Longitudinal 3.0T MRI analysis of changes in lymph node volume and apparent diffusion coefficient in an experimental animal model of metastatic and hyperplastic lymph nodes.

PURPOSE: To perform a longitudinal analysis of changes in lymph node volume and apparent diffusion coefficient (ADC) in healthy, metastatic, and hyperplastic lymph nodes. MATERIALS AND METHODS: Three groups of four female Copenhagen rats were studied. Metastasis was induced by injecting cells with a high metastatic potential in their left hind footpad. Reactive nodes were induced by injecting Complete Freund Adjuvant (CFA). Imaging was performed at baseline and at 2, 5, 8, 11, and 14 days after tumor cell injection. Finally, lymph nodes were examined histopathologically. RESULTS: The model was highly efficient in inducing lymphadenopathy: subcutaneous cell or CFA inoculation resulted in ipsilateral metastatic or reactive popliteal lymph nodes in all rats. Metastatic nodal volumes increased exponentially from 5-7 mm(3) at baseline to 25 mm(3) at day 14, while the control node remained 5 mm(3). The hyperplastic nodes showed a rapid volume increase reaching a plateau at day 6. The ADC of metastatic nodes significantly decreased (range 13%-32%), but this decrease was also seen in reactive nodes. CONCLUSION: Metastatic and hyperplastic lymph nodes differed in terms of enlargement patterns and ADC changes. Enlarged reactive or malignant nodes could not be differentiated based on their ADC values.

Trends in inflammatory status of the vaginal flora as established in the Dutch national screening program for cervical cancer over the last decade.

OBJECTIVE: To describe recent trends in the prevalence of cytologic patterns of the vaginal flora (koilocytosis, Trichomonas, dys-bacteriosis, Candida, Gardnerella, Actinomyces, Chlamydia trachomatis) over the last decade. STUDY DESIGN: From 1996 to 2005 > 500,000 cervical smears were screened in the context of the Dutch national screening program on a 5-year basis. Data from the first screening period were compared with those of the second screening period. RESULTS: Prevalences differed from 34.8 for dysbacteriosis to 0.2 for C trachomatis. Bacterial imbalance (dysbacteriosis, unequivocal Gardnerella and Trichomonas) showed a decline in all age groups. Cases of human papillomavirus (HPV)-related koilocytosis have dramatically increased among young women (30 and 35 years). CONCLUSION: Bacterial imbalance of the vaginal flora has significantly decreased during the past decade in all age cohorts. Campaigns on consciousness of vaginal hygiene might have contributed to this amazing effect. We ought to be concerned about the increase in HPV-related koilocytosis.

Is centralization of ovarian cancer care warranted? A cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of tertiary referral care for ovarian cancer patients in the Netherlands. METHODS: We collected clinical and registry data on 1077 newly diagnosed ovarian cancer patients treated from 1996-2003 in a random sample of Dutch hospitals. Decision modelling was used to compare the cost-effectiveness of treatment in general hospitals, semi-specialized hospitals, and tertiary care centers. The actual direct medical costs of ovarian cancer treatment were evaluated. Long-term outcomes in terms of costs, quality-adjusted life-years (QALYs), and incremental costs per QALY gained were estimated. To assess uncertainty, multivariable sensitivity analyses and scenario analyses were performed. RESULTS: Treatment of ovarian cancer patients in semi-specialized hospitals costs on average euro882 more than in general hospitals (95% confidence interval -720 to 2462) and yields 0.12 additional QALYs (95% CI 0.02 to 0.22), resulting in an incremental cost-effectiveness ratio (ICER) of euro7135. Patients treated in tertiary care centers incurred again higher costs (euro10,591, 95% CI 8757 to 12,480) and also higher QALYs (0.10, 95% CI 0 to 0.21), resulting in an ICER of euro102,642 compared to semi-specialized hospitals. If the optimal debulking rate in tertiary care centers would increase to 70%, costs could drop below euro30,000 per QALY. CONCLUSION: Current treatment of ovarian cancer patients in semi-specialized hospital settings is a cost-effective strategy, while treatment in tertiary care centers becomes only cost-effective when better surgical results would be achieved.

The impact of hospital type on the efficacy of chemotherapy treatment in ovarian cancer patients.

OBJECTIVE: The hospital type affects the surgical outcomes of ovarian cancer patients. In the present study, we wanted to investigate the effect of hospital type on chemotherapy efficacy. METHODS: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals were categorized by the number of medical oncologists working in a hospital and additionally by chemotherapy volume (< or =100, 101-200, or >200 patients yearly) and ovarian cancer patient-volume (< or =6, 7-12, >12 yearly). The outcomes were the proportions of patients achieving complete remission, recurrence rates, and disease-free and overall survival. Data were analyzed using multivariable logistic regression (complete remission and recurrence) and Cox regression (survival). RESULTS: Data of 761 of the 777 patients who received chemotherapy could be analyzed. Hospital type did not affect the complete remission rates, recurrence rates, or the disease-free survival. Overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume (hazard ratios both 0.8 (95% confidence interval=0.7-1.0)). CONCLUSIONS: Thus, hospital type did not influence the outcomes of first-line chemotherapy in ovarian cancer patients. However, overall survival was better in hospitals with 2 or more medical oncologists and in hospitals with a high ovarian cancer patient-volume, suggesting differences in second-line chemotherapy.

Specialized and high-volume care leads to better outcomes of ovarian cancer treatment in the Netherlands.

OBJECTIVE: We investigated the influence of hospital and gynecologist level of specialization and volume on surgical results and on survival of ovarian cancer patients. METHODS: Data were collected from 1077 ovarian cancer patients treated from 1996 to 2003 in a random sample of 18 Dutch hospitals. Hospitals and gynecologists were classified according to specialization (general, semi-specialized or specialized) and by volume (12 cases/year). Outcomes were percentage of adequately staged and optimally debulked patients and length of overall survival. Data were analyzed using multivariable logistic regression (surgical results) and Cox regression (survival). RESULTS: The level of specialization and the volume of hospitals and of gynecologists were strongly related to the proportion of adequately staged patients (adjusted odds ratio (OR) specialized hospitals 3.9 (95% confidence interval (CI) 2.0-7.6); specialized gynecologists 9.5 (95% CI 4.7-19)). Patients with stage III disease had a higher chance of optimal debulking when treated in specialized hospitals (adjusted OR 1.7 (95% CI 1.1-2.7)) or by high volume gynecologists (adjusted OR 2.8 (95% CI 1.4-5.7)). Overall survival was best in patients treated in specialized hospitals and by high-volume gynecologists. CONCLUSION: The specialization level of hospitals and the surgical volume of gynecologists positively influence outcomes of surgery and survival. Concentration of ovarian cancer care thus seems warranted.

Gardnerella infection as distinguished from cervical dysbacteriosis: the advantageous spin-off of cervical screening.

OBJECTIVE: To evaluate cytologic diagnoses of dysbacteriosis and Gardnerella infection and to obtain insight into the diagnostic problems of Gardnerella. STUDY DESIGN: One hundred randomly selected samples of each of 3 diagnostic series were rescreened by 2 pathologists, resulting in 2 rescreening diagnoses and a consensus diagnosis. A smear was considered unequivocal when the original O code and the O code of the consensus diagnoses were equal and discordant when the flora diagnoses of the 2 pathologists differed. RESULTS: Discordance was highest in the dysbacteriotic series (20%) and lowest in the healthy group (4%). Unequivocal diagnoses were established in 65% of the dysbacteriotic smears, 80% of the Gardnerella smears and 93% of the healthy smears. Misclassification of Gardnerella occurred in the presence of clusters of bacteria mixed with spermatozoa. CONCLUSION: Blue mountain cells in Gardnerella infection can be identified unequivocally in cervical smears. Because of the clinical importance of treating Gardnerella, such advantageous spin-offs of cervical screening should be exploited.

Cytologically diagnosed Gardnerella vaginalis infection and cervical (pre)neoplasia as established in population-based cervical screening.

OBJECTIVE: Cervical inflammation has been proposed as a cofactor in the development of cervical cancer. The purpose of this study was to document the prevalence of cervical (pre)neoplastic changes in asymptomatic women with a cytologically diagnosed Gardnerella vaginalis infection. STUDY DESIGN: Data were collected from 800,498 Dutch asymptomatic women, participating in the Dutch national screening program. Prevalences of (pre)neoplasia were calculated for G vaginalis smears using a healthy flora as reference. RESULTS: The prevalence of G vaginalis infection was 0.6 per thousand. The odds ratio for (pre)neoplasia was significantly higher in smears with G vaginalis infection compared with smears of women with a healthy vaginal flora (odds ratio, 10.3; 95% confidence interval, 6.6-16.1). CONCLUSION: Cytologically diagnosed G vaginalis smears show a strong covariation with the presence of cervical (pre)neoplasia. Future research should therefore focus on the exact causal relation between cytologic G vaginalis infection and the presence of (pre)neoplastic changes of the cervix.

Gardnerella vaginalis and Lactobacillus sp in liquid-based cervical samples in healthy and disturbed vaginal flora using cultivation-independent methods.

Our objective was to determine the morphotype of the adherent bacteria in liquid-based cytology (LBC) in smears with healthy and disturbed vaginal flora. And to use PCR technology on the same fixed cell sample to establish DNA patterns of the 16S RNA genes of the bacteria in the sample. Thirty samples were randomly selected from a large group of cervical cell samples suspended in a commercial coagulant fixative "(BoonFix)." PCR was used to amplify DNA of five bacterial species: Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus jensenii, Gardnerella vaginalis, and Mycoplasma hominis. The LBC slides were then analyzed by light microscopy to estimate bacterial adhesion. DNA of lactobacilli was detected in all cell samples. Seventeen smears showed colonization with Gardnerella vaginalis (range 2.6 x 10(2)-3.0 x 10(5) bacteria/mul BoonFix sample). Two cases were identified as dysbacteriotic with high DNA values for Gardnerella vaginalis and low values for Lactobacillus crispatus. The sample with the highest concentration for Gardnerella vaginalis showed an unequivocal Gardnerella infection. This study indicates that the adherence pattern of a disturbed flora in liquid-based cervical samples can be identified unequivocally, and that these samples are suitable for quantitative PCR analysis. This cultivation independent method reveals a strong inverse relationship between Gardnerella vaginalis and Lactobacillus crispatus in dysbacteriosis and unequivocal Gardnerella infection.

The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators.

The aim of the study was to explore whether expression of proliferation and hypoxia-related proteins differs in the central parts and the invasive front in endometrial carcinomas. Proliferation-associated proteins Ki67 and cyclin A; cell cycle regulators p16, p21, p53, cyclin D1, cyclin E, and cdk2; and hypoxia-inducible factor 1alpha and its downstream factors glucose transporter 1, carbonic anhydrase IX, and vascular endothelial growth factor were immunohistochemically stained in paraffin-embedded specimens from endometrioid (n = 33), mucinous (n = 1), and serous (n = 5) endometrial carcinomas. The percentages of positive cells at the invasive front and central tumor parts were scored and compared. Ki67 (P < .001), cyclin E (P = .018), p16 (P = .003), and cdk2 (.001) were expressed higher at the invasive front than centrally (Wilcoxon signed ranks test). Higher expression of these antigens at the invasive front was seen in 31 of 38 cases for Ki67, in 16 of 39 cases for cyclin E, in 15 of 39 cases for cdk2, and in 11 of 39 cases for p16. The other cell cycle proteins and the hypoxia-related factors did not show significant differences in expression between the central parts and the invasive front. Endometrial carcinomas clearly show an invasive front that is characterized by higher proliferation and progressive derailment of the cell cycle regulators cyclin E, p16, and cdk2, but not by an increased hypoxic response.

Hypoxia and angiogenesis in endometrioid endometrial carcinogenesis.

BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. METHODS: Expression of HIF-1alpha and proteins in the HIF-1alpha pathway (Glut-1, CAIX, VEGF) in paraffin-embedded specimens of normal (n=17), premalignant (n=17) and endometrioid endometrial carcinoma (n=39) was explored by immunohistochemistry, in relation to microvessel density (MVD). RESULTS: HIF-1alpha overexpression was absent in inactive endometrium but present in hyperplasia (61%) and carcinoma (87%), with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse) and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically). Diffuse HIF-1alpha was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p<0.001). CONCLUSION: HIF-1alpha and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1alpha in endometrial carcinogenesis.

Euthanasia and depression: a prospective cohort study among terminally ill cancer patients.

PURPOSE: To study the association between depression and the incidence of explicit requests for euthanasia in terminally ill cancer patients. PATIENTS AND METHODS: A prospective cohort study was conducted on 138 consecutive cancer patients with an estimated life expectancy of 3 months or less, in the period between September 1999 and August 2003. At inclusion, participants completed the Hospital Anxiety and Depression Scale. To identify "depressed mood" we used a cutoff score of 20. Kaplan-Meier curves and Cox regression analyses were used to assess the association between depressed mood and the risk of a request for euthanasia. RESULTS: Of 138 patients, 32 patients had depressed mood at inclusion. Thirty patients (22%) made an explicit request for euthanasia. The risk to request euthanasia for patients with depressed mood was 4.1 times higher than that of patients without depressed mood at inclusion (95% CI, 2.0 to 8.5). CONCLUSION: Depression in cancer patients with an estimated life expectancy of less than 3 months is associated with a higher likelihood to request for euthanasia. The question of whether depressed mood can adequately be treated in this terminally ill population, and if so, whether it would lower the incidence of requests for euthanasia needs further investigation.

The effectiveness of tension-free vaginal tape (TVT) and quality of life measured in women with previous urogynecologic surgery: analysis from The Netherlands TVT database.

OBJECTIVE: Long-term outcome of tension-free vaginal tape (TVT) in women with a history of surgery for urinary incontinence and/or prolapse. STUDY DESIGN: Prospective cohort study of 809 women. Twenty-eight teaching and 13 local hospitals, 54 gynecologists and urologists performed the TVTs. The Incontinence Impact Questionnaire (IIQ-7) and Urogenital Distress Inventory (UDI-6) were used to measure the results of the TVT procedure (preoperative at 2, 6, 12, 24, and 36 months postoperative). According the recommendation of the International Continence Society, the question "Do you experience urinary leakage during physical activity, coughing or sneezing?" was selected from the UDI to assess stress urinary incontinence. RESULTS: The decrease in IIQ/UDI mean scores was statistically significant. The UDI scores of women with a history of previous prolapse and/or incontinence surgery were not statistically different to the scores for primary cases after 3 years follow-up (P = .193). CONCLUSION: TVT is effective for women with recurrent stress urinary incontinence and/or previous prolapse surgery.

What determines a successful tension-free vaginal tape? A prospective multicenter cohort study: results from The Netherlands TVT database.

OBJECTIVE: The objective of this study was to report which preoperative and intraoperative factors influence the success of the tension-free vaginal tape procedure for stress urinary incontinence. STUDY DESIGN: This was a prospective cohort study of 809 patients. In 28 teaching hospitals and 13 local hospitals, 54 gynecologists and urologists performed the tension-free vaginal tape procedure. RESULTS: Before treatment and 2 years postoperatively, the following question from the Urogenital Distress Inventory for stress urinary incontinence was selected to define success or failure: "Do you experience urinary leakage during physical activity, coughing, or sneezing?" Secondary outcome measurement was the outcome of the doctor's question, "Do you leak during physical activity, coughing, or sneezing?" asked at the 2-year follow-up. Response rate was 78.7%. The success rate was significant higher in all analyses when the surgeons had performed more than 20 tension-free vaginal tape procedures (P = .003; beta = 1.918 [95% confidence interval 1.24-2.97]). General anesthesia had a negative effect on the success of the tension-free vaginal tape (P = .032; beta = 2.21 [95% confidence interval 1.07-4.55]). CONCLUSIONS: Inexperience of the surgeon with the tension-free vaginal tape procedure and general anesthesia had a negative effect on the result. We believe that the tension-free vaginal tape should be performed only by experienced surgeons.

Microscopic diagnosis of dysbacteriosis in stained vaginal smears in clinical practice.

Dysbacteriosis is a microscopical diagnosis. In women with dysbacteriosis, an overgrowth of coccoid bacteria and almost a complete absence of lactobacilli are observed in the (stained) vaginal smear. The aim of this study was to determine the accuracy of this microscopic diagnosis in clinical practice. The analysis concerned 342 consecutive cases in which the microscopy of the stained smears was performed by general practitioners trained in diagnosing dysbacteriosis. These smears were sent to the pathologist for confirmation of the microscopical diagnosis of the clinician. The cytological diagnoses of the pathologist, sometimes performed on restained slides when the quality of the staining was substandard, were considered as the "gold standard." In 92 of the 342 cases, dysbacteriosis was unequivocally established by the pathologist. Sensitivity and specificity of the microscopical diagnoses of the clinicians were 40% and 85%, respectively. There were 37 false-positive and 54 false-negative diagnoses of dysbacteriosis rendered by the clinicians. The most frequent reason for a false-negative diagnosis was an excess of lactobacilli in the smear. This study shows that even in stained smears it is difficult for clinicians to render a correct evaluation of the status of the vaginal flora.

Bipolar radio frequency endometrial ablation compared with balloon endometrial ablation in dysfunctional uterine bleeding: impact on patients' health-related quality of life.

OBJECTIVE: To compare health-related quality of life (HRQoL) after bipolar radio frequency ablation and thermal balloon ablation in women with dysfunctional uterine bleeding. DESIGN: Randomized clinical trial. SETTING: Teaching hospital. PATIENT(S): Women suffering from dysfunctional uterine bleeding. INTERVENTION(S): Bipolar radio frequency ablation and thermal balloon ablation. MAIN OUTCOME MEASURE(S): Patients were asked to complete HRQoL questionnaires at baseline, and at 2 days, 2 weeks, 3 months, 6 months, and 12 months after surgery. The questionnaires contained the medical outcomes study Short-Form 36 (SF-36), the Self-rating Depression Scale, the Rotterdam Symptom Checklist, State-Trait Anxiety Inventory, and a structured clinical history questionnaire. RESULT(S): Data on HRQoL were available on at least two different time points in 115 of 126 randomized patients. HRQoL improved significantly over time in both groups, except for the domain of general health in the SF-36. None of the dimensions showed a significant difference between both groups, neither was there a significant interaction between time and treatment effect. CONCLUSION(S): Both methods significantly improved HRQoL in women with dysfunctional uterine bleeding. However, despite better amenorrhea and satisfaction rates after bipolar radio frequency ablation, there was no difference in HRQoL between the two groups.

Accuracy of transvaginal ultrasonography in diabetic or obese women with postmenopausal bleeding.

OBJECTIVE: We sought to assess the accuracy of endometrial thickness measurement in the diagnosis of endometrial cancer in patients with obesity, diabetes, and hypertension and to evaluate whether patient characteristics influence endometrial thickness irrespective of the final diagnosis. METHODS: This was a prospective study of women not using hormone replacement therapy who presented with postmenopausal bleeding at 8 hospitals in The Netherlands. All women underwent transvaginal ultrasonography and, in the event that the endometrial thickness (double layer) was more than 4 mm, subsequent endometrial sampling. The performance of endometrial thickness measurement in the diagnosis of atypical hyperplasia and endometrial cancer was evaluated in subgroups of patients with diabetes, hypertension, and obesity by using receiver operating characteristic analysis. RESULTS: Overall, we included 594 consecutive women, of whom 62 (10%) had endometrial carcinoma and 6 (1%) had atypical hyperplasia. In these women, transvaginal ultrasonography had an area under the receiver operating characteristic curve of 0.87 (standard error [SE] 0.03). In the absence of (pre)malignancy, women with diabetes or obesity were found to have thicker endometria than women without these risk factors, whereas in women with a (pre)malignancy, this difference was not present. The area under the receiver operating characteristic curve decreased to 0.74 (SE 0.05) and 0.75 (SE 0.07) in diabetic women and obese women, respectively. The presence or absence of hypertension had no impact on the accuracy of transvaginal ultrasonography. CONCLUSION: In view of the decreased diagnostic accuracy in diabetic women and obese women, the clinical value of transvaginal endometrial thickness measurement in these women is questionable.

Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT.

OBJECTIVES: Two hormone replacement therapy (HRT) regimens of combined oral estradiol with either continuous intrauterine or cyclic oral progestin were compared for 2 years. METHODS: 200 perimenopausal women randomly received an intrauterine system with continuous levonorgestrel release (20 microg/24 h) combined with oral estradiol (2 mg daily), or a cyclic oral regimen of norethisterone acetate (1 mg on day 13-22) and estradiol (days 1-21; 2 mg, days 22-28; 1 mg). Efficacy on endometrial protection, vaginal bleeding patterns, blood loss and practical use were compared during 26 cycles. RESULTS: Endometrial protection was adequate in both regimens. The cyclic regimen induced a more regular bleeding pattern. The continuous local administration induced a reduction in bleeding (P=0.001) with an initial period of prolonged and frequent bleeding. 38% became amenorrhoeic. Women found both regimens acceptable. CONCLUSIONS: Continuous intrauterine Levonorgestrel administration by using an intrauterine system can well be recommended for use in combination with oestrogen replacement therapy in perimenopausal women.

Cost-effectiveness of the use of transvaginal sonography in the evaluation of postmenopausal bleeding.

OBJECTIVES: To assess the cost-effectiveness of transvaginal sonography (TVS) in the diagnostic work-up of women with postmenopausal bleeding. METHODS: We performed a decision analysis in which we estimated life expectancy and cost of four strategies for the evaluation of postmenopausal bleeding: TVS (I), TVS and office endometrial biopsy (II), TVS and hysteroscopy (III), and endometrial biopsy (IV). In strategies incorporating TVS, calculations were performed for three different cut-off values between 3 and 9 mm double layer. Expectant management, i.e. no diagnosis or treatment was considered to be the reference strategy to which the other four strategies were compared. Data were obtained from the published literature. In extensive sensitivity analyses, we varied patient's age, discount rate, prevalence of endometrial carcinoma and atypical hyperplasia, and costs. RESULTS: The strategy with endometrial biopsy and the strategy with TVS followed by endometrial biopsy in case of an increased endometrial thickness were the most cost-effective strategies. The strategy starting with endometrial biopsy was the most cost-effective when the prevalence of endometrial carcinoma was > or =15.3%, whereas the strategy with TVS and endometrial biopsy was the most cost-effective for women in which the prevalence of endometrial carcinoma was lower. In these strategies, a cut-off level for abnormality of 9 mm resulted in lowest cost per life-year gained. CONCLUSIONS: TVS is of use in women with postmenopausal bleeding and a probability of endometrial carcinoma below 15%.

Papanicolaou's nebular cells are related to HPV infection and HSIL.

Metaplastic cells with nebular cytoplasmic changes in the cervical smear are classified in the Dutch coding system for cervical screening as KOPAC O8 cells. Since these nebulated cells are already documented by Papanicolaou, we refer to these cells as Papanicolaou's nebular cells. We examined the simultaneous presence of these characteristic metaplastic cells and high-grade squamous intraepithelial lesion (HSIL) in a population-based data base from January 1991 and December 1996. The odds ratio (OR) of nebular cells concurring with HSIL increases with age. For the age cohort 30 years, the OR was 7.8 with a 95% confidence interval (CI) of 4.4-13.9. For the age cohort 60 years, the OR was 35.3 with a 95% CI of 7.8-159.2. Aiming to determine the nature of these nebular metaplastic cells, we performed Chlamydia and HPV PCR on 587 and 1,483 smears, respectively. With an OR of 0.9 [0.3-2.4] it is unlikely that Chlamydia plays a role in the appearance of these nebular cells in the smear. This study shows that with an OR of 5.9 [1.7-21.3] HPV is not only related to large koilocytosis but also to a nebular change of small metaplastic cells. This study reports that nebular changes of small metaplastic cells are related to cervical cancer and to HPV infection.

The role of hypoxia inducible factor-1alpha in gynecological cancer.

Understanding the mechanisms of carcinogenesis and progression of gynecological tumors is important as these insights might lead to improved diagnostic tools for the pathologist, improved prediction of prognosis, response to therapy, and eventually better biology-based disease management, thereby improving prognosis and quality of life for the individual patient. Hypoxia is an important event in carcinogenesis because it renders a more aggressive phenotype with increased invasiveness and proliferation, formation of metastases and poorer survival. Although selecting patients with hypoxic tumors may therefore be clinically important, there is no consensus as to the method best suited for routine assessment of hypoxia. One of the potential tumor hypoxia markers is hypoxia inducible factor 1 (HIF-1). HIF-1 is the key cellular survival protein under hypoxia, and is associated with tumor progression and metastasis in various solid tumors. In this review, we show that in gynecological cancers, HIF-1A is emerging as an important factor in carcinogenesis, and that overexpression of HIF-1A and its target genes CA9 and SLC2A1 seems associated with shorter progression free- and overall survival. Since hypoxia and HIF-1A expression are associated with treatment failure, targeting HIF-1A could be an attractive therapeutic strategy with the potential for disrupting multiple pathways crucial for tumor growth. Currently, HIF-1A inhibitors are being studied in clinical trials in recurrent ovarian- and cervical cancer, and trials in other gynecological cancers are expected.