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T Kuopio

Publications and source records attributed to T Kuopio.

At least 19 recordsLinked to original sources
PubMed2006

Lymph node status as a guide to selection of available prognostic markers in breast cancer: the clinical practice of the future?

Prognosticators evaluating survival in breast cancer vary in significance in respect to lymph node status. Studies have shown e.g. that HER2/neu immunohistochemistry or HER2/neu gene amplification analysis do perform well as prognosticators in lymph node positive (LN +) patients but are less valuable in lymph node negative (LN -) patients. We collected data from different studies and tried to evaluate the relative significance of different prognosticators in LN+/LN- patient groups. In LN+ patients HER2/neu and E-cadherin immunohistochemistry were the statistically most significant prognosticators followed by proliferation associated features (mitotic counts by SMI (standardised mitotic index) or MAI (mitotic activity index), or S-phase fraction). Bcl-2 immunohistochemistry was also significant but p53 and cystatin A had no significance as prognosticators. In LN- patients proliferation associated prognosticators (SMI, MAI, Ki-67 index, PCNA immunohistochemistry, S-phase fraction) are especially valuable and also Cathepsin D, cystatin A, and p53 are significant, but HER2/neu or bcl-2, or E-cadherin less significant or without significance. We find that in studies evaluating single prognosticators one should distinguish between prognosticators suitable for LN+ and LN- patients. This will allow the choice of best prognosticators in evaluating the prospects of the patient. The distinction between LN+ and LN- patients in this respect may also be of special value in therapeutic decisions.

Journal Article↗
PubMed2006

Role of mammography screening as a predictor of survival in postmenopausal breast cancer patients.

We examined the effect of population-based screening programme on tumour characteristics by comparing carcinomas diagnosed during the prescreening (N=341) and screening (N=552) periods. We identified screen detected (N=224), interval (N=99) and clinical cancer (N=229) cases. Median tumour size and proportion of axillary lymph node negative cases were 1.5 cm and 65% in the screen detected group, 2.0 cm and 44% in cases found outside the screening, and 3.2 cm and 41% in the cases from the prescreening period. Survival of the breast cancer patients was 66% (95% CI, 60-71%) in the prescreening era group and 73% (95% CI, 66-78%) in the screening era group after 10 years of follow-up. In the screening era group the survival of the screen detected cases was 86% (95% CI, 80-90%) and that of the clinical cancer cases 73% (95% CI, 66-78%) after 10 years. In multivariate analysis the risk of breast cancer death was not significantly different between the prescreening and screening periods (HR 0.82; 95% CI 0.59-1.12, P=0.21). Detection by screening was not an independent prognostic factor in multivariate analysis (HR 0.75; CI 95% 0.50-1.12; P=0.17).

Aged↗
PubMed2006

Ki67 immunohistochemistry: a valuable marker in prognostication but with a risk of misclassification: proliferation subgroups formed based on Ki67 immunoreactivity and standardized mitotic index.

AIMS: Counting mitotic figures is considered to be a reliable prognosticator, but evaluation of Ki67 immunohistochemistry has become more popular in evaluating proliferation. Our previous studies suggested an occasional discrepancy between mitotic figures and Ki67 fraction. The aim of this study was to investigate this more closely and also to study the associations between bcl-2 and p53 expression and proliferation. METHODS AND RESULTS: Two hundred and sixty-five infiltrating breast carcinomas were immunostained for Ki67, p53 and bcl-2. The standardized mitotic index (SMI) was determined. Four proliferation groups were based on Ki67 positivity fraction and SMI at optimal cut-off points. Cox's multivariate model was used to test the power of the prognosticators. SMI and nodal status were the most powerful individual prognosticators. Ki67 was an independent prognosticator if nodal status, tumour size, age and histological grade were included in the analysis but not if analysed with SMI. The group with low SMI and low Ki67 fraction had the best prognosis. Groups with high SMI had the poorest prognosis. The group with low SMI and high Ki67 fraction had a favourable prognosis. Bcl-2 negativity and p53 positivity correlated with proliferation. CONCLUSIONS: We have found a 'wrong positive' Ki67 group with favourable prognosis. SMI cannot be replaced by Ki67 because of the danger of misclassification of some patients.

Adult↗
PubMed2004

Predicting aggressive outcome in T1N0M0 breast cancer.

Despite the excellent overall prognosis, unpredictable breast cancer recurrences and deaths also occur among T1N0M0 patients. We have evaluated clinically applicable methods for identifying aggressive outcome in T1N0M0 breast cancer. The material is based on aggressive T1N0M0 invasive ductal and lobular carcinomas diagnosed in Turku University Hospital and Jyväskylä Central Hospital, Finland, during 1987-1997. We studied all the T1N0M0 breast cancers that had led to recurrency or death (n=21, 95% T1cN0M0) during the follow-up period (4-14 years). The study is based on statistical analyses of matched case-control data in which the prognostic factors of each individual patient with aggressive disease were compared with control patients (n=45) individually matched by tumour size, age at diagnosis, histological type of tumour and length of follow-up. The cancer cases were examined for clinically applicable conventional and immunohistochemical pathologic prognostic factors. High Ki-67 immunopositivity was the strongest prognosticator of breast cancer death or recurrence in T1N0M0 breast cancer. Also, high p53 immunopositivity, low oestrogen receptor immunopositivity and Her-2/neu oncogene amplification by chromogen in situ hybridisation were reliable indicators of unfavourable outcome. Our statistical methods also allowed us to determine for the present material a range of clinical significance for each immunohistochemical prognostic feature with the associated relative risk for breast cancer death and recurrence. The paper suggests guidelines for predicting aggressive outcome in T1N0M0 breast cancer.

Adult↗
PubMed2002

Morphometrical malignancy grading is a valuable prognostic factor in invasive ductal breast cancer.

The aim of the present study is to augment the prognostic power of breast cancer grading by elaboration of quantitative histopathological methods. We focus on the recently introduced morphometrical grading system in which the three grading sub-features of the WHO grading system are evaluated with the help of computerised nuclear morphometry, and quantitative methods for assessing mitotic activity and tubular differentiation. The prognostic value of the morphometrical grading system is now confirmed in a material of 159 cases of invasive ductal breast cancer. In the current material the morphometrical grading system very efficiently predicted the prognosis of breast cancer by dividing the patients into favourable (grade I), intermediate (grade II), and unfavourable (grade III) outcome (P<0.0001). The morphometrical grading system was especially efficient in identifying patients with the most unfavourable outcome. In our material the morphometrical grade III was associated with a 5.4-fold risk of breast cancer death. In light of the present results, the morphometrical grading can be applied to clinical use as an aid in treatment decisions of patients with invasive ductal breast cancer.

Adult↗
PubMed2002

Prognostication of invasive ductal breast cancer by quantification of E-cadherin immunostaining: the methodology and clinical relevance.

AIMS: We tried to improve the evaluation of E-cadherin immunostaining in paraffin sections, to distinguish the less aggressive variants of ductal infiltrating breast cancer from other variants. METHODS AND RESULTS: The method graded the membrane staining and estimated the fraction of area of cancer tissue stained at the respective staining grade, resulting in an immunohistochemical staining index. At the cut-point 0.35 the index divided all 157 patients (P=0.0188), and 57 node-positive patients (P= 0.0006) into two groups of different survival. In multivariate analysis (all patients) E-cadherin immunoscore was inferior to mitotic index (SMI) (P=0.0002), but still significant (P=0.0031). Among node-positive patients E-cadherin was even more powerful and superior (P=0.0001) to the still significant SMI (P=0.0023), and E-cadherin immunostaining and the mitotic activity (SMI) combined did not need the support of other prognosticators in the Cox model. CONCLUSIONS: The study suggests that E-cadherin immunostaining can be used efficiently in finding patients with favourable outcome among node-positive patients.

Adult↗
PubMed2002

Proliferation in African breast cancer: biology and prognostication in nigerian breast cancer material.

Three hundred cases of invasive breast carcinoma from the University of Calabar Teaching Hospital, Nigeria were subjected to evaluation of proliferative activity by mitotic counts. The prognostic significance and association with other prognostic factors were evaluated. The mitotic activity was expressed as mitotic activity index (MAI), and standardized mitotic index (SMI). Pearson's correlation and univariate and multivariate Cox's regression were used. The mean follow-up time was 25.9 months. The mean values of SMI and MAI were 42.6 mitotic figures per square millimeter and 30.5 mitotic figures per 10 high-power fields, respectively, and these were much higher than values reported for Europe or other Western countries. The SMI had a positive correlation with tumor size (r = 0.31, P <.0001), histologic grade (r = 0.68, P <.0001), nuclear area (r = 0.45, P <.0001), and negative correlation with fraction of fields with tubular differentiation (FTD; r = -0.56, P = <0.0001). There was no statistically significant difference in the mitotic activity between the postmenopausal and the premenopausal patients. Also, lymph node-positive patients had higher counts than did lymph node-negative patients. Earlier determined grading associated decision thresholds divided the patients into groups of favorable and unfavorable prognosis. However, the statistically optimal thresholds for Nigerian material were different (32 and 92 mitotic figures per square millimeter for SMI). Tumor size of 5 cm, SMI, and MAI were independent prognostic factors. Nigerian breast cancers are high-grade, high-stage, and high-proliferating cancers occurring in a younger population than those of the Western countries. Proliferation is also more active. Evaluation of SMI or MAI can improve the distinction between aggressive and less aggressive variants of breast cancer.

Adolescent↗
PubMed2001

Time course of female-to-male sex reversal in 38,XX fetal and postnatal pigs.

In an attempt to understand the etiology of intersexuality in pigs, we thoroughly analyzed the gonads of 38,XX (SRY negative) female to male sex-reversed animals at different developmental stages: during fetal life [50 and 70 days postcoitum (dpc)], just after birth [35 days postpartum (dpp)] and during adulthood. For each animal studied, we performed parallel histological and ultrastructural analyses on one gonad and RT-PCR analysis on the other gonad in order to define the expression profiles of sexually regulated genes: SOX9, 3beta-HSD, P450 aromatase, AMH, FOXL2, and Wnt4. Light and electron microscopic examination showed that testicular cords differentiated in XX sex-reversed gonads but were hypoplastic. Although the testicular cords contained gonia at the fetal stages, the germ cells had all died through apoptosis within a few weeks after birth. Ultrastructurally normal Leydig cells also differentiated, but later, and enclosed whorl-like residual bodies. At the fetal stages, three of the six genes studied in the intersex gonads presented, as early as 50 dpc, a modified expression profile corresponding to an elevated expression of SOX9 and the beginning of AMH and P450 aromatase gene transcription. In addition to genes involved in the testicular pathway, the same gonads expressed FOXL2, an ovarian-specific factor. The ovaries of true hermaphrodites were ineffective in ensuring correct folliculogenesis and presented abnormal expression profiles of ovarian specific genes after birth. These results indicate that the genes involved in this pathology act very early during gonadogenesis and affect the ovary-differentiating pathway with variable expressivity from ovarian germ cell depletion through to trans-differentiation into testicular structures.

Animals↗
PubMed2001

Decorin is produced by capillary endothelial cells in inflammation-associated angiogenesis.

Decorin is a small extracellular chondroitin/dermatan sulfate proteoglycan that has previously been shown to be involved in the angiogenesis-like behavior of endothelial cells (ECs) in vitro. There is also evidence that decorin plays a role in angiogenesis in vivo. In this study we sought to further explore the involvement of decorin in angiogenesis in vivo, especially in that associated with inflammation. We found by CD31 immunostaining of ECs that in giant cell arteritis there are capillary blood vessels not only in the adventitia as in uninvolved temporal artery wall, but also in the media and the external zone of the thickened intima. Localization of decorin by antiserum LF-30 in adjacent sections showed that in normal temporal artery wall decorin resides mainly in the media and the adventitia, whereas in inflamed temporal artery wall decorin is distributed throughout the vessel wall including the intima. Furthermore, the most intense reaction for decorin was evident in ECs of capillary neovessels within the media and the thickened intima of inflamed temporal artery wall. Decorin was also found in capillary ECs in certain pathological and physiological conditions in which the pivotal role of angiogenesis is more generally accepted. Pyogenic granulomas, granulation tissue of healing dermal wounds, and ovaries at different phases of follicle and corpus luteum formation all contained widely distributed CD31-positive capillaries. Decorin, on the other hand, was found in capillary ECs in pyogenic granulomas and granulation tissue, but not in those in the ovaries. The assessment of the degree of inflammation in the specimens with the presence of CD68-positive macrophages showed that the pyogenic granuloma, granulation tissue, and giant cell arteritis specimens were rich in macrophages around the decorin-positive capillaries. In contrast, the ovarian specimens were populated with fewer macrophages and even they were not located in close vicinity of capillaries negative for decorin. Our results confirm that decorin is involved in angiogenesis in vivo and, particularly, in conditions in which the inflammatory component is dominant.

Adult↗
PubMed2000

Quantitative thresholds for mitotic counts in histologic grading: confirmation in nonfrozen samples of invasive ductal breast cancer.

Increasing evidence in the medical literature suggests that freezing a sample before fixation causes changes in the histologically observed mitotic activity. In a recent study we determined quantitative thresholds for mitotic counts in invasive ductal breast cancer in both nonfrozen and frozen formalin-fixed specimens. Survival- and recurrence-based analyses of this study material indicated grading thresholds of 17 and 32 mitoses/mm(2) for standardized mitotic index (SMI) and 13 and 35 mitoses/10 high-power fields for mitotic activity index (MAI). The purpose of the present study is to confirm and adjust the introduced thresholds in only nonfrozen formalin-fixed samples. The SMI and MAI in 202 cases of nonfrozen formalin-fixed samples were analyzed to determine optimal cutpoints for prognostication of invasive breast cancer on the basis of mitotic activity. The SMI thresholds were identical in both the present nonfrozen specimens and the previous combined specimens. The optimal MAI thresholds in the nonfrozen material changed to 11 and 37 mitoses/10 high-power field. The confirmation and adjustment of the mitotic thresholds improved the prognostic significance of the method in the nonfrozen material, which will contribute to the clinical applicability of a morphometric grading system.

Adult↗
PubMed2000

Morphometric grading of breast cancer: thresholds for tubular differentiation.

We evaluated the degree of tubular differentiation in 172 samples of invasive ductal breast cancer in order to determine numerical thresholds for histological breast cancer grading. The tubular differentiation in each sample was defined as the fraction of fields showing tubular differentiation (FTD). The analysis was based on Kaplan-Meier curves reflecting survival and recurrence of disease, univariate and multivariate analyses of Cox's regression, and maximum efficiencies of ROC analysis. The minimum P-value cut-off for FTD was determined at 59%. The practical interpretation is that tubular differentiation in the neoplasm observed in at least 60% of microscopical fields in the tumour area indicates favourable prognosis of disease. The relative risks for breast cancer death for patients with FTD below 59% as compared with those with FTD above 59% were 6.7--and 6.3-fold (univariate and multivariate analyses respectively). Another threshold could be determined at FTD 23%, although this threshold was associated with clearly lower statistical significancies. The paper introduces two possible solutions for application of the thresholds to the morphometric breast cancer grading system. The study also emphasizes the clinical relevance of the evaluation of tubular differentiation in breast cancer. The consistent morphometric evaluation method was vital in allowing the full weight of the biological significance of tubular differentiation to emerge.

Adenocarcinoma↗
PubMed2000

Nuclear size and shape in fine needle aspiration biopsy samples of the prostate.

OBJECTIVE: To study the potential of nuclear size and shape estimates in interpreting fine needle aspiration biopsy (FNAB) samples of the prostate. STUDY DESIGN: Morphometry was used to outline nuclei of prostate cells. Cell groups were selected by an experienced cytologist. RESULTS: The mean area of nuclei in the most atypical cell groups among definitely malignant samples (n = 17) varied from 26.3 to 93.3 micron 2 and in normal prostate cells (n = 10) from 15.6 to 33.7 micron 2. Perfect distinction of definitely benign and slightly atypical samples (n = 13) from definitely malignant samples was possible when the samples were characterized by the weighted means of the mean nuclear areas of the cell groups in the samples. The means of individual cell groups allowed correct distinction in only 84.8% of cell groups. Shape factors did not have any diagnostic value. CONCLUSION: Morphometric nuclear size estimates from ethanol-fixed FNAB samples of the prostate are of diagnostic value and can potentially be used as part of multivariate diagnostic models when selected by an experienced cytologist according to strict criteria. However, measurement should be done from several cell groups (at least three of the most-atypical cell groups) in each sample.

Adenocarcinoma↗
PubMed1999

Immunohistochemical labelling for prostate-specific antigen in breast carcinomas.

Immunohistochemical detection of prostate-specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non-prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma. Sections of formalin-fixed, paraffin-embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow-up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32%) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA-negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.

Adult↗
PubMed1999

Characterization of the model for experimental testicular teratoma in 129/SvJ-mice.

An animal model of experimental testicular teratoma has been established to study how a teratoma affects the host testis and how the host testis reacts against the teratoma. 129/SvJ-mice were used as experimental animals. To induce the experimental testicular teratoma, male gonadal ridges from 12-day-old 129/SvJ-mouse fetuses were grafted into the testes of adult mice for 1-12 weeks. The developing tumour was analysed by light and electron microscopy and by immunocytochemical localization of transcription factors SOX9 and c-kit, glial fibrillary acidic protein (GFAP) and type IV collagen. Testicular teratoma was observed in 36 out of 124 testes with implanted fetal gonadal ridges (frequency 29%). One spontaneous testicular teratoma was observed in this material from 70 male mice (1.5%). One week after implantation intracordal clusters of cells were seen in embryonic testicular cords of the graft as the first sign of testicular teratomas. Four weeks after implantation the embryonic testicular cords had totally disappeared from grafts with teratomas, and the tumour tissue had enlarged the testis and invaded the interstitium of the host testis. It consisted of solitary pieces of immature cartilage as well as of glial cells and of primitive neuroepithelium. Six to eight weeks after implantation the tumour tissue had expanded so that the enlarged testis could be detected by macroscopic enlargement of the scrotum. The testicular tissue of the host had practically disappeared, and only solitary disrupted seminiferous tubules of the host were seen surrounding the teratoma. Neuroepithelial structures of some teratomas cultured for 8 weeks had cells with a granular nucleus as a sign of obvious apoptosis. Eleven to 12 weeks after implantation the growth of the teratoma had stopped, and the histology corresponded to that of a mature cystic teratoma. GFAP, SOX9 and type IV collagen were strongly positive in some parts of the tumours cultured for 4 and 8 weeks, while only occasional c-kit-positive areas were observed in tumours cultured for 8 weeks. As conclusions: (1) the metastasizing capacity of the experimental testicular teratoma is very low during 12 weeks, but the behaviour of the tumour in the testicular tissue of the graft is invasive; (2) the growth of experimental testicular teratomas cease 6-8 weeks after implantation of the fetal gonadal ridges with the obvious apoptosis of the immature tissue components; (3) the model of experimental testicular teratoma in the mouse is suitable for studying how the teratoma affects the host testis and how the host testis reacts to teratoma.

Animals↗
PubMed1999

The fraction of fields showing neoplastic tubules: a practical estimate of tubular differentiation in breast cancer.

AIMS: The purpose of the study is to evaluate histological measurement methods for quantitative assessment of the degree of tubular differentiation in breast cancer. METHODS AND RESULTS: We evaluated tubular differentiation in 20 cases of invasive breast cancer by four different assessment methods. Method 1 was the traditional subjective evaluation of the amount of malignant tubules in each sample. Method 2 evaluated the fraction of fields presenting tubular differentiation by registering the presence or absence of neoplastic tubular structures in each microscopic field. In method 3 the area fraction of malignant epithelial cells presenting tubular differentiation was assessed field-by-field and expressed as an average of the whole tumour area. Method 4 applied point counting for evaluating the fraction of malignant epithelial cells in tubular structures. By correlation and reproducibility analyses, method 1 was inferior to the other methods. Method 4 was accurate but too laborious and time-consuming for clinical use. Methods 2 and 3 were both efficient and reproducible and could be used interchangeably. With the time and effort used in the measurements taken into consideration method 2 was best applicable to clinical practice. CONCLUSION: Accurate evaluation of tubular differentiation in breast cancer is possible by defining the presence or absence of tubular differentiation in microscopic fields of a histological section. Assessment of the fraction of fields with tubular differentiation (FTD) is simple, unambiguous, objective and fast--even a large sample can be screened in less than 10 min. In our results, FTD has clear advantages over subjective or point counting-based evaluation methods of tubular differentiation.

Breast Neoplasms↗
PubMed1999

Influence of sampling practices on the appearance of DNA image histograms of prostate cells in FNAB samples.

Twenty-one fine needle aspiration biopsies (FNAB) of the prostate, diagnostically classified as definitely malignant, were studied. The Papanicolaou or H&E stained samples were destained and then stained for DNA with the Feulgen reaction. DNA cytometry was applied after different sampling rules. The histograms varied according to the sampling rule applied. Because free cells between cell groups were easier to measure than cells in the cell groups, two sampling rules were tested in all samples: (i) cells in the cell groups were measured, and (ii) free cells between cell groups were measured. Abnormal histograms were more common after the sampling rule based on free cells, suggesting that abnormal patterns are best revealed through the free cells in these samples. The conclusions were independent of the applied histogram interpretation method.

Biopsy, Needle↗
PubMed1998

Cellular and molecular changes during sex differentiation of embryonic mammalian gonads.

Structural and molecular changes during sex differentiation and development of mammalian gonads from early embryonic phase until sexual maturity have been studied by morphologic and immunocytochemical methods in vivo and in experimental culture. The strategy has been to identify cellular macromolecules whose genes are differently expressed in the two sexes and to formulate a hypothetical regulatory chain of sex determination. This approach should provide new possibilities for finding the missing links between the final structural genes and the early regulatory genes, which are differentially expressed before and during gonadal differentiation. On the basis of accumulated structural and molecular evidence, the early epithelial differentiation from the precursor cells via cell aggregates to testicular cords or ovarian follicles is not sexually regulated. The biological consequences of sex determination in the differentiation of the genital organs include changes in the pattern formation of the gonadal epithelia and concomitant alterations in the synthesis and organization of the structural macromolecules.

Animals↗