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1.  Assessment of HER2 status in breast cancer: overall positivity rate and accuracy by fluorescence in situ hybridization and immunohistochemistry in a single institution over 12 years: a quality control study 
BMC Cancer  2013;13:615.
Background
The gold standard of HER2 status assessment in breast cancer is still debated. Immunohistochemistry (IHC) and in-situ technology as fluorescent-labeled methodology (FISH) can be influenced by pre-analytical factors, assay-conditions and interpretation of test results. We retrospectively conducted this quality control study and analyzed HER2 test results in breast cancer within the routine diagnostic service in a single institution over a period of 12 years. We addressed the question how stable and concordant IHC and FISH methods are and whether HER2 positivity rate has changed over this period.
Methods
Data of 7714 consecutive HER2-FISH-assays in a period of 12 years (2001–2012) on breast cancer biopsies and excision specimens were retrospectively analyzed. From 2001 to 2004, FISH tests were performed from all cases with IHC score 3+ and 2+ (and in some tumors with IHC score 1+ and 0). From 2005–2010, HER2 status was only determined by FISH. From 2011–2012, all breast carcinomas were analyzed by both IHC and FISH. Scoring and cut-off-definition were done according to time-current ASCO-CAP and FDA-guidelines.
Results
Between 2001–2004, IHC score 3+ was diagnosed in 22% of cases, 69% of these 3+ cases were amplified by FISH. 6% of IHC score 0/1+ cases were amplified by FISH. There was a mean amplification rate of 15.8% (range 13 -19%) using FISH only HER2-assays (2005–2010). Starting 2008, a slight drop in the amplification rate from 17% to 14% was noticed due to the modified ASCO-criteria in 2007. From 2011–2012, 12% of cases were 3+ by IHC, 84% of them were amplified by FISH. Less than 1% of IHC score 0/1+ cases were amplified by FISH. Concordance between FISH and IHC increased from 83% to 97%.
Conclusions
Our quality control study demonstrates that HER2 positivity rate remained stable by FISH-technology but showed a significant variation by IHC over the analyzed 12 years. Improvement in concordance rate was due to standardization of pre-analytical factors, scoring and interpretation.
doi:10.1186/1471-2407-13-615
PMCID: PMC3879657  PMID: 24377754
HER2; Fluorescence in situ hybridization (FISH); Immunohistochemistry; Breast cancer
2.  The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer 
BMC Cancer  2013;13:50.
Background
Several classification systems are available to assess pathological response to neoadjuvant chemotherapy in breast cancer, but reliable biomarkers to predict the efficiency of primary systemic therapy (PST) are still missing. Deregulation of gap junction channel forming connexins (Cx) has been implicated in carcinogenesis and tumour progression through loss of cell cycle control. In this study we correlated Cx expression and cell proliferation with disease survival and pathological response to neoadjuvant chemotherapy in breast cancers using existing classification systems.
Methods
The expression of Cx26, Cx32, Cx43, Cx46 and Ki67 was evaluated in 96 breast cancer patients prior to and after neoadjuvant chemotherapy using duplicate cores in tissue microarrays (TMA). Cx plaques of <1μm were detected with multilayer, multichannel fluorescence digital microscopy. Current classifications to assess residual tumour burden after primary systemic therapy included the EWGBSP, CPS-EG, Miller-Payne, Sataloff and NSABP systems.
Results
In our cohort dominated by hormone receptor (ER/PR) positive and HER2 negative cases, only the CPS-EG classification showed prognostic relevance: cases with scores 1–2 had significantly better overall survival (p=0.015) than cases with scores 3–5. Pre-chemotherapy Cx43 expression correlated positively with hormone receptor status both before and after chemotherapy and had a negative correlation with HER2 expression pre-chemotherapy. There was a positive correlation between Cx32 and HER2 expression pre-chemotherapy and between Cx32 and Ki67 expression post-chemotherapy. A negative correlation was found between post-chemotherapy Cx46 and Ki67 expression. Decreased post-chemotherapy Cx26 expression (<5%) statistically correlated with better overall survival (p=0.011). Moderate or higher Cx46 expression (>20%) pre- and post-chemotherapy correlated with significantly better survival in the intermediate prognostic subgroups of EWGBSP TR2b (ppre-chemo=0.006; Sataloff TB (ppre-chemo=0.005; ppost-chemo=0.029) and in Miller-Payne G3 (ppre-chemo=0.002; ppost-chemo=0.012) classifications. Pre-chemotherapy, Cx46 expression was the only marker that correlated with overall survival within these subgroups.
Conclusion
Our results suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy.
doi:10.1186/1471-2407-13-50
PMCID: PMC3583680  PMID: 23374644
Breast cancer; Connexin; Gap junction; Preoperative chemotherapy; Prognosis
3.  Integrative genome-wide expression profiling identifies three distinct molecular subgroups of renal cell carcinoma with different patient outcome 
BMC Cancer  2012;12:310.
Background
Renal cell carcinoma (RCC) is characterized by a number of diverse molecular aberrations that differ among individuals. Recent approaches to molecularly classify RCC were based on clinical, pathological as well as on single molecular parameters. As a consequence, gene expression patterns reflecting the sum of genetic aberrations in individual tumors may not have been recognized. In an attempt to uncover such molecular features in RCC, we used a novel, unbiased and integrative approach.
Methods
We integrated gene expression data from 97 primary RCC of different pathologic parameters, 15 RCC metastases as well as 34 cancer cell lines for two-way nonsupervised hierarchical clustering using gene groups suggested by the PANTHER Classification System. We depicted the genomic landscape of the resulted tumor groups by means of Single Nuclear Polymorphism (SNP) technology. Finally, the achieved results were immunohistochemically analyzed using a tissue microarray (TMA) composed of 254 RCC.
Results
We found robust, genome wide expression signatures, which split RCC into three distinct molecular subgroups. These groups remained stable even if randomly selected gene sets were clustered. Notably, the pattern obtained from RCC cell lines was clearly distinguishable from that of primary tumors. SNP array analysis demonstrated differing frequencies of chromosomal copy number alterations among RCC subgroups. TMA analysis with group-specific markers showed a prognostic significance of the different groups.
Conclusion
We propose the existence of characteristic and histologically independent genome-wide expression outputs in RCC with potential biological and clinical relevance.
doi:10.1186/1471-2407-12-310
PMCID: PMC3488567  PMID: 22824167
DNA-microarray; SNP-array; RCC subgroups; Tissue microarray; Outcome
4.  Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx 
BMC Cancer  2011;11:217.
Background
Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections.
Objectives
To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease.
Methods
E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance.
Results
pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis.
Conclusion
These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx.
Level of evidence: 2b
doi:10.1186/1471-2407-11-217
PMCID: PMC3128007  PMID: 21639893
Head and Neck squamous cell carcinoma (HNSCC); oral cavity; oropharynx; E-Cadherin (ECAD); Immunohistochemistry; Sentinel node biopsy
5.  Insulin-like growth factor II mRNA binding protein 3 (IMP3) is overexpressed in prostate cancer and correlates with higher Gleason scores 
BMC Cancer  2010;10:341.
Background
The oncofetal protein insulin-like growth factor II mRNA binding protein 3 (IMP3) is an important factor for cell-migration and adhesion in malignancies. Recent studies have shown a remarkable overexpression of IMP3 in different human malignant neoplasms and also revealed it as an important prognostic marker in some tumor entities. To our knowledge, IMP3 expression has not been investigated in prostate carcinomas so far.
Methods
Immunohistochemical stainings for IMP3 were performed on tissue microarray (TMA) organized samples from 507 patients: 31 normal prostate tissues, 425 primary carcinomas and 51 prostate cancer metastases or castration-resistant prostate cancers (CRPC). IMP3 immunoreactivity was semiquantitatively scored and correlated with clinical-pathologic parameters including survival.
Results
IMP3 is significantly stronger expressed in prostate carcinomas compared to normal prostate tissues (p < 0.0001), but did not show significant correlation with the pT-stage, the proliferation index (MIB1), preoperative serum PSA level and the margin status. Only a weak and slightly significant correlation was found with the Gleason score and IMP3 expression failed to show prognostic significance in clinico-pathological correlation-analyses.
Conclusions
Although IMP3 is overexpressed in a significant proportion of prostate cancer cases, which might be of importance for novel therapeutic approaches, it does not appear to possess any immediate diagnostic or prognostic value, limiting its potential as a tissue biomarker for prostate cancer. These results might be corroborated by the fact, that two independent tumor cohorts were separately reviewed.
doi:10.1186/1471-2407-10-341
PMCID: PMC2909208  PMID: 20591150
6.  Periostin is up-regulated in high grade and high stage prostate cancer 
BMC Cancer  2010;10:273.
Background
Expression of periostin is an indicator of epithelial-mesenchymal transition in cancer but a detailed analysis of periostin expression in prostate cancer has not been conducted so far.
Methods
Here, we evaluated periostin expression in prostate cancer cells and peritumoural stroma immunohistochemically in two independent prostate cancer cohorts, including a training cohort (n = 93) and a test cohort (n = 325). Metastatic prostate cancers (n = 20), hormone refractory prostate cancers (n = 19) and benign prostatic tissues (n = 38) were also analyzed.
Results
In total, strong epithelial periostin expression was detectable in 142 of 418 (34.0%) of prostate carcinomas and in 11 of 38 benign prostate glands (28.9%). Increased periostin expression in carcinoma cells was significantly associated with high Gleason score (p < 0.01) and advanced tumour stage (p < 0.05) in the test cohort. Whereas periostin expression was weak or absent in the stroma around normal prostate glands, strong periostin expression in tumour stroma was found in most primary and metastatic prostate cancers. High stromal periostin expression was associated with higher Gleason scores (p < 0.001). There was a relationship between stromal periostin expression and shortened PSA relapse free survival times in the training cohort (p < 0.05).
Conclusions
Our data indicate that periostin up-regulation is related to increased tumour aggressiveness in prostate cancer and might be a promising target for therapeutical interventions in primary and metastatic prostate cancer.
doi:10.1186/1471-2407-10-273
PMCID: PMC2903527  PMID: 20534149
7.  Down-regulation of the pro-apoptotic XIAP associated factor-1 (XAF1) during progression of clear-cell renal cancer 
BMC Cancer  2009;9:276.
Background
Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. However, little is yet known about its potential implication in the tumour biology of clear-cell renal cell cancer (ccRCC).
Methods
This study assessed the expression of XAF1 protein in tumour tissue obtained from 291 ccRCC patients and 68 normal renal tissue samples, utilizing immunohistochemistry on a tissue-micro-array. XAF1 expression was correlated to clinico-pathological tumour features and prognosis.
Results
Nuclear XAF1 expression was commonly detected in normal renal- (94.1%) and ccRCC (91.8%) samples, without significant differences of expression levels. Low XAF1 expression in ccRCC tissue, however, was associated with progression of tumour stage (p = 0.040) and grade (p < 0.001). Low XAF1 tumour levels were also prognostic of significantly shortened overall survival times in univariate analysis (p = 0.018), but did not provide independent prognostic information.
Conclusion
These data suggest down-regulation of XAF1 expression to be implicated in ccRCC progression and implies that its re-induction may provide a therapeutic approach. Although the prognostic value of XAF1 in ccRCC appears to be limited, its predictive value remains to be determined, especially in patients with metastatic disease undergoing novel combination therapies of targeted agents with Interferon-alpha.
doi:10.1186/1471-2407-9-276
PMCID: PMC3087333  PMID: 19664236
8.  Brain-type and liver-type fatty acid-binding proteins: new tumor markers for renal cancer? 
BMC Cancer  2009;9:248.
Background
Renal cell carcinoma (RCC) is the most common renal neoplasm. Cancer tissue is often characterized by altered energy regulation. Fatty acid-binding proteins (FABP) are involved in the intracellular transport of fatty acids (FA). We examined the level of brain-type (B) and liver-type (L) FABP mRNA and the protein expression profiles of both FABPs in renal cell carcinoma.
Methods
Paired tissue samples of cancerous and noncancerous kidney parts were investigated. Quantitative RT-PCR, immunohistochemistry and western blotting were used to determine B- and L-FABP in tumor and normal tissues. The tissue microarray (TMA) contained 272 clinico-pathologically characterized renal cell carcinomas of the clear cell, papillary and chromophobe subtype. SPSS 17.0 was used to apply crosstables (χ2-test), correlations and survival analyses.
Results
B-FABP mRNA was significantly up-regulated in renal cell carcinoma. In normal tissue B-FABP mRNA was very low or often not detectable. RCC with a high tumor grading (G3 + G4) showed significantly lower B-FABP mRNA compared with those with a low grading (G1 + G2). Western blotting analysis detected B-FABP in 78% of the cases with a very strong band but in the corresponding normal tissue it was weak or not detectable. L-FABP showed an inverse relationship for mRNA quantification and western blotting. A strong B-FABP staining was present in 52% of the tumor tissues contained in the TMA. In normal renal tissue, L-FABP showed a moderate to strong immunoreactivity in proximal tubuli. L-FABP was expressed at lower rates compared with the normal tissues in 30.5% of all tumors. There was no correlation between patient survival times and the staining intensity of both FABPs.
Conclusion
While B-FABP is over expressed in renal cell carcinoma in comparison to normal renal tissues L-FABP appears to be reduced in tumor tissue. Although the expression behavior was not related to the survival outcome of the RCC patients, it can be assumed that these changes indicate fundamental alterations in the fatty metabolism in the RCC carcinogenesis. Further studies should identify the role of both FABPs in carcinogenesis, progression and with regard to a potential target in RCC.
doi:10.1186/1471-2407-9-248
PMCID: PMC2732640  PMID: 19622156
9.  The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer 
BMC Cancer  2008;8:369.
Background
The three far-upstream element (FUSE) binding proteins (FBP1, FBP2, and FBP3) belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear.
Methods
FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays.
Results
High rates of FBP1 and FBP3 expression were observed in all cancer types. There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p < 0.001 both). C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p < 0.001 and 0.09 resp.), but not in bladder or prostate cancer.
Conclusion
The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors.
doi:10.1186/1471-2407-8-369
PMCID: PMC2631590  PMID: 19087307

Results 1-9 (9)