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Biomedical subjects

S Manek

Publications and source records attributed to S Manek.

At least 19 recordsLinked to original sources
PubMed2006

Role of lymphangiogenesis in epithelial ovarian cancer.

We investigated the significance of lymphatic count, vascular count and angiogenic growth factors using immunohistochemistry in 108 tumour specimens of epithelial ovarian cancer with antibodies to lymphatic vessel endothelial hyaluronan receptor (LYVE-1), platelet endothelial cell adhesion molecule CD31, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) in epithelial ovarian cancer to understand the pathogenesis of metastasis in ovarian cancer. The effect of prognostic variables on progression-free and overall survival was assessed. On multivariate analysis, bulky residual disease after surgery was the best prognostic indicator (P<0.001) for progression-free and overall survival (P<0.001). Lymphatic count was statistically significant as a prognostic factor for progression-free (P=0.05) and overall survival (P=0.04). However, lymphatic count did not impact on survival curves. No correlation was found between lymphatic count and age, histological subtype, FIGO stage or residual disease. Vascular count, VEGF or TP expressions were not significant in either analysis. Lymphatic spread may be significant in aiding metastases in ovarian cancer but requires other biological factors to act in conjunction, as it does not have clearcut prognostic significance. Dissemination of ovarian cancer does not occur primarily through vascular or lymphatic routes but may occur through direct intraperitoneal spread of disease.

Adult↗
PubMed2006

Jaw1/LRMP, a germinal centre-associated marker for the immunohistological study of B-cell lymphomas.

Jaw1, also known as lymphoid-restricted membrane protein (LRMP), is an endoplasmic reticulum-associated protein. High levels of Jaw1/LRMP mRNA have been found in germinal centre B-cells and in diffuse large B-cell lymphomas of 'germinal centre' subtype. This paper documents Jaw1/LRMP expression at the protein level in human tissues by immunohistochemical and western blotting analysis using an antibody reactive with paraffin-embedded tissues. Jaw1/LRMP was highly expressed in germinal centre B-cells (in keeping with gene expression data), in 'monocytoid B-cells', and in splenic marginal zone B-cells. It was absent, or present at only low levels, in mature T-cells, although cortical thymocytes were weakly positive. Among lymphoid neoplasms, Jaw1/LRMP was found in germinal centre-derived lymphomas (follicle centre lymphoma, Burkitt's lymphoma, lymphocyte-predominant Hodgkin's disease) but not in T-cell neoplasms (with the exception of a single T lymphoblastic lymphoma). Classical Hodgkin's disease and myeloma lacked Jaw1/LRMP but many cases of chronic lymphocytic leukaemia (but not mantle zone lymphoma) were Jaw1/LRMP-positive. Approximately half of the marginal zone lymphomas were Jaw1/LRMP-positive. In diffuse large B-cell lymphomas, Jaw1/LRMP was found in three-quarters (24/32) of the cases classified phenotypically as being of 'germinal centre' type, but it was also expressed in almost half (13/28) of the 'non-germinal centre' cases. A similar proportion of 'non-germinal centre' cases were positive for the protein products of two other genes expressed highly in germinal centre cells (HGAL/GCET2 and PAG). The fact that all three of these proteins are expressed in a significant proportion of diffuse large B-cell lymphomas assigned to the 'non-germinal centre' category indicates that the immunophenotypic categorization of diffuse large B-cell lymphoma according to cellular origin may be more complicated than currently understood. Finally, the expression of Jaw1/LRMP in other types of lymphoma and in non-lymphoid tissues/tumours may be of interest in differential diagnosis and research.

Adrenal Glands↗
PubMed2005

Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome.

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumours, which are frequently carcinomas, and ossifying jaw fibromas. In addition, some patients may develop renal tumours and cysts. The gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, encodes a 531 amino acid protein called PARAFIBROMIN. To date 42 mutations, of which 22 are germline, have been reported and 97% of these are inactivating and consistent with a tumour suppressor role for HRPT2. We have investigated another four HPT-JT families for germline mutations, searched for additional clinical phenotypes, and examined for a genotype-phenotype correlation. Mutations were found in two families. One family had a novel deletional-insertion at codon 669, and the other had a 2 bp insertion at codon 679, which has been reported in four other unrelated patients. These five unrelated patients and their families with the same mutation were not found to develop the same tumours, thereby indicating an absence of a genotype-phenotype correlation. An analysis of 33 HPT-JT kindreds revealed that affected women in 13 HPT-JT families suffered from menorrhagia in their second to fourth decades. This often required hysterectomy, which revealed the presence of uterine tumours. This resulted in a significantly reduced maternal transmission of the disease. Thus, the results of our analysis expand the spectrum of HPT-JT-associated tumours to include uterine tumours, and these may account for the decreased reproductive fitness in females from HPT-JT families.

Adult↗
PubMed2003

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

SM047 immunoreactivity in peritoneal fluids.

SM047 is a recently developed monoclonal antibody generated against an ovarian adenocarcinoma cell line. A recent immunohistochemical study has shown that SM047 is strongly expressed in tissue sections of most ovarian serous adenocarcinomas. This study aimed to ascertain whether SM047 staining is of value in cytological preparations of peritoneal fluid. A total of 206 consecutive peritoneal fluids were stained immunocytochemically with SM047, CA125, monoclonal carcinoembryonic antigen (mCEA), Ber-EP4 and cytokeratins (CK7 and 20). SM047 positivity was present in reactive mesothelial cells in 117 of 141 (83%) benign cases in which these were present. SM047 positive tumour cells were present in 22 of 23 (96%) ovarian serous adenocarcinomas and in small numbers of gastric adenocarcinomas (two of three), mesotheliomas (one of two) and pancreatic adenocarcinomas (one of one). All six colorectal and two breast adenocarcinomas were negative with SM047. Reactive mesothelial cells in all cases were positive with CK7 and in most cases with CA125. They were negative with CEA, Ber-EP4 and CK20. All adenocarcinomas were positive with Ber-EP4 and mesothelial cells were always negative. All colorectal adenocarcinomas were positive with CK20. This study shows that SM047 staining may be of value in the diagnosis of an ovarian serous adenocarcinoma in peritoneal fluids. Negative staining helps to exclude a primary ovarian serous adenocarcinoma and is characteristic of colorectal adenocarcinoma. The small numbers of other malignancies in the study precludes a judgement of the value of SM047 staining in these neoplasms. SM047 staining may be useful, as part of a larger panel, in the work up of patients with peritoneal effusions.

Adenocarcinoma↗
PubMed2003

The effects of the levonorgestrel intrauterine system (Mirena coil) on endometrial morphology.

AIMS: The Mirena coil is a levonorgestrel releasing intrauterine device that is in widespread use. This study aims to document the endometrial morphology associated with this device. METHODS: Endometrial specimens from 75 women with the Mirena coil were reviewed and the histological features detailed. RESULTS: Morphological features found in most of the endometria were decidualisation of stroma (72 of 75 cases), atrophy of endometrial glands (65 of 75 cases), a surface papillary pattern (38 of 75 cases), and a stromal inflammatory cell infiltrate (59 of 75 cases). Additional common histological features were the presence of foci of stromal myxoid change (29 of 75 cases) and stromal haemosiderin pigment (24 of 75 cases). Reactive atypia of surface glands, glandular metaplastic changes, stromal necrosis, and stromal calcifications were found in small numbers of cases. CONCLUSION: The endometrial features are characteristic and relatively constant and are in keeping with the effects of both a progestogenic compound and a mechanical device. Pathologists should be aware of these histological features because the Mirena coil is in widespread use.

Adult↗
PubMed2002

Tamoxifen induction of angiogenic factor expression in endometrium.

Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre- and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre- but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen.

Adrenomedullin↗
PubMed2002

Retrospective study of management of uterine sarcomas at Oxford 1990-1998: role of adjuvant treatment.

We report a retrospective study of 47 consecutive patients with uterine sarcoma treated at the Churchill Hospital in Oxford between 1990-1998. The mainstay of treatment was surgery with adjuvant chemotherapy and radiotherapy reserved for selected patients with early stage disease. Overall 1 and 2 year survival was 49% and 30% respectively compared with 73% and 55% in the group who received adjuvant chemotherapy/radiotherapy. Median survival was 11 months for the group as a whole compared to 32.9 months in the adjuvant therapy group. This is a retrospective review with small numbers and considerable selection bias, however, given the poor survival of patients with this disease, adjuvant treatment should be considered in future trials of patients with uterine sarcoma.

Adult↗
PubMed2002

Reduplication cyst of appendix with mucinous carcinoma and Müllerian metaplasia: a case report.

This report describes a case of mucinous carcinoma and Müllerian metaplasia arising within an appendiceal duplication cyst found incidentally during an emergency Caesarian section. Intestinal duplication cysts are rare and although there are occasional reports of malignant transformation, this is the first case where Müllerian metaplasia was found concurrently with a malignancy. There was no previous history of endometriosis and no other abnormalities were found at surgery. Treatment included surgical excision. The patient is alive and well two years after removal of the cyst.

Adenocarcinoma, Mucinous↗
PubMed2001

Benign phyllodes tumour vs fibroadenoma: FNA cytological differentiation.

The differential diagnosis of fibroadenomas vs phyllodes tumours by fine needle aspiration (FNA) cytology is not possible in the majority of cases. The present study aims to look at common and dissimilar features to allow differentiation, if possible. We reviewed the FNA findings of 18 histologically proven phyllodes tumours and 18 fibroadenomas, checking in each case the epithelial features, the stromal features, and any atypia. Using a semi-quantitative score assessed by two observers we were able in most cases to distinguish a phyllodes tumour from a fibroadenoma. The most important criteria were larger stromal fragments, numerous plump stromal bare nuclei, and the higher ratio of stromal bare nuclei to epithelial bare nuclei in phyllodes tumours. In the present study, an original diagnosis of phyllodes tumour was made in 7/18 (38.9%) cases but with our criteria this could be improved to 15/18 (83.3%) cases. Therefore, the presence of specific stromal features in a dimorphic cellular pattern should suggest the correct diagnosis and differentiate its appearance from a cellular fibroadenoma.

Adult↗
PubMed2001

Linkage and association studies of the relationship between endometriosis and genes encoding the detoxification enzymes GSTM1, GSTT1 and CYP1A1.

An association between endometriosis and the glutathione S-transferase (GST) M1 null mutation has been reported in French and Slavic populations. We aimed to replicate this association of endometriosis in a UK population, and to test for association with the GSTT1 null mutation or the cytochrome P450 (CYP) 1A1 MspI polymorphism. We genotyped 148 women each with endometriosis (sporadic cases, n = 91; familial cases, n = 57), a population control of 95 male blood donors, and a control group of 53 women with a normal pelvis at hysterectomy. No significant differences were found between cases and controls in the frequencies of the GSTM1 and GSTT1 null mutations, or the CYP1A1 MspI polymorphism. However, the combination of the GSTM1 null genotype and the CYP1A1 MspI polymorphism was associated with a small increased risk of endometriosis, and this warrants further investigation. We also tested for linkage to the chromosome 1p13 region, to which GSTM1 has been mapped, in 52 sister-pairs with stage III-IV disease using three highly polymorphic microsatellite markers. However, there was no evidence of linkage, suggesting that this region may not be implicated in disease susceptibility.

Adult↗
PubMed2001

Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population.

The relationship between endometriosis and polymorphisms in the N-acetyl transferase 2 (NAT 2) gene was investigated in a UK population, as this gene has been previously implicated in the aetiology of the disease. Point mutations in the gene result in the variant alleles NAT 2 *5, *6 and *7 from the wild-type NAT 2 *4 allele. Homozygotes for the NAT 2 *4 wild type allele are fast NAT acetylators, while heterozygotes with one wild-type allele and a variant NAT 2 *5, *6 or *7 allele have reduced enzyme activity, and individuals with two variant alleles are slow acetylators. The NAT 2 *4/*6 genotype was significantly more common among affected women (35.2%) than population controls (8.1%; P = 0.0001) or unaffected women (4.2%; P = 0.02). Significantly more affected women (57.4%) were fast acetylators than were population controls (32.3%; P < 0.01) or unaffected women (33.3%; P < 0.05). These data suggest that altered NAT 2 enzyme activity may be a predisposition factor in endometriosis, or that NAT 2 alleles may be in linkage disequilibrium with a susceptibility allele in the same chromosomal region.

Adult↗
PubMed2000

Oxygenation and perfusion of rabbit tibialis anterior muscle subjected to different patterns of electrical stimulation.

Dual amperometric microelectrodes were used to measure local pO2 and perfusion at multiple sites in the fast-twitch tibialis anterior muscles of anaesthetized rabbits. Six muscles were stimulated continuously at 10, 5, or 2.5 Hz. For all three frequencies, perfusion declined to about 50% of resting levels and recovered after stimulation. These changes corresponded to a rise followed by a fall in extracellular pO2. The highest levels of pO2 were reached during stimulation at 10 Hz. Eight muscles were stimulated tetanically at 100 Hz for 200 ms with duty cycles that were varied between 1.3 and 20.0%. Perfusion rose to 8.7 +/- 2.0 ml s(-1) 100 g(-1) at a duty cycle of 5% and declined with further increases in duty cycle. pO2 was depressed for duty cycles less than 10% but rose above resting levels at higher duty cycles. It is suggested that the paradoxical combination of elevated pO2 and depressed perfusion is attributable to stimulation conditions that exceed the oxygen transport capacity of a fast muscle.

Animals↗
PubMed2000

Tamoxifen-associated postmenopausal adenomyosis exhibits stromal fibrosis, glandular dilatation and epithelial metaplasias.

AIMS: Adenomyosis is relatively rare in postmenopausal women but recent reports have described its occurrence in this age group in patients taking tamoxifen. This study describes the pathology of nine cases of adenomyosis in postmenopausal women who were taking this medication. METHODS AND RESULTS: The pathology of the nine tamoxifen-associated cases was compared to five cases of postmenopausal adenomyosis not associated with tamoxifen. Morphological features present within adenomyosis more often in those taking tamoxifen were cystic dilatation of glands (which sometimes resulted in grossly visible intramural cystic lesions), fibrosis of the stroma and various epithelial metaplasias. The proliferative activity within the adenomyosis, as determined by MIB1 staining, was higher in the tamoxifen group. CONCLUSIONS: The study supports an association between tamoxifen therapy and the presence of adenomyosis in postmenopausal women. The aforementioned morphological features are characteristic of polypoid and nonpolypoid surface endometrium associated with tamoxifen and their occurrence within the adenomyosis is likely to represent extension of the surface epithelial changes. Adenomyosis may be more common than is generally realized in women taking tamoxifen and may account for postmenopausal bleeding in these patients.

Aged↗
PubMed2000

Inhibin expression in normal and pre-eclamptic placental tissue.

Serum inhibin levels increase during normal pregnancy, but are significantly higher in patients with pre-eclampsia. The aim of this study was to demonstrate possible increased expression of inhibin within the placentas of women with pre-eclampsia compared with non-pre-eclamptic controls. Cellular expression of inhibin alpha and beta A subunits was studied using immunohistochemistry on formalin-fixed, paraffin-embedded placental sections from cases of pre-eclampsia (n = 23) and gestational age-matched non-pre-eclamptic controls (n = 16). Immunohistochemistry was performed using monoclonal antibodies against inhibin alpha and beta A subunits by the indirect immunoperoxidase technique. Intensity of staining was graded by a semiquantitative scoring method. Differences in distribution and intensity of staining between control and pre-eclamptic placentas were analyzed using a nonparametric Mann-Whitney U test. Staining for both inhibin alpha and beta A was predominantly confined to the cytoplasm of syncytiotrophoblast, with weak expression within intermediate trophoblast. The intensity of staining for inhibin alpha was significantly greater in the syncytiotrophoblast of pre-eclamptic patients (mean staining intensity controls = 0.97, disease = 1.87; p < 0.001). Inhibin beta A staining was generally stronger than for the alpha subunit, and was also significantly increased in pre-eclamptic patients compared with controls (mean controls = 1.72, disease 2.19; p < 0.05). This is the first evidence for increased placental inhibin presence in pre-eclampsia, suggesting increased inhibin production within the placenta, a finding that could account for increased serum inhibin levels in pre-eclampsia.

Cytoplasm↗