Publications by authors named "Pauliina Kronqvist"

42 Publications

Biochemical and clinical approaches in evaluating the prognosis of colon cancer.

Anticancer Res 2006 Nov-Dec;26(6C):4745-51

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

Background: Colorectal adenocarcinoma is a common malignant neoplasm in the Western world. To achieve optimal treatment results, the risk estimation of recurrence should be as accurate as possible.

Materials And Methods: Tissue material from tumour and normal mucosa was taken from six patients and was analysed to screen aberrantly expressed genes using cDNA microarray. Selected up-regulated genes were chosen for further analysis by immunohistochemistry. For this purpose a tissue array material of 114 colorectal cancer patients was obtained. In addition to the routinely used proliferation marker Ki-67, the analysed proteins included securin and CDC25B.

Results: Processes such as cellular defense, cell structure, motility and cell division were found to be notably represented among the most deregulated genes. A significant portion of the overexpressed genes included those functioning in the cell cycle. Immunohistochemical stainings of securin and CDC25B showed a consistent expression pattern with that of cDNA microarray analysis. There was no statistical association between the studied proliferation markers and survival. Instead, there was a significant association between the Dukes' class and the histological grade (p=0.04), but not between histological grade and survival. The survival of Dukes' B patients was significantly poorer if no regional lymph nodes were studied compared with the Dukes' B patients with even a single lymph node was studied (p=0.04, hazard ratio 2.7).

Conclusion: Tumour stage is superior in estimating the prognosis of patients with colonic cancer compared with the grading of cell cycle regulators or histological grade of the cancer. The study of regional lymph nodes is essential to identify the patients who would benefit from adjuvant chemotherapy.
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January 2007

Population-based mammography screening results in substantial savings in treatment costs for fatal breast cancer.

Breast Cancer Res Treat 2006 Jul 15;98(2):143-50. Epub 2006 Mar 15.

Financial Department, Health Office, Turku, Finland.

Aims: The aim was to assess the effect of population-based mammography screening on treatment costs for fatal breast cancer in Turku, Finland.

Materials And Methods: The study included 556 women with invasive breast cancer, diagnosed at the age of 40-74 years in 1987-1993: 427 in the screened group (screen-detected or interval cancer) and 129 in the unscreened group (not yet invited or refused screening). Both groups were followed up for 8 years from diagnosis.

Results: In the unscreened group, 32 (25%) patients died of breast cancer versus 49 (12%) in the screened group (p < 0.001). The non-discounted mean treatment costs were 2.8-fold for those dying of breast cancer compared to survivors: 26,222 euros versus 9,434 euros; the difference between means was 16,788 euros (95% CI 14,915-18,660) (p<0.001). The mean costs for fatal cases were high, irrespective of the way cancer was detected: 23,800 euros in the unscreened group versus 27,803 euros in the screened group; the difference between means was -4,003 euros (-10,810 to 2802) (p=0.245). In the unscreened group, patients with fatal breast cancer accounted for 41% (0.76/1.87 million euros) of the total treatment costs versus 29% (1.36/4.76 million euros) in the screened group. It was estimated that about one third of costs for fatal breast cancer were avoided through mammography screening, accounting for 72-81% of the estimated total treatment cost savings achieved by screening. About 31-35% of the screening costs for 1987 to 1993 were offset by savings in treatment costs.

Conclusions: Treatment costs for fatal breast cancer are high. Mammography screening results in substantial treatment cost savings, in which reduction of fatal disease is the key element.
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http://dx.doi.org/10.1007/s10549-005-9142-3DOI Listing
July 2006

Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness.

Clin Cancer Res 2006 Feb;12(4):1080-7

Turku Centre for Biotechnology, Turku University, Finland.

Purpose: Hypoxia in tumors is associated with poor prognosis and resistance to treatment. The outcome of hypoxia is largely regulated by the hypoxia-inducible factors (HIF-1alpha and HIF-2alpha). HIFs in turn are negatively regulated by a family of prolyl hydroxylases (PHD1-3). The PHD2 isoform is the main down-regulator of HIFs in normoxia and mild hypoxia. This study was designed to analyze the correlation of the expression and subcellular localization of PHD2 with the pathologic features of human carcinomas and HIF-1alpha expression.

Experimental Design: The expression of PHD2 was studied from paraffin-embedded normal tissue (n = 21) and head and neck squamous cell carcinoma (HNSCC; n = 44) by immunohistochemistry. Further studies included PHD2 mRNA detection and HIF-1alpha immunohistochemistry from HNSCC specimens as well as PHD2 immunocytochemistry from HNSCC-derived cell lines.

Results: In noncancerous tissue, PHD2 is robustly expressed by endothelial cells. In epithelium, the basal proliferating layer also shows strong expression, whereas the more differentiated epithelium shows little or no PHD2 expression. In HNSCC, PHD2 shows strongly elevated expression both at the mRNA and protein level. Moreover, PHD2 expression increases in less differentiated phenotypes and partially relocalizes from the cytoplasm into the nucleus. Endogenously high nuclear PHD2 is seen in a subset of HNSCC-derived cell lines. Finally, although most of the tumor regions with high PHD2 expression show down-regulated HIF-1alpha, regions with simultaneous HIF-1alpha and PHD2 expression could be detected.

Conclusions: Our results show that increased levels and nuclear translocation of the cellular oxygen sensor, PHD2, are associated with less differentiated and strongly proliferating tumors. Furthermore, they imply that even the elevated PHD2 levels are not sufficient to down-regulate HIF-1alpha in some tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-05-2022DOI Listing
February 2006

Association between high collagenase-3 expression levels and poor prognosis in patients with head and neck cancer.

Head Neck 2006 Mar;28(3):225-34

Department of Oncology and Radiotherapy, Turku University Hospital, P.O. Box 52, FIN-20521 Turku, Finland.

Background: Squamous cell carcinoma of the head and neck (HNSCC) is a common cancer type. The ability for curative treatment with surgery and radiotherapy (RT) is usually highly dependent on tumor stage at the time of diagnosis.

Methods: The purpose of this study was to determine whether the expression of a cancer-specific proteinase, collagenase-3 (matrix metalloproteinase-13 [MMP-13]), is associated with survival parameters in patients with HNSCC. We studied MMP-13 expression in tumors of 81 patients with stage I-IV HNSCC treated with surgery alone or in combination with radiotherapy.

Results: We found a subgroup of patients with high MMP-13 expression level in their tumors (>/=90% MMP-13-positive tumor cells) associated with unfavorable prognosis (median overall survival [OS], 11.8 vs 19.6 months, p = .032). In addition, the median disease-specific survival (DSS) time was markedly reduced in this subgroup (13.8 months vs 40.7 months, p = .062). When the subgroup of patients treated with a curative intent was studied, the same association was found in OS (13.8 vs 24.6 months, p = .023) and DSS (p = .004). In addition, there was a trend for association between >/=90% MMP-13 positivity and a recurrent tumor (p = .078) in curatively treated patients.

Conclusions: The short survival time associated with high MMP-13 expression levels could not be predicted by tumor size or local lymph node invasion. These results show that a high MMP-13 expression level is associated with aggressiveness of HNSCC and may have prognostic value in patient evaluation.
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http://dx.doi.org/10.1002/hed.20322DOI Listing
March 2006

A role for ADAM12 in breast tumor progression and stromal cell apoptosis.

Cancer Res 2005 Jun;65(11):4754-61

Institute of Molecular Pathology, University of Copenhagen, Denmark.

As in developmental and regenerative processes, cell survival is of fundamental importance in cancer. Thus, a tremendous effort has been devoted to dissecting the molecular mechanisms involved in understanding the resistance of tumor cells to programmed cell death. Recently, the importance of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-0262DOI Listing
June 2005

Mammographic screening reduces risk of breast carcinoma recurrence.

Cancer 2005 Feb;103(3):474-82

Department of Internal Medicine, University Hospital, University of Turku, Turku, Finland.

Background: The current report is a long-term evaluation of breast carcinoma recurrence, factors predicting recurrence, and postrecurrence prognosis in relation to patients' use of service screening, which has been provided in Turku, Finland, since 1987 for women ages 40-74 years.

Methods: The current study included 527 invasive breast carcinomas: 418 in the screening group (which included screen-detected and interval malignancies) and 109 in the nonscreening group (which included breast carcinomas detected before initial screening and those detected in patients who chose not to undergo screening). These breast carcinomas were diagnosed among women ages 40-74 years between 1987 and 1993, with follow-up extending until the end of 2001.

Results: In the screening group, the risk of recurrence was only approximately half of the corresponding risk in the nonscreening group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.39-0.83; P = 0.003). Five years after the primary diagnosis, 16% of patients in the screening group and 28% of patients in the nonscreening group (P = 0.001) had experienced recurrence; 10 years after diagnosis, the corresponding rates were 21% and 34%, respectively (P = 0.001). Postrecurrence prognosis was comparable for both detection groups (HR, 1.17; 95% CI, 0.70-1.94; P = 0.551), with approximately half of all patients dying of disease 5 years after recurrence. Detection of breast carcinoma via a method other than mammographic screening was associated with a high risk of recurrence on univariate analysis. On Cox multivariate analysis, risk factors for recurrence included lobular histologic type (HR, 2.23; 95% CI, 1.44-3.48; P < 0.001), poor histologic grade (HR, 2.02; 95% CI, 1.20-3.39; P = 0.008), and large tumor size (HR, 1.60; 95% CI, 1.07-2.37; P = 0.021).

Conclusions: Long-term data from a population-based program demonstrated that mammographic screening reduced patients' risk of breast carcinoma recurrence. Specifically, the risk for patients with screen-detected disease was only approximately half of the risk for patients with non-screen-detected disease. Nonetheless, postrecurrence prognosis was comparable for patients in both detection groups.
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http://dx.doi.org/10.1002/cncr.20793DOI Listing
February 2005

Treatment of squamous cell carcinoma of the oral cavity, oropharynx and hypopharynx--an analysis of 174 patients in south western Finland.

Acta Oncol 2003 ;42(7):756-62

Department of Oncology and Radiotherapy, Turku University Central Hospital, Turku, Finland.

The purpose of this study was to determine the efficacy and feasibility of full-dose preoperative radiation therapy (RT) in head and neck cancer presenting in the oral cavity, oro- and hypopharynx, within a single university hospital district. During a seven-year period, 1989 to 1995, 174 patients with squamous cell carcinoma (SCC) of the oral cavity (OC, 70% of all patients), oropharynx (OP, 15%) and hypopharynx (HP, 15%) were referred to Turku University Central Hospital. All patients were seen by a tumor board consisting of an ENT (ear-nose-throat) head and neck surgeon, a radiation oncologist and a dentist. Potentially curative treatment was given to 142 patients. Of these, 88 (62%) had preoperative RT, 6 (4%) postoperative RT, 34 (24%) definitive RT and 14 patients (10%) were treated with surgery only. The radiation dose was > or = 50 Gy. averagely 64 Gy. The major endpoints of the study were local control, overall survival and major complications of the combined treatment. The 5-year relative survival rate (RSR) was 40% for all, and 43% for patients treated with curative intent. For these, the local control at 5 years was 60%; the disease-specific 5-year survival rate was 65% for the patients with lingual SCC, 45% for those with other oral tumor localizations. 64% for the oropharynx patients and 47% for those with tumor in their hypopharynx, while it was 55% for all patients. The preoperative radiotherapy was fairly well tolerated. Ten (7%) of the patients treated with curative intent suffered major complications, and four patients had evidence of osteoradionecrosis. With the exception of patients with early SCC the outcome remains rather poor in this group of cancer patients who often have marked co-morbidity. In our opinion, preoperative radiotherapy to a dose of 62-64 Gy can safely be given, and remains a feasible means to treat patients with oral, oropharyngeal or hypopharyngeal cancer.
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http://dx.doi.org/10.1080/02841860310010907DOI Listing
January 2004

Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha 7 integrin, utrophin and associated glycoproteins.

Hum Mol Genet 2003 Oct 5;12(19):2467-79. Epub 2003 Aug 5.

Institute of Molecular Pathology, University of Copenhagen, Frederik V's vej 11, 2100 Copenhagen, Denmark.

Mouse models for genetic diseases are among the most powerful tools available for developing and testing new treatment strategies. ADAM12 is a disintegrin and metalloprotease, previously demonstrated to significantly alleviate the pathology of mdx mice, a model for Duchenne muscular dystrophy in humans. More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase. In the present study we demonstrated that ADAM12 may compensate for the dystrophin deficiency in mdx mice by increasing the expression and redistribution of several components of the muscle cell-adhesion complexes. First, we analyzed transgenic mice that overexpress ADAM12 and found mild myopathic changes and accelerated regeneration following acute injury. We then analyzed changes in gene-expression profiles in mdx/ADAM12 transgenic mice compared with their littermate controls and found only a few genes with an expression change greater than 2-fold between mdx/ADAM12 and mdx. The small changes in gene expression were unexpected, considering the marked improvement of the mdx pathology when ADAM12 is overexpressed, and suggested that significant changes in mdx/ADAM12 muscle might occur post-transcriptionally. Indeed, by immunostaining and immunoblotting we found an approximately 2-fold increase in expression, and distinct extrasynaptic localization, of alpha 7B integrin and utrophin, the functional homolog of dystrophin. The expression of the dystrophin-associated glycoproteins was also increased. In conclusion, these results demonstrate a novel way to alleviate dystrophin deficiency in mice, and may stimulate the development of new approaches to compensate for dystrophin deficiency in animals and humans.
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http://dx.doi.org/10.1093/hmg/ddg264DOI Listing
October 2003

Effect of freezing on histologic grading of invasive ductal breast cancer.

Anal Quant Cytol Histol 2003 Feb;25(1):47-52

Department of Pathology, University of Turku, Kiinamyllynkatu 10, SF-20520 Turku, Finland.

Objective: To quantify the histologic changes caused by freezing during tissue processing and their influence on histologic malignancy grading as a prognostic factor in invasive ductal breast cancer.

Study Design: We studied frozen and nonfrozen formalin-fixed, paraffin-embedded samples of 18 cases of invasive ductal breast cancer. Features associated with histologic malignancy grading of breast cancer--i.e., nuclear pleomorphism, mitotic index and tubular differentiation--were assessed by quantitative morphometric methods.

Results: In our material, frozen samples consistently had a smaller mean nuclear profile area than nonfrozen samples (mean difference, 32%). Frozen nuclei were also clearly less symmetric and uniform in shape than non-frozen nuclei. Moreover, frozen samples had consistently higher mitotic indices than nonfrozen samples (mean difference, 66%, with the standardized mitotic index). Tubular differentiation, as expressed in fraction of fields with tubular differentiation, increased by 16% as a result of sample freezing.

Conclusion: According to our results of morphometric measurement in invasive ductal breast cancer, great caution should be exercised when prognostic conclusions are based on frozen tissue samples.
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February 2003

Quantitation of erbB2 positivity for evaluation of high-risk patients.

Ann Med 2002 ;34(7-8):544-53

Department of Pathology, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland.

Background: Because trastuzumab therapy is expected to be effective in a large fraction of erbB2 (HER-2/neu) overexpressing breast cancers, it is important to find the optimal method for evaluation of erbB2 positivity, and the patient group at greatest risk of dying without this therapy.

Aim: We evaluated erbB2 immunopositivity in breast cancer with the aim of finding a high-risk group for primary trastuzumab therapy.

Methods: Three hundred and seventeen samples were evaluated with an immunostaining index. Optimal cut point was systematically tested, and the effect of bcl-2 status on survival in the high-risk group was studied.

Results: Among N+ patients the index value 1.5 reflected the biggest difference in survival. There was a significant correlation between erbB2 positivity and bcl-2 negativity. ErbB2 was a prognosticator among postmenopausal, N+, and postmenopausal N+ patients. In multivariate analysis, erbB2 was the best prognosticator among postmenopausal N+ patients. Six out of seven N+ patients with erbB2 index 1.5 or above died including all postmenopausal patients. Bcl-2 positivity was associated with longer survival in the erbB2 positive patient group.

Conclusions: The most obvious patients for primary trastuzumab therapy in breast cancer are N+ patients with high erbB2 immunostaining index (> 1.5) and bcl-2 negative immunostaining. In our material 2% of all breast cancer patients fell in this category. This patient group should be selected for testing trastuzumab in the primary treatment.
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http://dx.doi.org/10.1080/078538902321117751DOI Listing
April 2003

ADAM12 alleviates the skeletal muscle pathology in mdx dystrophic mice.

Am J Pathol 2002 Nov;161(5):1535-40

Institute of Molecular Pathology, University of Copenhagen, Denmark.

Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850802PMC
http://dx.doi.org/10.1016/S0002-9440(10)64431-8DOI Listing
November 2002

ADAM 12 protease induces adipogenesis in transgenic mice.

Am J Pathol 2002 May;160(5):1895-903

Institute of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark.

ADAM 12 (meltrin-alpha) is a member of the ADAM (a disintegrin and metalloprotease) family. ADAM 12 functions as an active metalloprotease, supports cell adhesion, and has been implicated in myoblast differentiation and fusion. Human ADAM 12 exists in two forms: the prototype membrane-anchored protein, ADAM 12-L, and a shorter secreted form, ADAM 12-S. Here we report the occurrence of adipocytes in the skeletal muscle of transgenic mice in which overexpression of either form is driven by the muscle creatine kinase promoter. Cells expressing a marker of early adipogenesis were apparent in the perivascular space in muscle tissue of 1- to 2-week-old transgenic mice whereas mature lipid-laden adipocytes were seen at 3 to 4 weeks. Moreover, female transgenics expressing ADAM 12-S exhibited increases in body weight, total body fat mass, abdominal fat mass, and herniation, but were normoglycemic and did not exhibit increased serum insulin, cholesterol, or triglycerides. Male transgenics were slightly overweight and also developed herniation but did not become obese. Transgenic mice expressing a truncated form of ADAM 12-S lacking the prodomain and the metalloprotease domain did not develop this adipogenic phenotype, suggesting a requirement for ADAM 12 protease activity. This is the first in vivo demonstration that an ADAM protease is involved in adipogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850877PMC
http://dx.doi.org/10.1016/S0002-9440(10)61136-4DOI Listing
May 2002