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1.
J Am Soc Nephrol ; 28(2): 520-531, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27436855

RESUMO

Thrombospondin type 1 domain-containing 7A (THSD7A) is a target antigen identified in adult membranous nephropathy (MN) along with the major antigen phospholipase A2 receptor 1 (PLA2R1). The prevalence of THSD7A-Ab-positive patients is unknown, and it is unclear whether the clinical presentation differs between patients positive for PLA2R1-Ab or THSD7A-Ab. We screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Compared with Western blot analysis, the IFT had a 92% sensitivity and a 100% specificity. The prevalence of THSD7A-associated MN in a prospective cohort of 345 patients with MN was 2.6%, and most were women. In this cohort, the percentage of patients with THSD7A-associated MN and malignant disease significantly exceeded that of patients with PLA2R1-associated MN and malignant disease. In all cohorts, we identified 40 patients with THSD7A-associated MN, eight of whom developed a malignancy within a median time of 3 months from diagnosis of MN. In one patient with THSD7A-associated MN and metastases of an endometrial carcinoma, immunohistochemistry showed THSD7A expression on the metastatic cells and within follicular dendritic cells of the metastasis-infiltrated lymph node. We conclude that the IFT allows sensitive and specific measurement of circulating THSD7A-Ab in patients with MN. Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA2R1-associated MN, and more intensive screening for the presence of malignancies may be warranted in those with THSD7A-associated MN.


Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Trombospondinas/imunologia , Adulto , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
2.
Genes Chromosomes Cancer ; 56(4): 314-327, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28035718

RESUMO

We recently described a case of a Thrombospondin Type-1 Domain containing 7A (THSD7A) associated membranous nephropathy in a female patient who was synchronously suffering from a THSD7A-positive malignancy. We here investigated the role of THSD7A as a new potential tumor antigen by evaluating over 20 000 tissue spots in more than 70 different tumor entities by immunohistochemistry using tissue microarrays. THSD7A expression was highly variable in different neoplasias with differing staining patterns. Both gain and loss of THSD7A expression compared to expression status in non-tumor tissue were linked to tumor-specific markers in the different tumor entities and were of prognostic value. The potential role of THSD7A in tumor development and therapy needs further investigation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Trombospondinas/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida
4.
Nat Genet ; 39(5): 655-60, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17417639

RESUMO

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Amplificação de Genes/genética , Sequência de Bases , Feminino , Dosagem de Genes/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
5.
Genes Chromosomes Cancer ; 53(3): 228-39, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24311521

RESUMO

In cancer therapy, the number of drugs targeting cells with characteristic molecular aberrations is continuously rising. However, application of these new drugs still is limited to a few tumor entities. The aim of this study was to test the concept of routinely identifying all possible cancer patients who might eventually benefit from targeted therapy. Therefore, all malignant tumors routinely submitted to our Institute of Pathology over a period of 4 months were brought into a tissue microarray format. Using "in situ" methods, tumors were analyzed for HER2, EGFR, and KIT status as examples for potential therapeutic target genes. In positive cases, target heterogeneity was excluded by analyzing all available large sections. Outside of tumor entities for which targeted drugs are already approved, the study revealed six tumors with homogeneously distributed HER2 overexpression/amplification (bladder, esophageal and colorectal) and seven tumors with homogeneous EGFR amplification (vulvar, ovarian, breast, esophageal and laryngeal, and adenocarcinoma of unknown primary). A total of 151 tumors showed KIT overexpression but none of seven sequenced cases showed KIT mutations. We furthermore report on a 69-year-old patient with homogeneously HER2-amplified metastatic colorectal cancer who is successfully treated by trastuzumab monotherapy. This study demonstrates that tissue microarray based screening for therapeutic target genes in tumors outside established indications represents a feasible approach suitable for routine application. The successful treatment of one patient with homogeneously HER2 positive metastatic colorectal cancer argues for the clinical utility of this approach at least in carefully selected, homogeneous cancers.


Assuntos
Neoplasias/tratamento farmacológico , Análise Serial de Tecidos/métodos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Estudos de Viabilidade , Feminino , Amplificação de Genes , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Trastuzumab
7.
Prostate ; 72(8): 898-903, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21956681

RESUMO

BACKGROUND: Loss of the Y chromosome is a frequently reported chromosomal abnormality in many tumor types. This study was undertaken to investigate the frequency of Y chromosome losses and this chromosomal abnormality might play a potential role in prostate cancer. METHODS: A preexisting prostate cancer tissue microarray (TMA) containing samples of 3,261 patients treated by radical prostatectomy with clinical follow-up data was used in this study. TMA sections were analyzed by fluorescence in situ hybridization (FISH) using a dual labeling probe for the centromeres of the X and Y chromosome. RESULTS: Unequivocal losses of the Y chromosome were seen in only 12 of 2,053 analyzable cases. No significant associations were found between Y loss and patient age, pT stage, and the risk of PSA recurrence. Interestingly, in our study the presence of Y losses was significantly associated with high Gleason grade (P = 0.0034). CONCLUSIONS: Loss of the Y chromosome is a rare event in prostate cancer. Y losses occur in much higher rates in most other cancer types. For this reason, we suggest that the expression of at least one Y chromosome gene is essential for prostate epithelial cells and it is possible that such a gene could represent a suitable target for future therapy of prostate cancer.


Assuntos
Envelhecimento/genética , Deleção Cromossômica , Cromossomos Humanos Y , Neoplasias da Próstata/genética , Idoso , Envelhecimento/patologia , Centrômero/patologia , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos
8.
Diagnostics (Basel) ; 12(5)2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35626366

RESUMO

We present an interesting image of an intense PSMA-positive follicular thyroid carcinoma incidentally detected by [68Ga]Ga-PSMA-11 PET/CT in a 76-year-old man with biochemical recurrence of prostate cancer. Immunohistochemical staining demonstrated PSMA expression in the endothelial cells of tumor tissue. This interesting image should remind colleagues to consider malignant thyroid neoplasia in PSMA-positive thyroid lesions.

9.
Diagnostics (Basel) ; 12(8)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36010284

RESUMO

We present an interesting image of a strikingly intense radioiodine accumulation of a histologically proven pancreatic adenocarcinoma mimicking metastasis of differentiated thyroid cancer in a 63-year-old woman with recurrence of papillary thyroid carcinoma undergoing radioiodine therapy. This interesting image should draw attention to considering pancreatic adenocarcinoma in radioiodine-positive pancreatic lesions.

10.
Int J Surg Pathol ; 27(6): 684-692, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30955388

RESUMO

Mixed adenoneuroendocrine carcinomas are rare and usually occur in the gastrointestinal tract. Although there have been several investigations regarding their developmental mechanism, the molecular origin of these tumors remains unclear. In this article, we present an exceedingly rare case of a mixed tumor of the urinary bladder with an adenocarcinomatous and a neuroendocrine component and a concomitant urothelial carcinoma in situ (CIS). Due to this extraordinary combination of tumor components, our goal was to extensively examine the 3 tumor components with regard to a representable common origin. Therefore, a comprehensive immunohistochemical analysis and review of the literature was performed. Besides expected outcome, our examination also revealed surprising staining results. Urothelial CIS, like the adenocarcinomatous component, showed strong staining for CDX2. In addition, parts of the adenocarcinoma were positive for synaptophysin like the neuroendocrine tumor component. All 3 components showed a significant overexpression of p53 and a moderate to strong membranous and cytoplasmatic staining for ß-catenin. To our knowledge, we are the first to describe a case of a mixed tumor of the urinary bladder with an adenocarcinomatous and a neuroendocrine component and a concomitant CIS. The components share striking molecular features that argue for a common clonal origin and a development of the invasive tumor via the urothelial precursor lesion.


Assuntos
Adenocarcinoma/diagnóstico , Carcinoma in Situ/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Neoplasias Complexas Mistas/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/análise , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/cirurgia , Cistectomia , Humanos , Imuno-Histoquímica , Masculino , Invasividade Neoplásica/patologia , Neoplasias Complexas Mistas/patologia , Neoplasias Complexas Mistas/cirurgia , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Urotélio/cirurgia
11.
Pathol Oncol Res ; 21(4): 1183-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26026893

RESUMO

Cancer is often heterogeneous both on a morphological and on a genetic level. Though resected tumors are often large, molecular tumor analysis is usually restricted to one tissue block. In this project we introduce a new tool for a high-throughput heterogeneity analysis of colorectal cancer. A heterogeneity tissue microarray (TMA) was manufactured from tissues of 340 patients with colorectal cancer. For this purpose 8 different tissue spots were taken from as many different cancer blocks per patient as possible (at least 4 different blocks). Additional tissue samples from 1 to 4 corresponding lymph node metastases were added from 134 patients. The system was then validated by analysing one parameter each known for minimal (p53) or substantial (HER2) heterogeneity in colorectal cancer. P53 alterations as detected by immunohistochemistry were seen in 174 (51.3 %) of 339 analyzable primary tumors of which 23 (13.2 % of positive cases) showed a heterogeneous distribution pattern. HER2 overexpression was seen in 18 (5.4 %) of 336 evaluable tumors. HER2 amplification occurred in 6 (33.3 %) of the 18 cases with HER2 overexpression. Genomic heterogeneity was more prevalent for HER2 alterations than for p53 alterations. For immunohistochemical expression analysis, 16 of 18 positive cases were heterogeneous (88.9 %) and for amplification 3 of 6 cases (50 %) were heterogeneous. Large section validation revealed, however a considerable fraction of heterogeneous cases were due to technical artifacts. In summary, our data suggest, that heterogeneity TMAs are a powerful tool to rapidly screen for molecular heterogeneity in colorectal cancer.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Amplificação de Genes/genética , Humanos , Imuno-Histoquímica/métodos , Metástase Linfática/genética , Metástase Linfática/patologia , Receptor ErbB-2/genética , Análise Serial de Tecidos/métodos , Proteína Supressora de Tumor p53/genética
12.
Anticancer Res ; 34(5): 2255-61, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24778028

RESUMO

AIM: To identify molecular features associated with clinico-pathological parameters in renal cell cancer. MATERIALS AND METHODS: Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging was employed for a kidney cancer tissue microarray containing tissue samples from 789 patients for which clinical follow-up data were available. RESULTS: A comparison of mass spectrometric signals with clinico-pathological features revealed significant differences between papillary and clear cell renal cell cancer. Within the subgroup of clear cell RCC, statistical associations with tumor stage (seven signals, p<0.01 each), Fuhrman grade (seven signals, p<0.0001 each), and presence of lymph node metastases (10 signals, p<0.01 each) were found. In addition, the presence of one signal was significantly linked to shortened patient survival (p=0.0198). CONCLUSION: Our data pinpoint towards various molecules with potential relevance in renal cell cancer. They also demonstrate that the combination of the MALDI mass spectrometry imaging and large-scale tissue microarray platforms represents a powerful approach to identify clinically-relevant molecular cancer features.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Análise Serial de Tecidos/métodos , Idoso , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Fenótipo
13.
PLoS One ; 7(6): e39018, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22745698

RESUMO

BACKGROUND: This study was conducted to evaluate the expression of the activated leukocyte cell adhesion molecule (ALCAM) in pancreatic cancer (PAC) and to determine whether or not the ectodomain shedding of ALCAM (s-ALCAM) could serve as a biomarker in the peripheral blood of PAC patients. MATERIAL AND METHODS: Tissue specimens and blood sera of patients with PAC (n = 264 and n = 116, respectively) and the sera of 115 patients with chronic pancreatitis (CP) were analyzed via ALCAM immunohistochemistry and s-ALCAM ELISA tests. Results were correlated with clinical, histopathological, and patient survival data (Chi-square test, Kaplan-Meier analysis, log-rank test, respectively). RESULTS: ALCAM was expressed in the majority of PAC lesions. Immunohistochemistry and serum ELISA tests revealed no association between ALCAM expression in primary tumors or s-ALCAM and clinical or histopathological data. Neither ALCAM nor s-ALCAM showed a significant impact regarding overall survival (p = 0.261 and p = 0.660, respectively). S-ALCAM serum levels were significantly elevated compared to the sera of CP patients (p<0.001). The sensitivity of s-ALCAM in detecting PAC was 58.6% at a specificity of 73.9% (AUC = 0.69). CONCLUSIONS: ALCAM is expressed in the majority of PAC lesions, but statistical analysis revealed no association with clinical or pathological data. Although significantly elevated in patients with PAC, the sensitivity and specificity of the s-ALCAM serum quantification test was low. Therefore, its potential as a novel diagnostic marker for PAC remains elusive and further investigations are required.


Assuntos
Antígenos CD/sangue , Antígenos CD/metabolismo , Moléculas de Adesão Celular Neuronais/sangue , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Fetais/sangue , Proteínas Fetais/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/sangue , Pancreatite Crônica/metabolismo
14.
J Clin Pathol ; 65(8): 693-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22639407

RESUMO

BACKGROUND AND AIM: Gastric carcinoma is the second most frequent cause of cancer-related death worldwide. As PTEN is a potential modifier of tumour response to trastuzumab, a recently approved therapy in metastatic HER2 positive gastric cancer, the existence of PTEN deletions in primary gastric cancer was investigated. METHODS: 230 primary gastric cancers were analysed in a tissue microarray format by dual labelling fluorescence in situ hybridisation for PTEN deletion. HER2 analysis was also performed. To study PTEN deletion heterogeneity, all available large tissue sections from primary cancer and corresponding metastases were analysed in seven patients. RESULTS: Eight of 180 interpretable primary gastric cancer spots showed PTEN deletions (4.4%), including seven hemizygous and one homozygous deletion. PTEN deletion was correlated with nodal (8 of 122 cases (6.6%); p=0.041) and distant metastases (4 of 19 (21.1%); p<0.001). Large section validation showed a homogeneous distribution of PTEN deletion. HER2 positivity was seen in one PTEN deleted case. CONCLUSION: Genomic PTEN deletion is a rare event in gastric adenocarcinoma but correlates with metastatic disease. The homogeneous distribution pattern indicates that this alteration occurs early in tumour development.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Deleção de Genes , PTEN Fosfo-Hidrolase/genética , Neoplasias Gástricas/genética , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Distribuição de Qui-Quadrado , Feminino , Predisposição Genética para Doença , Alemanha , Hemizigoto , Homozigoto , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor ErbB-2/análise , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Análise Serial de Tecidos/métodos
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