Prediction of non-muscle invasive bladder cancer outcomes assessed by innovative multimarker prognostic models.

BACKGROUND: We adapted Bayesian statistical learning strategies to the prognosis field to investigate if genome-wide common SNP improve the prediction ability of clinico-pathological prognosticators and applied it to non-muscle invasive bladder cancer (NMIBC) patients. METHODS: Adapted Bayesian sequential threshold models in combination with LASSO were applied to consider the time-to-event and the censoring nature of data. We studied 822 NMIBC patients followed-up >10 years. The study outcomes were time-to-first-recurrence and time-to-progression. The predictive ability of the models including up to 171,304 SNP and/or 6 clinico-pathological prognosticators was evaluated using AUC-ROC and determination coefficient. RESULTS: Clinico-pathological prognosticators explained a larger proportion of the time-to-first-recurrence (3.1 %) and time-to-progression (5.4 %) phenotypic variances than SNPs (1 and 0.01 %, respectively). Adding SNPs to the clinico-pathological-parameters model slightly improved the prediction of time-to-first-recurrence (up to 4 %). The prediction of time-to-progression using both clinico-pathological prognosticators and SNP did not improve. Heritability (h (2)) of both outcomes was <1 % in NMIBC. CONCLUSIONS: We adapted a Bayesian statistical learning method to deal with a large number of parameters in prognostic studies. Common SNPs showed a limited role in predicting NMIBC outcomes yielding a very low heritability for both outcomes. We report for the first time a heritability estimate for a disease outcome. Our method can be extended to other disease models.

In vivo reflectance confocal microscopy characterization of silver deposits in localized cutaneous argyria.

Localized cutaneous argyria is a rare condition secondary to skin deposition of silver following exposure to substances containing this metal. The clinical appearance and dermoscopy findings require deep melanocytic lesions and particularly melanoma metastasis to be ruled out. Silver deposits are usually confirmed by scanning electron microscopy and/or energy-dispersive X-ray spectroscopy. Herein we describe the in vivo reflectance confocal microscopy (RCM) features observed in one case of localized cutaneous argyria. These features include the presence of a hyperrefractile network in the papillary dermis and a periadnexal dotted bright pattern. In vivo RCM might be a useful tool for an early diagnosis of this uncommon entity.

Clinical-pathological differences and smoking habit depending on gender in a cohort of patients with transitional cell carcinoma of the bladder: retrospective study.

OBJECTIVES: The increased incidence of transitional cell carcinoma (TCC) of the bladder in men is known, generally attributed to greater exposure to the effect carcinogenic products. Although it has been reported that cancer-specific outcome can be particularly adverse in women due to socioeconomic or biological factors, clinical-pathological differences of TCC at the time of diagnosis have not been sufficiently studied. The aim of this study is to analyze whether there are gender-related differences in grade and tumor stage in primary bladder TCC. METHODS: All consecutive primary bladder TCC diagnoses made in our institution between 1990 and 2009 have been included. We retrospectively analyzed age, smoking, symptoms at presentation, tumor grade (WHO 1973), tumor size and number, and TNM stage, comparing men and women. Statistical analysis was conducted using the Mann-Whitney U test as non-parametric test and Chi-squared test to compare frequencies. RESULTS: We analyzed 1196 patients (992 males and 204 females) with a 5:1 ratio. We found significant differences in age (69 years vs. 73 years), smoking (46.5% vs. 11.2%)and muscle-invasive stage (12.1% vs. 18.1%). Correcting by tobacco consumption, never-smoker women have larger and more aggressive tumors with a frequency of muscle-invasive disease three times higher than male never-smokers and equaling to male current-smokers. CONCLUSION: TCC of the bladder is more frequent in males than females. In this series, women are older at the time of diagnosis and most often affected by muscle-invasive disease particularly in never-smokers. We need studies to analyze the potential impact of passive smoking to justify these results.

A transcriptional signature associated with the onset of benign prostate hyperplasia in a canine model.

BACKGROUND: Benign prostatic hyperplasia (BPH) represents the most frequent proliferative abnormality of the human prostate. In spite of the well-characterized architectural development of BPH, little is known about the cellular and molecular events that contribute to it. METHODS: We have developed an animal model to evaluate the follow-up of hormone-induced BPH and the analysis of the gene expression associated with BPH. Immunohistochemistry on human patient samples validated the BPH-related molecular alterations. RESULTS: Canine specific Affymetrix microarray analysis performed on sequential biopsies obtained from a beagle dog dynamic model characterized a number of genes altered during the onset of BPH. In addition to the genes involved in calcification, matrix remodeling, detoxification, cell movement, and mucosa protection (MGP, MMP2, TIMP2, ITIH3, GST, MT2A, SULT1A1, FKBP1B, MUC1, STRBP, TFF3), the up-regulation of TGFB3 and CLU indicated a complete adjustment of the transdifferentiation, senescence and apoptosis programs. The up-regulation of Clusterin was validated by RT-qPCR and immunohistochemistry, both in the dog dynamic model and in human samples, further confirming the suitability of the animal model for the study of the molecular alterations associated with BPH. CONCLUSIONS: Transcriptome analysis performed on a dynamic animal model that accurately mimicked the human clinic, allowed us to characterize a gene expression pattern associated with the onset of BPH.

Occupation and bladder cancer in a hospital-based case-control study in Spain.

OBJECTIVES: We investigated the association between occupation and bladder cancer in a hospital-based case-control study conducted in Spain. METHODS: 1219 patients with transitional cell carcinoma of the urinary bladder and 1271 controls selected from 18 hospitals in Spain between June 1998 and September 2000 provided detailed information on life-time occupational history, smoking habits, medical history, and other factors. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for each occupation and industry, adjusting for age, hospital region, smoking duration, and employment in a high-risk occupation for bladder cancer. RESULTS: Statistically significant increased risks were observed among men employed as machine operators in the printing industry (OR 5.4; 95% CI 1.6 to 17.7), among men employed in the transportation equipment industry (OR 1.6; 95% CI 1.1 to 2.6) and among those who had worked for >/=10 years in the electrical/gas/sanitary services (OR 3.9; 95% CI 1.5 to 10.4) and in hotels and other lodgings (OR 3.1; 95% CI 1.3 to 7.3). Men who worked as miscellaneous mechanics and repairers (OR 2.0; 95% CI 1.1 to 3.6) and as supervisors in production occupations (OR 2.1; 95% CI 1.2 to 3.6) also had excess risks for bladder cancer. Male farmers and those who worked in crop and livestock production had decreased risks for bladder cancer. We found no significant associations between occupation or industry and bladder cancer risk among women. CONCLUSIONS: We did not observe excess bladder cancer risk for many of the occupations identified as being a priori at high risk. Examination of more detailed job exposure information should help clarify these associations.

Primitive neuroectodermal tumor of the central nervous system with glial differentiation: a FISH study of an adult case.

Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS), a rare occurrence in adults, may show glial differentiation and can be misinterpreted as pure astrocytic neoplasms. Few fluorescence in situ hybridization (FISH) studies have been carried out on these tumors; isochromosome 17q was found to be the major chromosomal abnormality. We present the case of an adult in which we performed a FISH study of both the glial and neuronal components. A complex array of FISH changes, not including an isochromosome 17q were identified.

Expression of androgen, oestrogen alpha and beta, and progesterone receptors in the canine prostate: differences between normal, inflamed, hyperplastic and neoplastic glands.

The expression of receptor for androgen (AR), oestrogen alpha and beta (ERalpha and ERbeta) and progesterone (PR) was examined immunohistochemically in canine prostate specimens (normal, hyperplastic, inflamed [prostatitis] or neoplastic). AR immunolabelling was seen in 100% of epithelial cells of normal and hyperplastic tissue, the corresponding figures for inflamed and carcinomatous tissue being 74% and 65%, respectively. ERalpha labelling was seen in 85% of epithelial cells in normal prostate glands, the corresponding figures for hyperplastic, inflamed and neoplastic glands being 35%, 22% and 12%, respectively. ERbeta labelling was seen in 85% of epithelial cells of normal glands and in about 70% of such cells in glands showing pathological changes. On the other hand, PR expression (weak) in normal glands was observed in fewer epithelial cells (44%) than in hyperplastic (70%), inflamed (62%) or neoplastic (64%) glands.

Independent regulation of adherens and tight junctions by tyrosine phosphorylation in Caco-2 cells.

To study the role of tyrosine phosphorylation in the control of intercellular adhesion of intestinal cells, we have generated several clones of Caco-2 cells that express high levels of pp60v-src only after addition of butyrate. Expression of this oncogene in cells 5 days after confluence induced beta-catenin and p120-ctn tyrosine phosphorylation, redistribution of E-cadherin to the cytosol and disassembly of adherens junctions. However, tight junctions of Caco-2 cells at 5 days after confluence were not altered by expression of pp60v-src. Similar results were obtained when Caco-2 cells were incubated with phosphotyrosine phosphatase inhibitor orthovanadate. Although addition of this compound to postconfluent cells disrupt adherens junctions, tight junctions remain unaltered, as determined measuring monolayer permeability to mannitol or hyperphosphorylation of Triton-insoluble occludin. Modifications in tight junction permeability of Caco-2 were only observed at high concentrations of orthovanadate (1 mM). Interestingly, this tyrosine phosphorylation-refractory state was achieved after confluence since early postconfluent cells (day 2) showed a limited but significant response to low doses of orthovanadate. These results suggest that tight junctions of differentiated Caco-2 cells are uncoupled from adherens junctions and are insensitive to regulation by tyrosine phosphorylation.

Osteoblastic proliferation in bone biopsies from patients with end-stage chronic renal failure.

Osteoblasts have traditionally been considered to be terminally differentiated cells and therefore unable to divide. Data in recent years, however, indicate that cellular differentiation does not usually preclude preservation of proliferative ability and that most differentiated cells are able to divide under adequate stimuli. The aim of this study was to assess whether cubic osteoblasts undergo proliferation during the formation phase of the remodeling cycle under a stimulus that increased bone turnover. For that purpose, the osteoblastic proliferation index (OPI) was analyzed by DNA image cytometry in transiliac bone biopsies from 33 patients with chronic renal failure (23 men, 10 women; mean age 50.4 +/- 15.1 years) who have been classified into low (n = 13), normal (n = 15), and high (n = 15) bone turnover according to activation frequency (Ac.f). OPI was significantly higher (p < 0.002) in the high bone turnover group (13.90 +/- 4.72%) compared with the low (2.38 +/- 4.13%) and normal turnover groups (2.84 +/- 4.04%). There was a positive correlation between OPI and the following histomorphometric parameters: bone formation rate, surface referent (r = 0.76, p = 0.00001), activation frequency (r = 0.73, p = 0.00001), mineral apposition rate (r = 0.73, p = 0.00001), bone formation rate, volume referent (r = 0.71, p = 0.00001), and mineralizing surface (r = 0.62, p = 0.0001). This study shows that a rise in bone turnover is associated with a marked increase of bone-forming cell proliferation in patients with end-stage chronic renal failure. From this finding, it may be concluded that cubic osteoblasts do not behave as "terminally differentiated" cells in vivo, because a high proportion of them are still able to divide.

Reactive vascular lesion of nasal septum simulating angiosarcoma in a cocaine abuser.

We report the case of an exuberant ulcerative angiomatoid nasal lesion in a cocaine abuser. The lesion was made up of polymorphous endothelial cells with occasional mitoses, arranged in a lobular pattern with infiltrative-looking areas. There were extensive areas of thrombosis with focal recanalization. Intravascular proliferation was not observed. The clinical, radiological, and histological features suggested hemangiosarcoma as the main differential diagnosis, but the lobular architecture of the lesion and the widespread thrombosis favoured the diagnosis of a benign reactive process.

Malignant pigmented clear cell epithelioid tumor of the kidney: clear cell ("sugar") tumor versus malignant melanoma.

A 73-year-old woman presented with an hemorrhagic kidney tumor initially interpreted as a renal cell carcinoma (RCC). A retroperitoneal recurrence infiltrating the duodenal wall was made up of clear cells, some of which contained Fontana-Masson positive pigment, immunopositive for HMB-45, S-100 protein, actin, and vimentin. The same immunohistochemical profile was retrospectively reproduced in the kidney tumor, where melanosomes were also found ultrastructurally. Lipomatous differentiation was not observed. There was no history of malignant melanoma (MM), or stigmata of tuberous sclerosis. The patient died of disease 5 years after the initial diagnosis. This neoplasm can be considered as a malignant, pigmented, clear-cell epithelioid variant of angiomyolipoma, or "sugar" tumor of the kidney, with the peculiarity of having a previously unreported component of pigmented cells visible on light microscopy. This finding raises the possibility that the exceptional cases of MM reported in renal parenchyma may be pigmented variants of epithelioid angiomyolipoma rather than true MM.

Thymoma associated with CD4+ lymphopenia, cytomegalovirus infection, and Kaposi's sarcoma.

A case of thymoma with associated opportunistic infections, CD4/CD8 T-lymphocyte imbalance, low CD4-positive T-lymphocyte counts and Kaposi's sarcoma (KS) without HIV infection is reported. Cytomegalovirus inclusions were identified in the nuclei of some KS spindle and endothelial cells. It is known that KS has a high prevalence in AIDS patients and has occasionally been associated with other causes of immunosuppression. In previous studies, coexisting KS and thymoma were related to myasthenia gravis, corticosteroid treatment and excess CD8-positive T-lymphocyte counts. More recently an imbalance between CD4 and CD8 positive T lymphocytes has been identified in association with thymoma. The present case suggests that there may be a relationship between thymoma, CD4-positive lymphopenia, and KS.

Renal cell carcinoma with syncytial giant cell component.

We report a case of clear cell renal cell carcinoma in which a prominent multinucleated giant cell component was intermingled with clear, granular, and spindle cells. Histological, ultrastructural, cytometric, and cytogenetic features of giant cells were similar to those of mononucleated cells in the tumor, and therefore they were not from stromal or osteoclast derivation. These giant cells had homogeneous, finely granular, abundant cytoplasm, often with scalloped cell borders, and contained from 5 to more than 50 nuclei, all of them very similar in size and shape, with prominent central nucleoli. Occasionally, surrounding inflammatory cells were also engulfed in the cytoplasm. This syncytial appearance was more similar to that of some giant cell carcinomas from the lung than to the pleomorphic giant cells often encountered in high grade renal cell tumors. Although the patient is alive and free of disease 6 years after diagnosis, a longer follow-up will be required to assess the potential prognostic influence of this peculiar histological appearance.

Fine-needle aspiration of chromophobe renal-cell carcinoma metastatic to the thyroid gland.

Chromophobe renal cell carcinoma is an unusual variant of renal carcinoma that has less aggressive behavior than clear cell carcinomas. There are few documented cases of metastases, none of which occurred in the thyroid gland. A case is presented of chromophobe renal cell carcinoma metastatic to the thyroid eight years after right nephrectomy, suspected by FNA-biopsy and confirmed histologically. Although metastases of chromophobe renal cell carcinoma are rare, they may also present in thyroid, even many years after primary tumor diagnosis, just like clear cell carcinomas. Even though the FNA cytology of chromophobe renal cell carcinoma has distinctive features, in the context of the thyroid, it can be mistaken for a primary tumor of that organ. In our case, the history of a previous renal tumor was essential in suggesting a metastatic lesion, and histologic and ultrastructural features allowed its precise identification.

[Fiber-optic bronchoscopic biopsy of bronchial smooth muscle. Efficacy of the technique in individuals with normal lung function and patients with COPD]. / Biopsia de músculo liso bronquial mediante fibrobroncoscopia. Eficacia de la técnica en individuos con función pulmonar normal y en pacientes con EPOC.

BACKGROUND AND OBJECTIVES: The epithelium and airway smooth muscles of patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma undergo certain structural changes that are probably related to increased expression of inflammatory molecules and cell growth factors. Studying the relation between disease and changes in bronchial smooth muscle is difficult if investigation is restricted to samples from autopsies or thoracotomies. This study was designed to evaluate the probability of obtaining bronchial smooth muscle by endoscopic bronchial biopsy in patients with COPD and from individuals with normal lung function, the relation of disease to bronchial epithelial histology, and the potential usefulness of studying airway muscle remodeling events. METHODS: Forty-two patients undergoing diagnostic fiberoptic bronchoscopy were enrolled. Bronchial biopsies were taken systematically from the lobar and segmental dividing ridges. The epithelial structure was analyzed by conventional histology. The smooth muscle was identified by immunohistochemistry (anti-desmin antibody assay) and Western-blot analysis (anti-desmin, actin and myosin antibodies). RESULTS: Sixty-nine percent of the biopsies contained bronchial smooth muscle. The probability of obtaining smooth muscle was higher in segmental than in lobar biopsies (72 vs 30%, p < 0.05). This probability was unrelated to the presence of COPD or to signs of epithelial inflammation. The fragments allowed us to use electrophoresis to identify protein structures (myosin, actin, desmin) involved in muscle remodeling processes. CONCLUSIONS: Endoscopic biopsy of the bronchi allows us to obtain bronchial smooth muscle samples in a large percentage of patients, particularly when performed on segmental bronchi. The technique may be useful for future studies examining the processes of airway smooth muscle remodeling.

[Capillary density and respiratory function in the external intercostal muscle]. / Densidad capilar y función respiratoria en el músculo intercostal externo.

UNLABELLED: Changes in lung function have been related to adaptive structural modifications in respiratory muscles. OBJECTIVE: To evaluate the capillary density (Dcap) of the external intercostal muscle in patients with chronic obstructive pulmonary disease (COPD), and its possible relation to respiratory function. METHODS: Forty-two individuals (61 +/- 9 years old) underwent conventional lung function testing and evaluation of respiratory muscles (maximum pressures at rest and a tolerance test using Martyn's technique). The sample included 10 subjects with normal lung function and 32 COPD patients (FEV1 between 13 and 78% of reference), in stable phase and with no respiratory insufficiency (PaO2 > 60 mmHg). A local biopsy of the external intercostal muscle was taken from all subjects at the fifth intercostal space (anterior axillary [correction of axile]) on the non-dominant side. The sample was processed for morphometry and fiber typing with ATPase staining and for quantifying capillarity with Gomori's trichrome staining. RESULTS: The mean diameter was 61 +/- 10 micrograms, with type I fibers predominating (56 +/- 11%). Dcap was 2.8 +/- 0.6 capillaries/fiber (equivalent to 1.02 +/- 0.37 capillaries/mm2 of fibrillary surface). The number of capillaries/fiber was significantly higher in patients with severe COPD (FEV1 < 50% ref) than in controls (3.0 +/- 0.6 versus 2.3 +/- 0.5, p < 0.01) and was inversely related to FEV1 (r = -0.395, p < 0.01). Muscle capillarity was unrelated to other function variables, including markers of respiratory muscle function and gas exchange. CONCLUSION: The structural remodelling of external intercostal muscles in COPD patients also includes an increase in density of interfibrillary capillaries. This increase is proportional to the severity of obstruction and probably reflects an adaptive phenomenon.

[Familial recurrent paralysis of the brachial plexus. Tomaculous neuropathy]. / Paralysie récidivante familiale du plexus brachial. Neuropathie tomaculaire.

Familial recurrent plexopathy related to tomacular neuropathy is only the localized expression, with a familial predisposition, of a more diffuse disease. Such are the conclusions we drew from a study of 3 cases, in 2 families, of recurrent tomacular brachial plexopathy. In all 3 cases the condition was transmitted by the mother as an autosomal dominant trait. Biopsy of a sensory nerve was performed in 2 cases and showed, in one, typical images of myelinic degeneration at various stages, corresponding to the formation of tomacular tickenings. Tomacular brachial plexopathy must be distinguished from hereditary amyotrophic neuralgia.