Molecular classification of muscle-invasive bladder cancer based on a simplified immunohistochemical panel using GATA3, CK5/6 and p16.

The choice of therapy for muscle-invasive bladder cancer (MIBC) could be influenced by the tumor's molecular subtype. Currently, well-defined consensus subtypes are based on tumor microarray mRNA data. Clearly defined and easy-to-use surrogate molecular subtypes, based on immunohistochemistry (IHC) performed on whole slides, are needed to make subtyping cost-effective and useful in routine work and future research. To aid in the development of a simple immunohistochemical classifier, a retrospective single-center series of 92 cases of localized bladder cancer was identified. Routine IHC for GATA3, cytokeratins 5 and 6 (CK5/6), and p16 was performed on whole tissue blocks containing muscle-invasive disease. Electronic medical records were retrieved and searched for clinical variables, treatment, and survival data. The mean age was 69.6 years, and 73% were males. Conservative treatment was used in 55% of cases, while cystectomy with chemotherapy was used in 45%. GATA3 and CK5/6 expression divided cases into broad luminal and basal subtypes, respectively, while p16 expression was used to subclassify luminal cases into luminal papillary and luminal unstable types according to the consensus molecular classification. When subtyped in this way, GATA3 and CK5/6 negative cases showed worse overall survival. Molecular subtyping of MIBC on whole slides containing muscle-invasive tumor using only three commonly used, consensus-based antibodies, is a feasible and cost-effective method for detecting subtypes of invasive bladder cancer. Future work combining morphological analysis and IHC is needed to fully translate the consensus molecular classification into a comprehensive, cost-effective subtyping strategy.

New Insights into the Diagnosis, Molecular Taxonomy, and Treatment of Bladder Cancer.

This review aims to emphasize new insights into the diagnosis, classification, and therapy of bladder cancer (BC). Bladder cancer is a heterogeneous, complex disease on a morphological, molecular, diagnostic, and prognostic level. Cancer stage is still the most important attribute for prognosis and treatment, while early detection with optimal and rapid individual therapeutic and surveillance approach is crucial. The vast majority of patients have a superficial, non-muscle-invasive tumor associated with a good prognosis after resection and adjuvant intravesical maintenance immuno or chemotherapy if needed. On the other hand, muscle-invasive bladder cancer is a highly aggressive disease with high morbidity and mortality. However, it has become a model for oncology success over the last five years with many available targeted therapeutic modalities. Metastatic BC is now amenable to multimodal treatment combining cystectomy and neoadjuvant chemotherapy and immunotherapy and is a target for precision medicine. CONCLUSION: A new molecular taxonomy for bladder cancer has been proposed and provided insight into BC's carcinogenesis, with some possible effects on therapy decisions. However, this classification is still not applicable in routine clinical practice. It opens new questions regarding the interplay between tumor genetic signature, intratumoral heterogeneity, therapy implications, and tumor progression.

Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer.

Neuroendocrine breast cancer (NEBC) is a group of rare tumors, which could benefit from therapy targeting the somatostatin receptors (SSTRs). In particular, SSTR2A and SSTR5 are potential targets given their consistent expression in gastrointestinal and pancreatic primary and metastatic neuroendocrine cancers. Currently, there are no studies describing the expression of SSTRs in NEBC. The purpose of our study was to characterize the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of NEBC. Thirty-one primary NEBC cases were analyzed, and SSTR2A and SSTR5 immunohistochemistry performed and scored using the modified immunoreactive score proposed by Remmele and Stanger. All patients were females with a mean age of 66.6 years (SD = 14). 77% of cases were histological grade 2. SSTR2A showed a weak positivity in 11 cases (35.5%), moderate positivity in 6 cases (19.4%) and strong positivity in 5 cases (16.1%). Nine cases were negative for SSTR2A (29%). SSTR5 showed a weak positivity in 16 cases (51.6%), moderate positivity in 6 cases (19.4%), while no cases showed strong positivity. Nine cases were negative for SSTR5 (29%). Five cases were negative for both SSTR2A and SSTR5. A weak to moderate SSTR2A and SSTR5 expression was observed in 50-70% of the cases. A subset of NEBCs with strong SSR2A expression may benefit from SSTRs targeted therapy. These results need further validation in a larger series including metastatic NEBC, to provide potential therapeutic targets for patients with advanced disease.

Pleomorphic undifferentiated soft tissue sarcoma in patient with long standing inflammatory bowel disease

Inflammatory bowel disease (IBD) has been associated with the development of both gastrointestinal and extraintestinal malignancy. The role of therapy in the development of malignancy in IBD has been controversial. We present the case of a 40-year-old female patient with long-standing mild IBD, who developed an undifferentiated pleomorphic sarcoma of the inguinal region and provide a brief review of the relevant literature. While our case likely represents a coincidence of two unrelated pathological entities, clinicians should keep in mind the possibility of soft tissue sarcomas in patients chronically treated with anti-inflammatory agents.

Pleomorphic undifferentiated soft tissue sarcoma in patient with long standing inflammatory bowel disease.

Inflammatory bowel disease (IBD) has been associated with the development of both gastrointestinal and extraintestinal malignancy. The role of therapy in the development of malignancy in IBD has been controversial. We present the case of a 40-year-old female patient with long-standing mild IBD, who developed an undifferentiated pleomorphic sarcoma of the inguinal region and provide a brief review of the relevant literature. While our case likely represents a coincidence of two unrelated pathological entities, clinicians should keep in mind the possibility of soft tissue sarcomas in patients chronically treated with anti-inflammatory agents.

Lower body negative pressure reduces optic nerve sheath diameter during head-down tilt.

The microgravity ocular syndrome (MOS) results in significant structural and functional ophthalmic changes during 6-mo spaceflight missions consistent with an increase in cerebrospinal fluid (CSF) pressure compared with the preflight upright position. A ground-based study was performed to assess two of the major hypothesized contributors to MOS, headward fluid shifting and increased ambient CO2, on intracranial and periorbital CSF. In addition, lower body negative pressure (LBNP) was assessed as a countermeasure to headward fluid shifting. Nine healthy male subjects participated in a crossover design study with five head-down tilt (HDT) conditions: -6, -12, and -18° HDT, -12° HDT with -20 mmHg LBNP, and -12° HDT with a 1% CO2 environment, each for 5 h total. A three-dimensional volumetric scan of the cranium and transverse slices of the orbita were collected with MRI, and intracranial CSF volume and optic nerve sheath diameter (ONSD) were measured after 4.5 h HDT. ONSD increased during -6° (P < 0.001), -12° (P < 0.001), and -18° HDT (P < 0.001) and intracranial CSF increased during -12° HDT (P = 0.01) compared with supine baseline. Notably, LBNP was able to reduce the increases in ONSD and intracranial CSF during HDT. The addition of 1% CO2 during HDT, however, had no further effect on ONSD, but rather ONSD increased from baseline in a similar magnitude to -12° HDT with ambient air (P = 0.001). These findings demonstrate the ability of LBNP, a technique that targets fluid distribution in the lower limbs, to directly influence CSF and may be a promising countermeasure to help reduce increases in CSF.NEW & NOTEWORTHY This is the first study to demonstrate the ability of lower body negative pressure to directly influence cerebrospinal fluid surrounding the optic nerve, indicating potential use as a countermeasure for increased cerebrospinal fluid on Earth or in space.

Habituation of self-motion perception following unidirectional angular velocity steps.

We investigated whether the perceived angular velocity following velocity steps of 80°/s in the dark decreased with the repetition of the stimulation in the same direction. The perceptual response to velocity steps in the opposite direction was also compared before and after this unidirectional habituation training. Participants indicated their perceived angular velocity by clicking on a wireless mouse every time they felt that they had rotated by 90°. The prehabituation perceptual response decayed exponentially with a time constant of 23.9 s. After 100 velocity steps in the same direction, this time constant was 12.9 s. The time constant after velocity steps in the opposite direction was 13.4 s, indicating that the habituation of the sensation of rotation is not direction specific. The peak velocity of the perceptual response was not affected by the habituation training. The differences between the habituation characteristics of self-motion perception and eye movements confirm that different velocity storage mechanisms mediate ocular and perceptual responses.

Decreased hypothalamus volumes in generalized anxiety disorder but not in panic disorder.

BACKGROUND: The hypothalamus is a brain structure involved in the neuroendocrine aspect of stress and anxiety. Evidence suggests that generalized anxiety disorder (GAD) and panic disorder (PD) might be accompanied by dysfunction of the hypothalamus-pituitary-adrenal axis (HPA), but so far structural alterations were not studied. We investigated hypothalamic volumes in patients with either GAD or PD and in healthy controls. METHODS: Twelve GAD patients, 11 PD patients and 21 healthy controls underwent a 1.5T MRI scan. Hypothalamus volumes were manually traced by a rater blind to subjects' identity. General linear model for repeated measures (GLM-RM) was used to compare groups on hypothalamic volumes, controlling for total intracranial volume, age and sex. RESULTS: The hypothalamus volume was significantly reduced (p=0.04) in GAD patients, with significant reductions in both the left (p=0.02) and right side (p=0.04). Patients with PD did not differ significantly (p=0.73). Anxiety scores were inversely correlated with hypothalamic volumes. LIMITATIONS: The small sample size could reduce the generalizability of the results while the lack of stress hormone measurements renders functional assessment of the hypothalamus-pituitary-adrenal axis not feasible. CONCLUSIONS: The present study showed decreased hypothalamic volumes in GAD patients but not in those with PD. Future longitudinal studies should combine volumetric data with measurements of stress hormones to better elucidate the role of the HPA axis in GAD.

Enlarged hypothalamic volumes in schizophrenia.

Hypothalamic abnormalities in schizophrenia have been associated with endocrine dysfunctions and stress response. The hypothalamus is involved in several pathways found disrupted in schizophrenia (e.g., hypothalamic-pituitary-adrenal axis, HPA axis); however the available results on potential structural hypothalamic alterations are still controversial. The aim of the study was to investigate the volumes of the hypothalamus and the mammillary bodies in patients with schizophrenia and healthy controls. Twenty-six patients with schizophrenia and 26 healthy controls underwent a 3 Tesla magnetic resonance imaging (MRI) scan. Hypothalamus and mammillary bodies were manually traced by a rater who was blind to subjects' identity. The General Linear Model was used in group comparisons of the volumes of the hypothalamus and the mammillary bodies. The hypothalamus and mammillary body volumes were significantly larger in patients with schizophrenia than controls, with significant enlargement of the left hypothalamus and trends for significantly increased right hypothalamus and right mammillary body. The size of the mammillary bodies was inversely correlated with negative symptoms and directly correlated with anxiety. This study showed abnormally increased sizes of the hypothalamus and the mammillary bodies in schizophrenia. Mammillary bodies volumes were associated to negative symptoms and anxiety. Future longitudinal studies on the volumes of the hypothalamus and the mammillary bodies with respect to the levels of related hormones will clarify their role in modulating HPA axis in schizophrenia.

Altered white matter integrity and development in children with autism: a combined voxel-based morphometry and diffusion imaging study.

BACKGROUND: A combined protocol of voxel-based morphometry (VBM) and diffusion-weighted imaging (DWI) was applied to investigate the neurodevelopment of gray and white matter in autism. METHODS: Twenty children with autism (mean age= 7 ± 2.75 years old; age range: 4-14; 2 girls) and 22 matched normally developing children (mean age = 7.68 ± 2.03 years old; age range: 4-11; 2 girls) underwent magnetic resonance imaging (MRI). VBM was employed by applying the Template-o-Matic toolbox (TOM), a new approach which constructs the age-matched customized template for tissue segmentation. Also, the apparent diffusion coefficients (ADC) of water molecules were obtained from the analysis of DWI. Regions of interests (ROIs), standardized at 5 pixels, were placed in cortical lobes and corpus callosum on the non-diffusion weighted echo-planar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the ADC values. RESULTS: Compared to normal children, individuals with autism had significantly: (1) increased white matter volumes in the right inferior frontal gyrus, the right fusiform gyrus, the left precentral and supplementary motor area and the left hippocampus, (2) increased gray matter volumes in the inferior temporal gyri bilaterally, the right inferior parietal cortex, the right superior occipital lobe and the left superior parietal lobule, and (3) decreased gray matter volumes in the right inferior frontal gyrus and the left supplementary motor area. Abnormally increased ADC values in the bilateral frontal cortex and in the left side of the genu of the corpus callosum were also reported in autism. Finally, age correlated negatively with lobar and callosal ADC measurements in individuals with autism, but not in children with normal development. CONCLUSIONS: These findings suggest cerebral dysconnectivity in the early phases of autism coupled with an altered white matter maturation trajectory during childhood potentially taking place in the frontal and parietal lobes, which may represent a neurodevelopmental marker of the disorder, possibly accounting for the cognitive and social deficits.