V M Kosma

University of Kuopio, Kuopio, Eastern Finland Province, Finland

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Publications (182)860.72 Total impact

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    ABSTRACT: We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (<or=25.4 kg/m(2); OR, 0.33; 95% CI, 0.13-0.83). Significantly increased risk, on the other hand, was seen for postmenopausal women with the COMT-LL genotype and long-term (>30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (<or=12 years) at menarche (OR, 8.59; 95% CI, 1.85-39.8). Our study, therefore, suggests that the COMT genotype may define a portion of the individual breast cancer susceptibility that is associated with reproductive events and hormone exposure even if it does not seem to be a major overall risk factor for this malignancy.
    Cancer Epidemiology Biomarkers & Prevention 06/2001; 10(6):635-40. · 4.32 Impact Factor
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    ABSTRACT: To investigate the expression of catenins (alpha, beta, and gamma) in non-small cell lung carcinoma (NSCLC) and its relation to clinicopathological factors and prognosis. The expression of catenins was analysed immunohistochemically in 261 patients with resected NSCLC, diagnosed between 1978 and 1996 in eastern Finland: The cell proliferation index of the tumours was analysed by means of an image analyser. The staining results were compared with clinicopathological characteristics and survival. Normal catenin staining was found significantly more often in adenocarcinomas than in squamous cell carcinomas or anaplastic/large cell carcinomas. Reduced staining of alpha-catenin, beta-catenin, and gamma-catenin was related to poor differentiation of the tumour. The tumours with reduced staining of beta-catenin or gamma-catenin often had higher cell proliferation activity. Nuclear staining of beta-catenin and gamma-catenin was found in 16 (7%) and 29 (13%) cases, respectively. This nuclear staining correlated directly with increased cell proliferation and inversely with membranous staining. In survival analyses the predictors of overall and disease free survival were stage and tumour type. The expression of catenins did not affect survival. The expression of alpha-catenin, beta-catenin, and gamma-catenin is related to histological type and differentiation in NSCLC, although catenins have no independent prognostic value. However, this study supports the important role of the nuclear accumulation of beta-catenin and gamma-catenin in highly proliferative cells.
    Journal of Clinical Pathology 06/2001; 54(5):391-5. · 2.55 Impact Factor
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    ABSTRACT: We examined the feasibility of gene transfer to rabbit placenta using adenoviruses, plasmid/liposomes and plasmid/polyethyleneimine (PEI) complexes. Pregnant New Zealand White rabbits (n = 17) were anesthetized and local gene transfer was done via a catheter inserted in uterine arteries under direct angiographic control. Either nuclear targeted LacZ adenoviruses (1.0 x 10(10) p.f.u.), nuclear targeted LacZ plasmid (500 microg)/liposome (DOTMA:DOPE 1:1) complexes or nuclear targeted LacZ plasmid (250 microg)/PEI (25 kDa) complexes (charge ratio +/-4) were used. Animals were killed 3 days later and detection of the transgene expression was done by X-gal staining and RT-PCR. Adenovirus-mediated gene transfer resulted in a high transfection efficiency (34 +/- 10%) in placental trophoplastic cells. Very little, if any, transfection was seen in fetal membranes. Plasmid/liposomes and plasmid/PEI complexes led to a very low (<0.01%) transfection efficiency in trophoblastic cells, but some transfection was seen in fetal membranes. A total of 25 fetuses were analyzed for the presence of transgene at the time of death. In most fetuses expression of the LacZ gene was below the sensitivity of the X-gal staining, but expression was detected by PCR in 50%, 50% and 42% of the analyzed fetuses after adenoviral, plasmid/PEI and plasmid/liposome gene transfer, respectively. No major inflammatory changes were present in the transfected placentas as analyzed by general histology and macrophage- and T cell-specific immunostainings. We conclude that catheter-mediated intravascular gene transfer with adenoviruses can be used for the transfection of placental trophoplastic cells, but plasmid complexes are inefficient for this purpose. However, selective angiographically guided gene transfer also led to leakage of the vector to fetuses. Therefore, if gene therapy is developed for the treatment of placental disorders, the gene-vector combination should not be harmful to the fetus and the expression of the transgene should only occur in placenta.
    Gene Therapy 06/2001; 8(10):784-8. DOI:10.1038/sj.gt.3301444 · 4.20 Impact Factor
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    ABSTRACT: To evaluate the effects of 50 Hz magnetic fields (MF) on the development of cancer induced by ionizing radiation. A total of 150 female CBA/S mice were randomized into three equal groups at the age of 3-5 weeks. One of the groups served as a 'cage-control group'. The two other groups were exposed to ionizing radiation in the beginning of the study. One of these two groups was exposed 24 h per day, for 1.5 years, to a 50Hz vertical MF, the intensity of which varied regularly between 1.3, 13 and 130 muT. The other served as a control group and was sham-exposed to MF in similar, but unenergized, exposure racks. Body weights, clinical signs, and food and water consumption were recorded regularly. Haematological examination, and the histopathological analysis of all lesions and major tissues were performed on all animals. MF exposure did not increase the incidence of any primary neoplasms. However, the incidence of basophilic liver foci, a probable pre-neoplastic change in liver, was increased. The incidence of hepatocellular adenomas was unchanged, whereas the incidence of hepatocellular carcinomas was slightly, but not statistically significantly, elevated. It is concluded that overall the results of this study do not support a role for MF as a tumour promoter.
    International Journal of Radiation Biology 05/2001; 77(4):483-95. DOI:10.1080/09553000010024696 · 1.84 Impact Factor
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    ABSTRACT: Several epithelial tumours accumulate hyaluronan (HA) which promotes cancer cell invasion and metastasis. We analysed the expression of HA and its receptor CD44 and their prognostic value in 166 prostate cancer patients followed up for a mean of 13 years; standard deviation (S.D.) 2.7; range 8.7-21.4 years. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognising all forms of CD44. The peri- and intratumoral stroma from half of the patients strongly expressed immunohistochemically detectable HA in < or = 15% of the stromal area; the tumours in the remaining half expressed HA in > 15% of the area. The staining of cancer cells for HA was scored positive or negative, and for CD44 the median value of 80% of positive tumour cells was used as a cut-off point. The expression of HA in cancer cells was weakly associated with perineural infiltration of the tumour (P = 0.03) and high Gleason score (P = 0.002). There was also a significant inverse relationship between the expression of HA and CD44 in cancer cells (P < 0.001). The high level of HA in the peri-and intratumoral stroma was related to metastasis, high T-category, high Gleason score, perineural infiltration and high mitotic activity of the tumour (for all P < 0.001). There was a significant inverse relationship between the expression of CD44 in cancer cells and high level of strong expression of HA in the tumour stroma (P < 0.001). A low fraction of CD44-positive cells was related to a high TM-category, high Gleason score and rapid cell proliferation (for all P < 0.0001; M/V P value = 0.0013). In the univariate survival analysis, the high level of strong expression of HA in tumour stroma predicted an unfavourable outcome in the entire series (P = 0.003) and also in the M0 tumours (P = 0.07), while in T1-2 M0 tumours the prognostic value did not reach the level of statistical significance (P = 0.1). A low fraction of CD44-positive cells predicted a poor outcome in the entire series (P < 0.001) and also in M0 tumours (P = 0.003). Cancer cell-associated HA expression had no prognostic value in any tumour categories. In the multivariate analysis of prognostic factors, HA expression in the cancer cells or in the tumour stroma had no additional value to the standard prognostic factors TM-classification, Gleason score and CD44 expression. Our results show that stromal HA accumulation is related to several malignant features and adverse clinical outcome in prostate cancer. However, further studies based on uniformly treated patient cohorts are needed to establish the clinical significance of these findings in current clinical practice.
    European Journal of Cancer 05/2001; 37(7):849-56. DOI:10.1016/S0959-8049(00)00448-2 · 4.82 Impact Factor
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    ABSTRACT: This study was undertaken to examine if glutathione S-transferase (GST) M1, M3, P1, and T1 genotypes affected breast cancer risk in Finnish women. The study population consisted of 483 incident breast cancer cases and 482 healthy population controls. Genotyping analyses were performed by PCR-based methods, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for known or suspected risk factors for breast cancer. When the genes were studied separately, the only significant finding was between GSTM1 null genotype and postmenopausal breast cancer risk (OR, 1.49; 95% CI, 1.03-2.15). Conversely, when the potential combined effects of the at-risk genotypes were examined, significant associations were observed only among premenopausal women. Although only a moderate risk of breast cancer was seen for premenopausal women concurrently carrying the GSTM3*B allele containing genotypes and the GSTP1 Ile/ Ile genotype (OR, 2.07; 95% CI, 1.02-4.18), the risk rose steeply if they simultaneously lacked the GSTT1 gene (OR, 9.93, 95% CI, 1.10-90.0). A borderline significant increase in the risk of breast cancer was also seen for premenopausal women with the combination of GSTM1 null, GSTP1 Ile/Ile, and GSTT1 null genotypes (OR, 3.96; 95% CI, 0.99-15.8). Our findings support the view that GST genotypes contribute to the individual breast cancer risk, especially in certain combinations.
    Cancer Epidemiology Biomarkers & Prevention 04/2001; 10(3):229-36. · 4.32 Impact Factor
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    ABSTRACT: Microbial growth in buildings is associated with respiratory symptoms in the occupants. However, the specific effects of the microbes and the way they provoke clinical manifestations are poorly understood. In the current study, mice were exposed via intratracheal instillation to single doses of the spores of Streptomyces californicus, isolated from indoor air of a moisture-damaged building (2.2 x 10(7), 1.1 x 10(8), and 3.3 x 10(8) spores), or lipopolysaccharide (50 microg). Inflammation and toxicity in lungs were evaluated 24 h later. The time course of the effects was explored with the dose of 1.1 x 10(8) spores for up to 7 days. The microbial spores elevated proinflammatory cytokine (i.e., TNFalpha and IL-6) levels in bronchoalveolar lavage fluid (BALF) and in serum in a dose- and time-dependent manner and evoked expression of inducible nitric oxide synthase in BAL cells. Both TNFalpha and IL-6 responses peaked at 6 h after instillation, but TNFalpha leveled off more quickly than IL-6. The cytokine surge was followed by inflammatory cell recruitment into airways. Moreover, the spores increased dose- and time-dependently total protein, albumin, hemoglobin, and lactate dehydrogenase concentrations in BALF during the first 24 h. Histopathological examination of lungs confirmed the inflammatory changes. With the exception of macrophage and lymphocyte numbers, all parameters returned to control level at 7 days. In summary, these observations indicate that the spores of S. californicus are capable of provoking an acute inflammation in mouse lungs and can cause cytotoxicity. Thus, S. californicus can be considered as a species with potential to cause adverse health effects in occupants of moisture-damaged buildings.
    Toxicology and Applied Pharmacology 03/2001; 171(1):61-9. DOI:10.1006/taap.2000.9116 · 3.63 Impact Factor
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    ABSTRACT: The adhesion molecule CD44 standard (CD44s), and its variant isoforms v3 and v6 are associated with cell-to-cell adhesion. The down-regulation of CD44 standard and its variant isoform CD44v6 is linked with early cancer cell dissemination, but the relationship between CD44v3 and malignant features of prostate cancer (PC) has not been established previously. The expression of CD44s and its CD44v3 and CD44v6 isoforms was analysed by immunohistochemistry in 209 archival PC biopsy specimens to establish their prognostic value. Down-regulation of CD44s and CD44v6 was related to high T classification, metastasis, high Gleason score, DNA aneuploidy, high S-phase fraction, high mitotic index, perineural growth and dense amount of tumour infiltrating lymphocytes (p < 0.03 for all). Down-regulation of CD44s and CD44v6 was related to poor survival in the entire cohort (p < 0.0001), in M0 tumours (p < 0.001) and in T1-2M0 tumours (p < 0.05). In needle biopsies and TURP specimens, the prognostic impact of the investigated parameters was similar. In the multivariate analysis, T classification (p = 0.0009), presence of metastases (p < 0.0001), Gleason score (p = 0.0060) and CD44v6 (p = 0.0220) expression were independent prognostic factors. In M0 tumours, T classification (p < 0.0001) and CD44v6 (p = 0.003) independently predicted survival. Down-regulation of CD44s and its CD44v6 isoform is related to tumour malignancy and unfavourable prognosis in PC.
    European Urology 03/2001; 39(2):138-44. DOI:10.1159/000052428 · 12.48 Impact Factor
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    ABSTRACT: To investigate the expression of alpha, beta, and gamma catenins in oropharyngeal and hypopharyngeal squamous cell carcinoma and their relations to each other, as well as to clinical data, tumour differentiation, and prognosis. Primary tumours for analysis were obtained from 138 patients diagnosed with squamous cell carcinoma of the oropharynx or hypopharynx between 1975 and 1998 in eastern Finland. Immunohistochemistry was used to evaluate the expression of alpha, beta, and gamma catenins. The expression patterns of all catenins were related to clinical data and survival. The expression patterns of all three catenins were significantly interrelated. Reduced gamma catenin expression was significantly associated with poor histological differentiation. No association was found between alpha or beta catenin expression and clinicopathological characteristics. In univariate analysis, patients whose tumours had nuclear beta catenin expression had shorter overall survival than patients with no nuclear expression. In Cox multivariate analysis, nuclear beta catenin expression, tumour status (T class), and Karnofsky performance index were independent prognostic factors of overall survival. Reduced expression of gamma catenin is associated with dedifferentiation in primary squamous cell carcinoma of the oropharynx and hypopharynx. The fact that nuclear beta catenin expression independently predicts short overall survival suggests that it might be a valuable prognostic marker in pharyngeal squamous cell carcinoma.
    Journal of Clinical Pathology 02/2001; 54(1):42-7. · 2.55 Impact Factor
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    ABSTRACT: The prognostic value of hyaluronan (HA) was analyzed in a large number of patients (n = 261) with non-small-cell lung cancer (NSCLC) by staining archived tumor samples with a biotinylated HA-specific probe. The level of HA in the tumor cells and surrounding stroma was scored and compared with parallel CD44 stainings, clinicopathological factors and survival data. Adenocarcinomas were characterized by a low percentage of HA-positive cells with low staining intensity compared with squamous-cell and large-cell/anaplastic carcinomas. The HA signal in the peri-tumoral stroma was often higher than that in the uninvolved stroma in all subgroups of NSCLC. CD44 and HA associated with the cancer cells showed a strong positive correlation with each other. In the whole tumor material, dominated by squamous-cell carcinomas (n = 168), recurrences were more often found in cases showing a low percentage of cancer cell-associated HA. However, within the adenocarcinoma subgroup (n = 68), a high percentage of cell-associated HA was correlated with poor tumor differentiation. Also specific for the adenocarcinoma subgroup was the increased number of recurrences in cases with a strong stromal HA signal. In survival analysis of the whole material (n = 189), a low percentage of HA-positive cancer cells was associated with a shortened disease-free survival (DFS) together with stage and tumor type. However, in the subgroup of patients with adenocarcinoma (n = 49), a strong stromal signal for HA predicted poor DFS. The level of HA in the stroma of adenocarcinomas retained its prognostic value in Cox's multivariate analysis. These results indicate that the frequency and intensity of HA has a significant prognostic value in NSCLC, particularly when the histological subtypes are analyzed as separate entities.
    International Journal of Cancer 02/2001; 95(1):12-7. · 5.01 Impact Factor
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    ABSTRACT: To study the controversial role of transmembrane glycoprotein CD44 as a moderator of tumour spread and as a prognostic factor in gastric cancer. METHODS and The expression of all CD44 forms and that with exon v3 was assessed in 198 stage I-IV gastric adenocarcinomas using immunohistochemistry. CD44 expression was found in 72% and CD44v3 in 55% of the cases. The intensity of CD44 expression was associated with the level of invasion and with hyaluronan expression, while the frequency of CD44 positive cells was not significantly related to any of the clinical or histological features of the tumours. CD44v3 expression failed to show any association with the clinical or histological variables examined. Neither total CD44 nor CD44v3 expression affected survival. The most important prognostic factors in this cohort were the level of invasion, lymph node status, tumour size and vascular or perineural invasion. Changes in CD44 or CD44v3 expression level do not predict tumour spread or patient survival in gastric cancer.
    Histopathology 02/2001; 38(1):13-20. DOI:10.1046/j.1365-2559.2001.01038.x · 3.30 Impact Factor
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    ABSTRACT: To monitor the concentration of markers of cartilage and synovium metabolism in the knee (stifle) joint synovial fluid of young beagles subjected to immobilisation and subsequent remobilisation. The right hind limb of 17 dogs was immobilised in flexion for 11 weeks. Simultaneously, the contralateral left knee was exposed to increased weight bearing. The remobilisation period lasted 50 weeks. Litter mates served as controls. The concentration in joint lavage fluid of interleukin 1alpha (IL1alpha) was measured by immunoassay, the activity of phospholipase A(2) (PLA(2)) was determined by an extraction method, chondroitin sulphate (CS) concentration by precipitation with Alcian blue, hyaluronan (HA) by an ELISA-like assay using biotinylated HA-binding complexes, matrix metalloproteinase 3 (MMP-3), and tissue inhibitor of metalloproteinases 1 (TIMP-1) by sandwich ELISA, and synovitis was scored by light microscopy. Synovitis or effusion was absent in all experimental and control groups. Immobilisation decreased the joint lavage fluid levels of IL1alpha (p<0.05), TIMP (p< 0.05), and the concentration of CS down to 38% (p<0.05) in comparison with untreated litter mates with normal weight bearing. Immobilisation did not affect the activity of PLA(2), or the concentration of MMP-3 or HA in synovial fluid. Joint remobilisation restored the decreased concentrations of markers to control levels. Increased weight bearing did not change the concentrations of markers in comparison with the control joints with normal weight bearing. 11 weeks' joint immobilisation decreased the concentration of markers of cartilage and synovium metabolism in the synovial fluid, and remobilisation restored the concentrations to control levels. The changes in joint metabolism induced by immobilisation, as reflected by the markers, are thus different from those found in osteoarthritis, where increased levels of these markers are associated with enhanced degradation and synthesis. These findings suggest that the change induced in joint metabolism by immobilisation is reversible in its early stages.
    Annals of the Rheumatic Diseases 01/2001; 60(1):55-60. · 9.27 Impact Factor
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    ABSTRACT: The expression of inducible nitric oxide synthase (iNOS) was evaluated in prostate cancer and the results were compared with other prognostic factors and patients outcome. Clinical and histopathological data and follow-up information of 198 prostate cancer (PC) patients treated between the years 1973 and 1992 at Kuopio University Hospital, Finland were collected from patient files. Archival tumor specimens were used for immunohistochemical analysis of iNOS. The expression of iNOS was analysed by light microscopy and the expression was scored into 3 grades (negative weak or strong). iNOS was expressed in tumor cells and in inflammatory cells inside and around the tumor. Normal and hyperplastic prostate tissues adjacent to tumors were negative or weakly positive for iNOS. The strong iNOS expression in tumor cells was related to high T-classification (p=0.001), metastasis (p=0.06), high Gleason score (p=0.0004), DNA aneuploidy (p=0.0001) and perineural infiltration (p=0.0001). iNOS expression was not linked with the density of tumor infiltrating lymphocytes or the expression of p53. The mean values of Ki-67, mitotic index and S-phase fraction were higher in tumors strongly expressing iNOS. In univariate survival analysis the strong expression of iNOS was a significant predictor of poor survival in the entire cohort (p=0.0002) and in the MO patients (p=0.008), but was not an independent predictor of survival in Cox's multivariate analysis. iNOS has been related to stimulative and suppressive effects on cancer cell growth, but the prognostic value of iNOS has not been previously studied in PC. Here we could demonstrate an association between strong iNOS expression and rapid cancer cell proliferation rate, dedifferentiation and advanced stage cancer. The strong iNOS expression was a predictor of poor survival in univariate analysis, but was inferior to established prognostic factors in multivariate analysis.
    Anticancer research 01/2001; 21(4B):3101-6. · 1.87 Impact Factor
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    ABSTRACT: Merkel cell carcinoma is a rare, although increasingly recognized, malignant tumor of the skin. The most common site of occurrence is the head and neck (50%). Only five cases of this tumor on the auricle have been reported previously. We present a further such case. The incidence, clinical features, diagnosis, prognosis, and treatment of the Merkel cell carcinoma are discussed.
    Archiv für Klinische und Experimentelle Ohren- Nasen- und Kehlkopfheilkunde 01/2001; 257(10):558-60. DOI:10.1007/s004050000291 · 1.61 Impact Factor
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    ABSTRACT: The purpose of this study was to analyse the results of salvage surgery after failure of irradiation to control the primary T1-T2 glottic cancer. Ninety-eight patients with T1 and T2 squamous cell cancer of the glottic larynx were treated with curative intent by radiotherapy. The tumour recurred in 22 of the 98 (22%) patients. Surgical management consisted of total and frontolateral laryngectomy. Survival rates were calculated from the date of the salvage operation. Two of the 22 patients refused to undergo salvage surgery and one patient had pulmonary metastasis. Of the 19 patients who underwent salvage surgery, 14 (74%) had total laryngectomy and 5 (26%) had frontolateral laryngectomy. The operations were curative in 15 (79%) of the 19 patients. The overall 5-year survival rate after surgery was 78%. Stringent follow-up of patients with irradiated T1 and T2 glottic laryngeal cancer is essential to permit a successful salvage.
    Anticancer research 01/2001; 21(6A):4185-8. · 1.87 Impact Factor
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    ABSTRACT: The potential role of the polymorphism in the CYP17 gene was evaluated in a case-control study with 483 incident breast cancer patients and 482 population controls, all of homogenous Finnish origin. Our data disagree with the earlier suggestions that the minor A2 variant of CYP17 would pose an increased risk for developing advanced breast cancer. In contrast, a tendency of inverse association was found for premenopausal women carrying the A2 allele containing genotypes with a multivariate adjusted odds ratio of 0.58 approaching statistical significance (95% CI, 0.31-1.07). Agreeing with previous observations, the protective effect of later age at menarche (> or =13 years) was mainly limited to women with A1/A1 genotype, although this could only be seen in premenopausal women (odds ratio, 0.34; 95% CI, 0.15-0.76). Similarly, we found a remarkably lower risk for premenopausal women with at least one child (odds ratio, 0.22; 95% CI, 0.07-0.62) to be mainly attributable to the A1/A1 genotype. CYP17 genotypes may thus modify individual breast cancer proneness in certain subpopulations, although they appear not to have any major modifying role in the risk of this malignancy overall. Because these findings are based on relatively small numbers in stratified analysis, they should, however, be interpreted with caution before being confirmed in future studies.
    Cancer Epidemiology Biomarkers & Prevention 01/2001; 9(12):1343-8. · 4.32 Impact Factor
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    ABSTRACT: Background The pharyngocutaneous fistula is troublesome complication after total laryngectomy. Despite a large number of studies, there is still disagreement on factors predisposing to this complication.MethodsA retrospective analysis of pharyngocutaneous fistulas in 133 patients in whom total laryngectomy was performed.ResultsFistulas were found in 15% of the patients. Spontaneous closure was noted in 80%. Simultaneous laryngectomy and partial pharyngectomy or neck dissection increased the risk of fistula formation. Preoperative irradiation, short interval between radiotherapy and operation, and cobalt/roentgen radiation instead of photons predispose to this complication. The fistulas appeared earlier, and the sizes of fistulas were significantly larger in patients with previous irradiation than those in patients with no preoperative irradiation.Conclusions Postoperative pharyngocutaneous fistulas significantly increase patients' morbidity and hospital stay. Good surgical technique and postoperative treatment should be paid attention to patients with an increased risk of pharyngocutaneous fistula formation. © 2000 John Wiley & Sons, Inc. Head Neck 23: 29–33, 2001.
    Head & Neck 01/2001; 23(1):29 - 33. DOI:10.1002/1097-0347(200101)23:1<29::AID-HED5>3.0.CO;2-P · 3.01 Impact Factor
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    ABSTRACT: The expression of inducible nitric oxide synthase (iNOS) has been reported to be altered in a number of tumours, but its role in tumour biology is still unclear. iNOS was studied in a series of 157 colorectal carcinoma patients and its relation to tumour grade, stage, cell cycle regulators, cell proliferation as well as survival was assessed. iNOS intensity was moderate or intense in 37% of the tumours. iNOS intensity and percentage of positive cells were higher in Dukes A and B tumours than in Dukes C and D tumours, and low iNOS expression intensity was related to high histological grade. iNOS expression correlated positively with cell cycle regulators p21 and AP-2. There was also a high iNOS expression intensity and high fraction of iNOS positive cells in tumours with a high amount of tumour infiltrating lymphocytes (TILs). The cancer related survival was significantly lower among patients with a low signal for iNOS and low iNOS percentage in tumour epithelium. In multivariate analysis iNOS was not an independent prognostic factor. These results suggest that iNOS has a protective role in colorectal carcinogenesis, but further studies are required to establish the clinical significance of iNOS in colorectal cancer.
    Scandinavian Journal of Gastroenterology 12/2000; 35(11):1204-11. · 2.33 Impact Factor
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    ABSTRACT: Expression of transgene other than in the target tissue may cause side effects and safety problems in gene therapy. We analyzed biodistribution of transgene expression after intravascular and periadventitial gene delivery methods using the first generation nuclear-targeted lacZ adenovirus. RT-PCR and X-Gal stainings were used to study transgene expression 14 days after the gene transfer. After intravascular catheter-mediated gene transfer to rabbit aorta mimicking angioplasty procedure, the target vessel showed 1.1% +/- 0. 5 gene transfer efficiency. Other tissues showed varying lacZ gene expression indicating a systemic leakage of the vector with the highest transfection efficiency in hepatocytes (0.7% +/- 0.5). X-Gal staining of blood cells 24 h after the intravascular gene transfer indicated that a significant portion (1.8% +/- 0.8) of circulating monocytes was transfected. X-Gal-positive cells were also found in testis. After periadventitial gene transfer using a closed silicon capsule placed around the artery, 0.1% +/- 0.1 lacZ-positive cells were detected in the artery wall. Positive cells were also found in the liver and testis (<0.01%), indicating that the virus escapes even from the periadventitial space, although less extensively than during the intravascular application. We conclude that catheter-mediated intravascular and, to a lesser extent, periadventitial gene transfer lead to leakage of adenovirus to systemic circulation, followed by expression of the transgene in several tissues. Possible consequences of the ectopic expression of the transgene should be evaluated in gene therapy trials even if local gene delivery methods are used.
    The FASEB Journal 12/2000; 14(14):2230-6. DOI:10.1096/fj.00-0145com · 5.48 Impact Factor
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    ABSTRACT: Risk assessment of dioxins is currently based on induction of liver tumors in rats. The toxicity of dioxins is characterized by large sensitivity differences among animal species and even strains of the same species, which complicates the risk assessment. The significance of these differences in dioxin-induced carcinogenicity is not known. We therefore studied the liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats differing >1000-fold in their sensitivity to the acute lethaity of TCDD. Female rats were partially hepatectomized, initiated with nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered hepatic foci (AHF) were stereologically quantitated using glutathione S-transferase P as a marker. AHF were significantly (P < 0.001) and dose dependently increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at 1000 ng/kg/day and above, indicating a remarkable (approximately 100-fold) sensitivity difference between L-E and H/W rats. The same sensitivity difference but 10-fold less foci were observed between nonhepatectomized/noninitiated L-E and H/W rats. Induction of AHF was related to hepatotoxicity but not to cytochrome P4501A1 activity in the liver. Liver TCDD concentrations were similar in both strains. H/W rats are exceptionally resistant to induction of AHF by TCDD, and the resistance is associated with an altered transactivation domain of the aryl hydrocarbon receptor. Genetic differences may account for significant interindividual/intraspecies sensitivity differences in dioxin-induced carcinogenesis. Understanding the role of transactivation domain of the aryl hydrocarbon receptor in carcinogenesis is therefore likely to improve dioxin risk assessment.
    Cancer Research 12/2000; 60(24):6911-20. · 9.28 Impact Factor

Publication Stats

5k Citations
860.72 Total Impact Points

Institutions

  • 1986–2009
    • University of Kuopio
      • • Institute of Clinical Medicine, Pathology and Forensic Medicine
      • • Department of Pathology
      Kuopio, Eastern Finland Province, Finland
  • 2002
    • Oulu University Hospital
      Uleoborg, Oulu, Finland
  • 2001
    • Finnish Institute of Occupational Health
      Helsinki, Southern Finland Province, Finland
  • 1991–2001
    • Kuopio University Hospital
      • • Department of Urology
      • • Department of Surgery
      Kuopio, Province of Eastern Finland, Finland
  • 1999
    • Tampere University Hospital (TAUH)
      Tammerfors, Province of Western Finland, Finland
  • 1998
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 1995
    • University of Turku
      • Department of Pathology
      Turku, Province of Western Finland, Finland
  • 1988
    • University of Lausanne
      Lausanne, Vaud, Switzerland