Cervical cancer screening by enhanced cytology: application of novel markers

published_or_final_versio

Assessment of cell proliferation in hydatidiform mole using monoclonal antibody MIB1 to Ki-67 antigen

Aims - To assess the role of Ki67 immunoreactivity in predicting the clinical progress of hydatidiform mole. Methods - Tissue from 87 hydatidiform moles, 11 normal first trimester placentas, 11 normal term placentas and 17 spontaneous abortions were examined for expression of Ki67 antigen, using the monoclonal antibody MIB1. Results - Ki67 immunoreactivity was significantly higher in the tissue from normal first trimester placentas than in that from normal term placentas and spontaneous abortions. Among the 87 patients with hydatidiform moles studied, 20 developed persistent gestational trophoblastic disease and required subsequent treatment. There was no statistically significant difference in the Ki67 index between the 20 patients who developed persistent disease and those who did not. Conclusion-Hydatidiform moles which give rise to persistent trophoblastic disease do not have a higher proliferative rate than those which do not. The Ki67 index is not useful for predicting the prognosis of molar pregnancies.published_or_final_versio

Spontaneous pneumomediastinum in a scuba diver

Pneumomediastinum usually occurs following an airleak from the lungs, or from a perforated oesophagus. We report on a 30-year-old man who developed pneumomediastinum after scuba diving. The patient presented with acute onset of throat pain, odynophagia, and hoarseness of voice. The literature is reviewed for this condition.published_or_final_versio

p21(WAF1/CIP1) expression in gestational trophoblastic disease: correlation with clinicopathological parameters, and Ki67 and p53 gene expression

Background--The p21(WAF1/CIP1) gene mediates growth arrest by inhibiting G 1 cyclin dependent kinases and has been considered as a downstream effector of the tumour suppressor gene p53. Aim--To analyse the role of p21(WAF1/CIP1) in gestational trophoblastic disease. Methods--The immunohistochemical expression of p21(WAF1/CIP1) gene was measured in 33 placentas, 28 partial hydatidiform moles, 54 complete hydatidiform moles, and 13 choriocarcinomas in paraffin wax embedded tissue. The results were correlated with p53 (DO7) and Ki67 (MIB1) immunoreactivity as well as clinical progress. Results--p21(WAF1/CIP1) immunoreactivity was found predominantly in the nuclei of the syncytiotrophoblasts. p21(WAF1/CIP1) protein expression correlated with gestational age in normal placentas (p = 0.0001) but not in hydatidiform moles (p = 0.89). Complete hydatidiform moles and choriocarcinomas had a significantly higher p21(WAF1/CIP1) expression compared with normal placentas and partial hydatiform moles (p 0.05) in p21(WAF1/CIP1) expression between the 17 patients who developed persistent gestational trophoblastic disease and those who did not. Conclusions--This study suggests that p21(WAF1/CIP1) expression in trophoblastic disease may be induced by a p53 independent pathway. The proliferative activity of gestational trophoblastic diseases might not be determined solely by the control of the cell cycle operated by p21(WAF1/CIP1). p21(WAF1/CIP1) expression is not an accurate prognostic indicator of gestational trophoblastic disease.published_or_final_versio

Chromosome in situ hybridisation, Ki-67, and telomerase immunocytochemistry in liquid based cervical cytology

Aims: To assess the potential value of chromosome in situ hybridisation (CISH), Ki-67, and telomerase immunocytochemistry in liquid based cervical cytology to help detect carcinoma cells and precursors. Method: Sixty ThinPrep processed cervical cytology samples were studied: 23 cases within the normal limit, 13 low grade squamous intraepithelial lesions (LSILs), 10 high grade squamous intraepithelial lesions (HSILs), six squamous cell carcinomas, three endocervical adenocarcinomas, two cervical adenosquamous cell carcinomas, and three endometrial adenocarcinomas. CISH was performed with DNA probes specific for the pericentromeric regions of chromosome 11 and 16. Hybridisation signals were visualised with the streptavidin-biotin peroxidase technique. The monoclonal MIB1 and polyclonal TRT-H231 antibodies were used to detect Ki-67 and telomerase immunoreactivity, respectively. Results: Non-specific background staining was almost absent in CISH slides. Normal squamous and glandular cells showed a diploid chromosomal pattern. A relative gain in chromosomes 11 and 16 (aneusomy) was seen in HSIL and the carcinomas (p<0.0001 ). In MIB1 stained smears, normal cells and koilocytes showed inconspicuous immunoreactivity, whereas strongly immunoreactive nuclei were found in cancer cells and HSIL (p<0.0001). Not only carcinoma and HSIL cells, but also some normal cells, showed cytoplasmic staining for telomerase. Conclusions: These preliminary results indicate that ThinPrep processed cervical smears are suitable for CISH and immunocytochemical studies. The neoplastic squamous and glandular cells were easily identified based on nuclear aneusomy and strong Ki-67 immuoreactivity in the context of abnormal nuclear morphology. This is the first study to apply CISH in cervical cytology using an immunoenzymatic approach.published_or_final_versio

Telomerase activity in gestational trophoblastic disease

Aims - To investigate the pattern of telomerase activity in hydatidiform mole as compared with normal placenta and choriocarcinoma, and to determine the prognostic significance of telomerase activity in hydatidiform mole. Methods - Telomerase activity in 35 cases of hydatidiform mole, 35 normal placentas, one choriocarcinoma sample, and two choriocarcinoma cell lines (JAR, JEG3) was determined using the sensitive polymerase chain reaction based telomeric repeat amplification protocol (TRAP) assay. Two cases of breast carcinoma and two cases of ovarian carcinoma were also included as positive controls in the telomerase assay. Results - Telomerase activity was detected in 11 of 30 early placentas (36.7%), one of five term placentas (20%), five of 27 hydatidiform moles which regressed spontaneously (18.5%), and six of eight hydatidiform moles which developed persistent trophoblastic disease (75%) (including three which developed metastases). Hydatidiform moles which subsequently developed persistent disease, especially those which metastasised, were more likely to express telomerase activity (p < 0.01). However, there was no significant difference in the frequency of telomerase activity between early placentas and hydatidiform mole. Strong telomerase activity was observed in choriocarcinoma tissue, choriocarcinoma cell lines, and ovarian and breast carcinomas. Conclusions - Telomerase activation occurs in hydatidiform mole with a similar incidence to early normal placentas. This supports the concept that hydatidiform mole is essentially an abnormal conceptus. There is an association between telomerase activation and the development of persistent trophoblastic disease. Further study is warrant to confirm the prognostic significance of telomerase activity in hydatidiform mole.published_or_final_versio

Hypermethylation of SOX2 gene in hydatidiform mole and choriocarcinoma

This study investigated the expression and methylation profiles of SOX2, a stem cell-related transcription factor, in placentas and gestational trophoblastic disease. The methylation status of SOX2 promoter region in 55 hydatidiform moles, 4 choriocarcinoma, 23 first trimester, and 15 term placentas was evaluated by methylation-specific polymerase chain reaction. The methylated allele was found in 4.4% (1/23) of first trimester placentas, 26.7% (4/15) term placentas, and 56.4% (31/55) of hydatidiform moles and all choriocarcinoma samples and cell lines. A significant reduction in SOX2 messenger RNA expression was found in the hydatidiform moles (P = .027) when compared with that in the placentas. SOX2 messenger RNA expression was significantly correlated with SOX2 hypermethylation (P < .001). SOX2 expression was restored in choriocarcinoma cell lines following treatment to 5-Aza-2(')-deoxycytidine and/or Trichostatin A, demethylation and histone deacetylase inhibitors, respectively, and the response was synergistic. Epigenetic mechanisms may play important role on the transcriptional regulation of SOX2 and contribute to pathogenesis of gestational trophoblastic disease.link_to_subscribed_fulltex

Extremely stringent activation of p16<i>INK4a</i> prevents immortalization of uterine cervical epithelial cells without human papillomavirus oncogene expression

published_or_final_versio

Gastrointestinal bleeding of obscured origin due to cystic artery pseudoaneurysm

Cystic artery pseudoaneurysm is a rare condition, which usually arises from the complication of gallstone disease. Patients may present with Quinke's triad (epigastric pain, obstructive jaundice, and gastrointestinal bleeding). The results can be fatal if present with a ruptured pseudoaneurysm. We report a patient who presented with upper gastrointestinal bleeding, and later diagnosis was confirmed with a computer tomography scan of the abdomen and a three-vessel angiogram. Endovascular intervention was attempted. Although it failed, the patient was eventually cured with an open cholecystectomy. © 2015

P70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70 S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70 S6K is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70 S6K acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70 S6K in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70 S6K was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70 S6K colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70 S6K did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70 S6K stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70 S6K expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70 S6K specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70 S6K in tumor progression. © 2011 Macmillan Publishers Limited All rights reserved.postprin