Cytopathology in Finland.
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Biopsy, Fine-Needle↗
Biomedical subjects
P Klemi
Publications and source records attributed to P Klemi.
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↗
Customer fee and participation in breast-cancer screening.
Until 1997, breast screening by mammography was free for all women living in Turku, Finland. After this date, women born in certain years had to pay to be screened. We did a retrospective study, using data obtained from Statistics Finland, to ascertain whether or not the introduction of a fee affected attendance. We also assessed the effect of socioeconomic status on attendance. Our findings show that people who had to pay for mammography attended less often than women who were entitled to free screening, irrespective of their socioeconomic status.
Adolescent↗
Macrophage migration inhibitory factor in the human endometrium: expression and localization during the menstrual cycle and early pregnancy.
Macrophage migration inhibitory factor (MIF) was discovered as an activated T-lymphocyte-derived protein that inhibits the random migration of macrophages in vitro. Subsequently, knowledge of the physiological actions of MIF was extended to include its role as a proinflammatory cytokine that affects several functions of macrophages and lymphocytes. Previous reports have suggested an involvement of MIF in reproduction. However, no data are currently available on the presence of this cytokine in the human endometrium. In this study, the expression and tissue localization of MIF was evaluated in specimens of cycling endometrium, first trimester placenta bed biopsy, and isolated endometrial glands by Western blot analysis, immunohistochemistry, ELISA, and reverse transcription-polymerase chain reaction. The results demonstrated that MIF is expressed in human endometrium across the menstrual cycle and in early pregnancy. Immunohistochemical localization identified the protein in glandular epithelium, in stromal and predecidualized stromal cells of cycling endometrium, as well as in the decidua of first-trimester placenta. The proinflammatory features and specific actions of MIF on lymphoid cells suggest its potential involvement in several aspects of endometrial physiology.
Blotting, Western↗
Expression of fibroblast growth factor (FGF)-8 isoforms and FGF receptors in human ovarian tumors.
FGF-8 is a mitogenic growth factor, which is widely expressed during embryonic development but only at a very low level in adult tissues. Alternative splicing of the human FGF-8 gene potentially allows coding for 4 protein isoforms (a, b, e, f), which differ in their transforming capacity. The FGF-8 isoforms preferentially activate the receptors FGFR1IIIc, FGFR2IIIc, FGFR3IIIc and FGFR4. FGF-8 is over-expressed in human breast and prostate cancers. Expression has also been found in RT-PCR studies of human ovarian and testicular cancers. The present study was undertaken to examine which FGF-8 isoforms are expressed in ovarian cancer and whether FGF-8 receptors are also expressed. Specimens from 5 normal human ovaries and 51 ovarian tumors (1 benign tumor, 8 borderline malignancies, 42 malignant tumors of different histopathological types) were studied by RT-PCR and immunohistochemistry. FGF-8 isoform b was expressed in all ovarian tumors and in all 7 ovarian-cancer cell lines studied. Isoform a was co-expressed in 9 malignant ovarian tumors. FGF-8 mRNA was not detected by RT-PCR of 3 normal ovary samples. Immunohistochemical staining localized FGF-8 protein to cancer cells. In general, the increased intensity of FGF-8 staining was associated with loss of differentiation within the tumors (Bowker's test, p = 0.37). FGF-8 staining of surface epithelium observed on 2 normal ovaries was very faint. RT-PCR showed that FGFR1IIIc, FGFR2IIIc and FGFR4 were the FGF-8 receptors expressed in normal ovaries and in ovarian tumors. FGF-8 receptor immunoreactivity was preferentially found in normal ovary surface epithelium and tumor cells but also in some stromal cells. Collectively, our results show that ovarian cancers of a wide variety of histological types expressing receptors for FGF-8 have acquired the capacity of expressing FGF-8. This suggests that FGF-8 has an important role in ovarian tumorigenesis.
Adult↗
Luteal function declines after laparoscopic sterilization by Hulka or Filshie clips.
We evaluated the influence of laparoscopic sterilization by Hulka or Fishie clips on corpus luteum function. Changes in corpus luteum function were evaluated in 46 women, before and after sterilization by Hulka (n = 22) or Filshie clips (n = 24). The mean age of the participants was 37 years (range 31-43 years). All women were healthy with regular menstrual cycles. Serum progesterone (P) was measured in one cycle before, and 3 and 12 months after the sterilization on cycle day 20-24. Endometrial biopsies were performed in the luteal phase before and one year after the procedure. The women measured the basal body temperature daily and kept a menstrual diary. The luteal phase P concentrations declined after the sterilization and the values were at the lowest level 3 months after the procedure (27.9 +/- 14.3 nmol/L vs. 18.7 +/- 13.4 nmol/L, = 0.0016). The values seemed to have recovered by 12 months (23.0 +/- 14.0 nmol/L, = 0.114 vs. baseline). Endometrium tended to be out-of-phase more frequently 1 year after the sterilization than before the surgery (= 0.065). Laparoscopic tubal sterilization is associated with an increased risk of luteal phase deficiency. However, the change may be only temporary in nature.
Adult↗
Association of syndecan-1 with tumor grade and histology in primary invasive cervical carcinoma.
OBJECTIVES: The expression of syndecan-1, a cell surface heparan sulfate proteoglycan, is reduced during malignant transformation of squamous cells. Studies on squamous cell carcinoma of the head and neck have shown that syndecan-1-positive tumors are associated with longer overall and recurrence-free survival. The purpose of this study was to analyze syndecan-1 expression in invasive cervical carcinoma and to examine the association of syndecan-1 expression with prognostic factors and overall survival. METHODS: The study population consisted of 124 patients treated for primary invasive carcinoma of the uterine cervix at the Turku University Central Hospital during the years 1970-1988. The material consisted of 102 (82.3%) squamous cell carcinomas, 16 (12.9%) adenocarcinomas and 1 (0.8%) adenosquamous carcinoma, 1 (0.8%) small cell carcinoma, 1 (0. 8%) adenoid basal carcinoma, 1 (0.8%) carcinosarcoma, and 2 (1.6%) unclassified cervical carcinomas. Syndecan-1 expression was determined on paraffin-embedded tissue blocks using a human syndecan-1-specific monoclonal antibody B-B4 and immunohistochemistry. The expression of syndecan-1 was classified according to staining intensity as well as the percentage of positively stained tumor cells. RESULTS: Staining intensity was strong in 44 (36%) samples, while 24 (19%) specimens remained syndecan-1-negative. In 49 (40%) samples, the percentage of syndecan-1-positive cells was >/=90%. Syndecan-1 expression, as determined by >/=50% positively stained tumor cells, was associated with the grade of differentiation (P = 0.03) and squamous histology (P < 0.001), but was not associated with clinical stage (P = 0.16) or disease-free survival (P = 0.86). Age (P = 0.003) and clinical stage (P < 0.001) were significant prognostic factors, but syndecan-1 expression determined neither by percentage of positively stained tumor cells nor by staining intensity was associated with the outcome. CONCLUSIONS: In cervical carcinoma syndecan-1 is associated with histological differentiation grade and squamous histology, but does not predict clinical outcome.
Adult↗
Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas.
Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by invading tumor cells in squamous cell carcinomas (SCCs) of the head and neck. Here, we have further elucidated the role of MMP-13 in tumor invasion by examining its expression in invasive malignant tumors of the female genital tract. Using in situ hybridization, expression of MMP-13 mRNA was detected in 9 of 12 vulvar SCCs, primarily in tumor cells, but not in intact vulvar epithelium, in cervical SCCs (n = 12), or in endometrial (n = 11) or ovarian adenocarcinomas (n = 8). MMP-13 expression was especially abundant in vulvar carcinomas showing metastasis to lymph nodes and was associated with expression of membrane type 1 MMP by tumor cells and gelatinase-A (MMP-2) by stromal cells, as detected by immunohistochemistry. MMP-13 mRNAs were detected in 9 of 11 cell lines established from vulvar carcinomas and in 4 of 6 cell lines from cervical carcinomas, whereas endometrial (n = 10) and ovarian (n = 9) carcinoma cell lines were negative for MMP-13 mRNA. No correlation was detected between MMP-13 expression and p53 gene mutations in vulvar SCC cell lines. However, MMP-13 expression was detected in 5 of 6 vulvar and cervical SCC cell lines harboring HPV 16 or 68 DNA. These results show that MMP-13 is specifically expressed by malignantly transformed squamous epithelial cells, including vulvar SCC cells, and appears to serve as a marker for their invasive capacity.
Adult↗
Radiosensitivity of dermal and tumor fibroblasts derived from the same patient.
The in vitro radiosensitivity of dermal fibroblasts has been found to vary between individuals, and a number of studies have also shown that this parameter correlates with radiation-induced late injuries in clinical radiotherapy. In addition, certain genetic disorders are known to effect radiosensitivity, e.g. normal tissues of patients homozygous or heterozygous for the ataxia teleangiectasia gene show unusual sensitivity to radiation both in vivo and in vitro. Thus, it has been assumed that there is a genetically determined component resulting in a certain intrinsic cellular radiation response in an individual. To study this possible relationship between different cells of a specific patient, we established eight pairs of dermal and tumor fibroblast cultures. The donor patients had either adenocarcinoma of the uterus or squamous cell carcinoma (SCC) of the head and neck. The radiosensitivity of these strains was determined by a 96-well plate clonogenic assay, previously used by us for radiosensitivity testing of cancer cells. From a paired comparison, the values for the cell fraction surviving 2.0 Gy (SF2), of both fibroblast strains, were found to be on the same level in five out of eight cases. In patient 6, the SF2 of tumor fibroblasts was significantly higher than that of dermal fibroblasts (P=0.0014). In two additional cases the tendency was the same, but not statistically significant. As groups, the two types of fibroblasts did not differ from each other, mean SF2 values of 0.24+/-0.07 and 0.21+/-0.05, respectively. The SF2 of tumor fibroblasts from SCC patients proved to be significantly higher than that of the adenocarcinoma patients (P=0.030). These preliminary results indicate that the in vitro radiosensitivity of tumor fibroblasts correlates with normal cell sensitivity in many cases, but not in all. The radiosensitivity of tumor fibroblasts also seems to follow the level of in vitro radiosensitivity determined for the corresponding histological type of tumor cells. Further studies are needed to determine more closely the relationship between the radiosensitivities of tumor cells and tumor fibroblasts, thus evaluating the possibility of testing radiosensitivity from tumor fibroblasts in order to estimate tumor response.
Adenocarcinoma↗
Human papillomavirus, Epstein-Barr virus, human herpesvirus 8 and human cytomegalovirus involvement in salivary gland tumours.
Human papillomaviruses (HPV) are involved in the etiology of both benign and malignant epithelial lesions. The occurrence of HPV types 16 and 18 in gynecological squamous cell carcinomas is also well known. Of the herpesviruses, Epstein-Barr virus (EBV) is associated with, for example, undifferentiated nasopharyngeal carcinoma, endemic Burkitt's lymphoma and immunoblastic lymphoma, and human herpesvirus 8 (HHV-8) with Kaposi's sarcoma. As little is known about the etiological factors of salivary gland tumours, the presence of HPV, EBV, HHV-8 and human cytomegalovirus (CMV) in these tumours were examined. Fresh tissue samples obtained from 19 consecutive pleomorphic adenomas and 19 malignant salivary gland tumours were analyzed with polymerase chain reaction. Two samples showed EBV DNA positivity, a lymphoma of the parotid gland and a pleomorphic adenoma arising in the nasal cavity. HPV, HHV-8 and CMV DNA were not detected in any of the tumour samples. The results indicate that HPV, HHV-8 and CMV do not seem to have any role in the etiology of salivary gland neoplasms.
Adult↗
Regulation of CD44v6-containing isoforms during proliferation of normal and malignant epithelial cells.
CD44 is a family of molecules involved in cell-cell and cell-matrix interactions. Various isoforms of CD44 arise by insertion of one or more of the variant exons into the common backbone shared by all forms of CD44. In this work, we studied the expression of CD44 and exon v6-containing CD44 isoforms (CD44v6) in several nonmalignant and malignant conditions and the possibilities for regulating the expression of CD44v6. In primary squamocellular carcinomas of the head and neck, CD44 and CD44v6 were down-regulated in poorly differentiated tumors, whereas these molecules were uniformly expressed in the normal squamocellular epithelium, in proliferating skin diseases, and in nonmalignant tumors. When CD44v6 expression of original tumors and that of squamocellular carcinoma cell lines derived from them were compared, no CD44v6 up-regulation could be observed on in vitro growing cells. Moreover, several regulators were unable to up-regulate CD44v6 expression on cultured cell lines in vitro. When the same cell lines formed tumors after s.c. injection into severe combined immunodeficient mice, some of them up-regulated their CD44v6 expression. These data suggest that cell lines at certain differentiation stages can be induced to express CD44v6. Our results further indicate that CD44v6 positivity cannot be used as a universal indicator of tumor metastasis. Instead, the down-regulation of CD44v6 in squamocellular tumors is a sign of malignant transformation of the epithelium.
Adult↗
Syndecan-1: a new prognostic marker in laryngeal cancer.
The cell adhesion molecule syndecan-1 expression is induced during keratinocyte differentiation and reduced during the formation of squamous cell carcinomas (SCCs). A significant correlation between decreased syndecan-1 expression in head and neck SCC measured from frozen sections with immuohistochemical methods and clinical outcome are reported. The clinical relevance of the cellular proliferation marker Ki-67 is controversial in SCC of the head and neck. The purpose of this study was to determine the expression of syndecan-1 and Ki-67 in SCC of the larynx and correlate the results with known prognostic factors and clinical outcome. Paraffin-embedded samples of 100 patients with laryngeal SCC (44 glottic, 36 supraglottic, 20 transglottic) treated at Turku University Central Hospital were re-examined and divided into four histological grades of differentiation, four grades of keratinisation, and four grades of 104-9 (syndecan-1) immunostaining. The mitotic index was analysed as the number of mitoses per volume corrected high power fields. The relative number of Ki-67 positive cells was evaluated. The patients mean age was 64 years and the 5-year survival was 69%. In univariate analysis, intermediate or strong staining for syndecan-1 was associated with higher overall survival than those tumours with no or little syndecan-1 expression (p = 0.048). Nodal status (p = 0.0001), tumour size (p = 0.0004) and localisation (p = 0.0008), general condition (p = 0.0001), histological grade (p = 0.02) and patient age (p = 0.03) correlated with overall survival whereas the Ki-67 index (p = 0.093), mitotic index (p = 0.23) and grade of keratinisation (p = 0.90) failed to do so. The results suggest that syndecan-1 could be a useful prognostic factor in SCC of the larynx.
Adult↗
Viruses and interstitial cystitis: adenovirus genomes cannot be demonstrated in urinary bladder biopsies.
Microbes may be involved in the pathogenesis of interstitial cystitis (IC). Adenoviruses and BK virus (BKV) can infect epithelial cells in urinary bladder and they are causative agents for hemorrhagic cystitis. We therefore studied the presence of adenovirus and BKV genomes in urinary bladder tissue specimens of patients with IC using polymerase chain reaction (PCR) and in situ hybridization (ISH). Controls were specimens from cases with transitional cell carcinoma of the bladder. Nucleic acids were extracted from paraffin sections of the bladder tissue for PCR. Primers detecting all adenovirus types were used. In situ hybridization was carried out for the paraffin sections using digoxigenin-labeled DNA probes for adenovirus and BKV. The adenovirus DNA PCR was able to detect one to two infected cells/specimen. All the seven IC cases studied and six controls were negative for adenovirus DNA by PCR and ISH. The ISH test for BKV genomes was also considered negative in IC cases and controls. The specimens which were negative in PCR tests yielded a signal with beta-globin primers, thus being amplifiable. We conclude that adenovirus and BKV do not play a major pathogenetic role in interstitial cystitis.
Adenoviridae↗
Pituitary and ovarian expression of the endogenous follicle-stimulating hormone (FSH) subunit genes and an FSH beta-subunit promoter-driven herpes simplex virus thymidine kinase gene in transgenic mice; specific partial ablation of FSH-producing cells by antiherpes treatment.
The ovarian expression of the endogenous follicle-stimulating hormone beta-subunit (FSH beta) and common alpha-subunit (C alpha) genes, and a herpes simplex virus thymidine kinase (tk) transgene, driven by a 2.3 kb bovine FSH beta promoter, was studied in normal and transgenic (tg) mice, tk functions not only as a neutral reporter that enables the study of the promoter function but also as an exogenously inducible toxigene. Reverse transcription-PCR followed by Southern blot hybridization with a nested probe was used to show the expression of the gene at the mRNA level. Common alpha-subunit mRNA was detected in the pituitary gland and ovaries of normal adult mice. We have previously detected endogenous FSH beta and tg tk mRNAs in the mouse pituitary, testis and ovary. In this study, the cellular localization of the corresponding proteins was visualized by immunocytochemistry. In normal mouse ovaries a positive reaction with FSH beta and C alpha antisera was seen in some of the corpora lutea and most prominently in the interstitial cells. A positive reaction with the tk antiserum was seen in the same cell types of tg mouse ovaries, but not in those of non-tg mice. Cell-ablation-inducing treatment (gancyclovir, 20 mg/kg per day, for 14 days) of tg female mice reduced pituitary FSH concentrations by 52% (P < 0.05) but did not affect pituitary LH or plasma gonadotropins compared with non-tg females treated in the same way. A longer period of cell ablation induction (acyclovir 400 mg/kg per day, for 21 days) reduced not only pituitary but also plasma FSH concentrations (55 and 57% respectively; P < 0.05) without affecting LH. This treatment also reduced ovarian weight by 38% (P < 0.01). In conclusion, our results show first that the endogenous FSH beta and C alpha proteins are produced in the mouse ovary. Hence, endogenously synthesized FSH or its subunits may have a role in the paracrine regulation of ovarian function. Secondly, the FSH beta promoter directs the expression of tg tk in the pituitary gonadotrope cells, as shown by specific but partial ablation of FSH-producing cells after induction by gancyclovir and acyclovir. In the ovary, tk protein was localized to the same compartments as the endogenous gonadotropin subunit proteins. This further confirms our finding of ovarian expression of the FSH subunit genes.
Acyclovir↗
Characterization and radiosensitivity of UT-EC-2A and UT-EC-2B, two new highly radiosensitive endometrial cancer cell lines derived from a primary and metastatic tumor of the same patient.
UT-EC-2A was established from a patient with moderately differentiated Stage III endometrial adenocarcinoma with squamous metaplasia. UT-EC-2B was established from the same patient 17 months later from a metastasis in the left supraclavicular fossa. The origin of these cell lines was confirmed by DNA identity testing. Nude mice tumors produced by UT-EC-2A and UT-EC-2B cells recapitulated the histology of the original human tumors. Flow cytometric DNA contents of both primary and metastatic human tumors as well as corresponding nude mice tumors were diploid. The S-phase fractions of both cell lines were > or = 30%. The UT-EC-2A cell line was cytogenetically normal. The UT-EC-2B cell line had quite simple karyotype at low passage with an extra i(18p) and a deletion 21q, but at higher passages an additional three-way translocation 5;14;19 was observed. Radiosensitivity of the cell lines was tested with the 96-well plate clonogenic assay. The areas under the survival curves corresponding to the mean inactivation doses of UT-EC-2A and UT-EC-2B were 0.65 +/- 0.10 and 0.60 +/- 0.06 Gy, respectively. Measured survival at 2.0 Gy (SF2) was 0.042 for UT-EC-2A, 0.044 for UT-EC-2B, and 0.2 for skin fibroblasts. These cell lines are among the most radiosensitive human cancer cell lines described in the literature. Studying the characteristics of primary and metastatic cells derived from the same patient provides an opportunity to evaluate tumor progression.
Adenocarcinoma↗
Squamous cell carcinoma is highly sensitive to taxol, a possible new radiation sensitizer.
We studied the sensitivity of seven cell lines established from laryngeal carcinoma to the cytotoxic drug paclitaxel (Taxol) in vitro. In all four cell lines tested for growth inhibition, paclitaxel reduced growth at low concentrations, and in two cell lines growth was completely inhibited at a paclitaxel concentration of only 1 x 10(-8) M. Flow cytometric data showed a G2/M block in all seven cell lines after exposure to paclitaxel for 24 h at a concentration of 1 x 10(-8) M. This concentration is about one-one hundredth fold smaller than those measured in serum after a single intravenous dose of about 200 mg/m2. The high in vitro sensitivity of laryngeal cancer cell lines to paclitaxel,and the G2/M block suggest that the drug may potentially be used in conjunction with radiotherapy.
Carcinoma, Squamous Cell↗
Relation of DNA ploidy and proliferation rate to radiation sensitivity in squamous carcinoma cell lines.
OBJECTIVE: According to some clinical reports, DNA aneuploidy of squamous cell carcinomas is related to a more favorable response to radiotherapy than DNA diploidy, but it is not known whether this depends on differences in intrinsic cellular radiation sensitivity or on other factors involved during the course of radiotherapy. DESIGN: Using flow cytometry, we analyzed 30 newly established squamous carcinoma cell lines derived from head and neck carcinoma, and compared the nuclear DNA content with the inherent radiosensitivity and with the average doubling time determined from the in vitro growth curves. RESULTS: The nuclear DNA content expressed as the ratio between the Go/G1 peak of the cell line and the peak formed by chicken red blood cells varied from 3.13 to 6.41. The DNA content of cells obtained from nonmalignant lesions by fine-needle aspiration biopsy was from 2.66 to 2.80. No correlation was found between the nuclear DNA content and the inherent radiosensitivity of the carcinoma cells. CONCLUSIONS: The result suggests that the intrinsic cellular radiosensitivity of carcinomas does not increase in parallel with an increasing nuclear DNA content. Nor does the in vitro proliferation rate associate with either the nuclear DNA content or inherent radiosensitivity.
Biopsy, Needle↗
Magnetic resonance imaging of the uterus in vivo and in vitro at an ultra low magnetic field (0.02 T): assessment of its normal structure and of leiomyomas.
The purpose of this investigation was to analyze the normal anatomy and leiomyomas of the uterus with an ultra low field (0.02 T) magnetic resonance imaging (MRI) device. MR imaging was performed on 18 uteri, 11 of which were imaged both preoperatively (in vivo) and as an operative specimen (in vitro), 6 only as an operative specimen, and 1 only preoperatively. All uteri were examined histologically after imaging. The junctional zone was much better delineated in vivo than in vitro, indicating that its appearance on MR is partly due to blood flow. No structures contributing to its visibility in vitro could be demonstrated histologically. Twenty leiomyomas (size range 7-79 mm) in 12 uteri were found with MRI. They were slightly better discerned in vivo than in vitro. The leiomyomas, having no degenerative changes, had a signal intensity which was the same or lower than that of the myometrium. On images obtained in vitro the signal intensity of these leiomyomas relative to that of myometrium correlated directly with their muscular content (R = 0.74, p = .002). The authors conclude that the junctional zone is a sum of physiological and structural factors, the latter being responsible for its in vitro delineation. MR imaging of the uterus in vitro did not give more information than MR imaging in vivo. All leiomyomas larger than 10 mm could be detected, indicating that MR imaging at 0.02 T is an accurate method for the imaging of the uterine leiomyomas.
Female↗