ABSTRACT
In multivariate analysis, GS of the regular prostatectomy specimen was the only statistically significant parameter for pT2R1 prostate cancer.
ABSTRACT
BACKGROUND: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. PATIENTS AND METHODS: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC â T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. RESULTS: The 10-year DFS rates were 66.5% in the AC â T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC â T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC â T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. CONCLUSION: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC â T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00312208.
Subject(s)
Breast Neoplasms/drug therapy , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Drug-Related Side Effects and Adverse Reactions/physiopathology , Taxoids/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Chemotherapy, Adjuvant/adverse effects , Cyclophosphamide/adverse effects , Disease-Free Survival , Docetaxel , Doxorubicin/adverse effects , Drug-Related Side Effects and Adverse Reactions/classification , Female , Granulocyte Colony-Stimulating Factor/genetics , Humans , Lymphatic Metastasis , Middle Aged , Receptor, ErbB-2/genetics , Taxoids/adverse effectsABSTRACT
PURPOSE: To predict biochemical recurrence respecting the natural course of pT2 prostate cancer with positive surgical margin (R1) and no adjuvant/neoadjuvant therapy. METHODS: A multicenter data analysis of 956 patients with pT2R1N0/Nx tumors was performed. Patients underwent radical prostatectomy between 1994 and 2009. No patients received neoadjuvant or adjuvant therapy. All prostate specimens were re-evaluated according to a well-defined protocol. The association of pathological and clinical features, in regard to BCR, was calculated using various statistical tests. RESULTS: With a mean follow-up of 48 months, BCR was found in 25.4 %. In univariate analysis, multiple parameters such as tumor volume, PSA, Gleason at positive margin were significantly associated with BCR. However, in multivariate analysis, Gleason score (GS) of the prostatectomy specimen was the only significant parameter for BCR. Median time to recurrence for GS ≤ 6 was not reached; 5-year BCR-free survival was 82 %; and they were 127 months and 72 % for GS 3+4, 56 months and 54 % for GS 4 + 3, and 27 months and 32 % for GS 8-10. The retrospective approach is a limitation of our study. CONCLUSIONS: Our study provides data on the BCR in pT2R1-PCa without adjuvant/neoadjuvant therapy and thus a rationale for an individual's risk stratification. The data support patients and physicians in estimating the individual risk and timing of BCR and thus serve to personalize the management in pT2R1-PCa.
Subject(s)
Kallikreins/blood , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/diagnosis , Prostate-Specific Antigen/blood , Prostatectomy , Prostatic Neoplasms/blood , Prostatic Neoplasms/surgery , Adult , Aged , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Neoplasm, Residual , Prostatic Neoplasms/pathology , Retrospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: Ascites is a common complication of liver cirrhosis and represents the main cause of hospitalization among patients with cirrhosis. First-line therapy for those patients is the use of diuretics and dietary sodium restriction. However, 10 % of patients per year become therapy refractory to diuretic treatment with the need of repeated high-volume paracentesis or transjugular intrahepatic portosystemic shunt (TIPS). For these patients, an automated pump system (Alfapump/Sequana Medical) was developed. Here, we describe our single-center experience of ten consecutively implanted pump systems. PATIENTS AND METHODS: Between 08/13 and 11/14, ten Alfapump systems were implanted in patients with refractory ascites all suffering from liver cirrhosis. Those patients were treated as a bridge to transplant (4/10) or as an end-stage therapy (6/10). Median follow-up was 165 days (23-379 days). RESULTS: Postimplant, the need of paracentesis could be markedly reduced to a mean of 0.45 (0-4/month) per month. In eight patients, paracentesis was not needed after implantation of the pump system. The median daily output volume was 1000 ml/day (450-2000 ml/day). Prerenal insufficiency was a recurrent complication in the postoperative period. DISCUSSION: The Alfapump system is a useful system in the treatment of patients suffering from therapy refractory ascites. However, due to the high level of comorbidities, careful patient selection and postoperative monitoring are required.
Subject(s)
Ascites/etiology , Ascites/therapy , Liver Cirrhosis/complications , Prostheses and Implants , Female , Humans , Kidney Function Tests , Length of Stay/statistics & numerical data , Liver Function Tests , Male , Operative Time , Paracentesis , Patient Selection , Portasystemic Shunt, Transjugular Intrahepatic , Postoperative Complications/epidemiology , Treatment OutcomeABSTRACT
Prostate cancer is the most common cancer and the third leading cause of cancer-specific death in men in Western industrialized countries. Implementation of the prostate-specific antigen (PSA) blood test as an early detection tool has led to a significant reduction of prostate cancer mortality in the USA. Apart from an earlier detection of clinically relevant tumors, regular PSA testing increases the risk of over-detection and over-treatment of clinically indolent tumors. In our view, a reliable stratification of indolent tumors in active surveillance programs is the key in avoiding or reducing overtreatment of early diagnosed prostate cancers. Along with better risk stratification, the expansion of PSA screening should be discussed in order to reduce the still high numbers of palliative treatments, metastases, and prostate cancer-related deaths.
Subject(s)
Biomarkers, Tumor/blood , Diagnostic Errors/statistics & numerical data , Early Detection of Cancer/statistics & numerical data , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/diagnosis , Diagnostic Errors/prevention & control , Early Detection of Cancer/methods , Evidence-Based Medicine , Humans , Male , Prevalence , Prostatic Neoplasms/epidemiology , Reproducibility of Results , Risk Assessment/methods , Sensitivity and SpecificityABSTRACT
BACKGROUND: The Coxsackie- and Adenovirus Receptor (CAR) has been assigned two crucial attributes in carcinomas: (a) involvement in the regulation of growth and dissemination and (b) binding for potentially therapeutic adenoviruses. However, data on CAR expression in cancer types are conflicting and several entities have not been analysed to date. METHODS: The expression of CAR was assessed by immunohistochemical staining of tissue microarrays (TMA) containing 3714 specimens derived from 100 malignancies and from 273 normal control tissues. RESULTS: The expression of CAR was detected in all normal organs, except in the brain. Expression levels, however, displayed a broad range from being barely detectable (for example, in the thymus) to high abundance expression (for example, in the liver and gastric mucosa). In malignancies, a high degree of variability was notable also, ranging from significantly elevated CAR expression (for example, in early stages of malignant transformation and several tumours of the female reproductive system) to decreased CAR expression (for example, in colon and prostate cancer types). CONCLUSION: Our results provide a comprehensive insight into CAR expression in neoplasms and indicate that CAR may offer a valuable target for adenovirus-based therapy in a subset of carcinomas. Furthermore, these data suggest that CAR may contribute to carcinogenesis in an entity-dependent manner.
Subject(s)
Coxsackie and Adenovirus Receptor-Like Membrane Protein/metabolism , Neoplasms/metabolism , Adenoviridae Infections , Cell Transformation, Neoplastic/genetics , Coxsackievirus Infections , Gene Expression Regulation, Neoplastic , Humans , Protein Array AnalysisABSTRACT
UNLABELLED: AIB1 (amplified in breast cancer 1) is an estrogen receptorα (ERα) co-activator, known to be amplified and overexpressed in a fraction of breast cancers. It has been linked to prognosis and tamoxifen resistance. However, results have been ambiguous. The different functions of AIB1 in ERα-positive and -negative disease are poorly understood. Therefore, we analyzed the clinical significance of AIB1 in breast cancer with respect to ERα-status and characterized the subgroups. 2,197 breast carcinomas sampled on a pre-existing tissue microarray (TMA) were analyzed for AIB1 expression and amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: AIB1 expression was detected in 60 % of the tumors. It was associated with tumor size (p = 0.003), high histological grade (p < 0.0001), poor disease-specific, and overall survival (p = 0.0018 and p = 0.003). There was a strong inverse relationship between AIB1 and ERα expression (p < 0.0001). AIB1 overexpression was associated with increased Ki67 labeling index (p < 0.0001), even if analyzed for different ER expression levels. AIB1 amplification was found in 11 % of the carcinomas. It was associated with high histological grade (p = 0.0012), lymph node involvement (p = 0.0163), and poor disease-specific survival (p = 0.0032) but not with overall survival (p = 0.1672) or ER status (p = 0.4456). If ER-positive tumors were stratified according to their AIB1 amplification status, there was a significant worse disease-specific survival in cases showing AIB1 amplification (p = 0.0017). AIB1 expression is associated with unfavorable prognosis and tumor phenotype. It seems to unfold its oncogenic potential at least in part independent from its role as an ERα co-activator. AIB1 has an impact on cell cycle regulation in ERα-positive as well as ERα-negative tumors. Furthermore, AIB1 amplification characterizes a subgroup of ERα-positive breast cancer with worse outcome. Therefore, AIB1 might be helpful to identify those ERα-positive breast cancers patients who are candidates for adjuvant chemotherapy.
Subject(s)
Breast Neoplasms/metabolism , Nuclear Receptor Coactivator 3/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Gene Amplification , Gene Dosage , Gene Expression , Humans , Ki-67 Antigen/metabolism , Middle Aged , Nuclear Receptor Coactivator 3/genetics , PrognosisABSTRACT
BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) was found overexpressed in various cancer types suggesting its possible role in carcinogenesis. Analysis of IMP3 expression in head and neck squamous cell carcinomas (HNSCC) is rare so that we evaluated it using tissue microarray method. METHOD: Immunohistochemical analysis of IMP3 was performed on samples from over 400 patients. The expression was measured semiquantitative, subsequently divided into four categories (negative, weak, medium, or strong) and correlated with several available clinicopathologic parameters. RESULTS: For HNSCC, positive IMP3 expression was observed in patients with all tumor stages (pT1-4) and nodal stages (pN0-3), showing also significant statistical correlation (P=0.023 and P=0.0013, respectively). No further correlations were found. Separate analysis according to tumor localization (oral cavity, oropharyngeal, and laryngeal) showed a significant correlation of positive IMP3 expression and overall survival (P=0.038) only in patients with tumors of the oral cavity. Multivariate analysis showed IMP3 as an independent predictive marker for oral squamous cell carcinomas (OSCC). CONCLUSION: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression might be used as an independent prognostic factor in the subgroup of OSCC.
Subject(s)
Carcinoma, Squamous Cell/pathology , Head and Neck Neoplasms/pathology , Insulin-Like Growth Factor Binding Protein 3/analysis , Adult , Aged , Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/secondary , Cohort Studies , Disease-Free Survival , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic/genetics , Head and Neck Neoplasms/genetics , Humans , Immunohistochemistry , Insulin-Like Growth Factor Binding Protein 3/genetics , Laryngeal Neoplasms/pathology , Lymphatic Metastasis/pathology , Male , Middle Aged , Mouth Neoplasms/pathology , Neoplasm Grading , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Oropharyngeal Neoplasms/pathology , Prognosis , Protein Array Analysis , RNA, Messenger/analysis , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Overexpression of anti-apoptotic Bcl-2 plays a role in prostate cancer progression, particularly in transformation to androgen-independent disease. Androgen-independent prostate cancers have been shown to harbor Bcl-2 gene copy number gains frequently suggesting that this genetic alteration might play a role in Bcl-2 overexpression. The relation of Bcl-2 overexpression and copy number gains or translocation of the BCL-2 gene in prostate cancer under hormone-naïve conditions is unknown. METHODS: Prostate cancers of 3,261 hormone-naïve patients undergoing radical prostatectomy were arrayed in a TMA with one tissue core (diameter 0.6 mm) per tumor. Bcl-2 immunohistochemistry, analyzed for Bcl-2 expression level (negative, low, and high), was correlated with clinical, histopathological and molecular (Ki67, p53) tumor features, and biochemical failure. Cancers with high-level Bcl-2 expression were evaluated for genetic aberrations by fluorescence in situ hybridization (FISH). RESULTS: Bcl-2 expression was significantly up-regulated in tumors with aggressive phenotype as indicated by high Gleason score (P < 0.0001), advanced stage (P < 0.0001), and high proliferation index (P = 0.0114). The different Bcl-2 expression levels translated into significantly different survival curves showing better outcome for patients with lower Bcl-2 levels. The prognostic information obtained from the anti-apoptotic Bcl-2 was independent from the proliferation index (Ki67) of the cancer. FISH analysis detected no copy number gains or translocation of the Bcl-2 gene. CONCLUSION: Bcl-2 overexpression in prostate cancers under hormone-naïve conditions is not associated with increased copy numbers of the gene. This suggests that these frequently detected genetic alterations in androgen-independent tumors occur late in prostate cancer progression.
Subject(s)
Gene Dosage/genetics , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/genetics , Prostatic Neoplasms/surgery , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/genetics , Translocation, Genetic/physiology , Aged , Disease Progression , Humans , Male , Middle Aged , Prognosis , Prostatic Neoplasms/metabolism , Proto-Oncogene Proteins c-bcl-2/physiologyABSTRACT
BACKGROUND: Owing to controversial staging and classification of adenocarcinoma of the oesophago-gastric junction (AOG) before surgery, the choice of appropriate surgical approach remains problematic. In a retrospective study, preoperative staging of AOG and the impact of preoperative misclassification on outcome were analysed. METHODS: Data from patients with AOG were analysed from a prospectively collected database with regard to surgical treatment, preoperative and postoperative staging, and outcome. RESULTS: One-hundred and thirty patients with Siewert types I and II AOG who did not have neoadjuvant treatment were included in the study: 41 patients with an AOG type I who underwent oesophagectomy, 51 patients with an AOG staged before surgery as type I who underwent oesophagectomy but in whom the final histology showed a type II tumour, and 38 patients whose tumours were staged as AOG type II before and after operation who underwent gastrectomy. Among patients who had an oesophagectomy, lymph node metastases (P = 0.022), tumour relapse (P = 0.009) and recurrent distant metastases (P = 0.028) were significantly more frequent in patients with AOG type II; those with AOG type II had shorter overall survival than those with type I tumours (P = 0.024). Among those with AOG type II, recurrence-free survival was significantly shorter after oesophagectomy compared with extended gastrectomy (P = 0.019). Thoracoabdominal oesophagectomy had a favourable influence on outcome compared with the transhiatal approach. CONCLUSION: Accurate preoperative staging of AOG and appropriate surgical therapy are crucial for outcome. AOG type II is a more aggressive tumour with higher recurrence rates than AOG type I. These patients therefore benefit from more radical surgical treatment.
Subject(s)
Adenocarcinoma/surgery , Esophageal Neoplasms/surgery , Esophagogastric Junction/surgery , Stomach Neoplasms/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophagectomy/methods , Esophagectomy/mortality , Female , Gastrectomy/methods , Gastrectomy/mortality , Humans , Intraoperative Care/methods , Intraoperative Care/mortality , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging/methods , Neoplasm Staging/mortality , Preoperative Care/methods , Preoperative Care/mortality , Retrospective Studies , Stomach Neoplasms/mortality , Stomach Neoplasms/pathologyABSTRACT
Many genes and signalling pathways controlling cell proliferation, death and differentiation, as well as genomic integrity, are involved in cancer development. New techniques, such as serial analysis of gene expression and cDNA microarrays, have enabled measurement of the expression of thousands of genes in a single experiment, revealing many new, potentially important cancer genes. These genome screening tools can comprehensively survey one tumor at a time; however, analysis of hundreds of specimens from patients in different stages of disease is needed to establish the diagnostic, prognostic and therapeutic importance of each of the emerging cancer gene candidates. Here we have developed an array-based high-throughput technique that facilitates gene expression and copy number surveys of very large numbers of tumors. As many as 1000 cylindrical tissue biopsies from individual tumors can be distributed in a single tumor tissue microarray. Sections of the microarray provide targets for parallel in situ detection of DNA, RNA and protein targets in each specimen on the array, and consecutive sections allow the rapid analysis of hundreds of molecular markers in the same set of specimens. Our detection of six gene amplifications as well as p53 and estrogen receptor expression in breast cancer demonstrates the power of this technique for defining new subgroups of tumors.
Subject(s)
Breast Neoplasms/genetics , Genetic Techniques , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cyclin D1/genetics , Cyclin D1/metabolism , Female , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Mice , Oncogene Proteins v-myb , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Rabbits , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Retroviridae Proteins, Oncogenic/genetics , Retroviridae Proteins, Oncogenic/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Multiple different biologically and clinically relevant genes are often amplified in invasive breast cancer, including HER2, ESR1, CCND1, and MYC. So far, little is known about their role in tumor progression. To investigate their significance for tumor invasion, we compared pure ductal carcinoma in situ (DCIS) and DCIS associated with invasive cancer with regard to the amplification of these genes. Fluorescence in situ hybridization (FISH) was performed on a tissue microarray containing samples from 130 pure DCIS and 159 DCIS associated with invasive breast cancer. Of the latter patients, we analyzed the intraductal and invasive components separately. In addition, lymph node metastases of 23 patients with invasive carcinoma were included. Amplification rates of pure DCIS and DCIS associated with invasive cancer did not differ significantly (pure DCIS vs. DCIS associated with invasive cancer: HER2 22.7 vs. 24.2%, ESR1 19.0 vs. 24.1%, CCND1 10.0 vs. 14.8%, MYC 11.8 vs. 6.5%; P > 0.05). Furthermore, we observed a high concordance of the amplification status for all genes if in situ and invasive carcinoma of individual patients were compared. This applied also to the corresponding lymph node metastases. Our results indicate no significant differences between the gene amplification status of DCIS and invasive breast cancer concerning HER2, ESR1, CCND1, and MYC. Therefore, our data suggest an early role of all analyzed gene amplifications in breast cancer development but not in the initiation of invasive tumor growth.
Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Intraductal, Noninfiltrating/genetics , Gene Amplification , Gene Expression Regulation, Neoplastic , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Chi-Square Distribution , Cyclin D1/genetics , Estrogen Receptor alpha/genetics , Female , Genotype , Humans , In Situ Hybridization, Fluorescence , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Phenotype , Proto-Oncogene Proteins c-myc/genetics , Receptor, ErbB-2/genetics , Tissue Array AnalysisABSTRACT
The HER2 gene is amplified and overexpressed in about 15%-20% of breast cancers. For every newly diagnosed breast cancer HER2 testing is a standard routine procedure. This article focuses on a number of issues raised in the context of current HER2 testing in breast cancer. It particularly points out issues arising in the recently published ASCO-CAP (American Society of Clinical Oncology/College of American Pathologists) guideline recommendations for clinical testing of HER2. Despite the significant correlation between HER2 status determination by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), standard considerations of laboratory testing, such as test accuracy, reproducibility and precision as well as current data, favor FISH methods over IHC assay methods for the determination of HER2 status. Biological and technical considerations of HER2 testing are also important in clinical practice. For example, HER2 gene amplification is directly linked to the protein expression level in breast cancer; however, the HER2 protein is not consistently analyzed on formalin fixed tissues due to variability in fixation methods/times and the impact of this fixation on HER2 protein antigenicity. FISH is significantly less dependent on tissue fixation artifacts. Hence, FISH is more reproducible between both central and peripheral laboratories than IHC and is more accurate for HER2 measurement, as well as being more strongly correlated with responsiveness to trastuzumab and lapatinib treatment. Until other methods are able to ensure similar test accuracy, reproducibility, precision and predictive value, FISH is recommended as the primary HER2 testing modality for women with breast cancer who are candidates for HER2-targeted therapies.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Receptor, ErbB-2/genetics , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Drug Delivery Systems , Female , Formaldehyde , Gene Amplification/genetics , Humans , In Situ Hybridization, Fluorescence , Lapatinib , Practice Guidelines as Topic , Predictive Value of Tests , Prognosis , Quinazolines/therapeutic use , Tissue Fixation , Trastuzumab , Treatment OutcomeABSTRACT
Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.
Subject(s)
Breast Neoplasms/genetics , Gene Amplification , Neoplasms, Hormone-Dependent/genetics , Ovarian Neoplasms/genetics , Receptors, Estrogen/metabolism , Amino Acid Sequence , Breast/metabolism , Breast Neoplasms/metabolism , Chromosomes, Human, Pair 20 , Cloning, Molecular , Estradiol/metabolism , Estradiol/pharmacology , Female , Gene Dosage , Gene Expression Regulation, Neoplastic , Histone Acetyltransferases , Humans , In Situ Hybridization, Fluorescence , Ligands , Molecular Sequence Data , Neoplasms, Hormone-Dependent/metabolism , Nuclear Receptor Coactivator 1 , Nuclear Receptor Coactivator 2 , Ovarian Neoplasms/metabolism , Receptors, Estrogen/genetics , Transcription Factors/genetics , Transcriptional Activation , Transfection , Tumor Cells, CulturedABSTRACT
Oestrogen receptor alpha (ER) plays a critical, diverse and not fully understood role in endometrial carcinoma. Most endometrial carcinomas express ER and some of these tumours respond favourably to anti-oestrogen therapy. On the other hand, tamoxifen therapy constitutes a major risk factor for endometrial carcinoma development. Amplification of the ESR1 gene encoding ER was recently shown to constitute a mechanism for ER over-expression in breast carcinoma. This study was designed to determine the potential role of ESR1 amplifications in endometrial carcinoma. Tissue microarrays of 368 endometrial carcinomas and large sections of 43 cases of endometrial hyperplasia were analysed for ESR1 gene amplification and ER protein expression by means of fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH revealed ESR1 amplification in 40/176 (23%) cancers, 6/19 (32%) atypical complex hyperplasias, 3/10 (30%) complex hyperplasias without atypia and 2/14 (14%) simple hyperplasias without atypia. Strong ER protein expression was significantly linked to ESR1 amplification in endometrial carcinoma (p = 0.0036). These data indicate that ESR1 amplification might be one mechanism for ER over-expression in endometrial carcinoma, and suggest an early role for ESR1 amplification in the development of a significant fraction of endometrial carcinoma. Given the predictive role of ESR1 amplification for tamoxifen response in breast carcinoma, it will be interesting to investigate the response of ESR1-amplified endometrial cancers to anti-oestrogenic drugs.
Subject(s)
Endometrial Neoplasms/genetics , Estrogen Receptor alpha/genetics , Gene Amplification , Gene Expression Regulation, Neoplastic , Precancerous Conditions/genetics , Adult , Aged , Aged, 80 and over , Chi-Square Distribution , Endometrial Hyperplasia/genetics , Endometrial Hyperplasia/metabolism , Endometrial Hyperplasia/pathology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Estrogen Receptor alpha/analysis , Female , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Middle Aged , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Survival AnalysisABSTRACT
Principally there are two different types of bladder cancer. Non-invasive papillary low grade tumors (pTa G1-G2) are genetically stable, recur frequently but show a low risk of progression. On the other hand there are high grade tumors (pT1-4, carcinoma in situ), which are genetically unstable, show biologically aggressive behaviour and progress. The distinction between non-invasive (pTa) and minimal-invasive (pT1) is one of the most challenging areas in bladder pathology. Due to the lack of appropriate auxiliary analysis the diagnosis is based entirely on histopathology. P53 immunohistochemistry can be helpful in the assessment of recurring high grade neoplasia. Targeted therapy in bladder cancer is particularly interesting, since a high number of oncogenes are activated and overexpressed (e.g. HER2 and EGFR).
Subject(s)
Carcinoma in Situ/genetics , Carcinoma in Situ/pathology , Carcinoma, Papillary/genetics , Carcinoma, Papillary/pathology , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/pathology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Biopsy , Chromosomes, Human, Pair 9/genetics , DNA Mutational Analysis , Diagnosis, Differential , Disease Progression , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Neoplasm Invasiveness , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Receptor, ErbB-2/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics , Urinary Bladder/pathologyABSTRACT
BACKGROUND: In recent years, osteoid osteomas have been treated more frequently by means of percutaneous procedures. The main disadvantage in patients with suspected osteoid osteoma is the lack of histological verification. Our study presents the results that we obtained using a minimally invasive diamond bone-cutting system allowing histologic verification. MATERIALS AND METHODS: Six patients (age 10-20 years) with osteoid osteoma in the lower extremities were subjected to resection of the nidus using a minimally invasive water-cooled diamond bone-cutting system. All specimens were histologically processed and diagnosed. RESULTS: In all patients the nidus was resected successfully, and the diagnosis was histologically confirmed. The mean operating time was 22.8 min. All patients were allowed full weight-bearing immediately, and hospitalization was a maximum of 2 days. All patients were free of pain and relapse-free during the entire 2-year postoperative follow-up. CONCLUSION: In selected localizations with a clearly visible nidus, the minimally invasive diamond bone-cutting system presented here offers an alternative to the established surgical and percutaneous procedures for treating osteoid osteomas. This procedure combines the advantages of a minimally invasive technique with the option of histological verification of the diagnosis and correct nidus ablation.
Subject(s)
Bone Neoplasms/pathology , Bone Neoplasms/surgery , Minimally Invasive Surgical Procedures/instrumentation , Osteotomy/instrumentation , Adolescent , Bone Neoplasms/diagnostic imaging , Child , Diamond , Equipment Design , Equipment Failure Analysis , Female , Humans , Male , Minimally Invasive Surgical Procedures/methods , Osteotomy/methods , Surgery, Computer-Assisted/methods , Tomography, X-Ray Computed/methods , Treatment Outcome , Young AdultABSTRACT
Oncogenic wingless-related mouse mammary tumour virus (Wnt) signalling, caused by epigenetic inactivation of specific pathway regulators like the putative tumour suppressor secreted frizzled-related protein 1 (SFRP1), may be causally involved in the carcinogenesis of many human solid tumours including breast, colon and kidney cancer. To evaluate the incidence of SFRP1 deficiency in human tumours, we performed a large-scale SFRP1 expression analysis using immunohistochemistry on a comprehensive tissue microarray (TMA) comprising 3448 tumours from 36 organs. This TMA contained 132 different tumour subtypes as well as 26 different normal tissues. Although tumour precursor stages of, for example kidney, colon, endometrium or adrenal gland still exhibited moderate to abundant SFRP1 expression, this expression was frequently lost in the corresponding genuine tumours. We defined nine novel tumour entities with apparent loss of SFRP1 expression, i.e., cancers of the kidney, stomach, small intestine, pancreas, parathyroid, adrenal gland, gall bladder, endometrium and testis. Renal cell carcinoma (RCC) exhibited the highest frequency of SFRP1 loss (89% on mRNA level; 75% on protein level) and was selected for further analysis to investigate the cause of SFRP1 loss in human tumours. We performed expression, mutation and methylation analysis in RCC and their matching normal kidney tissues. SFRP1 promoter methylation was frequently found in RCC (68%, n=38) and was correlated with loss of SFRP1 mRNA expression (p<0.05). Although loss of heterozygosity was found in 16% of RCC, structural mutations in the coding or promoter region of the SFRP1 gene were not observed. Our results indicate that loss of SFRP1 expression is a very common event in human cancer, arguing for a fundamental role of aberrant Wnt signalling in the development of solid tumours. In RCC, promoter hypermethylation seems to be the predominant mechanism of SFRP1 gene silencing and may contribute to initiation and progression of this disease.
Subject(s)
Gene Expression Profiling , Intercellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , DNA Methylation , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Intercellular Signaling Peptides and Proteins/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Loss of Heterozygosity , Membrane Proteins/metabolism , Middle Aged , Neoplasms/genetics , Neoplasms/metabolism , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Array AnalysisABSTRACT
Amplification of 6p22 occurs in about 10-20% of bladder cancers and is associated with enhanced tumour cell proliferation. Candidate target genes for the 6p22 amplicon include E2F3 and the adjacent gene NM_017774. To clarify which gene is representing the main target, we compared the prevalence of the amplification and the functional role of both genes. Amplification of E2F3 and NM_017774 was analysed by fluorescence in situ hybridization on a bladder cancer tissue microarray composed of 2317 cancer samples. Both genes showed amplification in 104 of 893 (11.6%) interpretable tumours and were exclusively found co-amplified. Additional gene expression analysis by real-time polymerase chain reaction in 12 tumour-derived cell lines revealed that amplification of 6p22 was always associated with co-overexpression of E2F3 and NM_017774. Furthermore, RNA interference was used to study the influence of reduced gene expression on cell growth. In tumour cells with and without the 6p22 amplicon, knockdown of E2F3 always lead to unequivocal reduction of proliferation, whereas knockdown of NM_017774 was only capable to slow down cell proliferation in non-amplified cells. Our findings point out that E2F3 but not NM_017774 is driving enhanced proliferation of 6p22 amplified tumour cells. We conclude that E2F3 must be responsible for the growth advantage of 6p22 amplified bladder cancer cells.
Subject(s)
Chromosomes, Human, Pair 6 , E2F3 Transcription Factor/genetics , Gene Amplification , Urinary Bladder Neoplasms/genetics , Cell Proliferation/drug effects , Chromosomes, Artificial, Bacterial , Chromosomes, Artificial, P1 Bacteriophage , Gene Dosage , Gene Expression Regulation, Neoplastic , Humans , Prognosis , RNA, Small Interfering/pharmacology , Tissue Array Analysis/methodsABSTRACT
Abundant mRNA expression for a proliferation-inducing ligand (APRIL) from tumor necrosis factor (TNF) family is observed in many solid tumors. Here, we analyzed in situ the cellular source of APRIL in human solid tumors with anti-APRIL antibodies. In most cases, neutrophils present in the tumor stroma constituted the main source of APRIL. In cutaneous lesions such as melanoma or basal cell carcinoma, tumor-adjacent keratinocytes also produced APRIL. APRIL production by tumor cells themselves was a rare event, only observed in urothelial bladder cancer and squamous cell carcinoma. Detailed analysis revealed that APRIL dissociated from producing cells, and secreted APRIL was retained in the tumor lesions. A direct binding onto tumor cells via heparan sulfate proteoglycans (HSPG) was observed in in vitro experiments and confirmed in situ. Taken together, our analysis indicates a potential role for HSPG/APRIL interactions in the development of solid tumors.