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Two classifications for bladder cancer grade are widely used; the World Health Organization (WHO) 1973 and the WHO 2004. We evaluated inter-observer variability of both classifications and investigated which histologic criteria cause this variability. We found that reproducibility of both classifications is poor, as well as scoring of the individual histologic criteria. This suggests that descriptions of these criteria for grade are not specific enough. Background: Histologic grade is an important prognosticator in patients with non–muscle-invasive bladder cancer (NMIBC). Currently, 2 classifications for grade are widely used; the World Health Organization (WHO) 1973 and the WHO 2004. We compare inter-observer variability of both classifications and investigate which histologic criteria cause this variability. Furthermore, the prognostic value of both classifications was assessed. Patients and Methods: Three pathologists reviewed 328 bladder tissue samples of 232 patients with NMIBC in a blinded manner. WHO 1973 grade, WHO 2004 grade, histologic criteria of both classifications, and T-category were evaluated. Reproducibility was analyzed using the weighted Fleiss κ, association between criteria scores and grade with the χ2 test, and time-to-recurrence and time-to-progression with the log-rank test and Cox regression. Results: Reproducibility of both classifications was poor. The WHO 2004 showed better reproducibility (κ = 0.35; 95% confidence interval (CI), 0.29-0.42) compared with the WHO 1973 as a 3-tiered (κ = 0.24; 95% CI, 0.19-0.28), but not as a 2-tiered (G1 + G2 vs. G3) classification (κ = 0.36; 95% CI, 0.29-0.42). Reproducibility of individual criteria was poor (κ range, −0.05 to 0.25). All criteria were associated with grade (P

Purpose: Histological grade is an important prognostic factor in patients with non-muscle–invasive bladder cancer (NMIBC). However, interobserver variability is high. Previous studies have suggested that quantification of histological features is useful to objectify grading. We evaluated whether quantification of the mean nuclear area of the 10 largest nuclei (MNA-10), degree of aneuploidy (DNA index or DI) and mitotic activity index (MAI) are of diagnostic value for NMIBC grade. Additionally, prognostic value of the 3 measures was assessed. Material and methods: A consensus grade was determined by 3 uropathologists in 310 NMIBC tissues according to the World Health Organization (WHO) 1973 and the WHO2004. Logistic regression with forward selection was used to determine the optimal combination of measures (MNA-10, DI, and MAI) to diagnose grade 3 (G3) or high-grade (HG) NMIBC (WHO1973 and WHO2004, respectively). Results: In 310 tumors of 215 patients at least 1 of the measures (MNA-10, DI, or MAI) had been determined. The combination of MNA-10 and MAI was selected as the most diagnostic combination and resulted in a sensitivity of 94% (95% confidence interval [CI]: 87–100) at a specificity of 72% (95% CI: 66–78) for G3 tumors. For the diagnosis of HG tumors sensitivity was 92% (95% CI: 86–97) at a specificity of 76% (95% CI: 70–93). Conclusions: Determination of MNA-10 and MAI is promising for diagnosing G3 and HG bladder tumors. These findings warrant further studies on the diagnostic and prognostic value of proliferative and quantitative features in bladder cancer patients.

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.

Eosinophilic esophagitis (EoE) is a relatively new condition resulting in dysphagia or symptoms resembling gastroesophageal reflux disease, symptoms that also are common in patients with a history of esophageal atresia. We present 2 patients with persistent dysphagia after repair of esophageal atresia that was caused by EoE. Although the exact etiology and pathogenesis of EoE remain unclear, it is now generally accepted that it is the result of a T-helper cell 2-type immune response with a crucial role for the eosinophil-specific chemotaxis factor eotaxin 3 and eosinophils. Because there are genetic similarities between esophageal atresia and EoE, we speculate that patients with esophageal atresia are at increased risk for developing EoE. (C) 2012 Elsevier Inc. All rights reserved

Tracheal agenesis (TA) is a severe congenital disorder with often an unexpected emergency presentation. There is complete or partial absence of the trachea below the larynx, with presence or absence of a tracheoesophageal fistula (TOF). A neonate with TA is described, and another 48 cases found in literature are reviewed. Due to absence of a TOF, five cases were diagnosed prenatally because of congenital high airway obstruction syndrome (CHAOS). When a TOF is present, polyhydramnion and several other congenital malformations seen on the ultrasound examination should alert clinicians of potential tracheal problems. Prenatal magnetic resonance imaging (MRI) may provide a definitive diagnosis. Postnatal diagnosis is based on recognition of specific clinical signs in the newborn with TA: respiratory distress with breathing movement without appropriate air entry, no audible cry, and failed endotracheal intubation. Despite progress in surgical interventions, mortality remains high. Prenatal diagnosis of TA is possible, but only if a TOF is absent resulting in CHAOS. Prenatal diagnosis of polyhydramnion and other congenital malformation should alert clinicians of potential tracheal problems. Prenatal MRI may provide a definitive diagnosis.

Introduction Alexander disease is a rare disorder of the central nervous system with characteristic symmetric white matter abnormalities with frontal predominance on magnetic resonance (MR) images. Histopathology shows a lack of myelin in the affected white matter, variably interpreted as hypomyelination or demyelination. To increase our insight into the nature of the pathology leading to the MR imaging findings in Alexander disease, we applied serial MR imaging, spectroscopy, magnetization transfer (MT) imaging (MTI), and diffusion tensor imaging (DTI) in six patients with juvenile Alexander disease. Methods The MR imaging protocol comprised T1- and T2-weighted spin echo images and fluid-attenuated inversion recovery images. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and MT ratio (MTR) maps were generated, and MR spectroscopy concentrations were quantified for several metabolites. Results MR imaging showed similar cerebral white matter abnormalities in all patients, with only minor increase on prolonged follow-up, despite sometimes serious clinical progression. MR spectroscopy showed highly elevated levels of myo-inositol, lactate, and choline-containing compounds and decreased total N-acetyl-aspartate and N-acetyl-aspartyl-glutamate levels in the abnormal white matter. High values of ADC were observed, and both FA and MTR were attenuated. Conclusion The sequential MR imaging findings in Alexander disease provide strong evidence against active demyelination as sole explanation for the underlying pathology. An alternative explanation for our spectroscopic, DTI, and MTI findings—which would suggest demyelination—could be hyperplasia and hypertrophy of astrocytes, as seen in low grade gliomas.

Contains fulltext : 51320.pdf (Publisher’s version ) (Closed access) PURPOSE: To prospectively investigate whether quantitative magnetic resonance (MR) parameters, including magnetization transfer ratio (MTR), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and MR spectroscopic metabolite concentrations, allow for discrimination between different types of pathologic conditions that underlie signal intensity abnormalities in white matter. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Forty-one patients (19 male, 22 female; mean age, 15.4 years) and 41 control subjects (25 male, 16 female; mean age, 11.3 years) were included. Twelve patients had a hypomyelinating disorder; 14, a demyelinating disorder; five, a disorder characterized by myelin vacuolation; and 10, a disorder characterized by cystic degeneration. Regions of interest were selected within the parietal white matter and were transferred to the corresponding sections of the generated ADC, FA, and MTR maps to extract quantitative measurements. Linear discriminant analysis and univariate analysis of covariance were used for statistical evaluation. RESULTS: Linear discriminant analysis showed that 95% of patients were correctly classified by using total creatine, choline-containing compounds, myo-inositol, MTR, and ADC. In the hypomyelination group, all MR parameters were close to normal, with the exception of elevated total creatine (P = .03) and myo-inositol (P < .001) levels and decreased MTR values (P < .001). In the demyelination group, the levels of choline-containing compounds (P = .02) and myo-inositol (P < .001) were highly elevated. In the myelin vacuolation and cystic degeneration groups, high ADC values (P < .001) and variable decreases in all MR spectroscopic metabolites were seen. MTR was significantly reduced (P < .001) in the cystic degeneration group. CONCLUSION: Quantitative MR techniques can be used to discriminate between different types of white matter disorders and to classify white matter lesions of unknown origin with respect to underlying pathologic conditions.

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocvtes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2α (eIF2αP) and combined immunohistochemical and Western blot analysis of the down-stream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.

A myelin deficit in the cerebral white matter in infantile GM1 gangliosidosis is well established. Some have proposed this deficit to be secondary to axonal loss, while others argue for delayed or arrested myelination. We compared the frontal white and gray matter of two infants with GM1 gangliosidosis with four age-matched controls, using light microscopy with a quantitative analysis, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL), and electron microscopy (EM). In the GM1 cases, we found a marked decrease in the number of oligodendrocytes (85% in case 1 and 50% in case 2) and myelin sheaths (80% and 40%), with a mild decrease in axons (20% and 10%). Ultrastructurally, some naked axons and dilated cisterns of rough endoplasmic reticulum (RER) in oligodendrocytes were observed. There was no appreciable storage in remaining oligodendrocytes, nor obvious neocortical neuronal loss. An immunohistochemical decrease in proteolipid protein (PLP) and a more profound deficiency of myelin basic protein (MBP) indicate that this lesion is not simply the result of a delay or arrest in myelination and suggests a "dying-back" oligopathy. TUNEL-positive oligodendrocytes correlated with activated caspase-3 immunoreactivity. Amyloid precursor protein (APP)-immunoreactive aggregates were observed in proximal axons and meganeurites as well as in white matter axons. These data suggest that the myelin deficit results from a loss of oligodendrocytes and abnormal axoplasmic transport, perhaps consequent to massive neuronal storage of GM1.

Focal myositis is a rare idiopathic pseudotumour that mostly occurs in the extremities in adults.An 8-year-old boy presented with a few months history of swelling in the neck and fever. Ultrasound investigation revealed an inhomogenous mass consistent with lymphadenitis. After nine days of antibiotic therapy, the clinical picture of fever and swelling was unchanged. MRI imaging revealed continuity of the swelling in the sternocleidomastoid muscle and a malignant process was suspected. Microscopy showed no malignant cells, however, but a lymphoplasmocytic infiltration with fibrosis and degeneration of muscle fibres, consistent with focal myositis. No intervention was undertaken and one year after presentation the tumour had regressed almost entirely.Focal myositis can present as a cervical tumour. On ultrasound, the condition is hard to distinguish from lymphadenopathy or malignancy. In cases of insufficient response to empirical antibiotic therapy, focal myositis should be considered.

Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others. We compared oligodendrocytes of cerebral, cerebellar, and pontine white matter from 5 VWM patients with those of age-matched controls by light microscopy and immunohistochemistry using antibodies to activated caspase-3, bak, bax, bcl-2, survivin, and Ki-67, as well as by the TUNEL technique. Oligodendrocytes were identified morphologically and quantified using an ocular grid. We observed statistically significant increases in their densities at all sites; Ki-67-labeled oligodendrocytes were identified in 2 of 5 patients. Apoptotic oligodendrocytes were documented in 3 of 5 patients, while bcl-2 and survivin labeling was observed in 2 of 5 and 2 of 2 patients, respectively. There was a trend toward an increase in apoptotic labeling of oligodendrocytes that was strongest in the cerebrum, the major locus of VWM, in the youngest and most severely affected patients. These data conclusively demonstrate increased oligodendrocytic densities in VWM; the increase is not an artifact of white matter contraction. Our data also document that oligodendrocytes undergo apoptosis, perhaps in conjunction with major neurologic crises, and that a subset of oligodendrocytes are able to persist and proliferate. Conflicting proliferative, cell-death, and survival signals impact the oligodendrocytes of VWM.

OBJECTIVE: The objective of the study was to compare neonatal morbidity and long-term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN: We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS: At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P =.001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P =.12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION: Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants. © 2012 Mosby, Inc.