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Inflammatory Myofibroblastic Tumor of the Urinary Bladder: The Role of IgG4 and the Comparison of Two Immunohistochemical Antibodies and Fluorescence in Situ Hybridization for the Detection of ALK Alterations.
Histopathology
PUBLISHED: 11-20-2014
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We examined gene rearrangement and the expression of anaplastic lymphoma kinase (ALK) in urinary bladder inflammatory myofibroblastic tumor (IMT) using fluorescence in situ hybridization (FISH) and two immunohistochemical antibodies to ALK. We also investigated whether IMT represents an IgG4-related disease.
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Estimation of bacterioruberin by Raman spectroscopy during the growth of halophilic archaeon Haloarcula marismortui.
Appl Opt
PUBLISHED: 11-18-2014
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Halophilic archaea are interesting microorganisms that produce low biomass and metabolites, complicating their quantification. Raman spectroscopy (RS) is a powerful technique, which requires small samples, attractive for using in archaeal research. The objective of this work was the estimation of bacterioruberin content along with Haloarcula marismortui growth and their correlation with biomass concentration. RS was used to detect characteristic bands of bacterioruberin (vibrational modes C?CH, C?C, and C?C) in H. marismortui culture samples. The intensity of Raman spectra in bacterioruberin and the biomass concentration were adequately correlated. The highest production of bacterioruberin occurred at 60 h. RS is revealed as a reliable technique for the estimation of bacterioruberin in the biomass of H. marismortui, which could be considered as a promising qualitative and quantitative technique to assay metabolites in cell cultures.
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Effects of hormones on platelet aggregation.
Horm Mol Biol Clin Investig
PUBLISHED: 11-13-2014
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Abstract Platelets and their activation/inhibition mechanisms play a central role in haemostasis. It is well known agonists and antagonists of platelet activation; however, during the last years novel evidences of hormone effects on platelet activation have been reported. Platelet functionality may be modulated by the interaction between different hormones and their platelet receptors, contributing to sex differences in platelet function and even in platelet-mediated vascular damage. It has suggested aspects that apparently are well established should be reviewed. Hormones effects on platelet activity are included among them. This article tries to review knowledge about the involvement of hormones in platelet biology and activity.
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Non-acetogenic growth of the acetogen Acetobacterium woodii on 1,2-propanediol.
J. Bacteriol.
PUBLISHED: 11-12-2014
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Acetogenic bacteria can grow by the oxidation of various substrates coupled to the reduction of CO2 in the Wood-Ljungdahl pathway. Here we show that growth of the acetogen Acetobacterium woodii on 1,2-propanediol (1,2-PD) as sole carbon and energy source is independent of acetogenesis. Enzymatic measurements and metabolite analysis revealed that 1,2-PD is dehydrated to propionaldehyde, which is further oxidized to propionyl-CoA with concomitant reduction of NAD. NADH is reoxidized by reducing propionaldehyde to propanol. The potential gene cluster coding for the responsible enzymes includes genes coding for shell proteins of bacterial microcompartments. Electron microscopy revealed the presence of microcompartments as well as storage granula in cells grown on 1,2-PD. Gene clusters coding for the 1,2-PD pathway can be found in other acetogens as well but the distribution shows no relation to the phylogeny of the organisms.
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Small cell carcinoma of the prostate: Molecular basis and clinical implications.
Histol. Histopathol.
PUBLISHED: 11-11-2014
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Small cell carcinoma of the prostate (PSCC) is a rare and highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease, including metastases to bone, viscera, and the central nervous system. Histologically, PSCC is indistinguishable from its pulmonary counterpart. Although PSCC may occur in pure form, as in small cell lung carcinoma, it also occurs in conjunction with conventional glandular prostate carcinoma, and may evolve from conventional adenocarcinoma during the course of hormonal therapy. Immunohistochemical staining is extremely helpful in establishing the diagnosis, a prerequisite, as in small cell lung cancer, for optimal therapeutic strategy. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. Improvement in survival may depend upon the identi?cation of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. This review will discuss general aspects of PSCC, focusing on ways in which our understanding of PSCC has been advanced by studies of the histopathologic, immunohistochemical and molecular alterations in this disease.
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[Carbohydrate: current role in diabetes mellitus and metabolic disease].
Nutr Hosp
PUBLISHED: 11-04-2014
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There is a prevalence of diabetes mellitus (DM), unknown DM and stress hyperglycemia among hospital patients, and the nutritional treatment is a key part of care, where carbohydrates (CH) intake is a controversial issue. There is also a discussion on the increase of prevalence for DM, obesity and metabolic disease with refined CH or sugar.
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Meta-analysis of multiple outcomes: a multilevel approach.
Behav Res Methods
PUBLISHED: 11-02-2014
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In meta-analysis, dependent effect sizes are very common. An example is where in one or more studies the effect of an intervention is evaluated on multiple outcome variables for the same sample of participants. In this paper, we evaluate a three-level meta-analytic model to account for this kind of dependence, extending the simulation results of Van den Noortgate, López-López, Marín-Martínez, and Sánchez-Meca Behavior Research Methods, 45, 576-594 (2013) by allowing for a variation in the number of effect sizes per study, in the between-study variance, in the correlations between pairs of outcomes, and in the sample size of the studies. At the same time, we explore the performance of the approach if the outcomes used in a study can be regarded as a random sample from a population of outcomes. We conclude that although this approach is relatively simple and does not require prior estimates of the sampling covariances between effect sizes, it gives appropriate mean effect size estimates, standard error estimates, and confidence interval coverage proportions in a variety of realistic situations.
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Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model.
FASEB J.
PUBLISHED: 11-01-2014
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Although all KRas (protein that in humans is encoded by the KRas gene) point mutants are considered to have a similar prognostic capacity, their transformation and tumorigenic capacities vary widely. We compared the metastatic efficiency of KRas G12V (Kirsten rat sarcoma viral oncogene homolog with valine mutation at codon 12) and KRas G13D (Kirsten rat sarcoma viral oncogene homolog with aspartic mutation at codon 13) oncogenes in an orthotopic colorectal cancer (CRC) model. Following subcutaneous preconditioning, recombinant clones of the SW48 CRC cell line [Kras wild-type (Kras WT)] expressing the KRas G12V or KRas G13D allele were microinjected in the mouse cecum. The percentage of animals developing lymph node metastasis was higher in KRas G12V than in KRas G13D mice. Microscopic, macroscopic, and visible lymphatic foci were 1.5- to 3.0-fold larger in KRas G12V than in KRas G13D mice (P < 0.05). In the lung, only microfoci were developed in both groups. KRas G12V primary tumors had lower apoptosis (7.0 ± 1.2 vs. 7.4 ± 1.0 per field, P = 0.02), higher tumor budding at the invasion front (1.2 ± 0.2 vs. 0.6 ± 0.1, P = 0.04), and a higher percentage of C-X-C chemokine receptor type 4 (CXCR4)-overexpressing intravasated tumor emboli (49.8 ± 9.4% vs. 12.8 ± 4.4%, P < 0.001) than KRas G13D tumors. KRas G12V primary tumors showed Akt activation, and ?5 integrin, vascular endothelial growth factor A (VEGFA), and Serpine-1 overexpression, whereas KRas G13D tumors showed integrin ?1 and angiopoietin 2 (Angpt2) overexpression. The increased cell survival, invasion, intravasation, and specific molecular regulation observed in KRas G12V tumors is consistent with the higher aggressiveness observed in patients with CRC expressing this oncogene.-Alamo, P., Gallardo, A., Di Nicolantonio, F., Pavón, M. A., Casanova, I., Trias, M., Mangues, M. A., Lopez-Pousa, A., Villaverde, A., Vázquez, E., Bardelli, A., Céspedes, M. V., Mangues, R. Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model.
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Prostate changes related to therapy: with special reference to hormone therapy.
Future Oncol
PUBLISHED: 10-18-2014
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ABSTRACT? Hormone and radiation therapy have traditionally been used in prostate cancer (PCa). Morphological effects are often identified in needle biopsies and surgical specimens. A range of histological changes are seen in the non-neoplastic prostate and in the pre-neoplastic and neoplastic areas. Other ablative therapies, including cryotherapy, and emerging focal therapies, such as high-intensity focused ultrasound, photodynamic therapy and interstitial laser thermotherapy, may induce changes on the prostate. As new compounds are developed for prostate cancer treatment, it is important to document their effects on benign and neoplastic prostate tissue.
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The Yale-Brown Obsessive Compulsive Scale: A Reliability Generalization Meta-Analysis.
Assessment
PUBLISHED: 10-01-2014
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The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) is the most frequently applied test to assess obsessive compulsive symptoms. We conducted a reliability generalization meta-analysis on the Y-BOCS to estimate the average reliability, examine the variability among the reliability estimates, search for moderators, and propose a predictive model that researchers and clinicians can use to estimate the expected reliability of the Y-BOCS. We included studies where the Y-BOCS was applied to a sample of adults and reliability estimate was reported. Out of the 11,490 references located, 144 studies met the selection criteria. For the total scale, the mean reliability was 0.866 for coefficients alpha, 0.848 for test-retest correlations, and 0.922 for intraclass correlations. The moderator analyses led to a predictive model where the standard deviation of the total test and the target population (clinical vs. nonclinical) explained 38.6% of the total variability among coefficients alpha. Finally, clinical implications of the results are discussed.
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Intraductal carcinoma of the prostate: interobserver reproducibility survey of 39 urologic pathologists.
Ann Diagn Pathol
PUBLISHED: 08-26-2014
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The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, ?(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.
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Does prostate acinar adenocarcinoma with Gleason Score 3¿+¿3¿=¿6 have the potential to metastasize?
Diagn Pathol
PUBLISHED: 08-22-2014
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BackgroundThere is a worldwide debate involving clinicians, uropathologists as well as patients and their families on whether Gleason score 6 adenocarcinoma should be labelled as cancer.Case descriptionWe report a case of man diagnosed with biopsy Gleason score 6 acinar adenocarcinoma and classified as low risk (based on a PSA of 5 ng/mL and stage cT2a) whose radical prostatectomy specimen initially showed organ confined Gleason score 3¿+¿3¿=¿6, WHO nuclear grade 3, acinar adenocarcinoma with lymphovascular invasion and secondary deposit in a periprostatic lymph node. When deeper sections were cut to the point that almost all the slice present in the paraffin block was sectioned, a small tumor area (<5% of the whole tumor) of Gleason pattern 4 (poorly formed glands) was found in an extraprostatic position.ConclusionThe epilogue was that the additional finding changed the final Gleason score to 3¿+¿3¿=¿6 with tertiary pattern 4 and the stage to pT3a.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_190.
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Pseudoangiosarcomatous urothelial carcinoma of the urinary bladder.
Am. J. Surg. Pathol.
PUBLISHED: 08-19-2014
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The pseudoangiosarcomatous pattern has been described mostly in cutaneous and some visceral squamous cell carcinomas and is unique for its striking morphologic resemblance to angiosarcoma. Herein, we describe the clinicopathologic features of 7 pseudoangiosarcomatous urothelial carcinomas that occurred in the urinary bladder. The patients included 6 men and 1 woman ranging in age from 47 to 87 years (median 70 y). The pseudoangiosarcomatous morphology was observed in 7 urothelial carcinomas including 3 with squamous differentiation and comprised 35% to 85% of the invasive tumor. Histologically, the pseudoangiosarcomatous carcinomas were characterized by tumor cell discohesion and lysis that created pseudolumina formations surrounded by attached residual tumor cells. Detached degenerating tumor cells variably admixed with inflammatory cells were common in the false lumina. Partly intact urothelial carcinoma nests contained irregular or cleft-like spaces and disintegrating tumor cells with stretched intercellular bridges. The tumor was commonly associated with a dense collagenous matrix, often surrounding the lytic nests. Similar tumor cell discohesion and breakdown were observed in 3 tumors with foci of squamous cell differentiation, distinguished by the presence of dyskeratosis and keratin formation. All 7 tumors contained other nonpseudoangiosarcomatous carcinoma components such as conventional urothelial carcinoma (5), squamous differentiation (4), sarcomatoid spindle cell carcinoma (2), small cell carcinoma (1), micropapillary carcinoma (1), and glandular differentiation (1). The pseudoangiosarcomatous urothelial carcinomas were all (7/7) diffusely CK7 positive, most (6/7) were GATA3 positive, and none (0/7) expressed vascular-associated markers. There was no evidence to suggest that apoptosis (by TUNEL assay and cleaved caspase-3 immunostaining) or loss of the adhesion molecules CD138 and e-cadherin were possible causes for the tumor cell discohesion and breakdown. All 7 tumors were high stage at cystectomy and included 1 pT3a, 2 pT3b, and 4 pT4a tumors, and 3 had pelvic lymph node involvement. Follow-up data available in 6 cases revealed a poor outcome with an overall median survival of 8.5 months. In conclusion, we present an unusual morphology of bladder carcinoma that has a striking resemblance to a malignant vasoformative tumor. Our series showed that bladder pseudoangiosarcomatous carcinoma morphology is associated with a higher tumor stage at cystectomy, commonly admixed with other aggressive carcinoma variant morphologies, and portend a poorer outcome. Knowledge of this pattern is also important to avoid misdiagnosis, particularly in limited tissue samples.
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A Comparison of Procedures to Test for Moderators in Mixed-Effects Meta-Regression Models.
Psychol Methods
PUBLISHED: 08-11-2014
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Several alternative methods are available when testing for moderators in mixed-effects meta-regression models. A simulation study was carried out to compare different methods in terms of their Type I error and statistical power rates. We included the standard (Wald-type) test, the method proposed by Knapp and Hartung (2003) in 2 different versions, the Huber-White method, the likelihood ratio test, and the permutation test in the simulation study. These methods were combined with 7 estimators for the amount of residual heterogeneity in the effect sizes. Our results show that the standard method, applied in most meta-analyses up to date, does not control the Type I error rate adequately, sometimes leading to overly conservative, but usually to inflated, Type I error rates. Of the different methods evaluated, only the Knapp and Hartung method and the permutation test provide adequate control of the Type I error rate across all conditions. Due to its computational simplicity, the Knapp and Hartung method is recommended as a suitable option for most meta-analyses. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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Tuberous Sclerosis-associated Renal Cell Carcinoma: A Clinicopathologic Study of 57 Separate Carcinomas in 18 Patients.
Am. J. Surg. Pathol.
PUBLISHED: 08-06-2014
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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with characteristic tumors involving multiple organ systems. Whereas renal angiomyolipoma (AML) is common in TSC, renal cell carcinoma (RCC) is rarely reported. Fifty-seven RCCs from 13 female and 5 male TSC patients were reviewed. Age at surgery ranged from 7 to 65 years (mean: 42 y). Nine patients (50%) had multiple synchronous and/or metachronous RCCs (range of 2 to 20 RCCs) and 5 had bilateral RCCs (28%). Seventeen patients (94%) had histologically confirmed concurrent renal AMLs, including 15 with multiple AMLs (88%) and 9 (50%) with AMLs with epithelial cysts. None of the 15 patients with available clinical follow-up information had evidence of distant metastatic disease from 6 to 198 months after their initial surgery (mean: 52 mo). The 57 RCCs exhibited 3 major distinct morphologies: (1) 17 RCCs (30%) had features similar to tumors previously described as "renal angiomyoadenomatous tumor" or "RCC with smooth muscle stroma"; (2) 34 RCCs (59%) showed features similar to chromophobe RCC; and (3) 6 RCCs (11%) showed a granular eosinophilic-macrocystic morphology. Distinct histologic changes were also commonly present in the background kidney parenchyma and included cysts or renal tubules lined by epithelial cells with prominent eosinophilic cytoplasm, nucleomegaly, and nucleoli. Immunohistochemically, all RCCs tested showed strong nuclear reactivity for PAX8 and HMB45 negativity. Compared with sporadic RCCs, TSC-associated RCCs have unique clinicopathologic features including female predominance, younger age at diagnosis, multiplicity, association with AMLs, 3 recurring histologic patterns, and an indolent clinical course. Awareness of the morphologic and clinicopathologic spectrum of RCC in this setting will allow surgical pathologists to better recognize clinically unsuspected TSC patients.
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Total submission of lymphadenectomy tissues removed during radical prostatectomy for prostate cancer: possible clinical significance of large-format histology.
Hum. Pathol.
PUBLISHED: 07-17-2014
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Complete submission of lymphadenectomy specimens increases the number of recovered lymph nodes and the detection of metastatic disease. There are advantages with the whole-mount technique over complete sampling with standard cassettes in terms of time needed to sample the tissue, number of blocks to be cut, and slides to be examined. The clinical significance of the approach is that all lymph nodes are identified, including those that are not palpable. In particular, this approach avoids the fact that an individual lymph node is oversampled and counted according to number of pieces obtained by the pathologist, mainly in nodes with considerable size.
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Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference.
Am. J. Surg. Pathol.
PUBLISHED: 07-17-2014
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The bladder working group of the 2013 International Society of Urologic Pathology (ISUP) Conference on Best Practices Recommendation in the Application of Immunohistochemistry (IHC) in Urologic Pathology discussed 5 settings in which IHC is commonly used in clinical practice. With regard to markers for urothelial differentiation, the committee found that there is no ideal marker or established panel to confirm urothelial differentiation. On the basis of the differential diagnostic consideration, positivity for GATA3, CK20, p63, and either high-molecular weight cytokeratin (HMWCK) or cytokeratin (CK)5/6 is of value in proving urothelial differentiation in the appropriate morphologic and clinical context. With regard to the role of IHC in the distinction of reactive atypia from urothelial carcinoma in situ, the committee recommended that morphology remains the gold standard in this differential diagnosis and that, at best, the IHC panel of CK20/p53/CD44(s) has potential utility but is variably used and has limitations. The immunostaining pattern must be interpreted with strict morphologic correlation, because overreliance on IHC may be misleading, particularly in the posttreatment setting. IHC has no role in the distinction of dysplasia versus carcinoma in situ and in the grading of papillary urothelial carcinoma. IHC may have a limited but distinct role in staging of bladder cancer. In a subset of cases, depending on the clinical and histologic context, broad-spectrum cytokeratins (to identify early or obscured invasion) and desmin (distinction of muscle from desmoplasia and to highlight muscle contours for subclassification) may be helpful. Limited experience and conflicting data preclude smoothelin or vimentin to be recommended routinely for subclassifying muscle type at this time. In the workup of a spindled cell proliferation of the bladder and in limited specimens, we recommend an immunohistochemical panel of 6 markers including ALK1, SMA, desmin, cytokeratin (AE1/AE3), and p63 with either of HMWCK or CK5/6. Currently, there are no prognostic immunohistochemical or molecular studies that are recommended to be routinely performed on biopsy or resection specimens.
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Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology consensus conference.
Am. J. Surg. Pathol.
PUBLISHED: 07-16-2014
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Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.
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Reliability Generalization Study of the Yale-Brown Obsessive-Compulsive Scale for Children and Adolescents.
J Pers Assess
PUBLISHED: 07-11-2014
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The Yale-Brown Obsessive-Compulsive Scale for children and adolescents (CY-BOCS) is a frequently applied test to assess obsessive-compulsive symptoms. We conducted a reliability generalization meta-analysis on the CY-BOCS to estimate the average reliability, search for reliability moderators, and propose a predictive model that researchers and clinicians can use to estimate the expected reliability of the CY-BOCS scores. A total of 47 studies reporting a reliability coefficient with the data at hand were included in the meta-analysis. The results showed good reliability and a large variability associated to the standard deviation of total scores and sample size.
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The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.
PLoS Genet.
PUBLISHED: 07-01-2014
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The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p?=?0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p?=?0.15) and a modest decrease in overall survival (p?=?0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
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Contemporary update on pathology-related issues of adult renal neoplasms.
Anal Quant Cytopathol Histpathol
PUBLISHED: 06-07-2014
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This review gives an update on selected issues on renal neoplasia with special references to emerging new tumor entities (thyroid-like follicular renal cell carcinoma, succinic dehydrogenase B deficiency-associated renal cell carcinoma, and anaplastic lymphoma kinase [ALK] translocation renal cell carcinoma), tumor grading (the International Society of Urological Pathology grading system), and assessment of tumoral involvement of the renal sinus structures, including the sinus fat, the loose connective tissue, or any sinus-based endothelium-lined space.
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Contemporary update on pathology-related issues on routine workup of prostate biopsy: sectioning, tumor extent measurement, specimen orientation, and immunohistochemistry.
Anal Quant Cytopathol Histpathol
PUBLISHED: 06-07-2014
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While the prime goal of the needle biopsy is to diagnose prostatic adenocarcinoma (PCa), once PCa is detected further descriptive information regarding the type of cancer, amount of tumor, and grade in prostate needle cores forms the cornerstone for contemporary management of the patient and to assess the potential for local cure and the risk for distant metastasis. This review gives an update on selected pathology-related issues on routine workup of prostate biopsy with special references to adequate histologic sectioning necessary to maximize cancer yield, tumor extent measurements and methodologies, specimen orientation, and the role of immunohistochemistry in the evaluation of the prostate. Multiple factors influence the diagnostic yield of prostate biopsies. Many of these factors are fixed and uncontrollable. Other factors are controlled by the urologist, including number of cores obtained, method and location of biopsy, and amount of tissue obtained. The yield of cancer is also controlled by the pathologist and histotechnologist. It is necessary to report the number of cores submitted and the number of positive cores, thereby giving the fraction of positive cores. The percentage involvement by carcinoma with or without the linear extent of carcinoma of the single core with the greatest amount of tumor should also be provided. Using the marking technique, we can add a new pathological parameter: pathological orientation. Cancer or atypical lesions can be accurately located within the biopsy specimen and integrated to biopsy approach. Probably the most common use of immunohistochemistry in the evaluation of the prostate is for the identification of basal cells, which are absent with rare exception in adenocarcinoma of the prostate and in general positive in mimickers of prostate cancer. If a case is still considered atypical by a uropathology expert after negative basal cell staining, positive staining for alpha-methylacyl-CoA-racemase can help establish in 50% of these cases a definitive diagnosis of cancer.
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Primary renal osteosarcoma.
Am. J. Clin. Pathol.
PUBLISHED: 04-10-2014
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To investigate primary osteosarcoma (osteogenic sarcoma) of the kidney, a rare and aggressive neoplasm.
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Adult primary paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of spermatic cord leiomyosarcoma.
Diagn Pathol
PUBLISHED: 03-31-2014
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The aim of this report is related to adult primary paratesticular mesenchymal tumors with emphasis on a case presentation and discussion of the spermatic cord leiomyosarcoma. Primary paratesticular tumors are rare, only accounting for 7% to 10% of all intrascrotal tumors. In adults, more than 75% of these lesions arise from the spermatic cord, 20% being leiomyosarcoma. Tumor grade, stage, histologic type, and lymph node involvement are independently predictive of prognosis.
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Clear Cell Renal Cell Carcinoma (ccRCC) with Hemangioblastoma-like Features: A Previously Unreported Pattern of ccRCC with Possible Clinical Significance.
Eur. Urol.
PUBLISHED: 03-23-2014
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The morphological features and immunohistochemical findings of two cases of clear cell renal cell carcinoma with extensive hemangioblastoma-like features are described. To the best of our knowledge, this is the first description of such a pattern, the differential diagnosis being with renal hemangioblastoma, a rare tumor that could be considered a diffuse hemangioblastoma-like change in a clear cell renal cell tumor. Even though the clinical significance and therapeutic implications are not yet known, the hemangioblastoma-like pattern could have favorable prognostic significance based on the fact that the renal hemangioblastomas described so far have benign behavior.
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Understanding Pathologic Variants of Renal Cell Carcinoma: Distilling Therapeutic Opportunities from Biologic Complexity.
Eur. Urol.
PUBLISHED: 02-26-2014
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Once believed to represent a uniform malignant phenotype, renal cell carcinoma (RCC) is now viewed as a diverse group of cancers that arise from the nephron.
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Recurrent papillary urothelial neoplasm of low malignant potential. Subtle architectural disorder detected by quantitative analysis in DAXX-immunostained tissue sections.
Hum. Pathol.
PUBLISHED: 02-26-2014
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The aim of the study was to identify subtle changes in the so-called architectural predominant order in nonrecurrent and recurrent papillary urothelial neoplasm of low malignant potential (PUNLMP). Quantitative analysis was performed with a software package written in LabVIEW (National Instruments, Austin, TX) in DAXX-immunostained tissue sections. Twelve cases of PUNLMP with papillary fronds sectioned lengthwise through the core were investigated and subdivided as follows: 7 nonrecurrent and 5 recurrent PUNLMP cases. Six cases of normal urothelium (NU) were included. When an epithelial thickness threshold is set at 108 ?m (ie, 400 pixels), there is a complete separation between NU and PUNLMP; however, nonrecurrent and recurrent cases fall in the same range of thickness. In setting a nuclear elongation factor threshold at 2.1, there are differences between the 2 PUNLMP groups, recurrent PUNLMP and NU cases, showing a somewhat similar proportion of elongated nuclei. The nuclear orientation separates nonrecurrent from recurrent PUNLMP groups; however, NU cases do not appear as a separate group from the 2 PUNLMP groups. In combining epithelial thickness, nuclear elongation, and orientation in a multivariate analysis, the 2 PUNLMP groups appear separate between them and from NU. NU is less thickened than the 2 PUNLMP groups and shows a combination of elongated and less elongated nuclei. Elongated nuclei are more numerous in nonrecurrent PUNLMP, whereas the nuclei in recurrent PUNLMP are less elongated and less polarized than in the other group. Such finding can be used routinely to identify those PUNLMP patients who will have recurrence.
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Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder.
Hum. Pathol.
PUBLISHED: 02-24-2014
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Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies.
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Differences between en bloc resection and enucleation of retroperitoneal sarcomas.
Cir Esp
PUBLISHED: 01-28-2014
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Today, free margin surgery is the gold-standard management for soft-tissue sarcoma patients and one of the most important predictors of recurrence and survival. To obtain optimal results, a multidisciplinary approach is necessary. The aim of this study was to evaluate the evolution of patients with RPS treated by «en bloc«surgical resection versus those treated with enucleation in the first surgery.
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Molecular characteristics of urothelial neoplasms in children and young adults: a subset of tumors from young patients harbors chromosomal abnormalities but not FGFR3 or TP53 gene mutations.
Mod. Pathol.
PUBLISHED: 01-25-2014
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Urothelial neoplasms in children and young adult patients are rare and hypothesized to have a lower rate of recurrence and progression than those of older adults. Because of their rarity, data regarding molecular abnormalities in these tumors are limited. We studied molecular characteristics of urothelial neoplasms from patients under age 30 years using UroVysion fluorescence in situ hybridization (chromosomes 3, 7, 17, and 9p21) and DNA mutational analysis for the FGFR3 and TP53 genes. Seventeen tumors were identified in patients 6-26 years of age, including low-grade papillary urothelial carcinoma (n=10), high-grade papillary urothelial carcinoma (n=5), urothelial papilloma (n=1), and papillary urothelial neoplasm of low malignant potential (n=1). No tumor demonstrated mutation of FGFR3 or TP53. Chromosomal abnormalities were detected only in patients aged ?19 years: two low-grade urothelial carcinomas had loss of 9p21 as a sole chromosomal abnormality and three high-grade urothelial carcinomas had other or multiple chromosomal abnormalities. Under age 19 years, no tumor showed molecular abnormalities with either method (five low-grade papillary urothelial carcinomas and one each of high-grade papillary urothelial carcinoma, papillary urothelial neoplasm of low malignant potential, and urothelial papilloma). Our results support the idea that mutations of the FGFR3 and TP53 genes are rare or absent in urothelial neoplasms of young patients. In contrast, chromosomal abnormalities detected by UroVysion fluorescence in situ hybridization are sometimes present in patients above 19-20 years of age. This finding supports the recently proposed hypothesis that an age of 19-20 years separates distinct molecular pathways of urothelial carcinogenesis.
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Increased androgen receptor gene copy number is associated with TMPRSS2-ERG rearrangement in prostatic small cell carcinoma.
Mol. Carcinog.
PUBLISHED: 01-12-2014
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Small cell carcinoma of the prostate (PSCC) is a highly aggressive malignancy that often develops in patients previously treated with hormonal therapy for metastatic prostatic acinar adenocarcinoma. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer and shared by PSCC; however, the role of androgen receptor (AR) gene alterations and interaction with TMPRSS2-ERG rearrangement are incompletely understood in PSCC. Sixty-one cases of PSCC were examined for AR gene copy number and TMPRSS2-ERG rearrangement by fluorescence in situ hybridization (FISH) and AR protein expression by immunohistochemistry. Of 61 cases of PSCC, 51% (31/61) demonstrated increased AR gene copy number (FISH+), 54% (33/61) were positive for TMPRSS2-ERG gene fusion, and 38% (23/61) showed AR protein expression. Of the 31 AR FISH+ cases, 23 also showed TMPRSS2-ERG gene fusion, and 16 expressed AR protein. Of the 33 cases with TMPRSS2-ERG fusion, 28 were AR FISH+ or expressed AR protein. Statistically significant correlations were observed between AR gene copy number or AR protein expression and TMPRSS2-ERG gene fusion (P?=?0.001 and P?=?0.03, respectively). In summary, high AR gene copy number emerges during the development of PSCC, often in association with TMPRSS2-ERG rearrangement. This potential mechanism warrants further study. Improvement will come from understanding the biology of the disease and integrating new therapies into the treatment of this rare and aggressive tumor. © 2014 Wiley Periodicals, Inc.
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Seminal vesicle intraepithelial neoplasia versus basal cell hyperplasia in a seminal vesicle.
Eur. Urol.
PUBLISHED: 01-09-2014
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In the examination of >3000 radical prostatectomy specimens and their seminal vesicles (SVs), we came across a unique case of an intraepithelial abnormality in preexisting ducts and acini in the left SV of a 73-yr-old patient with prostatic adenocarcinoma. At low magnification, the epithelial lining was thicker than the surrounding normal ducts with obliteration of the acinar lumen. At high magnification, there were varying degrees of cell stratification. Prostate-specific antigen, prostate-specific acid phosphatase, prostate-specific membrane antigen, prostein (P501S), alpha-methylacyl-CoA racemase, and GATA binding protein 3 (GATA3) were negative; p63, 34betaE12, cytokeratin 5/6, and p53 were positive in cells in basal and suprabasal positions, whereas CA-125 was expressed in the luminal cells. The case shows morphologic and immunohistochemical features similar to those of basal cell hyperplasia of the prostate and is different from the early neoplastic epithelial changes of the SV in the transgenic adenocarcinoma mouse prostate model (ie, SV intraepithelial neoplasia). To the best of our knowledge, there are no previous reports of such a change in a human SV. The clinical significance of this lesion is not known and is overshadowed by the presence of prostate cancer.
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The Relationship between Species Diversity and Genetic Structure in the Rare Picea chihuahuana Tree Species Community, Mexico.
PLoS ONE
PUBLISHED: 01-01-2014
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Species diversity and genetic diversity, the most basic elements of biodiversity, have long been treated as separate topics, although populations evolve within a community context. Recent studies on community genetics and ecology have suggested that genetic diversity is not completely independent of species diversity. The Mexican Picea chihuahuana Martínez is an endemic species listed as "Endangered" on the Red List. Forty populations of Chihuahua spruce have been identified. This species is often associated with tree species of eight genera in gallery forests. This rare Picea chihuahuana tree community covers an area no more than 300 ha and has been subject of several studies involving different topics such as ecology, genetic structure and climate change. The overall aim of these studies was to obtain a dataset for developing management tools to help decision makers implement preservation and conservation strategies. However, this unique forest tree community may also represent an excellent subject for helping us to understand the interplay between ecological and evolutionary processes in determining community structure and dynamics. The AFLP technique and species composition data were used together to test the hypothesis that species diversity is related to the adaptive genetic structure of some dominant tree species (Picea chihuahuana, Pinus strobiformis, Pseudotsuga menziesii and Populus tremuloides) of the Picea chihuahuana tree community at fourteen locations. The Hill numbers were used as a diversity measure. The results revealed a significant correlation between tree species diversity and genetic structure in Populus tremuloides. Because the relationship between the two levels of diversity was found to be positive for the putative adaptive AFLP detected, genetic and species structures of the tree community were possibly simultaneously adapted to a combination of ecological or environmental factors. The present findings indicate that interactions between genetic variants and species diversity may be crucial in shaping tree communities.
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The expression patterns of p53 and p16 and an analysis of a possible role of HPV in primary adenocarcinoma of the urinary bladder.
PLoS ONE
PUBLISHED: 01-01-2014
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Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular events leading to its pathogenesis are not well delineated. The goal of this study was to investigate p53 and p16 expression, as well as HPV status, in a relatively large series of primary bladder adenocarcinomas.
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Urothelial dysplasia of the bladder: diagnostic features and clinical significance.
Anal. Quant. Cytol. Histol.
PUBLISHED: 12-19-2013
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The 2004 World Health Organization classification system for urothelial neoplasia identifies urothelial dysplasia (low-grade intraurothelial neoplasia) as a premalignant lesion of the urothelium. Although diagnostic criteria of urothelial dysplasia have been improved in recent years, there is a frequent lack of interobserver reproducibility. Follow-up studies suggest that dysplasia is a marker for urothelial instability and disease progression in up to 19% of patients, thus supporting an active clinical follow-up in these patients. The main differential diagnosis of urothelial dysplasia includes flat urothelial lesions with atypia, mainly flat (simple) urothelial hyperplasia, reactive urothelial atypia, urothelial atypia of unknown significance, and urothelial carcinoma in situ (high-grade intraurothelial neoplasia). In most cases, morphologic features alone suffice for diagnosis. Some cases may require a panel of immunohistochemical antibodies consisting of cytokeratin 20, p53 and CD44 for diagnosis. We present pathologic features and clinical significance of urothelial dysplasia with emphasis on differential diagnosis from common flat urothelial lesions with atypia.
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Granular cell tumor of the bladder: a case report.
Anal. Quant. Cytol. Histol.
PUBLISHED: 11-29-2013
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Granular cell tumor is usually a benign tumor, generally believed to be of neural origin, most commonly affecting the tongue and skin. Although it can present in any part of the body, the bladder is a rare location, with only 16 cases found in the English-language literature.
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MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study.
Mol. Cancer Ther.
PUBLISHED: 10-21-2013
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Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS. Mol Cancer Ther; 13(1); 1-11. ©2013 AACR.
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Handling and staging of renal cell carcinoma: the International Society of Urological Pathology Consensus (ISUP) conference recommendations.
Am. J. Surg. Pathol.
PUBLISHED: 09-13-2013
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The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a ?65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus," the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in <10% of radical nephrectomy specimens.
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Three-level meta-analysis of dependent effect sizes.
Behav Res Methods
PUBLISHED: 09-05-2013
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Although dependence in effect sizes is ubiquitous, commonly used meta-analytic methods assume independent effect sizes. We describe and illustrate three-level extensions of a mixed effects meta-analytic model that accounts for various sources of dependence within and across studies, because multilevel extensions of meta-analytic models still are not well known. We also present a three-level model for the common case where, within studies, multiple effect sizes are calculated using the same sample. Whereas this approach is relatively simple and does not require imputing values for the unknown sampling covariances, it has hardly been used, and its performance has not been empirically investigated. Therefore, we set up a simulation study, showing that also in this situation, a three-level approach yields valid results: Estimates of the treatment effects and the corresponding standard errors are unbiased.
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The reasons behind variation in Gleason grading of prostatic biopsies: areas of agreement and misconception among 266 European pathologists.
Histopathology
PUBLISHED: 08-14-2013
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The Gleason scoring system underwent revision at the International Society of Urological Pathology (ISUP) conference in 2005. It is not known how uropathologists have interpreted its recommendations.
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Atypical adenomatous hyperplasia of prostate lacks TMPRSS2-ERG gene fusion.
Am. J. Surg. Pathol.
PUBLISHED: 07-27-2013
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Atypical adenomatous hyperplasia (AAH) is a distinct entity in prostate pathology, defined as a well-circumscribed lobule of closely packed crowded small glands or acini. Although it has been proposed as a precursor lesion to prostate cancer, the biological nature of AAH is currently uncertain. The TMPRSS2-ERG fusion gene is a common recurrent chromosomal rearrangement in prostate cancer and in its precursor lesion, prostatic intraepithelial neoplasia. The prevalence of TMPRSS2-ERG alteration in AAH is unknown. Fifty-five separate prostate specimens containing AAH were investigated by fluorescence in situ hybridization and immunohistochemistry for TMPRSS2-ERG rearrangement. TMPRSS2-ERG rearrangements were not identified in AAH either by fluorescence in situ hybridization or by immunohistochemistry.
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Synchronous metastasis from lobular carcinoma and primary carcinoma of the endometrium in a patient after tamoxifen therapy.
Int. J. Gynecol. Pathol.
PUBLISHED: 07-26-2013
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Patients treated with tamoxifen often experience vaginal bleeding, generally because of benign endometrial lesions or, less often, because of endometrial carcinoma. A rare cause of vaginal bleeding in these patients is breast carcinoma metastasis in an endometrial polyp. We describe a 67-yr-old patient with metastasis of lobular breast carcinoma in an endometrial polyp and papillary serous endometrial carcinoma, both diagnosed simultaneously in a uterine curettage. The coexistence of the 2 cancers was confirmed by pathologic study of the hysterectomy specimen. To our knowledge, this is the first reported case of the synchronous presence of the 2 neoplastic diseases. Endometrial biopsies performed for endometrial disorders in patients who have breast cancer and have received tamoxifen should be studied carefully to avoid underdiagnosis.
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Malignant perivascular epithelioid cell neoplasm (PEComa) of the urinary bladder with TFE3 gene rearrangement: clinicopathologic, immunohistochemical, and molecular features.
Am. J. Surg. Pathol.
PUBLISHED: 06-26-2013
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Recently, a small subgroup of PEComas has been recognized to harbor rearrangements involving TFE3, a gene also involved in rearrangements in translocation-associated renal cell carcinomas and alveolar soft part sarcomas. The few TFE3 rearrangement-associated PEComas reported have exhibited distinctive pathologic characteristics contrasting to PEComas in general, including predominantly epithelioid nested or alveolar morphology and underexpression of muscle markers by immunohistochemistry. In this study, we report the clinicopathologic, immunohistochemical, and molecular features of a primary urinary bladder PEComa diagnosed by transurethral resection in a 55-year-old woman that clinically mimicked urothelial carcinoma. Light microscopy demonstrated mixed spindle cell and epithelioid morphology with the epithelioid component preferentially associated with blood vessels. Immunohistochemistry revealed positive staining for HMB45, tyrosinase, MiTF, cathepsin K, smooth muscle actin, and TFE3 protein. Fluorescence in situ hybridization for the TFE3 gene revealed a split signal pattern, indicating TFE3 rearrangement. X chromosome inactivation analysis demonstrated a clonal pattern despite the heterogenous appearance of the tumor. Unfortunately, despite surgical resection and sarcoma-directed therapy, the patient died of metastatic disease 12 months after diagnosis. This report adds to the known data regarding urinary bladder PEComas and PEComas with TFE3 rearrangement, indicating that both can pursue an aggressive course. Although the few reported TFE3-rearranged PEComas have predominantly lacked a spindle cell component and expression of smooth muscle actin and MiTF by immunohistochemistry, the findings in this study indicate that these features are sometimes present in TFE3-rearranged PEComas.
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[Biobanking: the basis for molecular research in uro-oncology].
Arch. Esp. Urol.
PUBLISHED: 06-25-2013
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The advances in cancer translational research, as well as the study of its changes and interactions, depend basically on the procurement of case series (individuals affected and non affected controls) which supply high quality samples and other associated data. Biobanks have shown they are indispensable tools for the advance of uro-oncological research.
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Immunohistochemical analysis of chromatin remodeler DAXX in high grade urothelial carcinoma.
Diagn Pathol
PUBLISHED: 06-22-2013
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The chromatin remodeler DAXX, a predominantly nuclear protein, regulates the status of chromatin organization. The aim of this exploratory immunohistochemical study was to evaluate DAXX protein expression in high grade invasive urothelial carcinoma (UC) of the bladder as a biological regulator of aggressiveness.
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Standardization of Gleason grading among 337 European pathologists.
Histopathology
PUBLISHED: 06-14-2013
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? The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7.
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Pathology of renal cell carcinoma: an update.
Anal. Quant. Cytol. Histol.
PUBLISHED: 05-25-2013
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The use of classic and newer methodologies, including histopathology, electron microscopy, immunohistochemistry, cytogenetics, and molecular diagnostic techniques, has greatly influenced distinctions between various types of renal carcinoma. The most recent World Health Organization classification of renal neoplasms encompassed nearly 50 distinctive renal neoplasms. These categories have been expanded during recent years, incorporating newer histotypes, thus suggesting that the next revision of this classification will incorporate some of the recently recognized entities. In this review we examine the clinicopathologic and genetic features of renal carcinomas most often seen in clinical practice. Emphasis is placed on defining risk categories by incorporating pathologic predictive paradmeters and tumor histotypes. Since pathology of renal cell cancer is a rapidly evolving field, we also include brief comments on newer tumor variants for which there currently is not enough clinicopathologic information to permit classification as distinctive tumor histotypes.
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Biomarkers in bladder cancer: Translational and clinical implications.
Crit. Rev. Oncol. Hematol.
PUBLISHED: 05-24-2013
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Bladder cancer is associated with high recurrence and mortality rates. These tumors show vast heterogeneity reflected by diverse morphologic manifestations and various molecular alterations associated with these disease phenotypes. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis would improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Recognition of two distinct pathways for urothelial carcinogenesis represents a major advance in the understanding and management of this disease. Nomograms for combining results from multiple biomarkers have been proposed to increase the accuracy of clinical predictions. The scope of this review is to summarize the major biomarker findings that may have translational and clinical implications.
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Human papillomavirus is not an etiologic agent of urothelial inverted papillomas.
Am. J. Surg. Pathol.
PUBLISHED: 05-18-2013
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Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases.
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Laser-assisted microdissection in translational research: theory, technical considerations, and future applications.
Appl. Immunohistochem. Mol. Morphol.
PUBLISHED: 05-18-2013
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Molecular profiling already exerts a profound influence on biomedical research and disease management. Microdissection technologies contribute to the molecular profiling of diseases, enabling investigators to probe genetic characteristics and dissect functional physiology within specific cell populations. Laser-capture microdissection (LCM), in particular, permits collation of genetic, epigenetic, and gene expression differences between normal, premalignant, and malignant cell populations. Its selectivity for specific cell populations promises to greatly improve the diagnosis and management of many human diseases. LCM has been extensively used in cancer research, contributing to the understanding of tumor biology by mutation detection, clonality analysis, epigenetic alteration assessment, gene expression profiling, proteomics, and metabolomics. In this review, we focus on LCM applications for DNA, RNA, and protein analysis in specific cell types and on commercially available LCM platforms. These analyses could clinically be used as aids to cancer diagnosis, clinical management, genomic profile studies, and targeted therapy. In this review, we also discuss the technical details of tissue preparation, analytical yields, tissue selection, and selected applications using LCM.
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Cystic partially regressed clear cell renal cell carcinoma: a potential mimic of multilocular cystic renal cell carcinoma.
Histopathology
PUBLISHED: 04-29-2013
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To study clear cell renal cell carcinomas with predominant cystic and sclerotic components, in which a solid epithelial component precluded a diagnosis of multilocular cystic renal cell carcinoma. We designated these tumours cystic partially regressed clear cell renal cell carcinoma.
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An interobserver reproducibility study on invasiveness of bladder cancer using virtual microscopy and heatmaps.
Histopathology
PUBLISHED: 04-07-2013
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The distinction between non-invasive (pTa) and invasive (pT1) non-muscle invasive bladder cancer (NMIBC) is subject to considerable interobserver variation. We aimed to generate a teaching set of images based on the diagnostic opinions of a panel of expert genitourinary pathologists.
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EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder.
Mod. Pathol.
PUBLISHED: 03-15-2013
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The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.
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Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence.
Fam. Cancer
PUBLISHED: 03-13-2013
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During the first 6 years of the Program of Genetic Counselling in Cancer of Valencia (eastern Spain), 310 mutations (155 in BRCA1 and 155 in BRCA2) in 1,763 hereditary breast (BC) and ovarian cancer (OC) families were identified. Of the mutations found 105 were distinct (53 in BRCA1 and 52 in BRCA2), eight new and 37 recurrent. Two of the novel mutations were frame-shift placed in exons 2 and 11 of BRCA1 and the remaining six were placed in BRCA2; four frame-shift (three in exon 11 and one in exon 23), one deletion of the entire exon 19 and one in the intervening sequence of exon 22. The BRCA1 mutations with higher recurrence were c.66_68delAG, c.5123C > A, c.1961delA, c.3770_3771delAG and c.5152+5G > A that covered 45.2% of mutations of this gene. The age of onset of BCs of c.68_69delAG mutation carriers occurs later than for the other recurrent mutations of this gene (45 vs. 37 years; p = 0.008). The BRCA2 mutations with higher recurrence were c.9026_9030delATCAT, c.3264insT and c.8978_8991del14 which represented 43.2% of all mutations in this gene, being the most recurrent mutation by far c.9026_9030delATCAT that represents 21.3% of BRCA2 mutations and 10.6% of all mutations. Probands with family histories of BC and OC, or OC and/or BC in at least two first degree relatives, were the more likely to have BRCA1/BRCA2 mutations (35.2% of the total mutations). And that most BRCA1mutations (73.19% mutations) occurred in probands with early-onset BC or with family history of OC.
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Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: the superiority of fluorescence in situ hybridization over ERG immunohistochemistry.
Hum. Pathol.
PUBLISHED: 02-28-2013
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Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.
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Towards personalized therapy for patients with malignant melanoma: molecular insights into the biology of BRAF mutations.
Future Oncol
PUBLISHED: 02-19-2013
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BRAF mutations have been identified as the most common oncogene mutation in melanomas, especially important in those originating on nonchronically sun-damaged skin. There is a large and continually growing body of evidence regarding the importance of this mutation in targeted therapy for melanoma. In this review, we outline these findings including: molecular pathways used by BRAF, the importance in nonmalignant neoplasms, histologic associations, the relationship of BRAF to KIT and NRAS mutations, and their impact on survival, as well as resistance mechanisms to BRAF inhibitors employed by melanoma. Understanding these topics and how they relate to one another may facilitate the development of new treatments and eventually improve the prognosis for those patients afflicted with this disease.
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Galectin-1 (GAL-1) expression is a useful tool to differentiate between small cell osteosarcoma and Ewing sarcoma.
Virchows Arch.
PUBLISHED: 02-11-2013
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Galectin-1 (GAL-1) is frequently expressed in osteosarcomas. Although a valuable diagnostic marker to differentiate between chondroblastic osteosarcomas and conventional chondrosarcomas, it has not been tested in the Ewing sarcoma family of tumors (ESFTs). We studied by immunohistochemistry GAL-1 expression in 43 osteosarcomas, 23 chondrosarcomas, and 217 genetically confirmed ESFTs using a tissue microarray. GAL-1 was expressed in 78 % of osteosarcomas, 33 % of chondrosarcomas, and 8 % of ESFTs. Osteoblastic and small cell osteosarcoma subtypes expressed GAL-1 in a high percentage of cells when compared with the other histological subtypes, whereas two chondroblastic osteosarcomas were negative. GAL-1 was mainly expressed in high-grade chondrosarcomas (grade III). ESFTs were rarely positive (8 %), and this was not related to the histological subtype nor to the clinical outcome. Although GAL-1 expression distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas and is usually negative in conventional chondrosarcomas, the final diagnosis needs to incorporate histopathology since some chondroblastic osteosarcomas fail to express GAL-1, while high-grade chondrosarcomas are GAL-1 positive. Since GAL-1 is frequently expressed in osteogenic tumors, including small cell osteosarcoma, but rarely positive in ESFTs, its expression seems a valuable tool for distinguishing between these lesions. GAL-1 immunoexpression is not indicative of prognosis in ESFT.
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Telomere shortening distinguishes inverted urothelial neoplasms.
Histopathology
PUBLISHED: 02-05-2013
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To investigate relative telomere length in inverted urothelial neoplasms, including inverted papilloma and urothelial carcinoma with an inverted growth pattern. Telomere shortening has been implicated as an early event in the development of epithelial malignancies in a number of organ systems.
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Novel markers of squamous differentiation in the urinary bladder.
Hum. Pathol.
PUBLISHED: 01-28-2013
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Urinary bladder squamous cell carcinoma and urothelial carcinoma with squamous differentiation are often high-grade and high-stage tumors that are thought to be associated with a poorer prognosis and response to therapy compared with urothelial carcinoma without divergent differentiation. Therefore, recognition of a squamous component is increasingly important in guiding prognosis and therapy. We investigated the expression of MAC387, desmoglein-3, and TRIM29 in pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation to determine whether they have utility as diagnostic biomarkers for squamous differentiation. Eighty-four cases were retrieved from participating institutions including 51 pure urinary bladder squamous cell carcinomas and 33 urothelial carcinomas with squamous differentiation. MAC387, desmoglein-3, and TRIM29 antibodies demonstrated positive staining in pure squamous cell carcinoma in 51 (100%), 46 (90%), and 48 (93%) cases, respectively. Urothelial carcinoma with squamous differentiation showed reactivity for MAC387, desmoglein-3, and TRIM29 in the squamous component for 32 (97%), 26 (79%), and 32 (97%) cases, respectively. MAC387 demonstrated a sensitivity of 99% and a specificity of 70% for squamous differentiation, whereas desmoglein-3 yielded a sensitivity of 86% and a specificity of 91%. No urothelial component showed greater than 10% labeling for desmoglein-3. TRIM29 labeling showed a sensitivity of 95%, but a poorer specificity of 33%. In summary, MAC387 and desmoglein-3 are reliable diagnostic markers for supporting the morphologic impression of squamous differentiation in urinary bladder carcinoma. Desmoglein-3 shows high specificity, whereas TRIM29 was most likely to demonstrate labeling in areas without light microscopically recognizable squamous differentiation.
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Distinguishing primary adenocarcinoma of the urinary bladder from secondary involvement by colorectal adenocarcinoma: extended immunohistochemical profiles emphasizing novel markers.
Mod. Pathol.
PUBLISHED: 01-25-2013
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Glandular neoplasms involving the urinary bladder carry a challenging differential diagnosis including primary and secondary processes. We investigated the potential diagnostic utility of cadherin-17 and GATA3 in 25 primary adenocarcinomas of the urinary bladder, as compared with other commonly used markers including ?-catenin and p63. Urothelial carcinoma with glandular differentiation (11), colorectal adenocarcinoma secondarily involving the bladder (25), and primary colorectal adenocarcinoma (22) were also analyzed and the results were compared using a Fisher exact test. Cadherin-17 was expressed in 23/25 primary bladder adenocarcinomas (92%), 23/25 colorectal adenocarcinomas involving the bladder (92%), 21/22 primary colorectal adenocarcinomas (95%) and entirely negative (0/11) in both components of urothelial carcinoma with glandular differentiation (P<0.001). In urothelial carcinoma with glandular differentiation, positive nuclear staining for GATA3 was evident in the urothelial component for 18% (2/11) and the glandular component for 9% (1/11) with additional tumors showing only cytoplasmic staining. Nuclear reactivity for GATA3 was not present in primary bladder adenocarcinoma and primary/secondary colorectal adenocarcinoma (P<0.05). Positive nuclear and cytoplasmic immunostaining for ?-catenin was evident in 21/22 primary colorectal adenocarcinomas (95%) and 23/25 cases of secondary involvement by colorectal adenocarcinoma (92%). In contrast, positive membranous and cytoplasmic staining for ?-catenin was observed in 23/25 primary bladder adenocarcinomas (92%) and 11/11 urothelial carcinomas with glandular differentiation (100%, P<0.001). p63 was expressed only in the urothelial component of urothelial carcinoma with glandular differentiation and not in the glandular component (P<0.001). In summary, cadherin-17 is a relatively specific and sensitive marker for primary adenocarcinoma of the urinary bladder, distinguishing it from urothelial carcinoma with glandular differentiation. However, it does not distinguish primary bladder adenocarcinoma from secondary involvement by colorectal adenocarcinoma. The pattern of reactivity for ?-catenin remains the most useful marker for distinguishing these two tumors.
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Dermatofibrosarcoma protuberans: a comprehensive review and update on diagnosis and management.
Semin Diagn Pathol
PUBLISHED: 01-19-2013
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Dermatofibrosarcoma protuberans (DFSP) is a rare superficial tumor characterized by high rates of local recurrence and low risk of metastasis. DFSP occurs most commonly on the trunk and proximal extremities, affects all races, and often develops between the second and fifth decade of life. The tumor grows slowly, typically over years. Histologically, several variants of DFSP have been described and should be well characterized to avoid misdiagnosis with other tumors. These include pigmented (Bednar tumor), myxoid, myoid, granular cell, sclerotic, atrophic DFSP, giant cell fibroblastoma, and DFSP with fibrosarcomatous areas. Of all these variants, only the DFSP with fibrosarcomatous areas is high grade, with a higher rate of local recurrence and distant metastasis. DFSP is genetically characterized by the t(17;22)(q22;q13), resulting in the fusion of alpha chain type 1 of collagen gene and platelet-derived growth factor beta gene. This translocation is present in 90% of DFSP and represents a very useful tool in the differential diagnosis of DFSP with other tumors with similar histology. The standard treatment is wide local excision with at least a 2-cm margin. However, local recurrence after apparently adequate surgical excision is well recognized. Mohs micrographic surgery would be the treatment of choice with a better cure rate and maximal conservation of tissue. When surgery is insufficient, clinical evidence has suggested that imatinib mesylate is a safe and effective treatment in DFSP, especially in cases of local advanced or metastatic disease. This article presents an overview of the state of the art in the clinicopathological management of this disease.
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Estimation of the predictive power of the model in mixed-effects meta-regression: A simulation study.
Br J Math Stat Psychol
PUBLISHED: 01-10-2013
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Several methods are available to estimate the total and residual amount of heterogeneity in meta-analysis, leading to different alternatives when estimating the predictive power in mixed-effects meta-regression models using the formula proposed by Raudenbush (1994, 2009). In this paper, a simulation study was conducted to compare the performance of seven estimators of these parameters under various realistic scenarios in psychology and related fields. Our results suggest that the number of studies (k) exerts the most important influence on the accuracy of the results, and that precise estimates of the heterogeneity variances and the model predictive power can only be expected with at least 20 and 40 studies, respectively. Increases in the average within-study sample size (N¯) also improved the results for all estimators. Some differences among the accuracy of the estimators were observed, especially under adverse (small k and N¯) conditions, while the results for the different methods tended to convergence for more optimal scenarios.
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PAX8 is expressed in the majority of renal epithelial neoplasms: an immunohistochemical study of 223 cases using a mouse monoclonal antibody.
J. Clin. Pathol.
PUBLISHED: 12-01-2011
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PAX8 is a cell lineage-specific transcription factor which plays a crucial role in the organogenesis of the kidney, thyroid gland and Müllerian duct. A previous study showed that PAX8 is a specific and sensitive marker for both renal and ovarian carcinomas. The purpose of this study is to investigate PAX8 expression using a new monoclonal PAX8 antibody in a larger number of renal epithelial neoplasms including clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma and renal oncocytoma.
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Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology.
J. Clin. Pathol.
PUBLISHED: 09-30-2011
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To collect information on current practices of European pathologists for the handling and reporting of nephrectomy specimens with renal tumours.
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Prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance.
BJU Int.
PUBLISHED: 08-26-2011
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The aim of the present paper was to review the morphological spectrum of prostatic intraepithelial neoplasia (PIN), its relationship to carcinoma of the prostate (PCa) and its clinical significance. We reviewed the literature on premalignant lesions of the prostate, with an emphasis on high grade prostatic intraepithelial neoplasia (HGPIN). HGPIN is the most likely precursor of PCa, according to almost all available evidence. HGPIN is characterized by cellular proliferations within pre-existing ducts and acini, with nuclear and nucleolar enlargement similar to PCa. The clinical importance of recognizing HGPIN is based on its association with PCa. In recent years, a significant decline from 36% to 22% in the predictive value of cancer after an initial diagnosis of HGPIN. A major factor contributing to the decreased incidence of cancer after a diagnosis of HGPIN on needle biopsy in the contemporary era is related to increased needle biopsy core sampling, which detects many associated cancers on initial biopsy. Some recent studies have suggested that molecular findings associated with HGPIN might be able to predict which men are more likely to have cancer on re-biopsy.
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The clinical and therapeutic implications of cancer stem cell biology.
Expert Rev Anticancer Ther
PUBLISHED: 08-03-2011
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Cancer stem cells (CSCs) have provided new insights into the tumorigenesis and metastatic potential of cancer. The discovery of CSCs has provided many new insights into the complexities of cancer therapy: tumor initiation, treatment resistance, metastasis, recurrence, assessment of prognosis and prediction of clinical course. Recent rapid advances in molecular analysis have contributed to the better understanding of the molecular attributes and pathways that give CSCs their unique attributes. Use of these molecular techniques has facilitated elucidation of specific surface markers and pathways that favor propagation of CSCs - allowing for targeted therapy. Furthermore, it has been discovered that a specific microenvironment, or niche, is essential for the genesis of tumors from CSCs. Therapeutic strategies that alter these microenvironments compromise CSC proliferation and constitute another method of targeted cancer therapy. We review the clinical and therapeutic implications of CSCs, with a focus on treatment resistance and metastasis, and the emerging approaches to target CSCs and their microenvironments in order to attain improved outcomes in cancer. It is noteworthy that CSCs are the only cells capable of sustaining tumorigenesis; however, the cell of origin of cancer, in which tumorigenesis is initiated, may be distinct from CSCs that propagate the tumor.
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Mixed epithelial and stromal tumors of the kidney: evidence for a single cell of origin with capacity for epithelial and stromal differentiation.
Am. J. Surg. Pathol.
PUBLISHED: 07-15-2011
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Mixed epithelial and stromal tumors are uncommon biphasic tumors of the kidney, with cystic and solid areas composed of a morphologically diverse stroma, including ovarian-like stroma and an epithelial component with considerable heterogeneity. Little is known about the histogenesis and clonal origins of these tumors. A total of 21 mixed epithelial and stromal tumors of the kidney from female patients who underwent radical or partial nephrectomies were examined. The epithelial and stromal components, and also adjacent non-neoplastic renal parenchymal tissues were separately laser microdissected from sections prepared from formalin-fixed and paraffin-embedded tissues for X chromosome inactivation analysis. Nineteen of the 21 tumors were informative. Seven of these informative cases showed random X chromosome inactivation pattern in both epithelial and stromal components of mixed epithelial and stromal tumors of the kidney. Nonrandom inactivation of the X chromosome was found in 12 of 19 informative tumors. The same pattern of nonrandom inactivation of the X chromosome was seen in both epithelial and stromal components in all 12 of the tumors with nonrandom X chromosome inactivation. Our data support the theory that the stroma and epithelium arise from a common cell of origin.
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Current pathology keys of renal cell carcinoma.
Eur. Urol.
PUBLISHED: 06-17-2011
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Renal cell carcinoma (RCC) in adults comprises a heterogeneous group of tumours with variable clinical outcomes that range from indolent to overtly malignant. The application of molecular genetic techniques to the study of renal neoplasms has resulted in an improved classification of these entities and a better understanding of the biologic mechanisms responsible for tumour development and progression. The current 2004 World Health Organisation classification of adult renal epithelial neoplasms has expanded rapidly with new categories recently incorporated.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.