Does serous tubal intraepithelial carcinoma (STIC) metastasize? The clonal relationship between STIC and subsequent high-grade serous carcinoma in BRCA1/2 mutation carriers several years after risk-reducing salpingo-oophorectomy.

OBJECTIVE: The majority of high-grade serous carcinomas (HGSC) of the ovary, fallopian tube, and peritoneum arise from the precursor lesion called serous tubal intraepithelial carcinoma (STIC). It has been postulated that cells from STICs exfoliate into the peritoneal cavity and give rise to peritoneal HGSC several years later. While co-existent STICs and HGSCs have been reported to share similarities in their mutational profiles, clonal relationship between temporally distant STICs and HGSCs have been infrequently studied and the natural history of STICs remains poorly understood. METHODS: We performed focused searches in two national databases from the Netherlands and identified a series of BRCA1/2 germline pathogenic variant (GPV) carriers (n = 7) who had STIC, and no detectable invasive carcinoma, at the time of their risk-reducing salpingo-oophorectomy (RRSO), and later developed peritoneal HGSC. The clonal relationship between these STICs and HGSCs was investigated by comparing their genetic mutational profile by performing next-generation targeted sequencing. RESULTS: Identical pathogenic mutations and loss of heterozygosity of TP53 were identified in the STICs and HGSCs of five of the seven patients (71%), confirming the clonal relationship of the lesions. Median interval for developing HGSC after RRSO was 59 months (range: 24-118 months). CONCLUSION: Our results indicate that cells from STIC can shed into the peritoneal cavity and give rise to HGSC after long lag periods in BRCA1/2 GPV carriers, and argues in favor of the hypothesis that STIC lesions may metastasize.

Characteristics of Lynch syndrome associated ovarian cancer.

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.

Outcome of BRCA1- compared with BRCA2-associated ovarian cancer: a nationwide study in the Netherlands.

BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome.

OBJECTIVE: Based on previous studies, standard gynecological screening consisting of annual transvaginal ultrasonography (TVU) was added with endometrial sampling in women with Lynch syndrome (LS). The aim of this study was to evaluate the additional value of endometrial sampling in detecting (pre)malignancies of the endometrial tissue in women with LS or first-degree relatives. METHODS: All women above 30 years of age with LS or first-degree relatives at 50% risk of LS are offered annual gynecological screening in our family cancer clinic. Endometrial screening results from January 2003-December 2007 (period I: standard screening by transvaginal sonography and serum CA125) were compared with screening results from January 2008-June 2012 (period II: standard screening added with endometrial sampling). RESULTS: Seventy five women (300 patient years) were screened annually. There were 266 screening visits, 117 in period I and 149 in period II. In period I, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II, two premalignancies were found. None of the lesions would have been missed without standard endometrial sampling. No interval endometrial cancers were detected in this study. CONCLUSION: In this study, annual endometrial screening seems an effective screening tool in the detection of premalignancies and early endometrial cancer in women with LS. Adding standard endometrial sampling to annual TVU has no additional value in the early detection of (pre)malignant endometrial lesions in women with LS in this study.

Genetic counseling of patients with ovarian carcinoma: acceptance, timing, and psychological wellbeing.

The new Dutch guidelines on hereditary and familial ovarian carcinoma recommend genetic testing of all patients with epithelial ovarian cancer (EOC). With this study, we aimed to obtain insight into (1) the acceptance and timing of the offer of genetic counseling in women with EOC, (2) reasons for accepting or declining genetic counseling, and (3) psychological differences between women who did and did not have genetic counseling. A multicenter questionnaire survey was performed in patients with EOC in four Dutch oncology centers. The questionnaire addressed whether, how, and when genetic counseling was offered, women's arguments to accept or decline genetic counseling, and included the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS). A total of 67 women completed the questionnaire, of which 43 had genetic counseling. Despite a wide variability in the timing of the offer of genetic counseling, 89% of the women were satisfied with the timing. No significant differences were found between the CWS and HADS scores for the timing of the offer of genetic counseling and whether or not women had genetic counseling. Taking the small sample size into account, the results tentatively suggest that genetic counseling may have limited impact on the psychosocial wellbeing of women with EOC. Therefore, we assume that implementation of the new guidelines offering genetic counseling to all patients with EOC will not cause considerable additional burden to these patients.

Routine follow-up intervals in patients with high-grade squamous intraepithelial lesions (HSIL) and free excision margins can safely be increased in the first two years after Large Loop Excision of the Transformation Zone (LLETZ).

OBJECTIVE: To assess the compliance of HSIL patients to the national Dutch routine follow-up protocol in the first 2 years after LLETZ and to determine if based on the status of excision margins, follow-up intervals could be modified. METHODS: A prospective cohort study was performed in patients, referred because of an abnormal Pap smear between 1996 and 2004 and treated for HSIL with LLETZ. The Dutch national routine follow-up protocol orders a Pap smear after 6, 12 and 24 months, respectively. Follow-up results were completed by using PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands. To assess compliance to the follow-up protocol, adequate follow-up was defined as three cervical smears taken after 6 (+/-3), 12 (+/-3) and 24 (+/-3) months, respectively. RESULTS: Compliance to the first 2 years follow-up protocol declined from 86.2% to 64.8% to 51.2% for first, second and third follow-up cervical smears, respectively. Patients with involved excision margins had a three times higher overall risk of developing a subsequent HSIL after LLETZ as compared to patients with free excision margins (HR: 3.2, 95% CI=1.3-7.9, p=0.01). Risk for diagnosing HSIL during the first 12 months of follow-up for patients with free excision margins was only 1%. CONCLUSIONS: Compliance to the Dutch national routine follow-up protocol in HSIL patients after LLETZ is only moderate. For HSIL patients with free excision margins after LLETZ the first cytological follow-up interval can safely be increased to 12 months.

[Insufficient basis for the inclusion of Human papillomavirus vaccination in the National Immunisation Programme in The Netherlands]. / Onvoldoende gronden voor opname van vaccinatie tegen Humaan papillomavirus in het Rijksvaccinatieprogramma.

The Dutch Minister of Health, Welfare and Sportintends to implement Human papillomavirus (HPV) vaccination for 12-year-old girls and catch-up vaccination for 13- 16-year-old girls, as part of the National Immunisation Programme from September 2009 onwards. However, due to a well-organised screening programme, cervical cancer is not an important public health problem in the Netherlands any more, which limits the possible impact of HPV vaccination. Vaccine trials thus far have involved a relatively small number ofparticipants with limited follow-up, so the efficacy of the vaccine in preventing cervical cancer is not yet known. There are no data on frequency and severity of possible adverse events and the vaccine has not yet been tested in the intention-to-vaccinate group of 12-year-old girls. Even when we assume that HPV16/18-related cervical cancer is prevented on a lifelong basis, the cost-effectiveness ratio of HPV vaccination is estimated not to be favourable. In conclusion, HPV vaccination does not seem to be urgent in the Netherlands. Therefore we advise studying the safety in 12-year-old girls first while at the same time waiting for the longer follow-up results of ongoing trials.

Severity and duration of menopausal symptoms after risk-reducing salpingo-oophorectomy.

OBJECTIVES: To reduce the risk of ovarian cancer, women with BRCA1/2 mutations are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) at a premenopausal age. Premenopausal RRSO results in acute menopause and is associated with various menopausal symptoms. This study investigates the severity and duration of subjective menopausal symptoms after premenopausal RRSO and associated factors. METHODS: We included 199 women who had undergone RRSO before age 52 in this cross-sectional study. The Menopause Rating Scale (MRS) was used to measure the level of psychological, somato-vegetative and urogenital symptoms (no/little, mild, moderate, or severe). Uni- and multivariate logistic regressions were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for having moderate or severe symptoms as compared to having no or mild symptoms. Duration of symptoms was investigated by calculating the time since RRSO. RESULTS: Sixty-nine percent (137/199) of the included women reported moderate or severe symptoms on the MRS, a mean of 7.9 years after RRSO. Fifty-seven percent (94/137) of these women reported severe urogenital symptoms, and about one-quarter reported severe psychological and/or somato-vegetative symptoms. Only psychological symptoms tended to improve over time (>=10 years). A personal history of breast cancer was independently associated with having moderate or severe menopausal symptoms (OR = 3.4; 95%CI = 1.6-7.1). CONCLUSIONS: The majority of women report moderate or severe menopausal symptoms, even 10 years after surgical menopause, and breast cancer survivors especially. To improve quality of life, follow-up care after RRSO should focus on these symptoms and be accessible for many years after RRSO.

Cognitive decline after major oncological surgery in the elderly.

BACKGROUND: Elderly patients undergoing oncological surgery experience postoperative cognitive decline. The aims of this study were to examine the incidence of cognitive decline 3 months after surgery and identify potential patient-, disease- and surgery-related risk factors for postoperative cognitive decline in onco-geriatric patients. METHODS: A consecutive series of elderly patients (≥65 years) undergoing surgery for the removal of a solid tumour were included (n = 307). Cognitive performance was assessed pre-operatively and 3 months postoperatively. Postoperative decline was defined as a decline in scores of cognitive tests of ≥25% on ≥2 of 5 tests. RESULTS: Of the patients who had completed the assessments, 117 (53%, 95% confidence interval [CI]: 47-60) had improved cognitive test scores, whereas 26 (12%, 95% CI: 7.6-16) showed cognitive decline at 3 months postoperatively. In patients aged >75 years, the incidence of overall cognitive decline 3 months postoperatively was 18% (95% CI: 9.3-27). In patients with lower pre-operative Mini-Mental State Examination (MMSE) score (≤26) the incidence was 37% (95% CI: 18-57), and in patients undergoing major surgery it was 18% (95% CI: 10.6-26). Of the cognitive domains, executive function was the most vulnerable to decline. CONCLUSION: About half of the elderly patients show improvement in postoperative cognitive performance after oncological surgery, whereas 12% show cognitive decline. Advanced age, lower pre-operative MMSE score and major surgery are risk factors for cognitive decline at 3 months postoperatively and should be taken into account in the clinical decision-making progress. Research to develop interventions to preserve quality of life should focus on this high-risk subpopulation.

[CanMEDS 2015: better doctors?]. / CanMEDS 2015: nog betere dokters?

Recently, the CanMEDS model, which forms the basis for competency-based learning in both undergraduate and postgraduate training, has been renewed by the introduction of CanMEDS 2015. The most prominent change is the emphasis on leadership skills, which is also reflected by the name change for the role of 'manager' to 'leader'. The addition of milestones provides clearly defined targets for learning and assessment, which facilitates the monitoring of the progression in competence. Furthermore, CanMEDS 2015 strongly focusses on the overall coherence of the separate competencies. CanMEDS, designed as a model that helps to train young doctors to become good doctors, also helps us - the trainers - to become better doctors ourselves.

Psychological factors associated with the intention to choose for risk-reducing mastectomy in family cancer clinic attendees.

OBJECTIVES: Women seeking counseling because of familial breast cancer occurrence face difficult decisions, such as whether and when to opt for risk-reducing mastectomy (RRM) in case of BRCA1/2 mutation. Only limited research has been done to identify the psychological factors associated with the decision for RRM. This study investigated which psychological factors are related to the intention to choose for RRM. MATERIALS & METHODS: A cohort of 486 cancer-unaffected women with a family history of breast cancer completed the following questionnaires prior to genetic counseling: the Cancer Worry Scale, Positive And Negative Affect Scale, Perceived Personal Control Scale, Hospital Anxiety and Depression Scale and State Anxiety Scale and questions regarding socio-demographic characteristics, family history, risk perception and RRM intention. Multivariate logistic regression was used to analyze the relation between psychological factors and women's intention to choose for RRM. RESULTS: Factors associated with RRM intention were high positive affect (OR = 1.86, 95%CI = 1.12-3.08), high negative affect (OR = 2.52, 95%CI = 1.44-4.43), high cancer worry (OR = 1.65, 95%CI = 1.00-2.72), high perceived personal control (OR = 3.58, 95%CI = 2.18-5.89), high risk-perception (OR = 1.85, 95%CI = 1.15-2.95) and having children (OR = 2.06, 95%CI = 1.21-3.50). CONCLUSION: Negative and positive affects play an important role in the intention for RRM. Furthermore, perceived personal control over the situation is associated with an intention for RRM. In addition to focusing on accurate risk communication, counseling should pay attention to the influence of perceived control and emotions to facilitate decision-making.

Early detection of breast and ovarian cancer in families with BRCA mutations.

Women at risk of breast and ovarian cancer due to a genetic predisposition may opt for preventive surgery or surveillance. The aim of this study was to determine the effectiveness of surveillance in families with a BRCA mutation. Sixty-eight BRCA-families underwent surveillance using annual mammography, transvaginal ultrasound, and estimation of CA125. Two hundred and two women had at least one breast examination, and 138 at least one examination of the ovaries. After a mean follow-up of 33 months, breast cancer was detected in 21 women, four with lymph node metastases. After a mean follow-up of 37 months, six advanced ovarian cancers were detected. The percentage of metastatic breast cancers in the current study appeared to be acceptable. However, because these women have a high-risk of developing breast cancer, they still have a substantial risk of developing metastatic disease under surveillance. Surveillance for ovarian cancer was not effective.

A phase I study of intraperitoneal topotecan in combination with intravenous carboplatin and paclitaxel in advanced ovarian cancer.

The aim of this study was to determine the maximum tolerated dose (MTD) of intraperitoneal (i.p.) topotecan combined with standard doses of intravenous (i.v.) carboplatin and paclitaxel and to investigate its pharmacokinetics. Women with primary ovarian cancer stage IIb - IV received six cycles of i.v. carboplatin and paclitaxel with escalating topotecan doses i.p. of 10, 15, 20 and 25 mg/m(2). Twenty-one patients entered this trial. Febrile neutropenia, thrombocytopenia requiring platelet transfusion and fatigue grade 3 were dose-limiting toxicities (DLT) at 25 mg/m(2) i.p. and 20 mg/m(2) i.p. of topotecan was considered to be the MTD. The mean plasma t(1/2) was 3.8 +/- 2.3 h for total topotecan and 4.4 +/- 3.9 h for active lactone. The area under the curve (AUC) was proportional with dose, R = 0.54, p < 0.05 for total topotecan and the peritoneal / plasma AUC ratio was 46 +/- 30. Fifteen patients who completed treatment had a median progression-free survival (PFS) of 27 months. In this setting the MTD of topotecan is 20 mg/m(2) i.p. The efficacy of this regimen should be explored further in a formal phase III study.

Presentations of endometrial activity after curative radiotherapy for cervical cancer.

OBJECTIVES: The treatment of choice for patients with advanced stage cervical cancer is (chemo)radiotherapy. Gynaecologic side effects consist of loss of ovarian function and destruction of the endometrium, resulting in infertility and premature ovarian failure. In premenopausal patients estrogens are prescribed to prevent climacteric symptoms. In general, no progestagens are added to the hormone replacement therapy because of the assumption of complete destruction of the basal layer of the endometrium after pelvic radiotherapy. The aim of this report is to show the different presentations of endometrial activity after curative radiotherapy in patients with cervical cancer. METHODS: Presentation of four patients who developed symptoms of residual endometrial activity. RESULTS: In two patients, proliferation of functional endometrium led to hematocolpos and hematometrum with abdominal pain. The third patient underwent ovarian transposition and developed regular periods 3 months after finishing the radiotherapy. The fourth patient underwent trachelectomy with radiotherapy because of narrow tumour free margins. She developed vaginal blood loss after starting estrogens. CONCLUSIONS: These patients show that in premenopausal patients, curative radiotherapy until 80Gy, may lead to symptoms of residual functional endometrium, e.g. hematometrum, hematocolpos, (ir)regular vaginal blood loss. In our opinion patients should be advised to use estrogens in combination with a progestogen, instead of unopposed estrogens, to prevent stimulation of residual functional endometrium. Tibolone may be an appropriate alternative hormone replacement therapy especially with the advantage of low androgen effects which might support the sexual functions, and the decrease of breast density.

Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.

BACKGROUND: Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO. METHODS: We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO. RESULTS: Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77). CONCLUSION: In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.

Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium.

Tamoxifen increases endometrial cell proliferation and the incidence of endometrial cancer in postmenopausal women. The purpose of this study was to evaluate apoptosis and apoptosis-related factors in endometrium in relation to tamoxifen exposure. We analyzed benign postmenopausal endometrium from breast cancer patients receiving tamoxifen (n = 35) and from controls (n = 24), and endometrial cancer tissue from tamoxifen-treated breast cancer patients (n = 15) and endometrial cancer from women without tamoxifen exposure (n = 51). Apoptosis was examined morphologically, and the percentage of apoptotic epithelial cells was defined as the apoptotic index. In the benign samples, the presence of apoptotic cells was also evaluated immunohistochemically by the expression of caspase-3 and the monoclonal antibody M30. The expression of Fas, FasL, and Bcl-2 was analyzed in all tissue samples. No differences were observed in the mean apoptotic index in benign endometrium in tamoxifen users (0.17%) versus controls (0.08%), or in tamoxifen-exposed (2.46%) versus nonexposed endometrial cancer (2.28%). However, the ratio of the apoptotic index with the previously reported proliferation index was lower in benign endometrium from tamoxifen users than in controls (0.02 +/- 0.026 vs. 0.05 +/- 0.03, Mann-Whitney U <0.005). In benign endometrium FasL was more frequently expressed in tamoxifen-users than in controls (chi(2) <0.05). We conclude that the apoptosis/proliferation ratio in benign endometrium from tamoxifen users is lower than in controls, indicating that the tamoxifen-induced higher proliferation is not compensated for by increased apoptosis. An imbalance between cell proliferation and apoptosis, and possibly suppression of the antitumor immune response by FasL overexpression in tamoxifen-exposed endometrium might play a role in the development of endometrial cancer in tamoxifen users.

The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium.

AIM: To study the effects of tamoxifen on the proliferation index and oestrogen receptor (ER) and progesterone receptor (PR) expression in postmenopausal endometrium. METHODS: A total of 125 endometrial specimens of postmenopausal women, comprising benign endometria from tamoxifen users (n = 35) and non-users (n = 24), and endometrial cancer from tamoxifen users (n = 15) and non-users (n = 51), were immunohistochemically examined using MIB-1, anti-ER, and anti-PR antibodies in endometrial epithelium and stroma. RESULTS: In benign endometrium the mean MIB-1 index in the epithelium was higher in tamoxifen users than in non-users (mean, 13% (SD, 13%) v mean, 2% (SD, 2%); p < 0.05), whereas in endometrial cancer the MIB-1 index was higher, but similar in tamoxifen users and non-users (mean, 32% (SD, 24%) and mean, 35% (SD, 18%)). The expression of ER was comparably high in benign epithelium from tamoxifen users and non-users (97% and 92%, respectively), but in endometrial cancer it was lower in tamoxifen users (60% and 88%; p < 0.05). The expression of PR in stromal cells was higher in tamoxifen users, both in benign (84% v 54%) and in malignant endometrium (33% v 10%; p < 0.05). CONCLUSION: The proliferation index (as measured by MIB-1) in benign endometrial epithelium is higher in tamoxifen users than in non-users, and this might play a role in the reported higher incidence of endometrial cancer in postmenopausal tamoxifen users. The increased expression of PR in stroma from tamoxifen users with both benign and malignant endometrium demonstrates an additional oestrogenic effect of tamoxifen on the endometrial stroma.