Harry Kujari

Pure and mixed mucinous carcinomas of the breast: A clinicopathologic analysis of 61 cases with long-term follow-up

Sixty-one mucinous carcinomas (MCs) of the female breast were followed-up for at least 18 years or until death (mean follow-up time, 26 years; median follow-up time, 23 years). The 61 MCs were compared with 441 unselected cases of breast carcinomas of all histologic types (reference carcinomas or RCs), which were follow-up for at least 21 years. When the MCs were divided into pure (PMCs) and mixed (MMCs) mucinous carcinomas, the 20-year cumulative corrected survival rate for operable cases in the PMC group was 79% +/- 11% (SE) and 28% +/- 13% for the MMC group. The difference is statistically significant (P less than .001). The PMCs had a significantly better survival rate (P less than .001) when compared with the RCs (20-year corrected survival rate, 41% +/- 3%). The survival rates for the MMCs and RCs did not differ significantly from each other. By Coxs multivariate analysis, pure histologic type and a tumor size less than 5cm were independent favorable prognostic factors in the MC group, but nodal status was closely related to the histologic type. Judging from the relative survival curves, no significant excess mortality of cancer occurred toward the end of the follow-up period in the PMC group.

Expression of syndecan-1 in human placenta and decidua

Syndecan-1 is a cell surface heparan sulphate proteoglycan, which binds to the extracellular matrix (ECM), growth factors and antithrombin III. The early expression of syndecan-1 during mouse embryonic development suggests a potential role in the communication between the embryo and the ECM of decidua. Using immunohistochemical methods, the present study showed that the expression of syndecan-1 in the trophoblast cells changes along trophoblast differentiation. The syncytiotrophoblasts in the chorionic villi exhibited an apical expression of syndecan-1. This suggests that the expression is restricted to non-migrating, non-proliferating trophoblasts. The mode of syndecan-1 expression by human placental trophoblasts is independent of gestational age. The expression is not changed in miscarriages. In pre-eclampsia, the staining for syndecan-1 on the villous syncytiotrophoblast is weaker compared to normal pregnancy, but in placental bed the expression is similar. The unique apical localization of syndecan-1 in chorionic villi, not detected in any other tissues, suggests a potential role in fetomaternal communication probably via growth factor binding and in anticoagulation of intervillous circulation.

Effect of ocular pigmentation on pilocarpine pharmacology in the rabbit eye. II. Drug response

Abstract The time course of the miotic response of pilocarpine in albino and pigmented rabbit eyes was studied after ocular application of 0.11. 0.43, 0.85 and 2.30 mg doses in eye drops and 0.85 and 2.30 mg doses in polymer matrices. When administered in eye drops ocular pigmentation delayed the onset of the peak effect of the 3 smallest pilocarpine doses. The magnitude of the peak effect was lower in pigmented than in albino eyes after 0.11 and 0.43 mg doses, but equal after larger doses. Ocular pigmentation increased the relative biophasic availability of 0.85 and 2.30 mg doses of pilocarpine. This was due to the slower elimination rate of pilocarpine from pigmented tissues. The relative biophasic availability of 0.11 and 0.43 mg doses of pilocarpine was not affected by the ocular pigmentation, because of the opposite effects of lower peak effect and slower elimination rate on biophasic availability in pigmented eyes. The administration of pilocarpine in polymer matrices increased the relative biophasic availability of the drug. When administered in polymer matrices, pilocarpine showed a typical time course of prolonged pulse-entry of the drug into the eye.

Novel hydroxysteroid (17β) dehydrogenase 1 inhibitors reverse estrogen-induced endometrial hyperplasia in transgenic mice

Local estrogen production plays a key role in proliferative endometrial disorders, such as endometrial hyperplasia and cancer. Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) is an enzyme that catalyzes with high efficiency the conversion of weakly active estrone into highly potent estradiol. Here we report that female transgenic mice expressing human HSD17B1 invariably develop endometrial hyperplasia in adulthood. These mice also fail to ovulate and have enhanced peripheral conversion of estrone into estradiol in a variety of target tissues, including the uterus. As in humans, endometrial hyperplasia in HSD17B1 transgenic female mice was reversible on ovulation induction, which triggers a rise in circulating progesterone levels, and in response to exogenous progestins. Strikingly, a treatment with an HSD17B1 inhibitor failed to restore ovulation yet completely reversed the hyperplastic morphology of epithelial cells in the glandular compartment, although less so in the luminal epithelium. The data indicate that human HSD17B1 expression enhances endometrial estrogen production, and consequently, estrogen-dependent proliferation. Therefore, HSD17B1 is a promising new therapeutic target in the management of estrogen-dependent endometrial diseases.

Intra-Tissue Steroid Profiling Indicates Differential Progesterone and Testosterone Metabolism in the Endometrium and Endometriosis Lesions

CONTEXT Aberrant sex steroid signaling is suggested to promote endometriosis growth by several mechanisms, and the tissue concentrations of sex steroids are key determinants of the hormone action. However, their concentrations are only superficially known in the endometrium and endometriosis lesions. OBJECTIVE This study sought to evaluate whether the tissue steroid hormone concentrations in endometriosis differ from the endometrium or serum. MAIN OUTCOME MEASURES Steroid analysis of serum and tissue specimens of women with endometriosis (n = 60) and healthy controls (n=16) was measured, and supporting data from quantitative RT-PCR for steroidogenic enzymes and explant cultures of a subset of specimens is provided. RESULTS Endometrial tissue progesterone (P4) concentrations reflected the serum P4 levels during the menstrual cycle, whereas in endometriosis lesions, the cycle-dependent change was missing. Remarkably high tissue T concentrations were measured in endometriosis lesions independent of the cycle phase, being 5-19 times higher than the corresponding serum levels. Tissue/serum ratio of T was further increased in patients with contraceptive medication. The altered tissue steroid concentrations in endometriosis were in line with the expression of various steroidogenic enzymes in the lesions, of which HSD3B2 showed constantly high expression, whereas CYP11A1 expression was low. Furthermore, the high concentration of sex steroids detected in the ovarian lesions involves their production by the lesion and by the adjacent ovarian tissue. CONCLUSIONS Endometriosis lesions present with progestin and androgen metabolism, which are different from that of the endometrium, and the lesions are characterized by high tissue T and a loss of cyclical changes in tissue P4 concentration.

A flow cytometric analysis of 23 carcinoid tumors.

Twenty‐three carcinoid tumors were investigated from paraffin‐embedded tissue with flow cytometry (FCM) in order to correlate the DNA ploidy with clinical variables. DNA aneuploidy was found in ten tumors (45%) and one tumor was classified as tetraploid. Diurnal urinary excretion of 5‐hydroxy indolic acetic acid (5‐HIAA) was known to be elevated in seven of eight diploid tumors and in four of seven aneuploid carcinoids with distant metastases. Six (55%) of the diploid tumors had not given rise to metastases at the time of diagnosis, compared with three (30%) of the aneuploid tumors. Six of seven patients with an aneuploid tumor and three of five patients with a diploid tumor, observed for at least 10 years, died of the disease. It was concluded that, unlike in earlier studies with static DNA cytometry, DNA aneuploidy is common in human carcinoid tumors and may occur in tumors secreting biogenic amines.

Prolonged pulse-entry of pilocarpine with a soluble drug insert

Apparent biophasic availability of pilocarpine was studied in the eyes of albino rabbits. Pilocarpine doses of 0.85 and 2.30 mg in aqueous solutions, 1.00 mg in oil and 0.85 mg in a solid insert, were applied ocularly. The insert was a water soluble polyvinylpyrrolidone (PVP) matrix, which released 80% of its pilocarpine content in 35 min in vitro. In the inferior fornix of the eye this insert gelled in about 5 min and dissolved in 1 h. Pupillary diameters were measured and converted to values for the response parameter (RP). Time delay and magnitude of peak response, apparent biophasic availability (area under the curve of RP vs time), and a constant for the apparent rate of elimination were calculated from RP values.The time delay for the peak response was 16.3–24.0 min, and the constant for apparent rate of elimination was 0.69–0.81 h−1. Neither time delay nor this constant was affected by the dose or the dosage form. Magnitude of the peak response and apparent biophasic availability were influenced by the vehicle and the dose: insert (0.85 mg) > oily solution (1.00 mg) > aqueous solution (2.30 mg) > aqueous solution (0.85 mg). The insert and oily solution did not show vehicle-controlled drug absorption and can be regarded as prolonged pulse-entry medication.

Pharmacokinetics and metabolism of 2-[18F]fluoro-2-deoxy-d-glucose (FDG) in mammary tumors of antiestrogen-treated rats

Attempts are being made to evaluate 2-[18F]fluoro-2-deoxy-D-glucose (FDG) as a noninvasive marker of therapy response in malignant tumors. We studied rats with 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinomas by measuring the differential absorption ratio (DAR) and the metabolites of FDG in tumor homogenates. Half the rats were treated with the antiestrogen toremifene for 14 days and half were untreated. The histology of the tumors was studied by morphometry. The animals were killed 15, 45 or 240 min after injection. Regardless of whether the rats received toremifene or not, the fractional change in tumor volume correlated better with the DAR at 15 min [r = 0.284 (untreated) and r = 0.721 (treated)] and at 240 min [r = 0.932 (untreated)], than at 45 min [r = -0.137 (untreated) and r = 0.265 (treated)]. Inverse relations were found for the fraction of unmetabolized FDG and change in tumor volume [r = 0.070 (45 min) and r = -0.872 (240 min) for untreated tumors and r = -0.963 (15 min) and r = -0.715 (45 min) for treated tumors]. The DAR and the fraction of unmetabolized FDG correlated also [r = -0.420 (15 min), r = -0.647 (45 min) and r = -0.976 (240 min) for untreated tumors, and r = -0.963 (15 min) and r = -0.213 (45 min) for treated tumors]. No significant therapy-induced morphometrical changes were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of nitric oxide synthase in normal and preeclamptic placental tissue and effects of glyceryl trinitrate and shear stress on placental blood flow

BACKGROUND To study the expression of constitutively expressed nitric oxide synthase (cNOS) as well as the effects of glyceryl trinitrate (GTN) and shear stress on normal and preeclamptic placental tissue. METHODS The expression of cNOS was studied using NADPH diaphorase activity reaction in seven normal and four preeclamptic placentas. The effect of GTN (n = 5) and shear stress induced by increasing the flow rate in the perfusion system (n = 5) was studied using an in vitro placental perfusion method. RESULTS No difference in the distribution of cNOS in placental tissue was found between preeclamptic and normal pregnancies. Shear stress did not affect the production of nitric oxide metabolites. GTN was able to dilate placental vasculature. CONCLUSIONS cNOS derived from syncytiotrophoblasts may not contribute to the development of preeclampsia. Placental vasculature responds to nitric oxide by vasodilation.

Factors predicting late mortality from breast cancer

Survival data of a cohort of 160 patients with breast cancer, who were still alive 10 years after the primary diagnosis, and who had been followed up for at least 22 years, were investigated to find out those factors that predict late mortality from breast cancer. The 13 factors investigated included age at diagnosis, histological type and grade, mitotic count, type of tumour margin, inflammatory cell reaction, extent of tumour necrosis, primary tumour size, axillary nodal status, DNA ploidy and index, S-phase fraction and occurrence of a second primary breast cancer. Advanced age at diagnosis (greater than 49 years, P = 0.002), occurrence of a second primary breast cancer during the follow-up (P = 0.01), and primary tumour size (T3-4, P = 0.03) were significantly associated with mortality from breast cancer after the 10th year of follow-up in a multivariate analysis, and the ductal invasive histological type (P = 0.03) and a large DNA index (greater than 1.2; P = 0.06) in univariate analyses.