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Introduction In the PURE-01 study, a proportion of patients (pts) with muscle-invasive bladder cancer (MIBC; T2-4N0M0) had residual invasive disease (ypT2-4) at radical cystectomy (RC) after neoadjuvant pembrolizumab (pembro). The pembro-induced alterations in immunotherapy-resistant tumors remain largely unstudied. We aimed to investigate the biological characteristics of pembro-resistant tumors in comparison to neoadjuvant chemotherapy (NAC)-resistant tumors. Methods Gene expression profiling was performed on 26 RC samples from pts with ypT2-4 disease post-pembro, of which 22 had matched pre-pembro transurethral resection of the bladder tumor (TURBT) samples. Matched cases were analyzed by differential gene expression, hallmark signatures, and molecular subtyping (Decipher Bladder, TCGA, Consensus and Lund classifiers). Unsupervised consensus clustering (CC) was used to compare the 26 post-pembro samples with 133 post-NAC samples and to 21 samples collected from the former tumor bed of NAC-treated patients (scar tissue), all derived from RC specimens. Results Molecular subtyping of the pre- and post-pembro samples revealed significant ‘subtype switching’ with only 41% of samples having concordant subtypes using the Decipher Bladder classifier. The post-pembro samples did not cluster with scar tissues on clustering but were highly associated with immune-infiltrated cases from the post-NAC cohort. Two major groups of post-pembro tumors were identified, the first defined by markedly higher immune, stromal, angiogenesis and epithelial-to-mesenchymal signature scores and the second by higher tumor purity, KRAS and reactive oxygen species signature scores. Checkpoint inhibitor genes (CD274, PDCD1LG2) were consistently expressed in both groups. Conclusions This study expands our knowledge of pembro-resistant tumors finding the molecular characteristics of these tumors is strikingly different from NAC-resistant tumors. Two distinct clusters of tumors were identified post-pembro, neither of which were characterized as having a scar-like character. A larger cohort will be required to further understand the clinical implications of these findings.

Background In PURE01 study (NCT02736266), neoadjuvant pembro resulted in 42% pT0 in patients (pts) with MIBC. pT0 pts had features suggesting pre-existing immunity or higher tumor mutational burden (TMB) may promote response. In this study, we investigated potential mechanisms for resistance to pembro, including FGFR3 genomic alterations (GA). Methods Pts enrolled in the PURE-01, which is still recruiting pts in its amended design, had predominant urothelial carcinoma histology and stage cT ≤ 4N0 MIBC. Biomarker analyses in the expanded cohort of 96 pts included PD-L1 combined positive score and comprehensive genomic profiling (FoundationCDx assay). In addition, TCGA MIBC (n = 405) and a prospective commercial cohort (PCC) of 415 MIBC pts from the clinical use of the Decipher Bladder TURB test from the GRID registry (NCT02609269) were analyzed. A single-sample genomic classifier (GC) was trained to identify FGFR3-active tumors (FGFR3+). Results In PURE01 cohort, despite a linear association of TMB with ypT0 in multivariable models (p = 0.017), there was no association between FGFR3 GA and pathological response nor with PD-L1 expression. FGFR3 GA were found in 17.6% ypT0 vs 20.7% in ypT3-4 disease (corrected p = 0.82). Applying the GC to the TCGA MIBC cohort, we found 45% of FGFR3+ cases had FGFR3 mutations vs 9% for the rest of the cohort. Applying the GC to the PCC, we found that the FGFR3+ tumors were Luminal (n = 14), Luminal Infiltrated (n = 10) or Luminal Papillary (n = 30). FGFR3+ pts showed significantly lower PD-L1 (-0.03 vs. 0.109, p Conclusions In our combined cohorts, FGFR3 GA did not correlate with response to pembro. FGFR3 GA are enriched in FGFR3+ tumors, which in turn tend to have lower immune activity, PD-L1 and PD-L2, suggesting FGFR3 activity may provide a potential tool for further discriminating the mechanisms underlying response and resistance to neoadjuvant pembro in MIBC. Clinical trial identification NCT02736266 (PURE01) NCT02609269 (GRID Registry). Legal entity responsible for the study The authors. Funding Decipher Bioscience. Disclosure A. Necchi: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Clovis; Advisory / Consultancy: Janssen. R. Madison: Full / Part-time employment: Foundation Medicine. J. Chung: Full / Part-time employment: Foundation Medicine. Y. Liu: Full / Part-time employment: Decipher Bioscience. J. Chung: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. E. Davicioni: Full / Part-time employment: Decipher Bioscience. E.A. Gibb: Full / Part-time employment: Decipher Bioscience. All other authors have declared no conflicts of interest.

Schizophrenia research has identified deficits in neurocognition, social cognition, and sensory processing. Because a cohesive model of “disturbed cognitive machinery” is currently lacking, we built a conceptual model to integrate neurocognition, social cognition, and sensory processing.In a cross-sectional study, the cognitive performance of participants was measured. In accordance with the Schedules for Clinical Assessment in Neuropsychiatry, the participants were assigned to either the schizophrenia group or the non-schizophrenic psychosis group. Exclusion criteria included substance abuse, serious somatic/neurological illness, and perceptual handicap. The male/female ratio, educational level, and handedness did not differ significantly between the groups.The data were analyzed using structural equation modeling. Based upon the results of all possible pairwise models correlating neurocognition, social cognition, and sensory processing, three omnibus models were analyzed. A statistical analysis of a pairwise model-fit (χ2, CFI, and RMSEA statistics) revealed poor interrelatedness between sensory processing and neurocognition in schizophrenia patients compared with healthy control participants. The omnibus model that predicted disintegration between sensory processing and neurocognition was statistically confirmed as superior for the schizophrenia group (χ2(53) of 56.62, p = 0.341, RMSEA = 0.04, CFI = 0.95). In healthy participants, the model predicting maximal interrelatedness between sensory processing/neurocognition and neurocognition/social cognition gave the best fit (χ2(52) of 53.74, p = 0.408, RMSEA = 0.03, CFI = 0.97). The performance of the patients with non-schizophrenic psychosis fell between the schizophrenia patients and control participants.These findings suggest increasing separation between sensory processing and neurocognition along the continuum from mental health to schizophrenia. Our results support a conceptual model that posits disintegration between sensory processing of social stimuli and neurocognitive processing.Keywords: Schizophreni, Psychosis, Cognition, Sensory processing, Disintegration, Structural equation modeling

Contains fulltext : 89004.pdf (Publisher’s version ) (Closed access) BACKGROUND: Deficits in emotion perception are a well-established phenomenon in schizophrenic patients and studies have typically used unimodal emotion tasks, presenting either emotional faces or emotional vocalizations. We introduced bimodal emotion conditions in two previous studies in order to study the process of multisensory integration of visible and audible emotion cues. We now build on our earlier work and address the regulatory effects of selective attention mechanisms on the ability to integrate emotion cues stemming from multisensory channels. METHODS: We added a neutral secondary distractor condition to the original bimodal paradigm in order to investigate modality-specific selective attention mechanisms. We compared schizophrenic patients (n=50) to non-schizophrenic psychotic patients (n=46), as well as to healthy controls (n=50). A trained psychiatrist used the Schedules of Clinical Assessment in Neuropsychiatry (SCAN 2.1) to diagnose the patients. RESULTS: As expected, in healthy controls, and to a lesser extent in non-schizophrenic psychotic patients, modality-specific attention attenuated multisensory integration of emotional faces and vocalizations. Conversely, in schizophrenic patients, auditory and visual distractor conditions yielded unaffected and even exaggerated multisensory integration. CONCLUSIONS: These results suggest that schizophrenics, as compared to healthy controls and non-schizophrenic psychotic patients, have modality-specific attention deficits when attempting to integrate information regarding emotions that stem from multichannel sources. Various explanations for our findings, as well as their possible consequences, are discussed. 01 september 2010

Contains fulltext : 77421.pdf (Publisher’s version ) (Closed access) Since Kraepelin called dementia praecox what we nowadays call schizophrenia, cognitive dysfunction has been regarded as central to its psychopathological profile. Disturbed experience and integration of emotions are, both intuitively and experimentally, likely to be intermediates between basic, non-social cognitive disturbances and functional outcome in schizophrenia. While a number of studies have consistently proven that, as part of social cognition, recognition of emotional faces and voices is disturbed in schizophrenics, studies on multisensory integration of facial and vocal affect are rare. We investigated audiovisual integration of emotional faces and voices in three groups: schizophrenic patients, non-schizophrenic psychosis patients and mentally healthy controls, all diagnosed by means of the Schedules of Clinical Assessment in Neuropsychiatry (SCAN 2.1). We found diminished crossmodal influence of emotional faces on emotional voice categorization in schizophrenics, but not in non-schizophrenia psychosis patients. Results are discussed in the perspective of recent theories on multisensory integration.

The design of a new HBsAg screening assay, the Hepanostika HBsAg Ultra is based on the use of monoclonal antibodies raised against native wild-type HBsAg and reactive with HBsAg in which the common ‘a’-determinant is modified by site-directed mutagenesis of four of the cysteine moieties. The design was checked using the same cysteine variants and samples from patients known to be infected with HBsAg variants. The results found were compared with other state-of-the-art commercial screening assays. The design of the Hepanostika HBsAg Ultra enabled detection of all variant HBsAg-positive samples in contrast to the other commercial assays. An additional 980 samples were tested to assess the specificity and sensitivity of the Hepanostika HBsAg Ultra. Screening of presumed negative serum and plasma samples resulted in a specificity of 100%. This makes the Hepanostika HBsAg Ultra the first screening assay with a design able to detect HBsAg variants with high sensitivity and specificity.

Item does not contain fulltext ABSTRACT Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is considered a rare inherited mitochondrial fatty acid oxidation disorder. Less than 10 patients have been reported, diagnosed on the basis of ethylmalonic aciduria and low SCAD activity in cultured fibroblast. However, mild ethylmalonic aciduria, a biochemical marker of functional SCAD deficiency in vivo, is a common finding in patients suspected of having metabolic disorders. Based on previous observations, we have proposed that ethylmalonic aciduria in a small proportion of cases is caused by pathogenic SCAD gene mutations, and SCAD deficiency can be demonstrated in fibroblasts. Another - much more frequent - group of patients with mild ethylmalonic aciduria has functional SCAD deficiency due to the presence of susceptibility SCAD gene variations, i.e. 625G>A and 511C>T, in whom a variable or moderately reduced SCAD activity in fibroblasts may still be clinically relevant. To substantiate this notion we performed sequence analysis of the SCAD gene in 10 patients with ethylmalonic aciduria and diagnosed with SCAD deficiency in fibroblasts. Surprisingly, only one of the 10 patients carried pathogenic mutations in both alleles, while five were double heterozygotes for a pathogenic mutation in one allele and the 625G>A susceptibility variation in the other. The remaining four patients carried only either the 511C>T or the 625G>A variations in each allele. Our findings document that patients carrying these SCAD gene variations may develop clinically relevant SCAD deficiency, and that patients with even mild ethylmalonic aciduria should be tested for these variations.

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Two additional patients with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency are described. An 11-month-old girl with nonconsanguineous parents had generalized seizures and no angiokeratoma. Biochemical investigation showed persistent slight oligosacchariduria; enzymatic analysis of plasma, leukocytes, and fibroblasts revealed profound alpha-NAGA deficiency. Heterozygote enzyme levels were found in both parents. The mother has epilepsy, and epilepsy is present in the father's family. A younger, clinically healthy brother also had the enzyme deficiency. Electron microscopy of lymphocytes from the index patient showed no vacuolization. Incubation of cultured fibroblasts with Helix pomatia lectin showed the presence of intracellular N-acetylgalactosamine-containing storage material, not present in a series of 12 normal fibroblast lines. Our cases cannot be classified definitely as infantile cases. Biochemically the diagnosis could easily have been missed. Urinary oligosaccharide pattern after resorcinol staining was identical to those previously described, but excretion was significantly lower than in the reported infantile cases and the bands disappeared after the urine was desalted. The enzyme defect in leukocytes would have been missed with one of the commercial substrates used. For this mild variant of alpha-NAGA deficiency, the clinical pattern is not yet clear; a longer follow-up period is needed.

Sir: [3-mannosidosis is a lysosomal storage disorder caused by deficiency of the enzyme ~-mannosidase. We would like to report a girl (parents were first cousins), who besides a [3-mannosidase deficiency had an ethanolaminuria. She was born at term. Birth length and weight are unknown. Her development during the 1st year was unremarkable. She walked at 15 months. In that period the parents became worried about speech development. Because of recurrent upper respiratory tract infections the adenoids were removed and tympanotubes inserted. Otological examination revealed a hearing-loss of 45 DB. She was admitted to our clinic because of absent speech development and anorexia. Physical examination at the age of 5 years 10 months showed a slightly built girl: height and weight below 3rd percentile, head circumference 10th percentile. Motor and mental development were seriously retarded. There were no joint contractures, but she stood with slightly flexed hips and knees. No hepatosplenomegaly was present. Electroencephalography demonstrated a non-specific abnormality without c~production. A CT-scan of the brain was normal. Oligosaccharides in urine, analysed according to Blom et al. [1] and Dorland et al. [3], showed a strong band which could be identified as the 13-mannosidosis disaccharide mannosyl-13(1-4)-N-acetylglucosamine. ~-Mannosidase activity was measured with minor modifications of the method described by Panday et al. [4]. The activity of 13-mannosidase in leucocytes was 4.7nmol/h per milligram protein (normal: 160-360). In plasma and cultured fibroblasts the activity of 13-mannosidase was not detectable (normal respectively: 160-300 nmol/h per milliliter, 115-455nmol/h per milligram protein). Heparan sulphamidase was normal. Furthermore we found an ethanolaminuria: 607-1010gmol/mmol creatinine (normal 35-130). The ethanolamine concentration in the serum was also elevated ranging from 38-70 gmol/1 (normal: traces). All hitherto described patients with [3-mannosidosis had mental retardation. Most of them had hearing loss with delayed development of expressive language. Striking is their susceptibility to respiratory and dermal infections. There is no uniform facial or skeletal dysmorphism. The significance or ethanolaminuria in our patient is not known. Wenger et al. [6] described a combined deficiency of 13-mannosidase and heparan sulphamidase. Vietor et al. [5] reported two sibs with ethanolaminuria and generalized storage disease, cardiomegaly, cerebral dysfunction and early death. It was argued that a marked increase in ethanolamine excretion could result from a deficiency of kinase enzyme involved in the synthesis of membrane phospholipid phosphatidylethanolamine. As suggested by Cole et al. [2] ethanolamine may result from accelerated breakdown of ethanolamine phospholipids (e.g. from myelin) without compensatory re-utilization in the synthesis of new lipids. However, there were no clinical signs of myelin disease in our patient. References