Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non-small cell lung cancer.

Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC).

Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin).

Computational pathology analysis of tissue microarrays predicts survival of renal clear cell carcinoma patients.

Renal cell carcinoma (RCC) can be diagnosed by histological tissue analysis where exact counts of cancerous cell nuclei are required. We propose a completely automated image analysis pipeline to predict the survival of RCC patients based on the analysis of immunohistochemical staining of MIB-1 on tissue microarrays. A random forest classifier detects cell nuclei of cancerous cells and predicts their staining.

Claudin-1 protein expression is a prognostic marker of patient survival in renal cell carcinomas.

Purpose: Claudin-1 is a tight junction protein described in normal tissues as well as in malignancies. We aimed to assess the diagnostic or prognostic significance of claudin-1 expression in renal cell carcinoma and to correlate the expression of claudin-1 with clinical, histopathologic, and prognostic parameters in renal cell carcinoma.

Experimental Design: A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissue from renal cell carcinomas and corresponding normal renal tissue from 318 patients.

Frequent expression of the novel cancer testis antigen MAGE-C2/CT-10 in hepatocellular carcinoma.

Cancer testis (CT) antigens are attractive targets for immunotherapy in cancer patients. Immunohistochemistry was used to study the expression of the CT antigens MAGE-C2/CT-10, MAGE-C1/CT-7, GAGE, MAGE-A4 and NY-ESO-1 in 146 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 37 extrahepatic cholangiocarcinomas and 32 gallbladder carcinomas. Immunopositivity was correlated with clinicopathological parameters, MHC Class 1 expression, intratumoral CD4+, CD8+ and FOXP3+ T cells and CD163+ antigen-presenting cells.

TTF1 expression in non-small cell lung carcinoma: association with TTF1 gene amplification and improved survival.

Acquired chromosomal aberrations play an important role in tumour development and progression. Such genetic alterations occur in a significant proportion of non-small cell lung carcinomas (NSCLCs) and include amplification of 14q13.3, which contains the TTF1 gene.

Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases.

The aggregate literature suggests that chromophobe renal cell carcinoma (RCC) is biologically a tumor of low malignant potential with reported 5-year and 10-year survival rates of 78% to 100% and 80% to 90%, respectively. The conventional prognostic parameters that determine the outcome of the tumors that progress remain to be fully characterized. Clinicopathologic features of 145 cases were correlated with outcome.

Immunophenotyping without antibodies. New perspectives for lymphoma characterization.

Aims: Accurate classification of haematological malignancies is a prerequisite for their correct diagnosis, prognosis and therapy. Clear classification of lymphomas is often hindered by the limited number of available cell surface protein markers that are suitable for immunophenotyping. A systematic and quantitative analysis of cell surface proteins is thus required to identify new protein markers on lymphoma subtypes in an unbiased and discovery-driven approach.

GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics.

GOLPH2 is coding the 73-kDa type II Golgi membrane antigen GOLPH2/GP73. Upregulation of GOLPH2 mRNA has been recently reported in expression array analyses of prostate cancer. As GOLPH2 protein expression in prostate tissues is currently unknown, this study aimed at a comprehensive analysis of GOLPH2 protein in benign and malignant prostate lesions.

[Von-Hippel-Lindau gene mutation types. Association of gene expression signatures in clear cell renal cell carcinoma].

Aims: The von-Hippel-Lindau (VHL) tumor suppressor is a multifunctional protein. VHL mutations are common in sporadic clear cell renal cell carcinoma (ccRCC). Different mutation types may specifically alter pVHL functions, which have significant impact on gene expression and, consequently, on the disease outcome.

[Molecular basis of targeted therapy in metastatic renal cancer].

The introduction of targeted therapy in metastatic renal cancer patients provides a whole array of individual therapeutic options. The basis for this treatment is the inactivation of the von Hippel-Lindau tumor suppressor gene, resulting in high expression of pro-angiogenic growth factors, e.g.

[Von-Hippel-Lindau (VHL) protein function by initiation and progression of renal cancer].

Germ line inactivation of the von-Hippel-Lindau (VHL) tumor suppressor gene causes von Hippel-Lindau hereditary cancer syndrome, and somatic mutations of this gene have been linked to the development of sporadic hemangioblastomas and clear cell renal carcinomas. The protein encoded by VHL, pVHL, has no known enzymatic activities but interacts with various partner proteins. In this review, various pVHL functions are highlighted.

Oestrogen receptor gene (ESR1) amplification is frequent in endometrial carcinoma and its precursor lesions.

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.

HER3 is a determinant for poor prognosis in melanoma.

Purpose: The epidermal growth factor receptor family member HER3 is overexpressed in diverse human cancers and has been associated with poor prognosis in breast, lung, and ovarian cancer. However, the relevance of HER3 with regard to its prognostic significance and function in primary melanoma and metastases remains largely elusive.

Experimental Design: HER3 protein expression was analyzed immunohistochemically using tissue microarrays of 130 primary melanoma and 87 metastases relative to established clinical variables.

Estrogen receptor gene amplification occurs rarely in ovarian cancer.

Amplification of the gene encoding estrogen receptor-alpha occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases. To study a potential role of estrogen receptor-alpha gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization for estrogen receptor-alpha gene amplification and immunohistochemistry for estrogen receptor expression.

Sporadic clear cell renal cell carcinoma but not the papillary type is characterized by severely reduced frequency of primary cilia.

Renal cysts and clear cell renal cell carcinoma are common clinical manifestations of people with germ-line mutations of the von Hippel-Lindau tumor suppressor gene, VHL. Recent cell biological evidence suggests that the VHL gene product, pVHL, functions to maintain the primary cilium, a microtubule-based antenna-like structure whose functional integrity is believed to have an important role in cell-cycle control. As VHL mutations are common in sporadic clear cell renal cell carcinoma, but not papillary renal cell carcinoma, we asked whether there is an association between VHL status and primary cilia in vivo.

pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation.

In patients with von Hippel-Lindau (VHL) disease, renal cysts and clear cell renal cell carcinoma (ccRCC) arise from renal tubular epithelial cells containing biallelic inactivation of the VHL tumour suppressor gene. However, it is presumed that formation of renal cysts and their conversion to ccRCC involve additional genetic changes at other loci. Here, we show that cystic lesions in the kidneys of patients with VHL disease also demonstrate activation of the phosphatidylinositol-3-kinase (PI3K) pathway.

Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer.

The purpose of our study was to demonstrate that distinct cytogenetic alterations in the most common subtype of renal cell cancer, clear cell renal cell carcinoma (ccRCC), are reflected in protein expression profiles. We performed conventional cytogenetics and immunohistochemical analysis for cytokeratins (CKs) on 126 ccRCCs. Protein expression was evaluated in situ using a semiautomated quantitative system.

Combined VHLH and PTEN mutation causes genital tract cystadenoma and squamous metaplasia.

Patients with von Hippel-Lindau (VHL) disease develop tumors in a range of tissues, but existing mouse models of Vhlh mutation have failed to reproduce these lesions. Epididymal cystadenomas arise frequently in VHL patients, but VHL mutation alone is believed to be insufficient for tumor formation, implying a requirement for cooperating mutations in epididymal pathogenesis. Here we show that epididymal cystadenomas from VHL patients frequently also lack expression of the PTEN tumor suppressor and display activation of phosphatidylinositol 3-kinase (PI3K) pathway signaling.

New derivatives of vitamin B12 show preferential targeting of tumors.

Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled ((57)Co and (111)In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue.

Renal cell carcinoma marker reliably discriminates central nervous system haemangioblastoma from brain metastases of renal cell carcinoma.

Aims: The distinction between central nervous system (CNS) metastases of clear cell renal cell carcinoma (RCC) and CNS haemangioblastoma still poses a challenge to the pathologist. Since both entities occur in von Hippel-Lindau disease, this aggravates the issue. The antibody renal cell carcinoma marker (RCC-ma) has been suggested to identify primary RCCs specifically, but its value for diagnosing metastases of RCC is controversial.

Use of intraoperative stereomicroscopy for preventing loss of metastases during frozen sectioning of sentinel lymph nodes in breast cancer.

Aims: Optimal detection of metastases in sentinel lymph nodes (SLN) remains controversial. To determine the reliability of intraoperative frozen sections, SLN protocol with one frozen section was compared with macroscopic SLN evaluation with consecutive complete SLN embedding.

Methods And Results: SLN from 135 consecutive breast cancer patients were analysed under a sereomicroscope.

N-glycoprotein profiling of lung adenocarcinoma pleural effusions by shotgun proteomics.

Background: Malignant pleural effusion of advanced lung adenocarcinoma may be a valid source for detection of biomarkers, such as N-glycosylated proteins (N-GP), because tumor cells grow during weeks in this liquid. The authors aimed for creation of N-GP effusion profiles from routine cytology specimens to detect relevant biomarkers.

Methods: Hundred microliters of malignant pleural effusions of 5 patients with lung adenocarcinoma and 5 nonmalignant controls were used for triplicate N-GP capture by solid-phase extraction.

EML4-ALK fusion lung cancer: a rare acquired event.

A recurrent gene fusion between EML4 and ALK in 6.7% of non-small cell lung cancers (NSCLCs) and NKX2-1 (TTF1, TITF1) high-level amplifications in 12% of adenocarcinomas of the lung were independently reported recently. Because the EML4-ALK fusion was only shown by a reverse transcription-polymerase chain reaction approach, we developed fluorescent in situ hybridization assays to interrogate more than 600 NSCLCs using break-apart probes for EML4 and ALK.

[Loss of metastatic deposits in breast sentinel lymph nodes during intra-operative frozen section analysis].

The intraoperative evaluation of sentinel lymph nodes is an ongoing debated issue. In this review we discuss different approaches to sentinel lymph node processing in an intra operative setting and in the consecutive embedding in paraffin. We propose a method, which uses routine intra operative examination of lymph nodes with stereo microscopy with selected frozen section analysis.