly considered as an alternative approach to assist the medico-legal diagnosis of death by drowning. Bacteria belonging to the genus Aeromonas may be suitable candidates for this application as they are ubiquitous in natural aquatic environments but are generally not part of the human microbiota. The research aims of this study were (i) to develop a sensitive, specific and rapid screening and confirmation method for Aeromonas species in tissue samples and (ii) to evaluate aseptic sternal puncture as a post-mortem sample technique and bone marrow as an alternative matrix to provide evidence of death by drowning. The presence of Aeromonas in tissue samples was verified by cultivation using the selective media Ampicillin Dextrin Agar (ADA) and Ryan's Aeromonas Medium. The use of ADA medium was found most optimal for the sensitive, inexpensive and quick detection of aeromonads in human tissue samples. Positive culture plates were confirmed by harvesting all colonies for DNA extraction and subsequent PCR amplification using Aeromonas genus-specific primers. Aeromonads were detected in lung swab, blood and bone marrow of drowned bodies (n = 3), but were negative in these three matrices for all negative controls (n = 90) tested. Bone marrow proved to be a suitable alternative matrix and can be sampled post-mortem by an aseptic sternal puncture. In conclusion, this study confirms previous indications that aeromonads in cultures from blood of water bodies can be considered a potential marker for drowning. Given the fact that the number of immersed bodies (drowned and non-drowned) included in this study is statistically not significant, however, more tissue samples need to be investigated to confirm the validity of these methods to aid the diagnosis of death by wet drowning. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND: Feasibility and long-term safety of laparoscopic removal of gastric gastrointestinal stromal tumors (GISTs) of the stomach is well established for lesions smaller than 2 cm. Our specific aim was to explore whether laparoscopic treatment is equally applicable for gastric GISTs larger than 2 cm. METHODS: Between 1997 and 2010, 31 consecutive patients presenting with a primary gastric GIST were scheduled for laparoscopic resection, irrespective of tumor size. Prerequisites for laparoscopic approach were the absence of metastases and the presence of a well-defined tumor on CT scanning without involvement of adjacent organs, the esophagogastric junction, or the pylorus of the stomach. Data were retrieved retrospectively from a prospectively collected database, including information on patient demographics, surgical procedure, complications, hospital stay, and recurrence. Diagnosis of GIST was based on microscopic analysis, including immunohistochemistry with a panel of antibodies: CD117, CD34, DOG1, S100, desmin, and smooth muscle actin. RESULTS: All 31 laparoscopic resections were carried out successfully. The most common symptoms were melena, anemia, and abdominal pain. In one case we performed a laparoscopic approach for a GIST with acute bleeding. Tumor size was smaller than 2 cm in 5 patients and larger than 2 cm in 26 patients. The median tumor size was 4.4 cm (range = 0.4-11.0 cm). Median blood loss was identical in both groups (20 ml), but duration of operation (60 vs. 103 min) and duration of hospital stay (6 vs. 8 days) were lower when tumor size was less than 2 cm. Only one patient (with tumor size CONCLUSION: The low morbidity rates and the long-term disease-free interval of 100% observed in our cohort indicate that laparoscopic resection is safe and effective in treating gastric GISTs, even for tumors larger than 2 cm. Comment in Combined laparoscopic and endoscopic excision of a gastric gist. [Surg Endosc. 2013]

Pseudomyxoma peritonei is only rarely seen in conjunction with primary ovarian tumors. It has been suggested that only ruptured mucinous tumors arising in ovarian mature cystic teratomas can result in this clinical picture. We describe a case of a late invasive recurrence of a mucinous intestinal-type borderline ovarian tumor arising from a mature teratoma after complete surgical debulking. Borderline ovarian tumors behave indolently in the overwhelming majority of cases, and the prognosis is therefore usually outstanding.

Objective Acinar cells display plasticity in vitro and in vivo and can activate a variety of differentiation programmes that may contribute to pancreatic diseases. The aims were to determine: (1) the differentiation potential of acinar cells under conditions which favour stem cell survival, and (2) its relationship to the phenotypes acquired by pancreatic epithelial cells in chronic pancreatitis. Design Murine acinar cells were cultured in suspension and their molecular phenotype was characterised by qRT-PCR, chromatin immunoprecipitation, immunocytochemistry and global transcriptome analysis. These findings were compared to the changes occurring in experimental chronic pancreatitis induced by pancreatic duct ligation and chronic caerulein administration. Results Acinar cells in suspension culture acquired a dedifferentiated phenotype characteristic of pancreatic embryonic progenitors, consisting of the co-expression of Ptf1a and Pdx1, presence of an embryonic-type PTF1 transcriptional complex, activation of the Notch pathway, and expression of additional pancreatic progenitor cell markers such as CpA1, Sox9 and Hnf1b. A senescence programme, associated with activation of Ras and ERK signalling, limited the proliferative capacity of the cells. A similar progenitor-like phenotype with activation of a senescence programme was observed in experimental chronic pancreatitis induced by pancreatic duct ligation or repeated caerulein administration, with the concomitant and differential activation of proliferation and senescence in distinct cell populations. Conclusions Acinar cells dedifferentiate into an embryonic progenitor-like phenotype upon suspension culture. This is associated with the activation of a senescence programme. Both processes take place in experimental chronic pancreatitis where senescence may contribute to limit tumour progression.

Aims This study aims to compare transverse images and vessel probe (VP) in MPR mode reconstructions obtained by 16-row MDCT with the histological findings in the preoperative T staging of esophageal cancer. Materials and methods Thirty-one patients (23 M, 8 F, mean age 63.2) with endoscopic and histological diagnosis of esophageal carcinoma underwent CT examination. Esophageal lumen was distended by CO 2 and a biphasic technique with 35s and 70s delay was used after intravenous injection of contrast material. Transverse and VP in MPR mode images were evaluated and the following parameters were considered: presence and location of the tumor; esophageal wall thickness and enhancement; depth of visceral wall invasion; periesophageal fat morphology and infiltration of adjacent organs. Preoperative staging was performed and then it was compared with the histological findings considered as reference standard. Results Sensibility, negative predictive and accuracy values were 67%, 64% and 79% by using axial images for preoperative T staging, while the use of VP increased the previous values up to 83%, 78% and 89%, respectively. Conclusions In the preoperative staging of esophageal cancer, VP in MPR mode reconstructions obtained by 16-row MDCT increase the sensibility and diagnostic accuracy values in the T parameter evaluation compared with axial images.

OBJECTIVE This study assesses β-cell replication in human donor organs and examines possible influences of the preterminal clinical conditions. RESEARCH DESIGN AND METHODS β-Cell replication was quantified in a consecutive series of n = 363 human organ donors using double immunohistochemistry for Ki67 and insulin. Uni- and multivariate analysis was used to correlate replication levels to clinical donor characteristics and histopathologic findings. RESULTS β-Cell replication was virtually absent in most donors, with ≤0.1% Ki67-positive β-cells in 72% of donors. A subpopulation of donors, however, showed markedly elevated levels of replication of up to 7.0% Ki67-positive β-cells. β-Cell replication was accompanied by the increased replication of glucagon-, somatostatin-, and CA19.9-positive cells. Prolonged life support, kidney dysfunction, relatively young donor age, inflammatory infiltration, and prolonged brain death before organ retrieval were all found to be significantly associated with an increased level (≥90th percentile) of β-cell replication, with the first three risk factors being independent predictors. Increased β-cell replication was most often noted in relatively young donors (≤25 years) who received prolonged (≥3 days) life support (68%); in contrast, it was rare in donors with a short duration of life support regardless of age (1%). Prolonged life support was accompanied by increased levels of CD68+ and LCA/CD45+ infiltration in the pancreatic parenchyma. CONCLUSION These results indicate that preterminal clinical conditions in (young) organ donors can lead to increased inflammatory infiltration of the pancreas and to increased β-cell replication.

Melanoma metastases are characterized by pronounced neo-angiogenesis and spontaneous bleeding frequently occurring within central nervous system metastases. Clinically apparent spontaneous hemorrhage within subcutaneous melanoma metastases, however, is a rare event that coincides with progression of such metastases. We report, to our knowledge the first observation, on regression of subcutaneous metastases with hemorrhage of the overlying skin in three patients with stage IV melanoma who participated in clinical trials on therapeutic vaccination. In two patients, loss of arterial flow on Doppler ultrasound imaging was documented in the metastasis at the time of hematoma formation. One patient suffered from an intracranial hemorrhage in a subcentimetric brain metastasis coincident with the hemorrhagic regression of some of his skin metastases.

International audience; Juvenile hormone (JH) controls insect development, metamorphosis and reproduction. In insect hemolymph a significant proportion of JH is bound to juvenile hormone binding protein (JHBP), which serves as a carrier supplying the hormone to the target tissues. To shed some light on JHBP passage within insect tissues, the interaction of this carrier with other proteins from Galleria mellonella (Lepidoptera) was investigated. Our studies revealed the presence of JHBP within the tracheal epithelium and fat body cells in both the membrane and cytoplasmic sections. We found that the interaction between JHBP and membrane proteins occurs with saturation kinetics and is specific and reversible. ATP synthase was indicated as a JHBP membrane binding protein based upon SPR-BIA and MS analysis. It was found that in G. mellonella fat body, this enzyme is present in mitochondrial fraction, plasma membranes and cytosol as well. In the model system containing bovine F(1) ATP synthase and JHBP, the interaction between these two components occurs with K(d)=0.86 nM. In hemolymph we detected JHBP binding to apolipophorin, arylphorin and hexamerin. These results provide the first demonstration of the physical interaction of JHBP with membrane and hemolymph proteins which can be involved in JHBP molecule traffic.

To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with recurrent high-grade glioma (HGG) after failure of surgery, radiation therapy, and chemotherapy.In this two-arm, open-label, phase II study patients were stratified according to their epidermal growth factor receptor (EGFR) gene amplification status. Cetuximab was administered intravenously at a dose of 400 mg/m(2) on week 1 followed by weekly dose of 250 mg/m(2). The primary end point for this study was the response rate in both study arms separately.Fifty-five eligible patients (28 with and 27 without EGFR amplification) tolerated cetuximab well. Three patients (5.5%) had a partial response and 16 patients (29.6%) had stable disease. The median time to progression was 1.9 months [95% confidence interval (CI) 1.6-2.2 months]. Whereas the progression-free survival (PFS) was6 months in the majority (n = 50/55) of patients, five patients (9.2%) had a PFS on cetuximab of9 months. Median overall survival was 5.0 months (95% CI 4.2-5.9 months). No significant correlation was found between response, survival and EGFR amplification.Cetuximab was well tolerated but had limited activity in this patient population with progressive HGG. A minority of patients may derive a more durable benefit but were not prospectively identified by EGFR gene copy number.

Ileocolic invagination in the adult may be caused by adenocarcinoma and lead to intestinal obstruction. We report a case of a cecal adenocarcinoma that was complicated by an ileocolic invagination in a 38 year old female, diagnosed on a contrast enhanced CT scan of the abdomen and highlights the importance of contrast enhanced CT for diagnosis of ileocolic invagination.

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerence in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.