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1.  Combination of Strong MMP-2 and Weak TIMP-2 Immunostainings Is a Significant Prognostic Factor in Endometrial Carcinoma 
Disease markers  2013;35(4):261-266.
Objective. The aim of this study was to evaluate the combined effects of MMP-2 and TIMP-2 protein immunoreactivities on the prognosis in endometrial carcinoma. Methods. Paraffin-embedded tissue samples from 225 primary endometrioid adenocarcinomas and 13 histologies other than endometrioid adenocarcinoma were immunohistochemically stained for MMP-2 and TIMP-2. Results. In Kaplan-Meier analysis, the 5-year cancer-specific survival rate of the endometrioid adenocarcinoma patients with negative MMP-2 and positive TIMP-2 staining was 100%, whereas only 78% of patients presenting with positive MMP-2 and negative TIMP-2 staining results were alive at that time. In Cox regression analysis, patients with positive MMP-2 and negative TIMP-2 immunostaining had a 4.7-fold relative risk of death from endometrial carcinoma compared to the group of patients with negative MMP-2 and positive or negative TIMP-2 immunoreaction. Conclusions. MMP-2 seems to be the main metalloproteinase determining the prognosis in endometrial carcinoma. Combination of strong MMP-2 and weak TIMP-2 immunostainings was the most potent prognostic marker for poor survival.
PMCID: PMC3810671  PMID: 24344400
2.  Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure 
Trophoblast cell (CTB) invasion into the maternal endometrium plays a crucial role during human embryo implantation and placentation. This invasion is facilitated by the activity of matrix metalloproteinases, which are regulated by tissue inhibitors of MMPs (TIMPs).
This study compares the serum levels of MMP-9, MMP-2/TIMP-2 complex, TIMP-1 and TIMP-2 in 129 patients with ongoing pregnancy (n = 40) or spontaneous early pregnancy failure (n = 89).
MMP-9 was markedly (p < 0.0001) elevated in missed abortions, as was MMP-2/TIMP-2 complex (p < 0.0005). However, the serum levels of TIMP-1 and TIMP-2 were markedly elevated (p < 0.0001) in ongoing pregnancies.
Human placentation is mediated by fetal trophoblastic cells that invade the maternal uterine endometrium. Trophoblast invasion requires a precisely regulated secretion of specific proteolytic enzymes able to degrade the endometrial basement membrane and extracellular matrix. The elevated levels of MMP-9 and MMP-2/TIMP-2 complex may play a role in spontaneous termination of pregnancy.
PMCID: PMC3566964  PMID: 23320481
MMP-2; MMP-9; TIMP-1; TIMP-2; Pregnancy; Pregnancy loss; Serum marker; Placentation
3.  Snail promotes an invasive phenotype in lung carcinoma 
Respiratory Research  2012;13(1):104.
Snail is a transcriptional factor which is known to influence the epitheliomesenchymal transition (EMT) by regulating adhesion proteins such as E-cadherin and claudins as well as matrix metalloproteases (MMP).
To evaluate the functional importance of snail, a transciptional factor involved in EMT in lung tumors, we investigated its expression in a large set of lung carcinomas by immunohistochemistry. Expression of snail and effects of snail knockdown was studied in cell lines.
Nuclear snail expression was seen in 21% of cases this being strongest in small cell lung carcinomas (SCLC). There was significantly greater snail expression in SCLC compared to squamous cell or adenocarcinoma. Positive snail expression was associated with poor survival in the whole material and separately in squamous cell and adenocarcinomas. In Cox regression analysis, snail expression showed an independent prognostic value in all of these groups. In several cell lines knockdown of snail reduced invasion in both matrigel assay and in the myoma tissue model for invasion. The influence of snail knockdown on claudin expression was cell type specific. Snail knockdown in these cell lines modified the expression of MMP2 and MMP9 but did not influence the activation of these MMPs to any significant degree.
The results show that snail plays an important role in the invasive characteristics of lung carcinoma influencing the survival of the patients. Snail knockdown might thus be one option for targeted molecular therapy in lung cancer. Snail knockdown influenced the expression of claudins individually in a cell-line dependent manner but did not influence MMP expressions or activations to any significant degree.
PMCID: PMC3546026  PMID: 23157169
Lung; Carcinoma; Snail; Claudin; MMP
4.  Oxidative stress and redox state-regulating enzymes have prognostic relevance in diffuse large B-cell lymphoma 
Oxidative stress and redox-regulating enzymes may have roles both in lymphomagenesis and resistance to lymphoma therapy. Previous studies from the pre-rituximab era suggest that antioxidant enzyme expression is related to prognosis in diffuse large B-cell lymphoma (DLBCL), although these results cannot be extrapolated to patient populations undergoing modern treatment modalities. In this study we assessed expression of the oxidative stress markers 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine and the antioxidant enzymes thioredoxin (Trx), manganese superoxide dismutase (MnSOD) and glutamate-cysteine ligase (GCL) via immunohistochemistry in 106 patients with DLBCL. All patients were treated with CHOP-like therapy combined with rituximab. Immunostaining results were correlated with progression-free survival, disease-specific survival and traditional prognostic factors of DLBCL.
Strong 8-OHdG immunostaining intensity was associated with extranodal involvement (p = 0.00002), a high International Prognostic Index (p = 0.002) and strong Trx (p = 0.011) and GCL (p = 0.0003) expression. Strong Trx staining intensity was associated with poor progression-free survival (p = 0.046) and poor disease-specific survival (p = 0.015). Strong GCL immunostaining intensity predicted poor progression-free survival (p = 0.049). Patients with either strong Trx or strong nitrotyrosine expression showed significantly poorer progression-free survival (p = 0.003) and disease-specific survival (p = 0.031) compared with the other patients.
The redox state-regulating enzymes GCL and Trx are promising markers in the evaluation of DLBCL prognosis in the era of modern immunochemotherapy.
PMCID: PMC3506993  PMID: 23210982
Antioxidant enzyme; Nitrotyrosine; Prognosis; Reactive oxygen species; Thioredoxin
5.  Long-term prognosis of breast cancer detected by mammography screening or other methods 
Breast Cancer Research : BCR  2011;13(6):R134.
Previous studies of breast cancer have shown that patients whose tumors are detected by mammography screening have a more favorable survival. Little is known, however, about the long-term prognostic impact of screen detection. The purpose of the current study was to compare breast cancer-specific long-term survival of patients whose tumors were detected in mammography screening compared with those whose tumors were detected by other methods.
Breast cancer patients diagnosed within five specified geographical areas in Finland in 1991 and 1992 were identified (N = 2,936). Detailed clinical, treatment and outcome data, as well as tissue samples, were collected. Women with in situ carcinoma, distant metastases at the time of primary diagnosis and women who were not treated surgically were excluded. The main analyses were performed after excluding patients with other malignancy or contralateral breast cancer, followed by sensitivity analyses with different exclusion criteria. Median follow-up time was 15.4 years. Univariate and multivariate analyses of breast cancer-specific survival were performed.
Of patients included in the main analyses (n = 1,884), 22% (n = 408) of cancers were screen-detected and 78% (n = 1,476) were detected by other methods. Breast cancer-specific 15-year survival was 86% for patients with screen-detected cancer and 66% for patients diagnosed using other methods (P < 0.0001, HR = 2.91). Similar differences in survival were observed in women at screening age (50 to 69 years), as well as in clinically important subgroups, such as patients with small tumors (≤ 1 cm in diameter) and without nodal involvement (N0). Women with breast cancer diagnosed on the basis of screening mammography had a more favorable prognosis than those diagnosed outside screening programs, following adjustments according to patient age, tumor size, axillary lymph node status, histological grade and hormone receptor status. Significant differences in the risk of having future contralateral breast cancer according to method of detection were not observed.
Breast cancer detected by mammography screening is an independent prognostic factor in breast cancer and is associated with a more favorable survival rate as well as in long-term follow-up.
PMCID: PMC3326576  PMID: 22204661
screening; mammography; prognosis; survival analysis
6.  Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study 
Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site.
We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes.
A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR.
Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.
PMCID: PMC3262199  PMID: 21914172
7.  Specific TP53 mutations predict aggressive phenotype in head and neck squamous cell carcinoma: a retrospective archival study 
Head & Neck Oncology  2011;3:20.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world in developed countries. Despite the intense research in the area of squamous cell carcinomas of head and neck (HNSCC), long-term survival rate has not changed significantly in this malignancy during recent decades.
In this study, we focused on TP53 mutations in specific regions, including DNA-binding surface, to determine whether mutations at specific locations of TP53 could be used to help in setting up prognosis and response to therapy of head and neck squamous cell carcinoma patients. We analysed TP53 mutations in 46 HNSCC by PCR-SSCP and sequencing and characterized how different TP53 mutations affect the patient outcome.
Tumours containing TP53 mutations in DNA-binding regions (L2, L3 and LSH motif) had a significantly poorer prognosis and response to radiotherapy than tumours outside those regions. Disease-specific 5-year survival of patients with TP53 mutations affecting DNA contacts was 43.5% while it was 77.8% (p < 0.05) in patients with TP53 mutations in other residues not involved in DNA contact. Moreover, nodal metastasis were more prevalent (although not statistically significantly) with TP53 mutations in DNA-binding surface regions. We noticed that the patients with TP53 mutations in L3/LSH motifs had a significantly poorer response (11.4% responding) to radiation than the patients with a wild type p53 (48.6%) or TP53 mutations outside the DNA-binding regions (40%) (p < 0.05).
These data indicate that a TP53 mutation in L2, L3 or LSH is worth pursuing as a marker for predicting prognosis and response to radiation among HNSCC patients.
PMCID: PMC3094329  PMID: 21513535
8.  8-hydroxydeguanosine and nitrotyrosine are prognostic factors in urinary bladder carcinoma 
Oxidative stress markers and peroxiredoxins are connected to cancer. A large set of urinary bladder carcinomas were studied for the expression of nitrotyrosine and 8-hydroxydeguanosine (8OHdG) , two markers indicating oxidative damage. Serum and urine 8-OHdG were assessed in a subset of patients. We also analysed immunohisto-chemically the expression of nrf2, keap1, all six peroxiredoxins (prx) and thioredoxin (trx) in these tumors. 15 % of the cases showed 8OHdG and 36 % nitrotyrosine positivity. Expression of nitrotyrosine and 8OHdG associated with a poor prognosis (p=0.050, p=0.011, respectively). Peroxiredoxin positivity ranged from 39 % to 84 % lowest expression being for prx 4 and highest for prx 3. Prx 4 expression associated with a poor prognosis (p=0.025) with high grade (p=0.044) and larger tumors (p=0.023). Cytoplasmic trx positivity was seen in 91 % and nuclear in 59 % of tumors. Nuclear and cytoplasmic trx associated with each other (p<0.001), and nuclear trx associated with prx 6 (p=0.001), prx 2 (p<0.001), and prx 5 (p<0.001). 8OHdG associated with nuclear trx positivity (p=0.002), inversely with prx 1 (p=0.025) and with keap1 (p=0.020). Nuclear nrf2 was associated with nitrotyrosine (p=0.042). The results show that the amount of oxidative stress in urinary bladder tumors affects the prognosis of the patients. Of antioxidative enzymes, prx4 associated with an unfavourable prognosis. Selective inhibition of prx4 expression might then be one additional option of treatment of bladder cancer.
PMCID: PMC3071659  PMID: 21487522
Urinary bladder; carcinoma; oxidative stress; peroxiredoxin; nrf2; keap1
9.  Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer 
The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer.
Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein.
1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor.
Running high-throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer.
PMCID: PMC3040126  PMID: 21262004
10.  p53 in head and neck cancer: Functional consequences and environmental implications of TP53 mutations 
Head & Neck Oncology  2010;2:36.
Although TP53 mutations in human tumours generally have been extensively studied, the significance of p53 in the aetiology of head and neck cancers is still incompletely characterized. In recent years, considerable interest has been focused on mutant forms of p53, the abnormal protein product of TP53 alleles with missense mutation that often accumulate in cancer cells.
We compared the nature of TP53 mutations in primary 46 head and neck squamous cell carcinomas (HNSCC) analyzed by PCR-SSCP and sequencing, immunohistochemistry, and using structural information available at IARC p53 database.
Sequencing confirmed 36 TP53 mutations in 23 tumours of the 39 mutations in 26 tumours found by PCR-SSCP. Only half (17) putatively affect the function of p53 protein. Of these 8 were in the L2 domain, three affected the LSH motif and three the L3 domain. Three were in other domains. Codon 259 (GAC > GAA) which is a very rare mutation was found in 4 samples in our study. There were indications of p53 aberrations being associated with the combined effect of smoking, alcohol and work history. Patients with a negative family history of cancer had more often TP53 mutations than patients with a positive family history (71% vs. 46%).
Our study contributes to the knowledge of cumulative chemical exposure and p53 aberrations in head and neck cancer, an area where literature is scarce.
PMCID: PMC3022569  PMID: 21159183

Results 1-10 (10)