Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer.

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were € 1400 per intervention, making the overall costs of both strategies comparable (difference € -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life.

Laparoscopy to Predict the Result of Primary Cytoreductive Surgery in Patients With Advanced Ovarian Cancer: A Randomized Controlled Trial.

Purpose To investigate whether initial diagnostic laparoscopy can prevent futile primary cytoreductive surgery (PCS) by identifying patients with advanced-stage ovarian cancer in whom > 1 cm of residual disease will be left after PCS. Patients and Methods This multicenter, randomized controlled trial was undertaken within eight gynecologic cancer centers in the Netherlands. Patients with suspected advanced-stage ovarian cancer who qualified for PCS were eligible. Participating patients were randomly assigned to either laparoscopy or PCS. Laparoscopy was used to guide selection of primary treatment: either primary surgery or neoadjuvant chemotherapy followed by interval surgery. The primary outcome was futile laparotomy, defined as a PCS with residual disease of > 1 cm. Primary analyses were performed according to the intention-to-treat principle. Results Between May 2011 and February 2015, 201 participants were included, of whom 102 were assigned to diagnostic laparoscopy and 99 to primary surgery. In the laparoscopy group, 63 (62%) of 102 patients underwent PCS versus 93 (94%) of 99 patients in the primary surgery group. Futile laparotomy occurred in 10 (10%) of 102 patients in the laparoscopy group versus 39 (39%) of 99 patients in the primary surgery group (relative risk, 0.25; 95% CI, 0.13 to 0.47; P < .001). In the laparoscopy group, three (3%) of 102 patients underwent both primary and interval surgery compared with 28 (28%) of 99 patients in the primary surgery group ( P < .001). Conclusion Diagnostic laparoscopy reduced the number of futile laparotomies in patients with suspected advanced-stage ovarian cancer. In women with a plan for PCS, these data suggest that performance of diagnostic laparoscopy first is reasonable and that if cytoreduction to < 1 cm of residual disease seems feasible, to proceed with PCS.

The diagnostic process of cervical cancer; areas of good practice, and windows of opportunity.

OBJECTIVE: Despite an extensive screening programme in The Netherlands, some cases of cervical cancer are still diagnosed in late stages of disease. The aim of the present study was to investigate which elements in the diagnostic process of cervical cancer may be improved. METHODS: This is a retrospective study of 120 patients with cervical cancer diagnosed between January 1st 2008 and June 1st 2010 at the University Medical Center Utrecht. Patient charts, referral information, and pathology results were analyzed. RESULTS: 39.1% of cancer cases were screen or interval detected; the other 60.9% of patients had not been screened, either due to non-attendance or because they fell outside the age range for screening. The final diagnosis of cervical cancer was established by biopsy in 77 (64.2%) and by excision of the cervical transformation zone in 35 (29.2%) of the patients. Fifteen (43%) of these excisions could have been avoided if biopsies would have been taken at the first examination, and had shown invasive cancer. CONCLUSIONS: Cervical cancer screening aims at early detection of precursor lesions to decrease the incidence of cancer. This in-depth analysis suggests that improvement of quality of care is to be expected from correct recognition of cervical cancer by physicians and adjustments of the screening programme to reach younger women and non-responders.

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.

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.

Inflammatory events as detected in cervical smears and squamous intraepithelial lesions.

The Dutch cytological coding system, KOPAC, enables to code for eight inflammatory events, that is koilocytosis (related to human papillomavirus (HPV)), Trichomonas, dysbacteriosis [related to bacterial vaginosis (BV)], Candida, Gardnerella, Actinomyces, Chlamydia, and non-specific inflammation (leucocytosis). This study presents an analysis of 1,008,879 smears. Of each smear, the age of the woman and the reason for smear taking (screening or indication) was available. The cytoscores (per mille) for these codes were calculated. For the screening smears, the cytoscores were for koilocytosis (HPV) 2.6, for Trichomonas vaginalis 1.9, for dysbacteriosis 31.4, for Candida albicans 9.8, for Gardnerella vaginalis 0.7, for Actinomyces 6.9, for Chlamydia 0.8, and for non-specific inflammatory changes 66.4. For the calculation of the Odds Ratio (OR), normal smears were used as a reference. The cytoscores for Chlamydia and Gardnerella covaried with high grade SIL (HSIL), with an OR of 7 and 12, respectively. In addition, the OR for Trichomonas vaginalis, for dysbacteriosis, and for leucocytosis proved to be significantly high in the indication smears. This study provides an oversight of HSIL and the full range of cervical infections as detected by cytology, proving that this infectious byproduct of screening can be very valuable.

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.

Microscopic diagnosis of vulvovaginal candidiasis in stained vaginal smears by Dutch general practitioners.

OBJECTIVE: To determine the accuracy of the microscopic diagnosis of vulvovaginal candidiasis (presence of [pseudo] hyphae and blastospores) in stained vaginal smears in clinical practice. STUDY DESIGN: General practitioners trained in diagnosing vulvovaginal candidiasis performed microscopy of 324 stained vaginal smears. These smears were sent to the pathologist for confirmation of the microscopic diagnosis of the clinician; cytologic diagnosis by the pathologist was considered the gold standard. RESULTS: In 104 of the 342 cases Candida was established by the pathologist. The clinicians made 24 false positive and 50 false negative diagnoses of Candida. Sensitivity and specificity of the microscopic diagnoses of the clinicians were 52% and 89%, respectively. The most frequent reason for a false positive diagnosis was presence of hairs, whereas the most frequent reason for a false negative diagnosis was understaining of the smear. CONCLUSION: This study shows that even in stained smears it is difficult for clinicians to recognize blastospores and (pseudo)hyphae. Efforts are clearly needed to improve the quality of the clinical diagnosis of vulvovaginal candidiasis.

Candida and dysbacteriosis: a cytologic, population-based study of 100,605 asymptomatic women concerning cervical carcinogenesis.

BACKGROUND: The objective of this study was to investigate whether the presence of vaginal Candida or dysbacteriosis predisposes women to an increased susceptibility for (pre)neoplasia over time. METHODS: A retrospective, longitudinal, cohort study was performed and was conducted in a population of 100,605 women, each of whom had 2 smears taken over a period of 12 years as part of the Dutch Cervical Screening Program. From these women, a cohort of 1439 women with Candida and a cohort of 5302 women with dysbacteriosis were selected as 2 separate study groups. The control cohort consisted of women who had completely normal cervical smears (n = 87,903 women). These groups were followed retrospectively over time. The odds ratios (OR) for squamous abnormalities in the follow-up smear for the women in these 3 cohorts were established. RESULTS: The dysbacteriotic cohort was significantly more likely to have low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL+) in their follow-up smear (OR, 1.85; 95% confidence interval [95% CI], 1.28-2.67 and OR, 2.00; 95% CI, 1.31-3.05, respectively) compared with women in the control group. In contrast, the Candida cohort had no significantly increased or decreased risk of developing SIL. The equivocal diagnosis 'atypical squamous cells of undetermined significance' was rendered significantly more often in the follow-up smear of both study cohorts (Candida cohort: OR, 1.42; 95% CI, 1.03-1.95; dysbacteriotic cohort: OR, 1.44; 95% CI, 1.22-1.71). CONCLUSIONS: The results from this study indicated that the presence of Candida vaginalis was not associated with an increased risk for SIL over time. In contrast, women with dysbacteriosis had a significantly increased risk of developing (pre)neoplastic changes. These findings should be taken into account in further research concerning predisposing factors for cervical carcinogenesis.

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.