Roy F.P.M. Kruitwagen

Endometrial epithelial cells in peritoneal fluid during the early follicular phase

Peritoneal fluid (PF) was obtained during the early follicular phase in 24 women at laparoscopy as part of infertility investigation. The cells present in PF were pelleted and cultured. Developing endometrial epithelial cell colonies were identified in 19 women (79%). Identification of these cell colonies was facilitated using the monoclonal antibody BW 495/36 as specific marker. The number of endometrial epithelial cell colonies showed a large variation (1 to 200 or more PF sample). No significant distinction in incidence and number of cell colonies was found between women with minimal (n = 11) and without endometriosis (n = 12). A significant correlation with number of cell colonies was found in women with infertility and no mechanical and male infertility factors. These data indicate that retrograde transport of viable endometrial cells during menstruation occurs in most women with patent tubes. Implications of the results for the relation between retrograde menstruation, endometriosis, and infertility are discussed.

Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis

Objective To estimate the disease burden of the most important complications of postoperative abdominal adhesions: small bowel obstruction, difficulties at reoperation, infertility, and chronic pain. Design Systematic review and meta-analyses. Data sources Searches of PubMed, Embase, and Central, from January 1990 to December 2012, without restrictions to publication status or language. Study selection All types of studies reporting on the incidence of adhesion related complications were considered. Data extraction and analysis The primary outcome was the incidence of adhesive small bowel obstruction in patients with a history of abdominal surgery. Secondary outcomes were the incidence of small bowel obstruction by any cause, difference in operative time, enterotomy during adhesiolysis, and pregnancy rate after abdominal surgery. Subgroup and sensitivity analyses were done to study the robustness of the results. A random effects model was used to account for heterogeneity between studies. Results We identified 196 eligible papers. Heterogeneity was considerable for almost all meta-analyses. The origin of heterogeneity could not be explained by study design, study quality, publication date, anatomical site of operation, or operative technique. The incidence of small bowel obstruction by any cause after abdominal surgery was 9% (95% confidence interval 7% to 10%; I2=99%). the incidence of adhesive small bowel obstruction was 2% (2% to 3%; I2=93%); presence of adhesions was generally confirmed by emergent reoperation. In patients with a known cause of small bowel obstruction, adhesions were the single most common cause (56%, 49% to 64%; I2=96%). Operative time was prolonged by 15 minutes (95% confidence interval 9.3 to 21.1 minutes; I2=85%) in patients with previous surgery. Use of adhesiolysis resulted in a 6% (4% to 8%; I2=89%) incidence of iatrogenic bowel injury. The pregnancy rate after colorectal surgery in patients with inflammatory bowel disease was 50% (37% to 63%; I2=94%), which was significantly lower than the pregnancy rate in medically treated patients (82%, 70% to 94%; I2=97%). Conclusions This review provides detailed and systematically analysed knowledge of the disease burden of adhesions. Complications of postoperative adhesion formation are frequent, have a large negative effect on patients’ health, and increase workload in clinical practice. The quantitative effects should be interpreted with caution owing to large heterogeneity. Registration The review protocol was registered through PROSPERO (CRD42012003180).

Ovarian stimulation and granulosa-cell tumour

Abstract Ovarian stimulation in the treatment of infertility is far from physiological because patients and their ovaries are exposed to high concentrations of gonadotropins. Many studies have focused on the two most common side-effects of ovarian stimulation—ie, hyperstimulation and multiple pregnancy. We describe 12 patients in whom granulosa-cell tumour was discovered after ovarian stimulation treatment with clomiphene citrate and/or gonadotropins. Although we cannot prove a causal link between the tumour and the medication, investigations in animals have shown a relation between gonadotropin exposition and the development of granulosa-cell tumours. The possible relation of ovarian stimulation and granulosa-cell tumours in human beings has not been published before. We postulate three explanations for this finding; first, the granulosa-cell tumour is present in the ovary, waiting for a hormonal trigger; second, increased follicle stimulating hormone concentrations are oncogenic to granulosa cell; and third, the onset of the granulosa-cell tumour during ovarian stimulation is coincidental. We recommend that ovarian stimulation is done only if there is a valid indication after proper assessment of the ovaries, and that women who have had ovarian stimulation are followed for longer than at present.

The Accuracy of Risk Scores in Predicting Ovarian Malignancy: A Systematic Review

OBJECTIVE: To perform a systematic review of the literature on the accuracy of prediction models in the preoperative assessment of adnexal masses. DATA SOURCES: Studies were identified through the MEDLINE and EMBASE databases from inception to March 2008. The MEDLINE search was performed using the keywords [“ovarian neoplasms”[MeSH] NOT “therapeutics”[MeSH] AND “model”] and [“ovarian neoplasms”[MeSH] NOT “therapeutics”[MeSH] AND “prediction”]. The Embase search was performed using the keywords [ovary tumor AND prediction], [ovary tumor AND Mathematical model], and [ovary tumor AND statistical model]. METHODS OF STUDY SELECTION: The search detected 1,161 publications; from the cross-references, another 116 studies were identified. Language restrictions were not applied. Eligible studies contained data on the accuracy of models predicting the risk of malignancy in ovarian masses. Models were required to combine at least two parameters. TABULATION, INTEGRATION, AND RESULTS: Two independent reviewers selected studies and extracted study characteristics, study quality, and test accuracy. There were 109 accuracy studies that met the selection criteria. Accuracy data were used to form two-by-two contingency tables of the results of the risk score compared with definitive histology. We used bivariate meta-analysis to estimate pooled sensitivities and specificities and to fit summary receiver operating characteristic curves. Studies included in our analysis reported on 83 different prediction models. The model developed by Sassone was the most evaluated prediction model. All models has acceptable sensitivity and specificity. However, the Risk of Malignancy Index I and the Risk of Malignancy Index II, which use the product of the serum CA 125 level, an ultrasound scan result, and the menopausal state, were the best predictors. When 200 was used as the cutoff level, the pooled estimate for sensitivity was 78% for a specificity of 87%. CONCLUSION: Based on our review, the Risk of Malignancy Index should be the prediction model of choice in the preoperative assessment of the adnexal mass.

Health-Related Quality of Life in Cervical Cancer Survivors: A Population-Based Survey

PURPOSE In a population-based sample of cervical cancer survivors, health-related quality of life (HRQoL) was assessed 2-10 years postdiagnosis. METHODS AND MATERIALS All patients given a diagnosis of cervical cancer in 1995-2003 in the Eindhoven region, The Netherlands, and alive after Jan 2006 were identified through the cancer registry. Generic HRQoL (36-Item Short-Form Health Survey, EQ-5D), cervical cancer-specific HRQoL (European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire cervical cancer module), and anxiety (6-item State Trait Anxiety Inventory) were assessed and compared with a reference population (n = 349). Data for tumor characteristics at diagnosis and disease progression were available. RESULTS A total of 291 women responded (69%), with a mean age of 53 +/- 13 (SD) years (range, 31-88 years). Treatment had consisted of surgery (n = 195) or a combination of therapies (n = 75); one woman had not been treated. Of all women, 85% were clinically disease free, 2% had a recurrence/metastasis, and in 13%, this was unknown. After controlling for background characteristics (age, education, job and marital status, having children, and country of birth), generic HRQoL scale scores were similar to the reference population, except for worse mental health in survivors. The most frequent symptoms were crampy pain in the abdomen or belly (17%), urinary leakage (15%), menopausal symptoms (18%), and problems with sexual activity. Compared with the 6-10-year survivors, more sexual worry and worse body image were reported by the 2-5-year survivors. Compared with surgery only, especially primary radiotherapy was associated with an increased frequency of treatment-related side effects, also after controlling for age and disease stage at diagnosis and follow-up. CONCLUSIONS Most cervical cancer survivors were coping well, although their mental health was worse than in the reference population. Even after 2-10 years, radiotherapy was associated with an increased frequency of treatment-related side effects.

High Concordance of Results of Testing for Human Papillomavirus in Cervicovaginal Samples Collected by Two Methods, with Comparison of a Novel Self-Sampling Device to a Conventional Endocervical Brush

ABSTRACT A user-friendly self-sampling method for collecting representative cervical cell material would lower the threshold for women to respond to the invitation for cervical screening. In the present article, we introduce such a device; we have evaluated its sensitivity and specificity to detect high-grade cervical intraepithelial neoplasia (CIN), via high-risk human papillomavirus (hrHPV) detection and liquid-based cytology (LBC), compared to endocervical brush samples obtained by gynecologists. Women who had a cervical smear reading of moderate dyskaryosis or worse or a repeat equivocal Pap smear result in the cervical screening program (n = 64) and healthy volunteers (n = 32) took a self-obtained sample at home prior to their visit to the gynecological outpatient department. At the outpatient department, an endocervical brush smear was taken, followed by colposcopy and biopsy whenever applicable. Both self-obtained samples and endocervical brush samples were immediately collected in Surepath preservation solution and used for LBC and hrHPV testing (by general primer-mediated GP5+/6+ PCR). hrHPV test results showed a good concordance between the two sample types (87%; κ = 0.71), with sensitivities for prevalent high-grade CIN that did not differ significantly (92% and 95%; P = 1.0). The hrHPV test on self-obtained samples proved to be at least as sensitive for high-grade CIN as cytology on endocervical brush samples (34/37 versus 31/37; P = 0.5). LBC showed a poor concordance between self-obtained and endocervical brush samples (60%; κ = 0.27). In conclusion, self-obtained samples taken by this novel device are highly representative of the hrHPV status of the cervix. In combination with hrHPV testing, the use of this device may have implications for increasing the attendance rate for cervical screening programs.

Lymph node metastasis in stages I and II ovarian cancer: A review

OBJECTIVES The purpose of this review is to determine the incidence of lymph node metastases in clinical stages I and II ovarian cancer. METHODS Relevant articles were identified from MEDLINE and EMBASE, supplemented with citations from reference lists from the primary studies. Eligibility was evaluated by two authors. Included studies were prospective or retrospective cohort studies, which analyzed patients with clinical early stage EOC who underwent a complete pelvic and para-aortic lymphadenectomy as a part of a staging laparotomy. RESULTS Fourteen studies were included in the analysis. The mean incidence of lymph node metastases in clinical stages I-II EOC was 14.2% (range 6.1-29.6%), of which 7.1% only in the para-aortic region, 2.9% only in the pelvic region, and 4.3% both in the para-aortic and pelvic region. Grade 1 tumors had a mean incidence of lymph node metastases of 4.0%, grade 2 tumors 16.5.8% and grade 3 tumors 20.0%. According to histological subtype, the highest incidence of lymph node metastases was found in the serous subtype (23.3%), the lowest in the mucinous subtype (2.6%). In unilateral tumors, pelvic lymph node metastases were found in 9.7% on both sides, 8.3% only at the ipsilateral side, and in 3.5% only at the contralateral side. CONCLUSIONS The incidence of lymph node metastases in clinical early stage EOC is considerable. Based on the scarce literature data, omitting a systematic lymphadenectomy can only be considered in grade I mucinous tumors.

Evaluation of adnexal masses with three-dimensional ultrasonography.

OBJECTIVE: To estimate whether three-dimensional ultrasonography and three-dimensional power Doppler investigation can contribute to the differentiation between benign and malignant ovarian masses. METHODS: Women scheduled for surgical treatment of an adnexal mass were included in a multicenter prospective study. All women underwent two-dimensional and three-dimensional ultrasonographic examination in the week before surgery. All parameters were compared in women with benign tumors, borderline tumors, and malignant tumors using receiver operating characteristic analysis and likelihood ratios. RESULTS: We included 181 women; 144 had a benign mass, 26 had a malignancy, and 11 had a borderline tumor. At three-dimensional ultrasonography, the most striking difference was found in the presence of central vessels in an adnexal mass. Central vessels assessed by three-dimensional ultrasonography were present in 15% (21 of 144) of the benign masses, 69% (18 of 26) of the malignant masses, and 27% (3 of 11) of the masses of borderline malignancy. The likelihood ratios for presence of central vessels for a mass being malignant and/or borderline was 4.9 (95% confidence interval 2.1–12). Mean gray index and flow index were also significantly different between the groups, but other features were not. CONCLUSION: The central localization of vessels in an adnexal mass, as observed by three-dimensional ultrasonography, the mean gray index, and the flow index are potentially important parameters for distinguishing benign from malignant adnexal masses. LEVEL OF EVIDENCE: II-2

Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients

Malnutrition, weight loss, and muscle wasting (sarcopenia) are common among women with advanced ovarian cancer and have been associated with adverse clinical outcomes and survival. Our objective is to investigate overall survival (OS) related to changes in skeletal muscle (SM) for patients with advanced ovarian cancer treated with neoadjuvant chemotherapy and interval debulking.

Reproductive and hormonal factors in association with ovarian cancer in the Netherlands Cohort Study.

Parity, oral contraceptive use, and hysterectomy are known to protect against ovarian cancer, whereas the effect of other reproductive factors remains unclear. The authors investigated the association between several reproductive and hormonal factors and the risk of epithelial invasive ovarian cancer among postmenopausal women participating in the Netherlands Cohort Study on Diet and Cancer. Information on reproductive history and exogenous hormone use was obtained through a self-administered questionnaire at baseline in 1986. After 16.3 years of follow-up, 375 cases and 2,331 subcohort members were available for case-cohort analysis. Ovarian cancer risk was reduced for parous women, with increasing parity, and for hysterectomized women. Moreover, the authors found evidence that oral contraceptive use is protective against ovarian cancer, even when initiated at an older age. In addition, a reduced risk was observed for each year reduction in age at natural menopause and per year reduction in total menstrual life span. A small increased risk was observed with prolonged time to pregnancy, but no difference was found between ever-married nulliparous women and never-married nulliparous women. Moreover, no associations were observed for age at first birth, age at menarche, age at first and last use of oral contraceptives, and use of hormone replacement therapy.