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1.
Ann Pathol ; 43(6): 479-482, 2023 Nov.
Article in French | MEDLINE | ID: mdl-36906453

ABSTRACT

Myoepithelial neoplasms of soft tissue represent a rare entity which has been described only recently when compared to salivary gland tumors with whom they share histopathological and molecular features. The most common locations are the superficial soft tissues of the limbs and limb girdles. However, they can rarely occur in the mediastinum, abdomen, bone, skin and visceral organs. Benign forms (myoepithelioma and mixed tumor) are more frequent than myoepithelial carcinoma and the latter mostly affects children and young adults. Diagnosis is mainly based on histology, which shows a proliferation of myoepithelial cells of variable morphology with or without glandular structures in a myxoid background, and immunohistochemistry, which shows co-expression of epithelial and myoepithelial markers. Molecular tests are not mandatory, but in selected cases FISH analysis can prove useful as about 50% of myoepitheliomas show EWSR1 (or rarely FUS) rearrangements and mixed tumors show PLAG1 rearrangements. Here, we present a case of a mixed tumor of the soft tissue occuring in the hand with expression of PLAG1 in immunohistochemistry.


Subject(s)
Adenoma, Pleomorphic , Myoepithelioma , Salivary Gland Neoplasms , Soft Tissue Neoplasms , Humans , Adenoma, Pleomorphic/pathology , Biomarkers, Tumor/analysis , Immunohistochemistry , Myoepithelioma/diagnosis , Myoepithelioma/chemistry , Myoepithelioma/metabolism , Salivary Gland Neoplasms/pathology , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/pathology
3.
4.
Ann Pathol ; 39(2): 167-171, 2019 Apr.
Article in French | MEDLINE | ID: mdl-30554833

ABSTRACT

Clear cells sarcomas (CCS) are exceptionally rare in the tongue, with, to our knowledge, only three previous reports in anglo-saxon literature. Through our case, we will discuss the differential diagnosis of clear cells tumors of the tongue and bring this tumour closer to the newly described entity of the gastrointestinal tract named "clear cells sarcoma-like gastrointestinal (SCCLGI)", recently renamed "gastrointestinal neuroectodermal tumour (GNET)". SCCLGI/GNET share morphological and molecular characteristics with SCC but had until then been observed only in the digestive tract. Our case could be a lingual localization of a SCCLGI/GNET. SCC and SCCLGI/GNET characteristic molecular profil involves EWSR1-ATF1 [t(12; 22) (q13; q12)] and EWSR1-CREB1 [t(2; 22) (q34; q12)] fusion genes, but it is not specific of these tumours.


Subject(s)
Neuroectodermal Tumors/pathology , Sarcoma, Clear Cell/pathology , Tongue Neoplasms/pathology , Adult , Diagnosis, Differential , Female , Gastrointestinal Neoplasms/pathology , Humans
5.
Clin Nucl Med ; 43(4): e118-e121, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29401145

ABSTRACT

F-FDG PET/CT and MRI were performed in a 44-year-old woman to characterize a mass of the anterior tongue. MR images showed a voluminous mass, well circumscribed and enhanced heterogeneously after gadolinium chelates injection. There was an intense uptake on PET/CT. Pathological examination and molecular analysis revealed the diagnosis of clear cell sarcoma of the tongue. We present a case of clear cell sarcoma of the tongue, which includes imaging features. It is an extremely rare tumor, with only 3 cases previously reported in the literature.


Subject(s)
Magnetic Resonance Imaging , Positron Emission Tomography Computed Tomography , Sarcoma, Clear Cell/diagnostic imaging , Tongue Neoplasms/diagnostic imaging , Adult , Female , Fluorodeoxyglucose F18 , Humans
6.
J Mol Diagn ; 18(2): 205-14, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26752307

ABSTRACT

Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Colorectal Neoplasms/genetics , Laboratory Proficiency Testing/standards , Lung Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Colorectal Neoplasms/pathology , France , Genetic Testing/standards , Genotyping Techniques/standards , Humans , Lung Neoplasms/pathology , Microsatellite Instability , Time Factors
7.
Sci Transl Med ; 6(244): 244ra91, 2014 Jul 09.
Article in English | MEDLINE | ID: mdl-25009231

ABSTRACT

Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Molecular Targeted Therapy , Muscles/pathology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Animals , Autocrine Communication/drug effects , Butylhydroxybutylnitrosamine , Cell Line, Tumor , Cell Proliferation/drug effects , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Hepatocyte Nuclear Factor 3-alpha/metabolism , Humans , Keratins/metabolism , Male , Mice , Middle Aged , Muscles/drug effects , Neoplasm Invasiveness , Phenotype , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Survival Analysis , Transcriptome/genetics , Treatment Outcome , Urinary Bladder Neoplasms/genetics
8.
PLoS One ; 7(12): e48993, 2012.
Article in English | MEDLINE | ID: mdl-23272046

ABSTRACT

TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18-0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28-0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23-1.36] (p = 0.12) and OR = 0.99 [0.37-2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.


Subject(s)
Gene Expression Regulation, Neoplastic , Mutation , Receptor, Fibroblast Growth Factor, Type 3/genetics , Tumor Suppressor Protein p53/genetics , Urinary Bladder Neoplasms/genetics , Disease Progression , Female , Genes, p53 , Humans , Male , Medical Oncology/methods , Prevalence
9.
J Pathol ; 227(3): 315-24, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22422578

ABSTRACT

The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation.


Subject(s)
Carcinoma/genetics , Gene Deletion , Genes, p16 , Homozygote , Mutation , Receptor, Fibroblast Growth Factor, Type 3/genetics , Urinary Bladder Neoplasms/genetics , Carcinoma/enzymology , Carcinoma/mortality , Carcinoma/secondary , Chi-Square Distribution , DNA Mutational Analysis , Disease-Free Survival , France , Gene Dosage , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Multivariate Analysis , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Recurrence, Local , Neoplasm Staging , Phenotype , Prognosis , Proportional Hazards Models , Prospective Studies , Time Factors , Urinary Bladder Neoplasms/enzymology , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology
10.
BMC Cancer ; 11: 323, 2011 Jul 29.
Article in English | MEDLINE | ID: mdl-21801386

ABSTRACT

BACKGROUND: Primary leiomyosarcoma of the seminal vesicle is exceedingly rare. CASE PRESENTATION: We report a case of a 59-year-old man with tumour detected by rectal symptoms and ultrasonography. Computed tomography and magnetic resonance imaging suggested an origin in the right seminal vesicle. Transperineal biopsy of the tumour revealed leiomyosarcoma. A radical vesiculo-prostactectomy with bilateral pelvic lymphadenectomy was performed. Pathological examination showed a grade 2 leiomyosarcoma of the seminal vesicle. The patient received adjuvant radiotherapy. He developed distant metastases 29 months after diagnosis, and received chemotherapy. Metastatic disease was controlled by second-line gemcitabine-docetaxel combination. Fifty-one months after diagnosis of the primary tumour, and 22 months after the first metastases, the patient is alive with excellent performance status, and multiple asymptomatic stable lung and liver lesions. CONCLUSIONS: We report the eighth case of primary leiomyosarcoma of the seminal vesicle and the first one with a so long follow-up.


Subject(s)
Genital Neoplasms, Male/diagnosis , Leiomyosarcoma/diagnosis , Seminal Vesicles/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Docetaxel , Genital Neoplasms, Male/therapy , Humans , Leiomyosarcoma/therapy , Liver Neoplasms/prevention & control , Liver Neoplasms/secondary , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Lymph Node Excision , Male , Middle Aged , Prostatectomy , Radiotherapy, Adjuvant , Taxoids/administration & dosage , Treatment Outcome , Gemcitabine
11.
BMC Med Genomics ; 3: 59, 2010 Dec 16.
Article in English | MEDLINE | ID: mdl-21162720

ABSTRACT

BACKGROUND: Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied. METHODS: BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets. RESULTS: Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression. CONCLUSIONS: Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.


Subject(s)
Birt-Hogg-Dube Syndrome/genetics , Genes, Mitochondrial , Kidney Neoplasms/genetics , Up-Regulation , Adenoma, Oxyphilic/genetics , Carcinoma, Renal Cell/genetics , DNA-Binding Proteins/metabolism , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Humans , Mitochondrial Proteins/metabolism , Oxidative Phosphorylation , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Proto-Oncogene Proteins/genetics , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics
12.
Eur Urol ; 57(4): 699-707, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19428174

ABSTRACT

BACKGROUND: Lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are highly prevalent in aging men and are strongly linked. Alpha1-blockers such as alfuzosin are effective monotherapies for LUTS. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil are the first-line treatment for ED. Both drugs act by two different mechanisms of action on common urogenital target organs and, thus, may have additive effects. OBJECTIVES: We evaluated in vitro the effects of alfuzosin, tadalafil, and the combination of both on human detrusor and prostatic smooth muscle. DESIGN, SETTING, AND PARTICIPANTS: Prostatic and bladder tissue were obtained from patients (n=20 and n=17, respectively) undergoing cystoprostatectomy for bladder cancer. MEASUREMENTS: In organ baths, isolated prostatic strips and isolated bladder strips were incubated with vehicle, tadalafil (10⁻6 M and 10⁻5 M), alfuzosin (3×10⁻8 M or 10⁻6 M and 10⁻5 M) or a combination. Concentration-response curves (CRCs) to norepinephrine were generated on prostatic strips and detrusor strips precontracted with carbachol. Strips were also submitted to electrical field stimulation (EFS). RESULTS AND LIMITATIONS: When alfuzosin and tadalafil were combined, the maximal relaxation to norepinephrine on carbachol-precontracted detrusor strips was significantly increased compared with tadalafil alone, and EFS-induced detrusor contractions were better inhibited compared with each compound alone. Tadalafil significantly inhibited norepinephrine-induced prostatic strip contractions by reducing the maximal effect, whereas alfuzosin shifted the CRC of norepinephrine to the right. Combining both tadalafil and alfuzosin resulted in a greater relaxant effect. Likewise, the combination was more effective at reducing EFS-induced contractions compared with each compound alone. CONCLUSIONS: The combination of alfuzosin and tadalafil exerts an additive effect of inhibiting adrenergic smooth muscle tone of prostatic tissue and EFS-induced detrusor contractions and conversely, of enhancing adrenergic relaxation of detrusor precontracted with carbachol. These experiments provide experimental support for the clinical investigation of the combination of α1-blockers and PDE5 inhibitors in the treatment of LUTS.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/pharmacology , Carbolines/pharmacology , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Phosphodiesterase 5 Inhibitors/pharmacology , Prostate/drug effects , Quinazolines/pharmacology , Urinary Bladder/drug effects , Adrenergic alpha-Agonists/pharmacology , Aged , Carbachol/pharmacology , Cholinergic Agonists/pharmacology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Electric Stimulation , Humans , In Vitro Techniques , Male , Norepinephrine/pharmacology , Tadalafil
13.
Ann Pathol ; 29(5): 428-30, 2009 Oct.
Article in French | MEDLINE | ID: mdl-20004849

ABSTRACT

We report the case of a 48-year-old female patient who had a Crohn's disease treated by corticosteroids. The patient developed severe cardiac failure, which was refractory to treatment with inotropic agents. At necropsy, examination of the heart revealed myocardial abscesses. On microscopic study, we diagnosed an aspergillar myocarditis. Aspergillar myocarditis is a rare and fatal localisation in disseminated aspergillosis. Diagnosis is difficult and treatment, usually initiated late, is ineffective.


Subject(s)
Aspergillosis/pathology , Cardiomyopathies/microbiology , Fatal Outcome , Female , Humans , Middle Aged
14.
Cancer Res ; 69(21): 8256-64, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19843858

ABSTRACT

Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents.


Subject(s)
Kidney Neoplasms/pathology , Kidney Pelvis/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/pathology , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Female , Gene Expression Profiling , Humans , Immunoenzyme Techniques , Integrases/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Pelvis/metabolism , Lasers , Loss of Heterozygosity , Male , Mice , Mice, Transgenic , Microdissection , Oligonucleotide Array Sequence Analysis , PTEN Phosphohydrolase/physiology , Phosphatidylinositol 3-Kinases/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , TOR Serine-Threonine Kinases , Urinary Bladder Neoplasms/genetics
15.
J Clin Oncol ; 27(17): 2809-15, 2009 Jun 10.
Article in English | MEDLINE | ID: mdl-19380452

ABSTRACT

PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) -positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer. PATIENTS AND METHODS Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point. Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71). CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.


Subject(s)
Breast Neoplasms/drug therapy , Ki-67 Antigen/metabolism , Taxoids/therapeutic use , Adult , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Biomarkers/metabolism , Breast Neoplasms/diagnosis , Breast Neoplasms/metabolism , Disease-Free Survival , Docetaxel , Epirubicin/therapeutic use , Female , Humans , Ki-67 Antigen/genetics , Lymphatic Metastasis , Middle Aged , Prognosis , Receptors, Estrogen/metabolism , Treatment Outcome
16.
Histol Histopathol ; 24(4): 425-35, 2009 04.
Article in English | MEDLINE | ID: mdl-19224445

ABSTRACT

OBJECTIVE: The prognostic significance of microvessel density in ovarian cancer is still a matter of debate. Classically, the degree of vascularisation is assessed in areas of high vascular density (hot spots), considered as regions of increased probability of metastasis. Since ovarian tumours have a particular progression and dissemination behaviour, vascularisation outside hot spots may also contribute to their evolution. METHODS: In the present study, the degree of tumour vascularisation was estimated both in whole histogical sections and in hot spots, in 235 patients with ovarian carcinoma, using fully automatic image analysis methods. Six parameters were estimated: mean microvessel density (MVD) and mean microvessel surface fraction (MSP) on the whole section, mean and maximum values of MVD and MSP inside hot spots (MVDHS1, MSPHS1 and MVDHS2, MSPHS2). Relationships between vascular parameters and clinicopathologic features were analysed. RESULTS: In stage III-IV patients multivariate analysis showed that stage IV disease (hazards ratio (HR)=1.72, p=0.001), post-surgical residual disease 1cm (HR=2.86, p<0.001), upper MVD tercile (HR=1.45, p<0.022) and medial MVDHS1 tercile (HR=1.36, p=0.060) retained an independent prognostic value upon overall survival. CONCLUSION: Our results suggest that quantification of blood vessels, both on the whole histological section and in hot spots might be helpful in evaluating prognosis in advanced ovarian carcinomas.


Subject(s)
Adenocarcinoma/blood supply , Adenocarcinoma/mortality , Neovascularization, Pathologic/mortality , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Microvessels/pathology , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/pathology , Prognosis
17.
J Sex Med ; 6(3): 836-47, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19143907

ABSTRACT

INTRODUCTION: Phosphodiesterase 5 inhibitors (PDE5) such as sildenafil are first-line treatment for erectile dysfunction (ED). Alpha1 (alpha1)-adrenoceptor antagonists such as doxazosin are indicated for the treatment of patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). ED and LUTS/BPH are conditions that are often associated. Accordingly, alpha1-adrenoceptor antagonists and PDE5 inhibitors will be often prescribed in real life setting together. AIM: To evaluate the effects of the combination of sildenafil and doxazosin on human cavernosal and prostatic tissue. METHODS: Prostatic and erectile tissues were obtained from nine to 12 patients, respectively. Patients underwent cystoprostatectomy for infiltrating bladder cancer or penile surgery for penile implant, congenital curvature or Peyronie's disease. MAIN OUTCOME MEASURES: In organ baths, prostatic and cavernosal strips were submitted to either concentration-response curves (CRC) to phenylephrine (Phe) or norepinephrine (NE), respectively, in presence of vehicle, sildenafil (10(-6) M, 10(-5) M), doxazosin (10(-8) M, 3.10(-8) M, or 10(-7) M), or a combination of both. Continuous electrical field stimulation (EFS; 32 Hz, 5 ms, 5 seconds, 300 mA) was performed on prostatic strips which were incubated with sildenafil 10(-6) M or vehicle before the successive addition of doxazosin (10(-7) M, 10(-6) M) or vehicle. Cavernosal strips were pre-incubated with doxazosin (10(-9) M, 10(-8) M) or vehicle, then CRC to sildenafil were constructed on NE (3.10(-6) M) precontracted cavernosal strips. RESULTS: Combination of sildenafil and doxazosin exerted a greater relaxing effect on CRC to Phe or NE compared with each compound alone in both tissues. Sildenafil significantly enhanced the relaxing effect of doxazosin on EFS-induced contractions in prostatic strips. Doxazosin significantly increased the ability of sildenafil to inhibit NE-induced contractions in cavernosal strips. CONCLUSIONS: Sildenafil and doxazosin reduced adrenergic tone of prostatic and cavernosal smooth muscle and their combination provided a significant benefit when targeting relaxation of both tissues. These experiments provide support for further clinical evaluation of the sildenafil and doxazosin combination in ED patients with LUTS/BPH.


Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Doxazosin/pharmacology , Erectile Dysfunction/drug therapy , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Penis/metabolism , Phosphodiesterase Inhibitors/therapeutic use , Piperazines/therapeutic use , Prostate/drug effects , Sulfones/therapeutic use , Adrenergic alpha-Antagonists/pharmacokinetics , Adult , Doxazosin/pharmacokinetics , Drug Combinations , Erectile Dysfunction/diagnosis , Humans , Male , Penile Erection , Phosphodiesterase 5 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Piperazines/administration & dosage , Purines/administration & dosage , Purines/therapeutic use , Sildenafil Citrate , Sulfones/administration & dosage
18.
Am J Surg Pathol ; 32(5): 656-70, 2008 May.
Article in English | MEDLINE | ID: mdl-18344867

ABSTRACT

We report clinicopathologic features of a large series of renal translocation carcinomas from a multicentric study. Diagnosis was performed by cytogenetic examination of fresh material and/or by immunochemistry with antibodies directed against the C-terminal part of transcription factor E3 (TFE3) and native transcription factor EB (TFEB) proteins. Clinical data, follow-up, and histologic features were assessed. Antibodies against CK7, CD10, vimentin, epithelial membrane antigen, AE1-AE3, E-cadherin, alpha-methylacyl-coenzyme A racemase, melan A, and HMB45 were tested on tissue microarrays. Whole-genome microarray expression profiling was performed on 4 tumors. Twenty-nine cases were diagnosed as TFE3 and 2 as TFEB renal translocation carcinomas, including 13 males and 18 females, mean age 24.6 years. Two patients had a previous history of chemotherapy and 1 had a history of renal failure. Mean size of the tumor was 6.9 cm. Thirteen cases were > or = pT3 stage. Twelve cases were N+ or M+. Mean follow-up was 29.5 months. Three patients presented metastases and 5 have died. Mixed papillary and nested patterns with clear and/or eosinophilic cells represented the most consistent histologic appearance, with common foci of calcifications regardless of the type of translocation. Using a 30 mn incubation at room temperature, TFE3 immunostainings were positive in only 82% of our TFE3 translocation carcinomas. Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme A racemase in all cases. An expression of E-cadherin was observed in two-third of cases. Cytokeratins were expressed in less than one-third of cases. Melanocytic markers were expressed at least weakly in all cases except two. Unsupervised clustering on the basis of the gene expression profiling indicated a distinct subgroup of tumors. TRIM 63 glutathione S-transferase A1 and alanyl aminopeptidase are the main differentially expressed genes for this group of tumors. Our results suggest that these differentially expressed genes may serve as novel diagnostic or prognostic markers.


Subject(s)
Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Gene Expression Profiling , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Translocation, Genetic , Adolescent , Adult , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/analysis , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/chemistry , Child , Cytogenetic Analysis , Female , Gene Expression Regulation, Neoplastic , Genome , Humans , Infant , Kidney Neoplasms/chemistry , Male , Neoplasm Proteins/analysis , Nephrectomy , Tissue Array Analysis
19.
J Urol ; 178(4 Pt 1): 1184-8; discussion 1188, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17698122

ABSTRACT

PURPOSE: We evaluated the results, accuracy and clinical incidence of our standard procedure of percutaneous biopsy for solid renal masses. MATERIALS AND METHODS: From March 1999 to April 2005, 119 percutaneous core biopsies of renal masses were performed. Biopsies were proposed when there was no formal evidence for a carcinoma diagnosis on computerized tomography. RESULTS: Benign lesions were diagnosed in 24 biopsies (20.1%), including oncocytoma in 13, angiomyolipoma in 5 and chronic pyelonephritis in 5. Malignancy was identified in 70 biopsies (58.8%), including 57 renal carcinomas (conventional renal cell in 41, papillary in 12 and chromophobe in 4), 4 transitional cell carcinomas, 8 metastases and 1 lymphoma. For 25 biopsies (21%) no accurate diagnosis was possible, including 12 that showed inflammatory tissue and 13 with normal or necrotic tissue. These inconclusive biopsies prompted repeat biopsy in 13 patients, in whom a total of 11 malignant lesions were diagnosed. A total of 64 nephrectomies were performed with a biopsy accuracy for histopathological tumor type and Fuhrman nuclear grade of 86% and 46%, respectively. A period of watchful waiting was proposed for 31 patients (34.2%) and no renal malignancies were found. Computerized tomography showed stabilization or disappearance of the initial renal mass. CONCLUSIONS: Percutaneous renal tumor biopsies are safe, cost-effective and often conclusive for an acute histological diagnosis. This procedure could be decisive for choosing the optimal treatment, particularly to avoid nephrectomy for benign lesions. Biopsies should not be considered a routine procedure but they could be indicated when there is a lack of radiological evidence in elective patients.


Subject(s)
Biopsy , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Kidney/pathology , Nephrostomy, Percutaneous , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/surgery , Diagnosis, Differential , Female , Follow-Up Studies , Humans , Kidney/diagnostic imaging , Kidney Diseases/diagnostic imaging , Kidney Diseases/pathology , Kidney Diseases/surgery , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Predictive Value of Tests , Retrospective Studies , Tomography, X-Ray Computed
20.
Eur J Radiol ; 60(2): 243-9, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16962279

ABSTRACT

OBJECTIVE: Aschoff's center of proliferation (ACP), poses significant problems of differential diagnosis both in imagery and histology with infiltrating carcinoma. Up to now the criteria of Tabar and Dean (classical criteria) are considered as diagnostically relevant. MATERIAL: A retrospective study of 113 cases, enabled us to study their clinical, radiological and histological aspects. RESULTS: The ACP is a subclinical and seldom palpable entity (12%). The radiological signs of ACP are quite variable. The classical criteria lack specificity and are observed only in 48% of our stellate images. Whereas the frequency of microcalcifications is high (58.5% of the cases), their presence and their type are not predictive of an associated malignancy. The echographic diagnosis of ACP could be made in 55% of the cases but the echographic semiology lacked specificity. We noticed an associated atypical epithelial hyperplasia in 28.5% of the cases, intraductal or lobular in situ carcinoma in 9% and/or a ductal invasive carcinoma in 2% of the cases. Neither tumor size, age of the patients, nor any radiological signs were predictive of such an association. CONCLUSIONS: The classical criteria are not completely reliable and are observed only in half of our stellate images, whereas microcalcifications are often present but are not predictive of an associated malignancy.


Subject(s)
Adenocarcinoma/pathology , Breast Neoplasms/pathology , Breast/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Adenocarcinoma/diagnostic imaging , Adult , Aged , Aged, 80 and over , Breast Neoplasms/diagnostic imaging , Calcinosis/diagnostic imaging , Calcinosis/pathology , Carcinoma in Situ/diagnostic imaging , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Lobular/diagnostic imaging , Diagnosis, Differential , Female , Humans , Hyperplasia/diagnostic imaging , Hyperplasia/pathology , Incidence , Mammography , Middle Aged , Neoplasm Invasiveness , Neoplasm Staging , Observer Variation , Predictive Value of Tests , Retrospective Studies , Sensitivity and Specificity , Ultrasonography, Mammary
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