Publications by authors named "Teijo Kuopio"

40 Publications

Immune cell score, PD-L1 expression and prognosis in esophageal cancer.

Acta Oncol 2021 Jan 13:1-11. Epub 2021 Jan 13.

Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2020.1868571DOI Listing
January 2021

The expression and prognostic relevance of programmed cell death protein 1 in tongue squamous cell carcinoma.

APMIS 2020 Dec 19;128(12):626-636. Epub 2020 Oct 19.

Haartman Institute, University of Helsinki, Helsinki, Finland.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor which plays an important role in a patient's immune responses to microbial and cancer antigens. It is expressed in tumor-infiltrating lymphocytes (TILs) with many different malignancies. The aim of the study was to evaluate PD-1 expression and its prognostic value in tongue cancer. The data of tongue squamous cell carcinoma (TSCC) patients (N = 81) treated in Tampere University Hospital between 1999 and 2013 were used. Control data consisted of patients with non-malignant tongue mucous membrane lesions (N = 48). The formalin-fixed paraffin-embedded samples were stained immunohistochemically and scanned via digital microscope. The staining of PD-1 was examined semi-quantitatively. The density and intensity of PD-1 + cells were significantly higher in TSCC than in control samples. The expression of PD-1 correlated with better survival. The expression of PD-1 could be a potential prognostic marker in TSCC. Further research using larger sample size is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apm.13084DOI Listing
December 2020

Immunophenotype based on inflammatory cells, PD-1/PD-L1 signalling pathway and M2 macrophages predicts survival in gastric cancer.

Br J Cancer 2020 Nov 18;123(11):1625-1632. Epub 2020 Sep 18.

Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.

Background: Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1).

Methods: After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival.

Results: The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26-0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis.

Conclusions: High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-020-01053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687887PMC
November 2020

Ex vivo assessment of targeted therapies in a rare metastatic epithelial-myoepithelial carcinoma.

Neoplasia 2020 09 6;22(9):390-398. Epub 2020 Jul 6.

Misvik Biology Oy, Turku, Finland; University of Sheffield, Department of Oncology and Metabolism, South Yorkshire, Sheffield, UK. Electronic address:

Epithelial-myoepithelial carcinoma (EMC) is a rare subtype of salivary gland neoplasms. Since the initial description of the cancer, just over 300 cases have been reported. EMCs occupy a biphasic cellular differentiation-state defined by the constitution of two cell types representing epithelial and myoepithelial lineages, yet the functional consequence of the differentiation-state heterogeneity with respect to therapy resistance of the tumors remains unclear. The reported local recurrence rate of the cases is approximately 30%, and while distant metastases are rare, a significant fraction of these cases are reported to receive no survival benefit from radio- or chemotherapy given in addition to surgery. Moreover, no targeted therapies have been reported for these neoplasms. We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial-myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial-myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage composition of EMC could be an important factor to be assessed when novel treatments are being evaluated for management of metastatic EMC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341452PMC
September 2020

MicroRNAs Associated With Biological Pathways of Left- and Right-sided Colorectal Cancer.

Anticancer Res 2020 Jul;40(7):3713-3722

School of Medicine, Institute of Clinical Medicine, Clinical Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

Background/aim: MicroRNAs (miRNAs) regulate the development of colorectal cancer (CRC). We aimed to investigate miRNAs and their relation to cancer-related signaling pathways in site-specific CRC.

Materials And Methods: We used a total of 24 left- and right-sided Finnish CRC samples (discovery cohort) and The Cancer Genome Atlas public mature miRSeq dataset of 201 CRC samples (validation cohort). MiRNA differential expression and biological pathway analyses were performed using DESeq2 and the DIANA/mirPath tool, respectively.

Results: We found 17 significantly differentially up-regulated [false discovery rate (FDR) <0.05] miRNAs in left-sided CRC ("left miRNAs"), and 15 in right-sided CRC ("right miRNAs"). The left miRNAs participate in the mTor, Wnt, PI3K-Akt signaling pathways (FDR<0.05). The right miRNAs participate in the TGF-β signaling pathway. We also observed that both cohorts share six miRNAs. One of these (hsa-miR-196b-5p) was significantly (FDR<0.05) up-regulated in left-sided CRC. The rest of them (hsa-miR-625-3p, hsa-miR-155-5p, hsa-miR-625-5p, hsa-miR-31-5p and hsa-miR-330-5p) showed significant (FDR<0.05) up-regulation in right-sided CRC.

Conclusion: Left and right miRNAs are associated with predominant biological pathways of left- and right-sided CRC, respectively. Our results may be beneficial for classifying CRC and for future biomarker studies of site-specific CRC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14360DOI Listing
July 2020

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma.

BMC Cancer 2020 Jun 23;20(1):590. Epub 2020 Jun 23.

Misvik Biology Ltd, Karjakatu 35 B, FI-20520, Turku, Finland.

Background: Ex vivo drug screening refers to the out-of-body assessment of drug efficacy in patient derived vital tumor cells. The purpose of these methods is to enable functional testing of patient specific efficacy of anti-cancer therapeutics and personalized treatment strategies. Such approaches could prove powerful especially in context of rare cancers for which demonstration of novel therapies is difficult due to the low numbers of patients. Here, we report comparison of different ex vivo drug screening methods in a metastatic urachal adenocarcinoma, a rare and aggressive non-urothelial bladder malignancy that arises from the remnant embryologic urachus in adults.

Methods: To compare the feasibility and results obtained with alternative ex vivo drug screening techniques, we used three different approaches; enzymatic cell viability assay of 2D cell cultures and image-based cytometry of 2D and 3D cell cultures in parallel. Vital tumor cells isolated from a biopsy obtained in context of a surgical debulking procedure were used for screening of 1160 drugs with the aim to evaluate patterns of efficacy in the urachal cancer cells.

Results: Dose response data from the enzymatic cell viability assay and the image-based assay of 2D cell cultures showed the best consistency. With 3D cell culture conditions, the proliferation rate of the tumor cells was slower and potency of several drugs was reduced even following growth rate normalization of the responses. MEK, mTOR, and MET inhibitors were identified as the most cytotoxic targeted drugs. Secondary validation analyses confirmed the efficacy of these drugs also with the new human urachal adenocarcinoma cell line (MISB18) established from the patient's tumor.

Conclusions: All the tested ex vivo drug screening methods captured the patient's tumor cells' sensitivity to drugs that could be associated with the oncogenic KRAS mutation found in the patient's tumor cells. Specific drug classes however resulted in differential dose response profiles dependent on the used cell culture method indicating that the choice of assay could bias results from ex vivo drug screening assays for selected drug classes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07092-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313172PMC
June 2020

A prognostic model based on cell-cycle control predicts outcome of breast cancer patients.

BMC Cancer 2020 Jun 16;20(1):558. Epub 2020 Jun 16.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: A prognostic model combining biomarkers of metaphase-anaphase transition of the cell cycle was developed for invasive breast cancer. The prognostic value and clinical applicability of the model was evaluated in comparison with the routine prognosticators of invasive breast carcinoma.

Methods: The study comprised 1135 breast cancer patients with complete clinical data and up to 22-year follow-up. Regulators of metaphase-anaphase transition were detected immunohistochemically and the biomarkers with the strongest prognostic impacts were combined into a prognostic model. The prognostic value of the model was tested and evaluated in separate patient materials originating from two Finnish breast cancer centers.

Results: The designed model comprising immunoexpressions of Securin, Separase and Cdk1 identified 8.4-fold increased risk of breast cancer mortality (p < 0.0001). A survival difference exceeding 15 years was observed between the majority (> 75%) of patients resulting with favorable as opposed to unfavorable outcome of the model. Along with nodal status, the model showed independent prognostic impact for all breast carcinomas and for subgroups of luminal, N+ and N- disease.

Conclusions: The impact of the proposed prognostic model in predicting breast cancer survival was comparable to nodal status. However, the model provided additional information in N- breast carcinoma in identifying patients with aggressive course of disease, potentially in need of adjuvant treatments. Concerning N+, in turn, the model could provide evidence for withholding chemotherapy from patients with favorable outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07045-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296704PMC
June 2020

Image-based ex vivo drug screen to assess targeted therapies in recurrent thymoma.

Lung Cancer 2020 07 4;145:27-32. Epub 2020 May 4.

Misvik Biology Oy, Turku, Finland; University of Sheffield, Sheffield, UK. Electronic address:

Objectives: Thymoma is a rare malignancy derived from the thymic epithelial cells. No standard salvage treatments are available for recurrent thymoma and due to the low number of cases, alternative treatment regimens have been assessed only in small case series with varying success. The aim of this study was to use an image-based ex vivo drug screening strategy to assess efficacy of a large panel of anti-cancer agents for thymoma using patient derived tumor cells.

Materials And Methods: Vital tumor and tumor associated cells were used to assess the efficacy of 147 anti-cancer drugs including approved and experimental agents. Drug efficacy was analyzed at single cell resolution using image-based high content drug screening to assess tumor cell specific responses. Molecular profiling and histopathology was used to confirm the drug targets identified by the screen.

Results: The ex vivo drug screen identified selective sensitivity of the cancerous epithelial thymoma cells to EGFR-, HDAC- and mTOR-inhibition. Histopathology confirmed high protein level expression of EGFR in the patient's tumor. Patient was initiated treatment with Cetuximab resulting in stable disease after relapse on five different chemotherapy regimens.

Conclusion: The results show that the image-based ex vivo therapy efficacy screening strategy can be used to identify patient and tumor relevant drug sensitivity patterns in thymoma. The results also warrant continued research on EGFR as a biomarker and therapy target in recurrent thymomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.04.036DOI Listing
July 2020

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? - Somatic mutational profiles vs. ovarian and colorectal carcinomas.

Oncotarget 2020 Apr 7;11(14):1244-1256. Epub 2020 Apr 7.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Inherited DNA mismatch repair (MMR) defects cause predisposition to colorectal, endometrial, ovarian, and other cancers occurring in Lynch syndrome (LS). It is unsettled whether breast carcinoma belongs to the LS tumor spectrum. We approached this question through somatic mutational analysis of breast carcinomas from LS families, using established LS-spectrum tumors for comparison. Somatic mutational profiles of 578 cancer-relevant genes were determined for LS-breast cancer (LS-BC, = 20), non-carrier breast cancer (NC-BC, = 10), LS-ovarian cancer (LS-OC, = 16), and LS-colorectal cancer (LS-CRC, = 18) from the National LS Registry of Finland. Microsatellite and MMR protein analysis stratified LS-BCs into MMR-deficient (dMMR, = 11) and MMR-proficient (pMMR, = 9) subgroups. All NC-BCs were pMMR and all LS-OCs and LS-CRCs dMMR. All but one dMMR LS-BCs were hypermutated (> 10 non-synonymous mutations/Mb; average 174/Mb per tumor) and the frequency of MMR-deficiency-associated signatures 6, 20, and 26 was comparable to that in LS-OC and LS-CRC. LS-BCs that were pMMR resembled NC-BCs with respect to somatic mutational loads (4/9, 44%, hypermutated with average mutation count 33/Mb vs. 3/10, 30%, hypermutated with average 88 mutations/Mb), whereas mutational signatures shared features of dMMR LS-BC, LS-OC, and LS-CRC. Epigenetic regulatory genes were significantly enriched as mutational targets in LS-BC, LS-OC, and LS-CRC. Many top mutant genes of our LS-BCs have previously been identified as drivers of unselected breast carcinomas. In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147090PMC
April 2020

Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota-A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?

Cancers (Basel) 2019 Nov 15;11(11). Epub 2019 Nov 15.

Faculty of Sport and Health Sciences, University of Jyväskylä, 40620 Jyväskylä, Finland.

Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased and mRNA and IL6 excretion. Murine C26 tumors expressed more and mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11111799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896205PMC
November 2019

Clonal Evolution of MEK/MAPK Pathway Activating Mutations in a Metastatic Colorectal Cancer Case.

Anticancer Res 2019 Nov;39(11):5867-5877

Central Finland Central Hospital, Jyväskylä, Finland.

Background/aim: The aim of this study was to examine clonal heterogeneity, to test the utility of liquid biopsy in monitoring disease progression and to evaluate the usefulness of ex vivo drug screening in a BRAF L597Q-mutated colorectal cancer (CRC) patient developing metastases during adjuvant therapy.

Materials And Methods: Next generation sequencing (NGS) and droplet digital PCR (ddPCR) were performed in samples from tumor tissues and liquid biopsies. Live cancer cells from a metastatic lesion were used in ex vivo drug sensitivity assays.

Results: We found evidence of continued dependence of MEK/MAPK pathway activation, but different activating mutations in primary tumor and metastases. Liquid biopsy based BRAF L597Q ddPCR testing was a sensitive personalized biomarker predicting the rise of clinically aggressive metastatic disease. Ex vivo drug sensitivity assays with BRAF L597Q mutated cells showed response to MEK/MAPK targeted therapies.

Conclusion: The rare BRAF L597Q mutation may be associated with aggressive tumor behavior in CRC. Liquid biopsy can be used to capture clinically relevant tumor features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.13791DOI Listing
November 2019

Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival.

Nat Commun 2019 09 6;10(1):4022. Epub 2019 Sep 6.

Applied Tumor Genomics Research Program, Faculty of Medicine University of Helsinki, Biomedicum Helsinki, PO Box 63,  (Haartmaninkatu 8), FI-00014, Helsinki, Finland.

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC, likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11770-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731219PMC
September 2019

Performance of Finnish biobanks in nationwide pulmonary carcinoid tumour research.

Virchows Arch 2020 Feb 5;476(2):273-283. Epub 2019 Aug 5.

HUSLAB, Department of Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, Helsinki, Finland.

Finnish hospital-integrated biobanks administer millions of formalin-fixed paraffin-embedded tissue samples collected within the clinical diagnostics. According to the Finnish Biobank Act, these samples can be coupled with patients' clinical follow-up data and the data retrieved from national health registries. We collected a nationwide pulmonary carcinoid tumour series from Finnish biobanks to study prognostic factors as well as to explore how the number of tumours found in the Finnish biobanks corresponds to the number of tumours registered by the Finnish Cancer Registry (FCR). Finnish biobanks identified 88% of the tumours registered by the FCR and were able to deliver 63%. The main reasons for lacking samples were paucity of resected primary tumour tissue, incompatible primary diagnosis, and the absence of tissue blocks in the archives. The main bottleneck in the sample application process was retrieving patient data. Altogether, we received 224 tumour samples with appropriate patient data and identified six prognostic factors for shorter disease-specific survival: age over 56 years at the time of diagnosis, tumour size over 2.5 cm, atypical histology, Ki-67 proliferation index higher than 2.5%, hilar/mediastinal lymph node involvement at the time of diagnosis, and the presence of metastatic disease. In conclusion, the Finnish biobank infrastructure offers excellent opportunities for tissue-based research. However, to be able to develop the biobank operations further, involving more medical knowledge in the sample and data acquisition process is a necessity. Also, when working with tissue samples collected over decades, histological expertise is essential for re-evaluation and re-classification of the samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-019-02625-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028842PMC
February 2020

PD-1 and PD-L1 expression in pulmonary carcinoid tumors and their association to tumor spread.

Endocr Connect 2019 Aug;8(8):1168-1175

Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-19-0308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686949PMC
August 2019

Combined prognostic value of CD274 (PD-L1)/PDCDI (PD-1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status.

Mod Pathol 2019 06 5;32(6):866-883. Epub 2019 Feb 5.

Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland.

The CD274 (programmed cell death ligand-1, PD-L1)/PDCD1 (programmed cell death-1, PD-1) pathway is crucial suppressor of the cytotoxic immune response. Antibodies targeting CD274 or PDCD1 have been revealed to be effective in several malignancies. In colorectal cancer, the response to CD274/PDCD1 blockage is associated with microsatellite instability. However, the value of CD274/PDCD1 for predicting response to treatment or survival benefit is still unclear. The aims of the study were (1) to clarify differences in immune microenvironment and expression of checkpoint proteins (CD274/PDCD1) in DNA mismatch repair-proficient, mismatch repair-deficient, and hereditary Lynch syndrome-associated colorectal cancer, and (2) to assess the prognostic value of these factors and their combinations. Ninety-four mismatch repair-deficient colorectal cancers, 100 age, sex, and AJCC/UICC stage-matched mismatch repair-proficient colorectal cancers, and 48 Lynch syndrome-associated colorectal cancers were analyzed. Using whole section samples, detailed analysis of immune cell score, PDCD1, and CD274 expression was performed. Overlapping of CD274 expression in tumor and immune cells was almost complete (95%). Immune cell score and CD274/PDCD1 positivity were significantly more frequent in mismatch repair-deficient than in mismatch repair-proficient colorectal cancers (70% vs. 41% (high immune cell score); 81% vs. 49% (PDCD1), 23% vs. 1% (CD274 on tumor cells) and 68% vs. 30% (CD274 on immune cells), P < 0.001), and were associated strongly with each other. Although the independent impact of immune cell score, PDCD1, and CD274 on immune cells was moderate, the immunoprofile parameter combining the above three factors appeared to be a strong independent prognostic factor for disease-specific survival and overall survival (P = 0.001) and had suggestive impact on disease-free survival (P = 0.011). Our results encourage the use of immune cell score analysis together with PDCD1 and CD274 detection to improve the prognostic evaluation of colorectal cancer patients. Particularly, the analyses from whole tissue sections are encouraged to allow reliable and cell-specific analyses of CD274 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0219-7DOI Listing
June 2019

Epidemiological, clinical and molecular characterization of Lynch-like syndrome: A population-based study.

Int J Cancer 2019 07 7;145(1):87-98. Epub 2019 Jan 7.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32085DOI Listing
July 2019

EGFR gene copy number decreases during anti-EGFR antibody therapy in colorectal cancer.

Hum Pathol 2018 12 8;82:163-171. Epub 2018 Aug 8.

Department of Pathology, University of Turku, 20520 Turku, Finland; Department of Pathology, Turku University Hospital, 20520 Turku, Finland.

Epidermal growth factor receptor (EGFR) gene copy number (GCN) increase is associated with a favorable anti-EGFR antibody treatment response in RAS wild-type metastatic colorectal cancer. However, there are limited and comparative data regarding the EGFR GCN in primary colorectal cancer tumors and corresponding metastases or the effect of anti-EGFR antibody treatment on EGFR GCN in recurrent disease. In addition, little is known about the potential EGFR GCN changes during anti-EGFR therapy in comparison with other treatment regimens. EGFR GCN was analyzed by EGFR immunohistochemistry-guided silver in situ hybridization in primary and corresponding recurrent local or metastatic tumors from 80 colorectal cancer patients. GCN levels were compared between KRAS wild-type patients having received anti-EGFR therapy and patients having received other forms of treatment after primary surgery. The EGFR GCN decrease between primary and recurrent tumors was more pronounced among the anti-EGFR-treated patients than among patients not treated with anti-EGFR therapy (P = .047). None of the patients experiencing an EGFR GCN increase of at least 1.0 between the primary and recurrent tumors were treated with anti-EGFR antibodies. When including only patients with distant metastases, an EGFR GCN decrease of at least 1.0 was more common among the anti-EGFR-treated patients than among patients not treated with anti-EGFR therapy (P = .028). Our results suggest that anti-EGFR antibody treatment is associated with EGFR GCN decrease between the primary and recurrent colorectal adenocarcinomas, whereas no GCN change is observed among patients receiving other forms of treatment after primary surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2018.07.028DOI Listing
December 2018

Proliferation-associated miRNAs-494, -205, -21 and -126 detected by in situ hybridization: expression and prognostic potential in breast carcinoma patients.

J Cancer Res Clin Oncol 2018 Apr 23;144(4):657-666. Epub 2018 Jan 23.

Department of Pathology, Turku University Hospital, and Institute of Biomedicine, University of Turku, Turku, Finland.

Purpose: To visualize by in situ hybridization (ISH) the levels of a set of proliferation-associated miRNAs and to evaluate their impact and clinical applicability in prognostication of invasive breast carcinoma.

Methods: Tissue specimen from breast carcinoma patients were investigated for miRNAs-494, -205, -21 and -126. Prognostic associations for levels of miRNAs were analyzed based on complete clinical data and up to 22.5-year follow-up of the patient material (n = 285). For detection of the miRNAs, an automated sensitive protocol applying in situ hybridization was developed.

Results: MiRNA-494 indicated prognostic value for patients with invasive breast carcinoma. Among node-negative disease reduced level of miRNA-494 predicted 8.5-fold risk of breast cancer death (p = 0.04). Altered levels and expression patterns of the studied miRNAs were observed in breast carcinomas as compared to benign breast tissue.

Conclusions: The present paper reports for the first time on the prognostic value of miRNA-494 in invasive breast cancer. Particularly, detection of miRNA-494 could benefit patients with node-negative breast cancer in identifying subgroups with aggressive disease. Based on our experience, the developed automatic ISH method to visualize altered levels of miRNAs-494, -205, -21 and -126 could be applied to routine pathology diagnostics providing that conditions of tissue treatment, especially fixation delays, are managed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-018-2586-8DOI Listing
April 2018

PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival.

BMC Cancer 2017 Oct 27;17(1):705. Epub 2017 Oct 27.

Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20510, Turku, Finland.

Background: PTTG1-interacting protein (PTTG1IP) is an oncogenic protein, which participates in metaphase-anaphase transition of the cell cycle through activation of securin (PTTG1). PTTG1IP promotes the shift of securin from the cell cytoplasm to the nucleus, allowing the interaction between separase and securin. PTTG1IP overexpression has been previously observed in malignant disease, e.g. in breast carcinoma. However, the prognostic value of PTTG1IP in breast carcinoma patients has not previously been revealed.

Methods: A total of 497 breast carcinoma patients with up to 22-year follow-up were analysed for PTTG1IP and securin immunoexpression. The results were evaluated for correlations with the clinical prognosticators and patient survival.

Results: In our material, negative PTTG1IP immunoexpression predicted a 1.5-fold risk of breast cancer death (p = 0.02). However, adding securin immunoexpression to the analysis indicated an even stronger and independent prognostic power in the patient material (HR = 2.5, p < 0.0001). The subcellular location of securin was found with potential prognostic value also among the triple-negative breast carcinomas (n = 96, p = 0.052).

Conclusions: PTTG1IP-negativity alone and in combination with high securin immunoexpression indicates a high risk of breast cancer death, resulting in up to 14-year survival difference in our material.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-017-3694-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658989PMC
October 2017

Separase is a marker for prognosis and mitotic activity in breast cancer.

Br J Cancer 2017 Oct 31;117(9):1383-1391. Epub 2017 Aug 31.

Institute of Biomedicine, Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Turku 20510, Finland.

Background: Cancer cell proliferation is a critical feature in classifying and predicting the outcome of breast carcinoma. Separase has a central role in cell cycle progression in unleashing sister-chromatids at anaphase onset. Abnormally functioning separase is known to lead to chromosomal instability.

Methods: The study comprises 349 breast carcinoma patients treated in Central Hospital of Central Finland. The prognostic value, role as a proliferation marker and regulatory interactions of separase are evaluated by immunohistochemical and double- and triple-immunofluorescence (IF) detections based on complete clinical data and >22-year follow-up of the patient material.

Results: In our material, abnormal separase expression predicted doubled risk of breast cancer death (P<0.001). Up to 11.3-year survival difference was observed when comparing patients with and without separase expressing cancer cell mitoses. Particularly, abnormal separase expression predicted impaired survival for luminal breast carcinoma (P<0.001, respectively). In multivariate analyses, abnormal separase expression showed independent prognostic value. The complex inhibitory interactions involving securin and cyclin B1 were investigated in double- and triple-IFs and revealed patient subgroups with aberrant regulation and expression patterns of separase.

Conclusions: In our experience, separase is a promising and clinically applicable proliferation marker. Separase expression shows strong and independent prognostic value and could be developed into a biomarker for treatment decisions in breast carcinoma, particularly defining prognostic subgroups among luminal carcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2017.301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672940PMC
October 2017

Immunoscore in mismatch repair-proficient and -deficient colon cancer.

J Pathol Clin Res 2017 Jul 19;3(3):203-213. Epub 2017 Jul 19.

Department of PathologyCentral Finland Central HospitalJyväskyläFinland.

The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and mutation status. Rectal cancer cases ( = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% ( < 0.001); 5-year disease-specific survival (DSS) rates were 47, 55, 75, 80, and 89% ( < 0.001); and 5-year overall survival (OS) rates were 40, 44, 66, 61, and 76% ( < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite-stable (MSS) and microsatellite-instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cjp2.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527320PMC
July 2017

The Expression of Cohesin Subunit SA2 Predicts Breast Cancer Survival.

Appl Immunohistochem Mol Morphol 2016 10;24(9):615-621

*Department of Pathology, University of Turku and Turku University Hospital †Department of Medical Statistics, Medical Faculty, University of Turku, Turku ‡Department of Pathology, Jyväskylä Central Hospital, Jyväskylä §Department of Pathology, Pori Central Hospital, Pori, Finland.

Cohesin is one of the main regulators of sister chromatid separation during the metaphase/anaphase transition. It is a multiprotein complex consisting of 4 core subunits, one of those being the SA2 subunit. SA2 plays the final role in dismantling the cohesion complex from the sister chromatids and also functions in DNA double-strand break repair and gene regulation. There is increasing evidence regarding the involvement of both overexpression and underexpression of cohesin in cancer. Here, we present expression patterns of SA2 in different types of human breast tissue, and the prognostic analysis in the material from breast cancer patients with long-term follow-up. SA2 immunoexpression was evaluated in benign, precancerous, and malignant breast tissue, and was classified into low-intensity or high-intensity groups. The DNA content was determined by image cytometry on breast cancer cell imprints. Prognostic analyses were based on 445 breast cancer patients with upto 20 years' follow-up. SA2 immunoexpression was equally high in both benign and precancerous breast tissue. Instead, 72% of the invasive breast cancers showed deficient SA2 expression. These patients were also associated with an unfavorable outcome as indicated by a 1.6-fold risk of breast cancer death (P=0.0208). The majority (75%) of the patients with low SA2 expression were alive 6.0 years after the diagnosis, whereas the majority of the patients with high SA2 expression survived 17.6 years after the diagnosis. No statistically significant association could be detected between SA2 immunoexpression and DNA aneuploidy. Our results and previous literature indicate that decreased SA2 immunoexpression is associated with malignant breast disease and a particularly unfavorable course of disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAI.0000000000000240DOI Listing
October 2016

[Diagnosis and treatment of Lynch syndrome].

Duodecim 2016 ;132(3):233-40

Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years. This would allow the selection of patients to be referred for gene testing as well as identification of mutation carriers, for whom a regular colonoscopy follow-up is arranged at an interval of 2 to 3 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2016

Interleukin-6 increases expression of serine protease inhibitor Kazal type 1 through STAT3 in colorectal adenocarcinoma.

Mol Carcinog 2016 12 14;55(12):2010-2023. Epub 2015 Dec 14.

Department of Clinical Chemistry, Medicum, University of Helsinki, Helsinki, Finland.

Inflammation promotes colorectal cancer (CRC) tumorigenesis, but the underlying molecular mechanisms are still being uncovered. Proinflammatory cytokine interleukin-6 (IL-6) stimulates survival signaling in CRC; inflammatory signals also regulate production and activity of proteases and their inhibitors. Over-expression of serine protease inhibitor Kazal type 1 (SPINK1) predicts an unfavorable outcome in colon cancer. The SPINK1 gene contains an IL-6 responsive element, suggesting it could act as an acute phase reactant. We assessed the connection between IL-6 and SPINK1, and the function and mechanism of this signaling. Our results show that Colo205 and HT-29 cells express and secrete SPINK1, and both fibroblast-derived and recombinant IL-6 further increased the SPINK1 levels. Concurrently CRC cells augmented the IL-6 production in fibroblasts. In CRC tissues cancer cells were positive for SPINK1, whereas IL-6 was found in stromal cells. In Colo205 cells IL-6 also stimulated the secretion of trypsin-1 and -2, the key targets of SPINK1 protease inhibition, whereas in HT-29 cells trypsin-1 and -2 levels remained constantly low. Functionally, both IL-6 and SPINK1 increased the motility of the CRC cells. Mechanistically, IL-6 activated the canonical STAT3 pathway and inhibition of STAT3 phosphorylation decreased the levels of SPINK1, trypsin-1 and -2. Taken together, our results indicate a novel link between inflammatory signals originating from the tumor microenvironment and increased SPINK1 levels. This finding has potential therapeutic implications for targeted therapy, as it confirms that SPINK1 acts as an acute phase reactant and that it participates in the paracrine crosstalk with the tumor microenvironment of colon cancer. © 2015 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mc.22447DOI Listing
December 2016

[Circulating cell-free DNA as biomarker for cancer *header*].

Duodecim 2015 ;131(5):424-32

The rapid accumulation of mutations in cancers and the resulting clonal heterogeneity frequently lead to generation of drug-resistant populations of cancer cells. Examinations requiring a tissue biopsy are invasive, making real-time monitoring of the disease difficult. One alternative to support tissue-based testing is fluid biopsy. Malignant cells release to the patient's circulation DNA, which contains somatic mutations and epigenetic changes characteristic of each cancer. Sufficiently sensitive methods of investigation enable the detection of tumor DNA in the blood sample, whereby it can be utilized e.g. in the monitoring of disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2015

Expression pattern of carbonic anhydrase IX in Medullary thyroid carcinoma supports a role for RET-mediated activation of the HIF pathway.

Am J Pathol 2014 Apr 8;184(4):953-965. Epub 2014 Feb 8.

Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia. Electronic address:

Medullary thyroid carcinoma is a relatively rare tumor with poor prognosis and therapy response. Its phenotype is determined by both genetic alterations (activating RET oncoprotein) and physiological stresses, namely hypoxia [activating hypoxia-inducible factor (HIF)]. Here, we investigated the cooperation between these two mechanisms. The idea emerged from the immunohistochemical analysis of carbonic anhydrases (CA) IX and XII expression in thyroid cancer. Although CAXII was present in all types of thyroid carcinomas, CAIX, a direct HIF target implicated in tumor progression, was associated with aggressive medullary and anaplastic carcinomas, and its expression pattern in medullary thyroid carcinomas suggested contribution of both hypoxic and oncogenic signaling. Therefore, we analyzed the CA9 promoter activity in transfected tumor cells expressing RET and/or the HIF-α subunit. We showed that overexpression of both wild-type and mutant RET can increase the CA9 promoter activity induced by HIF-1 (but not HIF-2) in hypoxia. Similar results were obtained with another HIF-1-regulated promoter derived from the lactate dehydrogenase A gene. Moreover, inhibition of the major kinase pathways, which transmit signals from RET and regulate HIF-1, abrogated their cooperative effect on the CA9 promoter. Thus, we brought the first experimental evidence for the crosstalk between RET and HIF-1 that can explain the increased expression of CAIX in medullary thyroid carcinoma and provide a rationale for therapy simultaneously targeting both pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2014.01.002DOI Listing
April 2014

Low cdc27 and high securin expression predict short survival for breast cancer patients.

APMIS 2013 Oct 12;121(10):945-53. Epub 2013 Jun 12.

Department of Pathology, University Hospital of Turku, Turku, Finland.

Cell cycle regulators cdc27 and securin participate in control of the mitotic checkpoint and survey the mitotic spindle to maintain chromosomal integrity. This is achieved by their functions in metaphase-anaphase transition, DNA damage repair, enhancement of mitotic arrest and apoptosis. We report on the roles of cdc27 and securin in aneuploidy and prognosis of breast cancer. The study comprises 429 breast cancer patients with up to 22 years of follow-up. DNA content was determined by image cytometry, and immunopositivity for cdc27 and securin was based on tissue microarrays. An inverse association between cdc27 and securin expression was observed in both image cytometric and immunohistochemical analyses. Low cdc27 and high securin expression identified patients with significant difference in disease outcome. Cdc27 and securin immunoexpression identified patients at risk of early cancer death within five years from diagnosis. In multivariate analysis, the combination of cdc27 and securin immunohistochemistry was the strongest predictor of cancer death after lymph node status. We demonstrate, for the first time in human breast cancer, the prognostic value of cdc27 and securin immunohistochemistry. Cdc27 and securin appear promising biomarkers for applications in predicting disease progression, prognostication of individual patients and potential in anti-mitotic drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apm.12110DOI Listing
October 2013

Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases.

Breast Cancer Res 2012 Jun 12;14(3):R90. Epub 2012 Jun 12.

Department of Medical Genetics, Biomedicum Helsinki, P,O,Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014.

Introduction: Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.

Methods: MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.

Results: The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.

Conclusions: Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/bcr3205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446353PMC
June 2012

Securin predicts aneuploidy and survival in breast cancer.

Histopathology 2012 Mar 19;60(4):586-96. Epub 2012 Jan 19.

Departments of Pathology, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, Turku, Finland.

Aims: Securin is known to participate in maintaining chromosomal integrity during the cell cycle through regulation of metaphase-anaphase transition, DNA damage repair, and apoptosis. The aim of this study was to investigate the role of securin in aneuploidy and prognosis in human breast cancer.

Methods And Results: The study was based on 603 breast cancer patients with up to 20 years of follow-up. DNA content was determined by image cytometry on cell imprints, and securin immunohistochemistry was performed on tissue microarrays of breast cancer tissue. We show, for the first time in human breast cancer, that high-level securin expression predicts abnormal DNA content, with up to 9.8-fold odds for aneuploid DNA content (P = 0.0007). Securin also shows strong independent prognostic value for disease-specific survival, with a significant difference in survival time between patients with low-level and high-level securin expression.

Conclusions: The main result of the present study is the association of aneuploidy and securin expression. According to our results, securin immunohistochemistry is also a potential new prognosticator for treatment decisions concerning breast cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2559.2011.04107.xDOI Listing
March 2012

Absence of cytomegalovirus from the gastrointestinal tract of patients with active Crohn's disease.

In Vivo 2012 Jan-Feb;26(1):151-5

Department of Gastroenterological Surgery, Jyväskylä Central Hospital, Keskussairaalantie 19, FIN-40620 Jyväskylä, Finland.

Background: Cytomegalovirus (CMV) infection reportedly is detectable in the gastrointestinal mucosa of patients with chronic inflammatory bowel disease. One view is that CMV infection is of clinical significance in patients with Crohn's disease with severe colitis not responding to steroid therapy. In this study, we evaluated the prevalence of CMV infection in our own patients with Crohn's disease treated with colon resection.

Patients And Methods: The study included 16 consecutive patients with Crohn's disease with colitis who underwent surgery for colonic disease. Histology and immunohistochemistry were used to examine the CMV infection in their surgical specimens by means of enzymatic antigen retrieval, mouse monoclonal antibody, clone CMV01, and a sensitive polymer detection system.

Results: All 16 patients underwent colon resection, three of them undergoing emergency surgery. No CMV infection was found in their surgical specimens.

Conclusion: CMV infection seems not to play a major role in the pathogenesis of Crohn's colitis requiring surgery. However, further prospective studies with larger number of patients are needed to determine the role of CMV in active Crohn's colitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2012