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.

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.

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.

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.

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.

[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.

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.

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.

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.

Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers.

OBJECTIVE: Women with a BRCA1/2 mutation or members of a hereditary breast ovarian cancer family (HBOC) have an increased risk of developing ovarian cancer. The only effective strategy to reduce this risk is a risk reducing salpingo-oophorectomy (RRSO). The aim of this study was to evaluate the short-term surgical outcome and safety of a RRSO. PATIENT AND METHODS: Included were all consecutive women with a BRCA1/2 mutation or members of a HBOC family who visited our Family Cancer Clinic between September 1995 and March 2006, and choose for RRSO. RESULTS: 159 women were included, of which 97 (61.0%) BRCA1 and 32 (20.1%) BRCA2 mutation carriers, and 30 women of a HBOC family (18.9%). The median age at RRSO was 42.9 years (30.3-61.1) in the BRCA1 group, 48.4 years (33.5-66.9) in the BRCA 2 group and 46.4 (32.8-68.7) years in the HBOC group (p=0.02). The median body mass index (BMI) was 24.9 kg/m(2), 30.1% were overweighed (BMI 25-30) and 18.7% were obese (BMI>30). The RRSO was performed by primary laparoscopy (n=154) or laparotomy (n=5). Intraoperatively, one (0.6%) major complication occurred and laparoscopy was converted to laparotomy. In one patient (0.6%) a minor complication occurred. Post-operatively five minor complications (3.1%) were observed. Median hospital stay was 1 day (0-13 days). CONCLUSION: Laparoscopic RRSO in BRCA1/2 mutation carriers seems to be a safe procedure with a low intraoperative and post-operative complication rate (1.3% and 3.1% respectively), a low conversion rate (0.6%) and a short median hospital stay (1.0 day).

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.

Reflective professionalism: interpreting CanMEDS' "professionalism".

Residency training in the Netherlands is to be restructured over the coming years. To this end a general competence profile for medical specialists has been introduced. This profile is nearly the same as the Canadian CanMEDS 2000 model, which describes seven general areas of medical specialist competence, one of which is professionalism. In order to establish a training programme for residents and their instructors based on this competence, it is necessary to develop a vision that does justice to everyday medical practice. The two most prevailing views of professionalism--as personal, or as a behavioural characteristic--fall short of this. Only when professionalism is understood as reflective professionalism does it encompass the fundamental contextuality of medical treatment. This means that the focus of training and assessment must be shifted to accountability for treatment.

Exogenous steroids for menopausal symptoms and breast/endometrial cancer risk.

A literature search was performed to collect information concerning hormone replacement therapy (HRT) for menopausal symptoms by exogenous steroids and breast and endometrial cancer risk. Relevant studies in English were selected from Medline. HRT can alleviate vasomotor symptoms at least partially. HRT in women >50 years of age induces increased risk of breast and endometrial cancer. In women <50 years of age, HRT does not completely negate the breast cancer risk reduction by premature menopause. No data exist on endometrial cancer risk in these young women taking HRT. In conclusions, the decision to use HRT should be weighed against the risks and discouraged in women older than 50 years of age and after breast cancer. Counseling should be performed in an individual manner.

Association between the CHEK2*1100delC germ line mutation and estrogen receptor status.

Already published data were further analyzed regarding the association between the CHEK2*1100delC germ line mutation and estrogen receptor (ER) status in patients with breast cancer. The CHEK2*1100delC mutation was more prevalent among the patients with a positive ER status (4.2% versus 1.0%). An ER-negative status was beside CHEK2*1100delC mutation and independently associated with an earlier of age onset of breast cancer. There was a trend that an ER-negative status, beside the presence of a CHEK2*1100delC mutation, was associated with a worse disease-free survival. There might be an association between ER status and a CHEK2*1100delC mutation. More studies with larger number of patients are needed to further investigate the relation between CHEK2*1100delC and ER status.