Publications by authors named "Pasi Hirvikoski"

26 Publications

  • Page 1 of 1

Multiparametric MRI prior to radical prostatectomy identifies intraductal and cribriform growth patterns in prostate cancer.

BJU Int 2019 12 19;124(6):992-998. Epub 2019 Jun 19.

Departments of Urology, Pathology and Radiology, and Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objectives: To evaluate the diagnostic value of multiparametric prostate magnetic resonance imaging (mpMRI) prior to radical prostatectomy with curative intent for the detection of cribriform architecture (CA) and intraductal prostate cancer (IDC), which have recently been demonstrated to be adverse pathological features.

Patients And Methods: The study included 124 men who underwent mpMRI prior to radical prostatectomy at our centre. Preoperative mpMRI, prostatectomy histology and clinical follow-up details were reviewed retrospectively. The diagnostic value of mpMRI was evaluated on the basis of the detection rate. Secondly, the prognostic significance of CA/IDC among grade group (GG)2 cancers with regard to biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier analysis, with the log rank test and Fisher's exact test.

Results: Pathological examination of radical prostatectomy specimens identified CA/IDC in 89 of 124 cases (71%) and mpMRI identified 86/95 of tumours including any CA/IDC with a sensitivity of 90.5% (95% confidence interval 82.8-95.6%). When localization of the lesions was compared, there was an association between the highest Prostate Imaging-Reporting and Data System classification and the highest pathological grade in 106 of the 124 cases (85.5%). In patients with GG2 lesions, BCR occurred in 11 of 31 (35.5%) with CA/IDC and two of 21 (9.5%) without CA/IDC (P = 0.034).

Conclusion: Multiparametric MRI has good sensitivity for detection of pathological primary prostate cancer, including most cases with CA/IDC; however, reliable prediction of GG2 tumours with CA/IDC for individual risk stratification remains challenging.
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http://dx.doi.org/10.1111/bju.14812DOI Listing
December 2019

Tumor-infiltrating lymphocytes associate with outcome in nonendemic nasopharyngeal carcinoma: a multicenter study.

Hum Pathol 2018 11 18;81:211-219. Epub 2018 Jul 18.

University of Turku, Institute of Biomedicine, Pathology, P.O. Box 20520, Turku, Finland.

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population-based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin-stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P < .001). In multivariable analysis, NPC cases with low intratumoral TILs had poor overall survival with a hazard ratio (HR) of 2.55 and 95% confidence interval (95% CI) of 1.60 to 4.05 (P < .001). Cases with low intratumoral TILs also had poor disease-specific survival (HR, 2.02; 95% CI, 1.16-3.52; P = .015). Keratinized tumors with low intratumoral TILs were associated with an even poorer overall survival (HR, 3.94; 95% CI, 2.17-7.15; P < .001) and a poor disease-specific survival (HR, 2.97; 95% CI, 1.46-6.05; P = .009). Our study demonstrates that the evaluation of TILs is simple and can be assessed routinely in NPC.
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http://dx.doi.org/10.1016/j.humpath.2018.07.009DOI Listing
November 2018

Lesion size on prostate magnetic resonance imaging predicts adverse radical prostatectomy pathology.

Scand J Urol 2018 Apr 1;52(2):111-115. Epub 2018 Jan 1.

a Departments of Diagnostic Radiology, Pathology and Surgery , Medical Research Center Oulu, Oulu University Hospital and University of Oulu , Oulu , Finland.

Objectives: To investigate the value of the maximal lesion diameter on preoperative multiparametric/bi-parametric magnetic resonance imaging for estimating the risk of adverse radical prostatectomy pathology.

Patients And Methods: Consecutive patients (n = 162) with prostate multiparametric or biparametric magnetic resonance images acquired before prostatectomy were retrospectively stratified into two groups: 65 patients with normal MRI (n = 18) or a suspicious lesion <15 mm in diameter (n = 47), and 97 patients with a lesion diameter ≥15 mm. The presence of extraprostatic extension, margin positivity, seminal vesicle invasion, and lymph node metastasis was examined in these groups using logistic regression analysis, including preoperative clinical parameters (prostate-specific antigen concentration, biopsy Gleason grade group, clinical T-stage, and D'Amico risk group).

Results: The prevalence of extraprostatic extension, margin positivity, and seminal vesicle invasion was 53.1% (86/162), 22.8% (37/162), and 17.9% (29/162), respectively. Lymphadenectomy was performed in 64 men, of whom 14 had lymph node metastasis. Lesion diameter ≥15 mm strongly predicted extraprostatic extension (Odds ratio: 7.94, 95% confidence interval: 3.87-16.28, p < 0.001), margin positivity (Odds ratio: 7.86, 95% confidence interval 2.63-23.51, p < 0.001), and seminal vesicle invasion (Odds ratio: 7.57, 95% confidence interval 2.18-26.22, p = 0.001). Lesion diameter ≥15 mm was an independent risk factor for adverse prostatectomy pathology. Lesion diameter ≥20 mm, but not ≥15 mm, was a significant risk factor for lymph node metastasis.

Conclusion: Magnetic resonance imaging lesion diameter ≥15 mm is an independent risk factor for extraprostatic extension, margin positivity and seminal vesicle invasion.
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http://dx.doi.org/10.1080/21681805.2017.1414872DOI Listing
April 2018

Epidemiological and treatment-related factors contribute to improved outcome of oropharyngeal squamous cell carcinoma in Finland.

Acta Oncol 2018 Apr 17;57(4):541-551. Epub 2017 Nov 17.

a Department of Otorhinolaryngology-Head and Neck Surgery , University of Helsinki, Helsinki University Hospital , Helsinki , Finland.

Background: Treatment for oropharyngeal squamous cell carcinoma (OPSCC) has changed, as the proportion of human papilloma virus (HPV)-related disease has increased. We evaluated nationwide information on its management and outcome during the treatment paradigm change period.

Methods: We included all patients diagnosed and treated for OPSCC at the five Finnish university hospitals from 2000 to 2009. Patient records and pathology registries provided the clinicopathological data. p16 staining was performed on primary tumor samples of patients who had received treatment with curative intent.

Results: A total of 674 patients were diagnosed and treated for OPSCC and the incidence increased along the study period. Of the evaluable tumors 58.5% were p16-positive and the number of p16-positive tumors increased along the years. The treatment was given with curative intent for 600 patients and it was completed in 564. Of them, 47.9% underwent primary surgery and 52.1% received definitive oncological treatment. Also, the treatment protocol changed towards a more oncological approach. Among patients treated with curative intent the five-year overall, disease-specific and disease-free survival rates were 60.1, 71.5 and 57.0%. In multivariate analysis, p16-positivity seemed to relate to reduced disease mortality in lateral and anterior-wall disease. Depending on primary tumor localization, also sex, classes T3-4, presence of regional metastasis and radiotherapy modality had an association with disease mortality.

Conclusion: The incidence of p16-positive OPSCC and delivery of definitive oncological treatment increased in Finland during the study period. An improved survival outcome compared with the previous nationwide investigation was observed in this subset of patients.
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http://dx.doi.org/10.1080/0284186X.2017.1400688DOI Listing
April 2018

Feasibility of Prostate PAXgene Fixation for Molecular Research and Diagnostic Surgical Pathology: Comparison of Matched Fresh Frozen, FFPE, and PFPE Tissues.

Am J Surg Pathol 2018 Jan;42(1):103-115

Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute.

Advances in prostate cancer biology and diagnostics are dependent upon high-fidelity integration of clinical, histomorphologic, and molecular phenotypic findings. In this study, we compared fresh frozen, formalin-fixed paraffin-embedded (FFPE), and PAXgene-fixed paraffin-embedded (PFPE) tissue preparation methods in radical prostatectomy prostate tissue from 36 patients and performed a preliminary test of feasibility of using PFPE tissue in routine prostate surgical pathology diagnostic assessment. In addition to comparing histology, immunohistochemistry, and general measures of DNA and RNA integrity in each fixation method, we performed functional tests of DNA and RNA quality, including targeted Miseq RNA and DNA sequencing, and implemented methods to relate DNA and RNA yield and quality to quantified DNA and RNA picogram nuclear content in each tissue volume studied. Our results suggest that it is feasible to use PFPE tissue for routine robot-assisted laparoscopic prostatectomy surgical pathology diagnostics and immunohistochemistry, with the benefit of significantly improvedDNA and RNA quality and RNA picogram yield per nucleus as compared with FFPE tissue. For fresh frozen, FFPE, and PFPE tissues, respectively, the average Genomic Quality Numbers were 7.9, 3.2, and 6.2, average RNA Quality Numbers were 8.7, 2.6, and 6.3, average DNA picogram yields per nucleus were 0.41, 0.69, and 0.78, and average RNA picogram yields per nucleus were 1.40, 0.94, and 2.24. These findings suggest that where DNA and/or RNA analysis of tissue is required, and when tissue size is small, PFPE may provide important advantages over FFPE. The results also suggest several interesting nuances including potential avenues to improve RNA quality in FFPE tissues and confirm recent suggestions that some DNA sequence artifacts associated with FFPE can be avoided.
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http://dx.doi.org/10.1097/PAS.0000000000000961DOI Listing
January 2018

Microbes of the tonsils in PFAPA (Periodic Fever, Aphtous stomatitis, Pharyngitis and Adenitis) syndrome - a possible trigger of febrile episodes.

APMIS 2015 Jun 23;123(6):523-9. Epub 2015 Apr 23.

Department of Pediatrics, Oulu University Hospital and Medical Research Center, University of Oulu, Oulu, Finland.

Periodic Fever, Aphtous stomatitis, Pharyngitis, and Adenitis (PFAPA) is a childhood febrile syndrome that is often cured by tonsillectomy (TE). We hypothesized that microbes present in the tonsils may act as a trigger for the activation of inflammasomes and investigated the microbiology of the tonsils in PFAPA patients and controls. We recruited 31 consecutive children who underwent TE due to PFAPA; 24 children who underwent TE due to other reasons served as controls. We cultured all the samples for bacteria, mycobacteria, yeasts, and viruses and used PCR for 15 viruses. Also biofilm formation and histologic findings were identified. The samples of the patients yielded Candida albicans more often than did the controls (16 vs 0%, p = 0.003). Staphylococcus aureus occurred in only 10% of the patients, but in 38% of the controls (p = 0.01). Varicella zoster and Herpes simplex viruses occurred less often in patients than in controls. Biofilm was present in 55% of PFAPA tonsils, but in only 24% of the controls (p = 0.03). The microbes found in the tonsils of PFAPA patients showed significant differences from those of controls. This may in part explain the efficacy of TE in PFAPA.
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http://dx.doi.org/10.1111/apm.12383DOI Listing
June 2015

Identification of androgen-regulated genes in human prostate.

Mol Med Rep 2012 Sep 19;6(3):466-72. Epub 2012 Jun 19.

Department of Surgery, Oulu University Hospital, and Department of Pathology, University of Oulu, FIN-90029 Oulu, Finland.

Androgens are essential for the development of the prostate and prostate cancer. We examined androgen-regulated gene expression in the human prostate. Samples from benign and malignant prostate tissue and samples containing prostate tissue obtained from prostate cancer patients three days after surgical castration were further processed as probes for a GeneChip array. The comparison of gene expression profiles in castrated samples and in benign or malignant prostate tissue samples revealed androgen-regulated genes. We further evaluated the genes which were differentially expressed in benign and malignant prostate samples. The androgen-regulated expression of dual specificity phosphatase 1 (DUSP1) was confirmed in the LNCaP prostate cancer cell line, as the expression of DUSP1 increased with androgen treatment over the course of time. The expression of the genes CRISP3, PCA3, OR51E2, HOXC6, AGR3, AMACR and SLC14A1 was affected by castration in addition to differential expression in the benign and malignant prostate. These sample results require further investigation for the role of AGR3 and SLC14A1 in prostate cancer as these associations have not been reported previously.
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http://dx.doi.org/10.3892/mmr.2012.956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493087PMC
September 2012

Absent Toll-like receptor-9 expression predicts poor prognosis in renal cell carcinoma.

J Exp Clin Cancer Res 2011 Sep 19;30:84. Epub 2011 Sep 19.

Department of Surgery, Oulu University Hospital, PO Box 21, 90029 OYS, Finland.

Background: Toll-like receptor 9 (TLR9) is a cellular DNA-receptor whose activation with cognate ligands triggers an immune reaction, with increased production of inflammatory cytokines. The aim of this study was to examine the expression of TLR9 in renal cell carcinoma (RCC), which is generally renowned of its immunogenic nature. We also evaluated the prognostic value of TLR9 in RCC.

Methods: TLR9 expression in RCC was characterized with immunohistochemistry in a retrospective study population of 152 RCC patients who underwent renal surgery. The TLR9 staining intensity was compared with clinical parameters.

Results: Of the studied tumours, 112 (81%) exhibited cytoplasmic TLR9 immunostaining. No association was detected between cytoplasmic TLR9 immunoexpression intensity and stage, nuclear grade, histological subtype or tumour necrosis. Cytoplasmic TLR9 immunoexpression was, however, a marker of favourable RCC specific survival both in univariate analysis and in multivariate regression model.

Conclusions: We conclude that TLR9 expression is an independent prognostic marker of RCC and the absence of TLR9 expression is related to poorer prognosis in RCC.
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http://dx.doi.org/10.1186/1756-9966-30-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182949PMC
September 2011

Lymphoepithelial carcinoma: two case reports and a systematic review of oral and sinonasal cases.

Head Neck Pathol 2011 Dec 23;5(4):327-34. Epub 2011 Jun 23.

Department of Diagnostics and Oral Medicine, Institute of Dentistry, Oulu University Hospital, University of Oulu, PO Box 5281, 90014 Oulu, Finland.

Lymphoepithelial carcinoma (LEC) is a rare malignancy. Histologically, it is an undifferentiated carcinoma with an intermixed reactive lymphoplasmacytic infiltrate. Herein, we report two cases of LEC in the head and neck region that presented to Oulu University Hospital. Our first case is a 30-year-old man with LEC in the left maxillary sinus. The second case is a 49-year-old man with LEC in the soft palate and uvula with regional lymph node metastases at diagnosis. In addition, a systematic review of the literature from 1980 to 2010 was performed with MEDLINE and cross-references were searched manually. Case reports and clinical series of oral, oropharyngeal, nasal, and paranasal sinus LECs were reviewed revealing a total of 110 cases. Most of the oral cases were found in the tonsils (n = 29), oropharynx (n = 19), and in oral mucosa (n = 18), while sinonasal cases (n = 40) were mainly in the paranasal sinuses and nasal cavity. From 37 case reports, including ours, the median age was 58 and 62 years for sinonasal and oral/oropharyngeal LECs, respectively. Oral and oropharyngeal LECs have a 70.0% tendency to metastasize and 16.6% spread locally. In contrast, none of the nasal and paranasal LECs metastasized, but 60% spread locally. Epstein-Barr virus (EBV) had been detected in 87.5% of all tested LEC cases. Treatment of LECs, during the last decade, has largely consisted of surgery, combined with radiotherapy or chemoradiation. Although local spread or nodal metastases are fairly common at the time of diagnosis, the mortality rate of adequately treated LEC patients is low.
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http://dx.doi.org/10.1007/s12105-011-0278-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210216PMC
December 2011

Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family.

Cancer Lett 2011 Mar 13;302(2):113-8. Epub 2011 Jan 13.

Laboratory of Cancer Genetics, Department of Clinical Genetics and Biocenter Oulu, University of Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland.

A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2010.12.020DOI Listing
March 2011

Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies.

Authors:
Xiaohong R Yang Jenny Chang-Claude Ellen L Goode Fergus J Couch Heli Nevanlinna Roger L Milne Mia Gaudet Marjanka K Schmidt Annegien Broeks Angela Cox Peter A Fasching Rebecca Hein Amanda B Spurdle Fiona Blows Kristy Driver Dieter Flesch-Janys Judith Heinz Peter Sinn Alina Vrieling Tuomas Heikkinen Kristiina Aittomäki Päivi Heikkilä Carl Blomqvist Jolanta Lissowska Beata Peplonska Stephen Chanock Jonine Figueroa Louise Brinton Per Hall Kamila Czene Keith Humphreys Hatef Darabi Jianjun Liu Laura J Van 't Veer Flora E van Leeuwen Irene L Andrulis Gord Glendon Julia A Knight Anna Marie Mulligan Frances P O'Malley Nayana Weerasooriya Esther M John Matthias W Beckmann Arndt Hartmann Sebastian B Weihbrecht David L Wachter Sebastian M Jud Christian R Loehberg Laura Baglietto Dallas R English Graham G Giles Catriona A McLean Gianluca Severi Diether Lambrechts Thijs Vandorpe Caroline Weltens Robert Paridaens Ann Smeets Patrick Neven Hans Wildiers Xianshu Wang Janet E Olson Victoria Cafourek Zachary Fredericksen Matthew Kosel Celine Vachon Helen E Cramp Daniel Connley Simon S Cross Sabapathy P Balasubramanian Malcolm W R Reed Thilo Dörk Michael Bremer Andreas Meyer Johann H Karstens Aysun Ay Tjoung-Won Park-Simon Peter Hillemanns Jose Ignacio Arias Pérez Primitiva Menéndez Rodríguez Pilar Zamora Javier Benítez Yon-Dschun Ko Hans-Peter Fischer Ute Hamann Beate Pesch Thomas Brüning Christina Justenhoven Hiltrud Brauch Diana M Eccles William J Tapper Sue M Gerty Elinor J Sawyer Ian P Tomlinson Angela Jones Michael Kerin Nicola Miller Niall McInerney Hoda Anton-Culver Argyrios Ziogas Chen-Yang Shen Chia-Ni Hsiung Pei-Ei Wu Show-Lin Yang Jyh-Cherng Yu Shou-Tung Chen Giu-Cheng Hsu Christopher A Haiman Brian E Henderson Loic Le Marchand Laurence N Kolonel Annika Lindblom Sara Margolin Anna Jakubowska Jan Lubiński Tomasz Huzarski Tomasz Byrski Bohdan Górski Jacek Gronwald Maartje J Hooning Antoinette Hollestelle Ans M W van den Ouweland Agnes Jager Mieke Kriege Madeleine M A Tilanus-Linthorst Margriet Collée Shan Wang-Gohrke Katri Pylkäs Arja Jukkola-Vuorinen Kari Mononen Mervi Grip Pasi Hirvikoski Robert Winqvist Arto Mannermaa Veli-Matti Kosma Jaana Kauppinen Vesa Kataja Päivi Auvinen Ylermi Soini Reijo Sironen Stig E Bojesen David Dynnes Ørsted Diljit Kaur-Knudsen Henrik Flyger Børge G Nordestgaard Helene Holland Georgia Chenevix-Trench Siranoush Manoukian Monica Barile Paolo Radice Susan E Hankinson David J Hunter Rulla Tamimi Suleeporn Sangrajrang Paul Brennan James McKay Fabrice Odefrey Valerie Gaborieau Peter Devilee P E A Huijts R A E M Tollenaar C Seynaeve Gillian S Dite Carmel Apicella John L Hopper Fleur Hammet Helen Tsimiklis Letitia D Smith Melissa C Southey Manjeet K Humphreys Douglas Easton Paul Pharoah Mark E Sherman Montserrat Garcia-Closas

J Natl Cancer Inst 2011 Feb 29;103(3):250-63. Epub 2010 Dec 29.

Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Sciences, Rockville, MD 20852, USA.

Background: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.

Methods: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.

Results: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.

Conclusions: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
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http://dx.doi.org/10.1093/jnci/djq526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107570PMC
February 2011

HuR expression is a marker of poor prognosis in renal cell carcinoma.

Tumour Biol 2011 Jun 16;32(3):481-7. Epub 2010 Dec 16.

Department of Surgery, Oulu University Hospital, PO Box 21, 90029 OYS, Oulu, Finland.

The HuR protein is a nucleocytoplasmic protein which plays an important role in the regulation of mRNA stability, and dysregulation of its expression has been linked to carcinogenesis. We studied 152 patients with primary renal cell carcinoma (RCC) who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of HuR and cyclooxygenase-2 (COX-2) was determined by immunohistochemistry using monoclonal antibodies. The immunostaining results were associated with patient age, clinical stage, Fuhrman grade and patient outcome. Cytoplasmic expression of HuR and COX-2 was positive in 37 (25%) and 22 (15%) of the tumours, respectively. The expression of HuR was associated with stage. The expression of COX-2 was associated with stage and nuclear grade. The RCC-specific survival was reduced in patients whose tumours expressed HuR or COX-2. The hazard ratio (HR) of patients with HuR-expressing tumours was 2.18 (95% confidence interval (CI), 1.16-4.09; p = 0.015) and the HR of patients with COX-2-expressing tumours was 2.29 (95% CI, 1.15-4.54; p = 0.018). In the Cox regression analysis the only independent prognostic factor was stage (p < 0.001). Treatment of an RCC cell line (769-P) with HuR-targeted small interfering RNA resulted in the reduced expression of HuR and COX-2. We conclude that cytoplasmic HuR expression is associated with reduced RCC-specific survival. The HuR protein regulates the expression of COX-2 in RCC cells, which is one potential mechanism of action for the HuR-associated aggressive behaviour of RCC.
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http://dx.doi.org/10.1007/s13277-010-0141-6DOI Listing
June 2011

Zeb1 and twist are more commonly expressed in metastatic than primary lung tumours and show inverse associations with claudins.

J Clin Pathol 2011 Feb 2;64(2):136-40. Epub 2010 Dec 2.

Department of Internal Medicine, Respiratory Research Unit, Clinical Research Center, Oulu University Hospital, Oulu, Finland.

Background: Zeb1 and twist regulate expression of genes which take part in epitheliomesenchymal transition (EMT). Claudins are tight junctional proteins regulating polarity and paracellular permeability of epithelial cells.

Aims And Methods: To study Zeb1 and twist in 289 primary and 54 metastatic lung tumours and their relation to expression of claudins 1-5 and 7 by immunohistochemistry.

Results: Metastatic tumours showed a significantly lower expression of zeb1 and twist (33.0% and 38.0% vs 5.0% and 14.5%, p<0.001 for both) and they also had a significantly lower expression of claudin 1 (p<0.001), claudin 4 (p<0.001), claudin 5 (p=0.001) and claudin 7 (p<0.001) than did primary tumours. Primary lung tumours showed a strong inverse association between zeb1 and claudin 1 (p=0.024) and claudin 2 (p=0.003). For twist an inverse association was found with claudin 5 (p=0.007). In metastatic tumours zeb1 was inversely associated with claudin 7 (p=0.050) and twist with claudin 5 (p=0.025). Overexpression of claudin 5 was associated with decreased survival (p=0.017). For zeb1 or twist, no association with survival was observed in primary or metastatic tumours.

Conclusions: According to protein expression, involvement of zeb1 and twist in EMT in primary lung tumours is relatively infrequent. Carcinomas metastatic to the lung showed a significantly higher expression of these transcriptional factors than primary lung tumours, indicating their probable importance in the metastatic process. Zeb1 and twist were inversely associated with several claudins, indicating a role in their down-regulation.
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http://dx.doi.org/10.1136/jcp.2010.086678DOI Listing
February 2011

Anillin expression is a marker of favourable prognosis in patients with renal cell carcinoma.

Oncol Rep 2011 Jan;25(1):129-33

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

The clinical course of renal cell carcinoma (RCC) can be difficult to predict. In this study we evaluated the prognostic value of anillin and Ki-67 in predicting survival in RCC. Immunohistochemical analysis using anillin and Ki-67 antibodies was performed on tissue microarrays constructed from paraffin-embedded specimens from 152 patients with primary RCC. The mean follow-up time was 90 months. Levels of anillin and Ki-67 staining were correlated with clinical factors, pathological features and survival. Anillin expression in cytoplasmic and nuclear fractions of the RCC cell line 786-O was examined using Western blot analysis. Cytoplasmic anillin immunopositivity was detected in 121 (83%) tumours. Nuclear anillin expression was present in 40 (27%) tumours and increased Ki-67 activity in 98 (66%) tumours. A positive association was found between nuclear anillin and Ki-67 proliferation activity (p=0.005). The mean RCC-specific survival times for anillin immunopositive and immunonegative tumours were 158 (95% CI 143-173) and 109 (78-141) months, respectively, with p=0.03. Increased Ki-67 activity showed a tendency towards a poorer prognosis, although this was not statistically significant. In the Cox regression analysis for cytoplasmic anillin, nuclear anillin or Ki-67 rate, and age, gender, stage and nuclear grade, the only significant factor in RCC-specific survival was stage (p<0.001). Western blot analysis showed anillin expression in both nuclear and cytosolic fractions of the RCC cell line. To conclude, anillin expression can be observed both in the cytoplasm and nuclei in patients with RCC. Cytoplasmic anillin expression is a marker of favourable prognosis in RCC patients.
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January 2011

Impact of smoking on the expression of claudins in lung carcinoma.

Eur J Cancer 2011 Mar 22;47(4):620-30. Epub 2010 Nov 22.

Department of Internal Medicine, Respiratory Research Unit, Clinical Research Center, Oulu University Hospital, Aapistie 5A, Oulu, Finland.

Rationale: Tight junctions regulate the paracellular permeability and orientation of cells and claudins are key components of tight junctions.

Objectives: To study the influence of cigarette smoke on claudin expression in vitro and in lung cancer patients.

Methods: We studied the effect of smoking on claudin expression by exposing a bronchial cell line (BEAS-2B) and two carcinoma cell lines (SK-LU1 and SK-MES1) to tobacco smoke for 48 h and analysed their claudin mRNA expression. The relation between smoked pack years and protein expression of claudins 1-5 and 7 in 344 lung cancer patients was determined by immunohistochemistry.

Measurements And Main Results: In BEAS-2B cells and SK-LU1 cells, an initial increase was followed by a decline in the mRNA expression of several claudins. In SK-MES1 cells, no evident elevation in claudin expression was observed. Intense claudin 1 and 4 positivity was found more often in cancer samples of smokers and ex-smokers compared to non-smokers (p<0.001 and p=0.003, respectively). Heavy smokers with longer than 40 pack-years consumption had more often intense claudin 1 (p=0.011), 4 (p=0.050) or 7 (p=0.058) expression in squamous cell carcinoma compared to non-smokers or smokers with fewer pack-years. Claudin 1 positivity predicted a better survival in adenocarcinoma (p=0.044) and in squamous cell carcinoma (p=0.027) and claudin 4 positivity in adenocarcinoma only (p=0.048). In squamous cell carcinoma, claudin 7 positivity was associated with a better survival (p=0.011).

Conclusions: Bronchial BEAS-2B cells and SK-LU1 cells respond to tobacco smoke by changing their claudin mRNA synthesis and resulting tight junction permeability changes may thus contribute to tobacco induced carcinogenesis both during initiation and progression. This concept is strengthened by findings in the clinical tumour material, where tobacco consumption was associated with claudin expression.
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http://dx.doi.org/10.1016/j.ejca.2010.10.017DOI Listing
March 2011

Evaluation of neuroendocrine markers in renal cell carcinoma.

Diagn Pathol 2010 May 12;5:28. Epub 2010 May 12.

Department of Surgery, PO Box 21, Oulu University Hospital, FIN-90029 Oulu, Finland.

Background: The purpose of the study was to examine serotonin, CD56, neurone-specific enolase (NSE), chromogranin A and synaptophysin by immunohistochemistry in renal cell carcinomas (RCCs) with special emphasis on patient outcome.

Methods: We studied 152 patients with primary RCCs who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of neuroendocrine (NE) markers was determined by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, clinical stage, Fuhrman grade and patient outcome.

Results: Eight percent of tumours were positive for serotonin, 18% for CD56 and 48% for NSE. Chromogranin A immunostaining was negative and only 1% of the tumours were synaptophysin immunopositive. The NSE immunopositivity was more common in clear cell RCCs than in other subtypes (p = 0.01). The other NE markers did not show any association with the histological subtype. Tumours with an immunopositivity for serotonin had a longer RCC-specific survival and tumours with an immunopositivity for CD56 and NSE had a shorter RCC-specific survival but the difference was not significant. There was no relationship between stage or Fuhrman grade and immunoreactivity for serotonin, CD56 and NSE.

Conclusions: Serotonin, CD56 and NSE but not synaptophysin and chromogranin A are expressed in RCCs. However, the prognostic potential of these markers remains obscure.
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http://dx.doi.org/10.1186/1746-1596-5-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876076PMC
May 2010

Sorbitol dehydrogenase expression is regulated by androgens in the human prostate.

Oncol Rep 2010 May;23(5):1233-9

Department of Pathology, University of Oulu, Oulu, Finland.

Sorbitol is an intermediate in the polyol pathway, which converts from glucose to fructose by sorbitol dehydrogenase (SORD). Androgens are essential for the development of prostate cancer. We studied castration-induced gene expression changes in the human prostate using the GeneChip array, and identified SORD as being androgen-regulated in the human prostate. A putative androgen-responsive regulatory region at the SORD 5' promoter was identified using promoter deletion constructs in a luciferase reporter assay in COS-7 cells. Chromatin immunoprecipitation assay was used to assess the binding of androgen receptor to suggested androgen responsive regulatory region. Finally, the expression of SORD in the human prostate was evaluated in 29 prostate tissue samples by immunohistochemistry. The expression of SORD decreased after castration. Androgen supplementation to the LNCaP prostate cancer cell line led to a 7.5-fold increase in SORD mRNA expression. Furthermore, a chromatin immunoprecipitation assay proved that the androgen receptor can bind to this putative androgen-responsive regulatory region. Finally, the expression of SORD in the human prostate was localised to epithelial cells of both benign and malignant prostate tissue by immunohistochemistry. In prostate cancer, increased immunostaining was associated with high Gleason patterns and high serum prostate-specific antigen concentrations. These results show that SORD is a novel androgen-regulated gene in the human prostate and suggest the need for more detailed analysis of the physiological role of SORD in the prostate.
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http://dx.doi.org/10.3892/or_00000755DOI Listing
May 2010

Evaluation of myosin VI, E-cadherin and beta-catenin immunostaining in renal cell carcinoma.

J Exp Clin Cancer Res 2010 Jan 14;29. Epub 2010 Jan 14.

Department of Surgery, PO Box 21, Oulu University Hospital, FIN-90029 Oulu, Finland.

Background: Renal cell carcinoma (RCC) is a cancer of increasing incidence and mortality. Currently, there are no immunohistochemical prognostic markers for RCCs in routine use. The aim of this study was to examine for the first time the immunostaining of myosin VI in RCCs as well as its association with E-cadherin and beta-catenin immunostaining and the prognostic significance of these markers in RCCs.

Methods: Our study population consisted of 152 patients who underwent surgery for RCCs between 1990 and 1999. The tumours were examined with three immunohistochemical markers: myosin VI, E-cadherin and beta-catenin.

Results: The immunostaining for cytoplasmic myosin VI was common (72%). One-third of the tumours were immunopositive for nuclear myosin VI. Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades (p = 0.04 and p = 0.005, respectively), but not stages. There was no significant association between myosin VI immunostaining and the histological subtype of RCC. Nuclear myosin VI was associated with the nuclear expression of beta-catenin. A direct association could also be proven between membranous E-cadherin and cytoplasmic beta-catenin. Cytoplasmic myosin VI immunostaining was a marker of poorer prognosis in multivariate Cox regression model adjusted with stage and Fuhrman grade with hazard ratio 2.4 (95% confidence interval 1.1 to 5.0 with p = 0.024).

Conclusions: Cytoplasmic myosin VI immunopositivity and nuclear beta-catenin immunostaining were associated with lower Fuhrman grades, and there was a strong positive relationship between E-cadherin immunostaining and beta-catenin immunostaining in RCCs. Cytoplasmic myosin VI immunostaining was associated with poorer prognosis in RCCs.
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http://dx.doi.org/10.1186/1756-9966-29-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2837630PMC
January 2010

Myosin VI is a modulator of androgen-dependent gene expression.

Oncol Rep 2009 Nov;22(5):991-5

Department of Pathology, University of Oulu, Oulu University Hospital, Oulu, 90029 OYS, Finland.

Myosin VI, one of the so-called unconventional myosins, is an actin-based molecular motor involved in intracellular vesicle and organelle transport. In human prostate, myosin VI is expressed in prostate epithelium. We examined the effect of myosin VI downregulation in the LNCaP human prostate cancer cell line using an RNA interference approach. Further, the expression of myosin VI in human prostate tissue was examined using immunohistochemistry. The expression of androgen receptor (AR) and E-cadherin was examined in myosin VI knocked-down cells and control cells. We determined 3H-testosterone uptake in the myosin knocked-down LNCaP cells. Next, we cotransfected LNCaP cells with the myosin VI-specific small interfering RNA (siRNA) duplex and an androgen-responsive luciferase reporter construct and then measured luciferase activity after androgen induction. To clarify whether myosin VI and the AR are interacting proteins, we performed immunoprecipitation studies using myosin VI and AR polyclonal antibodies in androgen-induced LNCaP cells. We confirmed previous results of myosin VI overexpression in human prostate cancer tissue, as in some cases malignant epithelium was more intensively stained than benign epithelium. We found that the expression of AR decreased as a result of myosin VI knock-down. Decreased myosin VI levels did not significantly influence the testosterone uptake of the LNCaP cell line. Instead, we noted a decreased activity of the androgen-regulated mouse mammary tumor virus promoter-reporter vector construct in LNCaP cells cotransfected with myosin VI siRNA duplexes. Finally, we detected the interaction between AR and myosin VI by immunoprecipitation. We propose that myosin VI is a modulator of androgen-dependent gene transcription via interaction with the AR. Thus, myosin VI is a potential therapeutic target for prostate cancer as it could be used as a modulator of AR-dependent gene expression.
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http://dx.doi.org/10.3892/or_00000526DOI Listing
November 2009

Increased BTB-Kelch type substrate adaptor protein immunoreactivity associates with advanced stage and poor differentiation in renal cell carcinoma.

Oncol Rep 2009 Jun;21(6):1519-23

Department of Surgery, Oulu University Hospital, Oulu, 90029 OYS, Finland.

Renal cell carcinoma (RCC) is a malignancy with increasing incidence. Despite the well-known prognostic factors - the stage, grade and histological subtype - the clinical course of RCC can seem quite random. The aim of this study was to evaluate markers of the oxidative system as candidate prognostic factors for RCC. Our study population consisted of 152 patients who underwent operation for RCC between 1990 and 1999. The tumours were examined with three immunohistochemical markers of the oxidative system, thioredoxin (Trx), NF-E2-related factor (Nfr2) and BTB-Kelch type substrate adaptor protein (Keap1). Cytoplasmic Keap1 staining was related to poorer prognosis in renal cancer-specific survival. The difference was statistically significant (P=0.02). Keap1 staining was associated with a more advanced stage and a higher nuclear grade. Cytoplasmic Trx staining was associated with a trend of better prognosis in renal cancer-specific survival. Nfr2 staining was not a prognostic factor in renal cancer-specific survival. In RCC, Keap1 is associated with a more advanced disease, a higher grade and a poorer prognosis.
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http://dx.doi.org/10.3892/or_00000383DOI Listing
June 2009

Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer.

Acta Oncol 2008 ;47(1):120-3

Department of Oncology, Kuopio University Hospital, Kuopio, Finland.

The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored.
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http://dx.doi.org/10.1080/02841860701518074DOI Listing
July 2008

Prostatic acid phosphatase is not a prostate specific target.

Cancer Res 2007 Jul;67(14):6549-54

Research Center for Molecular Endocrinology and WHO Collaborating Centre, Biocenter Oulu, University of Oulu, Finland.

Prostatic acid phosphatase (PAP) is currently evaluated as a target for vaccine immunotherapy of prostate cancer. This is based on the previous knowledge about secretory PAP and its high prostatic expression. We describe a novel PAP spliced variant mRNA encoding a type I transmembrane (TM) protein with the extracellular NH(2)-terminal phosphatase activity and the COOH-terminal lysosomal targeting signal (YxxPhi). TM-PAP is widely expressed in nonprostatic tissues like brain, kidney, liver, lung, muscle, placenta, salivary gland, spleen, thyroid, and thymus. TM-PAP is also expressed in fibroblast, Schwann, and LNCaP cells, but not in PC-3 cells. In well-differentiated human prostate cancer tissue specimens, the expression of secretory PAP, but not TM-PAP, is significantly decreased. TM-PAP is localized in the plasma membrane-endosomal-lysosomal pathway and is colocalized with the lipid raft marker flotillin-1. No cytosolic PAP is detected. We conclude that the wide expression of TM-PAP in, for instance, neuronal and muscle tissues must be taken into account in the design of PAP-based immunotherapy approaches.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1651DOI Listing
July 2007

Characterization of androgen-regulated expression of CYP3A5 in human prostate.

Carcinogenesis 2007 May 20;28(5):916-21. Epub 2006 Nov 20.

Department of Pathology, University of Oulu and University Hospital of Oulu, FIN-90014 Oulu, Finland.

Testosterone is needed for the growth and development of the prostate. Androgen deprivation therapy is used for the treatment of prostate cancer. CYP3A5 is a human drug-metabolizing cytochrome P450 enzyme that metabolizes testosterone to the inactive 6beta-hydroxylated metabolite. We identified CYP3A5 as a novel androgen-regulated gene in human prostate by GeneChip analysis of human prostate tissues obtained from patients 3 days after therapeutic castration and from control patients. We further showed androgen induction of CYP3A5 messenger RNA (mRNA) in LNCaP prostate cancer cell line. Immunoblotting studies revealed CYP3A5 protein expression in all prostate samples studied. Immunohistochemistry and in situ hybridization was used for localization of CYP3A5 expression in prostate tissue. CYP3A5 was detected both in luminal and in basal epithelial cells of human prostate. Androgen response element was identified in the CYP3A5 proximal promoter and in electrophoretic mobility shift assay androgen receptor was found to bind this element. Androgen induction was abolished by mutation of the response element. We suggest that CYP3A5 is a part of an autoregulatory feedback loop controlling prostate cell exposure to androgens.
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http://dx.doi.org/10.1093/carcin/bgl222DOI Listing
May 2007

Renal cell carcinoma MIB-1, Bax and Bcl-2 expression and prognosis.

J Urol 2004 Dec;172(6 Pt 1):2158-61

Department of Urology, Pathology, University of Tampere, Tampere, Finland.

Purpose: Proliferation and programmed cell death (apoptosis) are key factors in oncogenesis and tumor progression. In carcinogenesis important regulators of apoptosis are members of the Bcl-2 family. In this family the Bcl-2 gene has an inhibitory effect on apoptosis, while Bax promotes cell death. In renal cell carcinoma (RCC) the associations between Bcl-2 proteins and RCC prognosis have been controversial. We evaluated Bax and Bcl-2 levels in RCC, and their associations with prognosis, proliferation and traditional prognostic factors.

Materials And Methods: Our prospective study population comprised 138 consecutive patients who underwent radical nephrectomy for RCC. Immunostaining and semiquantitative indices for Ki-67 (MIB-1), Bax and Bcl-2 were estimated. Their associations with prognosis were explored.

Results: On univariate analysis according to survival statistically significant differences were achieved by Bax (positive vs negative HR 3.04, 95% CI 1.27 to 7.23), Bcl-2 (positive vs negative HR 0.43, 95% CI 0.23 to 0.81), MIB-1 (continuous HR 1.03, 95% CI 1.001 to 1.064), Fuhrman nuclear class (4 vs 1 plus 2 HR 8.15, 95% CI 3.13 to 21.20) and stage (4 vs 1 HR 60.04, 95% CI 13.99 to 257.68). Only stage (HR 47.96, 95% CI 10.85 to 212.03) and Fuhrman classification (HR 4.32, 95% CI 1.60 to 11.65) attained statistical significance on Cox regression multivariate analysis.

Conclusions: In our prospective study Bax and Bcl-2 showed a statistically significant association with prognosis in RCC but did not achieve the status of independent prognostic factors. Further studies are needed to clarify the role of the apoptotic process in tumor progression and prognosis.
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http://dx.doi.org/10.1097/01.ju.0000144334.97639.bfDOI Listing
December 2004

Peroxiredoxins, a novel protein family in lung cancer.

Int J Cancer 2004 Sep;111(4):514-21

Department of Internal Medicine, University of Oulu and Oulu University Hospital, Oulu, Finland.

Cigarette smoke, the major risk factor for lung cancer, induces an accumulation of reactive oxygen species. These have multiple effects on cell defense, cell proliferation and cell death. Thus, compounds involved in the regulators of redox balance can be hypothesized to play a fundamental role in both carcinogenesis and tumor progression. Here, we have evaluated the expressions of all 6 peroxiredoxins (Prxs I-VI) in lung carcinomas. Prxs represent a protein family with the capability of breaking down hydrogen peroxide; thus, they can participate in cellular antioxidant defense, regulate cell proliferation and increase drug resistance of cultured cells. Altogether 92 cases were investigated by immunohistochemistry, including 32 adenocarcinomas, 45 squamous cell, 9 small cell and 6 other carcinomas. Additionally, 11 cases with adenocarcinoma or squamous cell carcinoma were studied by Western analysis and/or by RT-PCR. Prxs I, II, IV and VI were particularly elevated in lung carcinomas as assessed by immunohistochemistry and/or RT-PCR. Western analysis revealed that Prxs I and IV were significantly elevated in tumors compared to nonmalignant tissue (p = 0.04 and 0.002, respectively). There were remarkable variations in Prx expression in various tumor subtypes, the most striking being Prx IV expression, which was mainly associated with adenocarcinoma. Elevated Prx VI expression was associated with high-grade squamous cell carcinoma (p = 0.03) and Prx II expression, with advanced tumor stage (p = 0.01). Our results suggest that Prxs may have effects on the progression of lung cancer.
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http://dx.doi.org/10.1002/ijc.20294DOI Listing
September 2004