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Background Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast cancer (IDC) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA. Methods We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry. Results Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in five cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC. Cytoplasmic staining of PDCD4 increased from normal to IDC, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue. Conclusion Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes.

Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment. Immune checkpoint blockade (ICB) has shown promising activity in patients with advanced endometrial cancer, however its potential in the context of loco-regional disease remains unclear. Here the authors report the results of a phase I trial of neoadjuvant pembrolizumab (anti-PD1) in patients with mismatch repair deficient resectable endometrial cancer.

ObjectivesWe studied the impact of the COVID-19 pandemic on the care of patients with epithelial ovarian cancer (EOC) in the Netherlands.MethodsData of the Netherlands Cancer Registry was used to perform a retrospective cohort study on women of 18+ years diagnosed with EOC in the period 2017–2020 who were treated in the Netherlands. Waiting times and treatment characteristics were compared for the period before the COVID-19 pandemic (2017–2019) with the period during the COVID-19 pandemic (2020).ResultsDuring the pandemic, more women were diagnosed with FIGO stage IV (28.7%) compared to the period before the pandemic (23.7%, p=0.034). Mean time between first hospital consultation and first treatment did not differ significantly between both periods; for stage I-IIA it was 34 days during the pandemic and 36 days before the pandemic, for stage IIB-IIIC it was 35 vs 37 days and for stage IV 37 vs 35 days, respectively. Time between cytoreductive surgery (CRS) and adjuvant chemotherapy was significantly shorter during the pandemic for stage IIB-IIIC (24 days vs 30 days before the pandemic, p<0.001).ConclusionsIn the Netherlands during the COVID-19 pandemic (2020), an increase in FIGO stage IV EOC was observed compared to the period before the pandemic (2017–2019). This might be due to patient-delay and/or delay in referral or to the introduction of HIPEC for stage IIIC. A decrease in the interval between CRS and adjuvant chemotherapy was observed. A decrease in elective procedures and treatments may be an important cause of the reduction in waiting time for chemotherapy.

ObjectivesWe evaluated the experience of caregivers on the healthcare of gynaecological cancer patients during the first wave (March-June) of the COVID-19 pandemic in 2020 in the Netherlands.MethodsAn online questionnaire was sent to gynaecologists, gynaecological oncologists, medical- and radiation oncologists throughout the Netherlands. The self-developed questionnaire consisted of questions about gynaecological cancer in general and endometrial, ovarian, cervical and vulvar cancer specifically.ResultsSixty-four (63%) physicians participated: 33 gynaecologists (52%), 13 gynaecological oncologists (20%), 7 medical oncologists (11%) and 11 radiation oncologists (17%). Fifty-nine percent of the respondents (35/59) reported a change in the way of contact with patients during the ‘diagnostic phase’ : patients were more often contacted by telephone during the pandemic (80%, 28/35, e.g. first consult or discussing results). For ovarian cancer 17% (4/23) reported a change in type of surgery and 22% (11/49) in (neo)adjuvant treatment (e.g. delay, more cycles, referral). For endometrial 21% (12/56), cervical 26% (7/27) and vulvar cancer 32% (6/19) longer waiting times for surgery were reported (3% <1 week, 58% 1–3 weeks, 39% >3 weeks). Eighty-nine percent of the respondents (46/52) reported a change in follow-up: 91% (42/46) reported follow-up consultation by telephone or video, 63% (32/51) reported postponed follow-up appointments.ConclusionsThe questionnaire showed that during the first wave of the COVID-19 pandemic, most caregivers experienced a different way of contact during the diagnostic and follow-up phase. Consultation by telephone could a good alternative in the follow-up phase, e.g. for low risk patients without symptoms, even after the pandemic.

ObjectivesWe assessed the importance of extensive processing of risk-reducing salpingo-oophorectomy (RRSO) specimens with regard to 1) detecting serous tubal intra-epithelial carcinoma (STIC) or high-grade serous carcinoma (HGSC) at RRSO and 2) development of HGSC in the follow-up after normal RRSO in BRCA1/2 germline pathogenic variant (gPV) carriers.MethodsFrom Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) study, BRCA1/2 gPV carriers who underwent RRSO between 1995 and 2018 were included. Pathology reports of RRSOs were retrieved from the Dutch pathology registry and extent of processing was assessed. To confirm diagnoses of STIC/HGSC at RRSO or HGSC after normal RRSO, tissue slides of RRSO specimens with (pre)malignancy and from women who developed HGSC after RRSO were reviewed. Fisher’s exact and Mann-Whitney U test were used to compare the extent of processing between the groups.ResultsIn total 2557 women, of which 1624 BRCA1, 930 BRCA2, and 3 with both BRCA1/2 gPV with 10.5 years of median follow-up were included. 8 isolated STICs and 30 HGSCs at RRSO were found, with 16 HGSCs after normal RRSO. Women with STIC/HGSC at RRSO more often had totally embedded fallopian tubes and ovaries (81.6 and 84.2 versus 61.1 and 65.9% respectively; p=0.01 and p=0.02). Women who did not have their RRSO specimen totally embedded had a 6 times higher risk to develop HGSC during follow-up.ConclusionsExtensive processing of RRSO specimens of BRCA1/2 gPV carriers increased detection of STIC/HGSC at RRSO and subsequently resulted in a risk-reduction for developing HGSC after normal RRSO.

ObjectivesWe investigated the prevalence and reproductive and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2 germline pathogenic variant (gPV) carriers.MethodsBRCA1/2 gPV carriers who underwent RRSO between 1995 and 2018 were identified in the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) study. Pathology reports were screened and RRSO specimens with any reported epithelial abnormality and of women with HGSC after normal RRSO were histologically reviewed. Clinical characteristics of women with and without HGSC at RRSO were compared to estimate the association between risk factors and HGSC at RRSO.Results2557 women of which 1624 BRCA1, 930 BRCA2 and 3 women with both BRCA1/2 gPV, were included. Median age at time of RRSO was 43.0 years (range: 25.3–73.8) for BRCA1 gPV carriers and 46.8 years (range: 27.6–77.9) for BRCA2 gPV carriers. At RRSO 24 (1.5%) BRCA1 and 6 (0.6%) BRCA2 gPV carriers had HGSC. In 73.3% the primary site of HGSC was the fallopian tube. For both BRCA1 gPV and BRCA2 gPV carriers, older age at RRSO was associated with an increased risk of HGSC at RRSO, while long-term use of oral contraceptive pill (OCP) was protective.ConclusionsHGSC was detected in 1.5% (BRCA1 gPV) and 0.6% (BRCA2 gPV) of RRSO specimens from asymptomatic carriers, with most HGSC lesions found in the fallopian tube. Our results support the fallopian tube hypothesis, highlight the importance of timely RRSO and total removal of fallopian tubes and show protective effects of OCP on HGSC.

To study the impact of the COVID-19 pandemic and consequent lockdown on the number of diagnoses of gynaecological malignancies in the Netherlands. We performed a retrospective cohort study using data from the Netherlands Cancer Registry (NCR) on women of 18 years and older diagnosed with invasive endometrial, ovarian, cervical or vulvar cancer in the period 2017–2021. Analyses were stratified for age, socioeconomical status (SES) and region. The incidence rate of gynaecological cancer was 67/100.000 (n = 4832) before (2017–2019) and 68/100.000 (n = 4833) during (2020) the COVID-19 pandemic. Comparing the number of diagnoses of the two periods for the four types of cancer separately showed no significant difference. During the first wave of COVID-19 (March-June 2020), a clear decrease in number of gynaecological cancer diagnoses was visible (20–34 %). Subsequently, large increases in number of diagnoses were visible (11–29 %). No significant differences in incidence were found between different age groups, SES and regions. In 2021 an increase of 5.9 % in number of diagnoses was seen. In the Netherlands, a clear drop in number of diagnoses was visible for all four types of gynaecological cancers during the first wave, with a subsequent increase in number of diagnoses in the second part of 2020 and in 2021. No differences between SES groups were found. This illustrates good organisation of and access to health care in the Netherlands. •The decrease in incidence was mainly visible during the first wave of COVID-19.•Differences in COVID-19 burden across the country did not impact the incidence.•No differences in incidence were found for SES and age before and during COVID-19.

BackgroundVulvar squamous cell carcinoma (VSCC) is a rare cancer for which the cornerstone of treatment is surgery with high complication rates. The unmet need is a less radical and more effective treatment for VSCC.Primary ObjectivesTo investigate the impact of mono-immunotherapy pembrolizumab as neoadjuvant treatment for primary resectable VSCC patients.Study HypothesisSome primary VSCC patients display a specific immune profile which is associated with better survival. In other tumors, this profile is associated with a better response to programmed cell death protein 1 (PD-1) checkpoint blockade which may reinvigorate tumor-specific T cells. This potentially results in a reduced tumor load and less radical surgery and/or adjuvant treatment in patients with this immune profile.Trial DesignThis is an investigator-initiated, prospective, single arm, multicenter, phase II clinical trial.Inclusion CriteriaPatients with VSCC clinical stage International Federation of Gynecology and Obstetrics (FIGO) I-III (2021) eligible for primary surgery, with at least one measurable lesion of at least one dimension ≥10 mm in the largest diameter, are included in this study.Main Exclusion CriteriaPatients not suitable for surgery and/or previously treated with immunomodulatory agents, and/or who suffer from comorbidities that may interfere with PD-1 blockade, are excluded from the study.EndpointsThe clinical efficacy of neoadjuvant pembrolizumab in VSCC is measured by an objective change in tumor size according to the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) and documented by calipers using standardized digital photography with a reference ruler. In addition, the activation, proliferation, and migration of T cells in the tumor will be studied. The secondary endpoints are pathological complete responses at the time of surgery, feasibility, and safety.Sample Size40 patients with FIGO I-III (2021) primary VSCC will be enrolled.Estimated Dates for Completing Accrual and Presenting ResultsThe intervention phase started in July 2023 and will continue until July 2025. The expected completion of the entire study is July 2026.Trial Registration NumberNCT05761132

BackgroundSince 2015, Dutch guidelines have recommended BRCA1/2 pathogenic variant testing for all patients with epithelial ovarian cancer. Recently, recommendations shifted from germline testing to the tumor-first approach, in which tumor tissue is tested first, and subsequent germline testing is performed only in those with BRCA1/2 tumor pathogenic variants or a positive family history. Data on testing rates and on characteristics of patients missing out on testing remain scarce.ObjectiveTo evaluate BRCA1/2 testing rates in patients with epithelial ovarian cancer and compare testing rates of germline testing (performed from 2015 until mid-2018) versus tumor-first testing (implemented mid-2018).MethodsA consecutive series of 250 patients diagnosed with epithelial ovarian cancer between 2016 and 2019 was included from the OncoLifeS data-biobank of the University Medical Center Groningen, the Netherlands. Testing rates were analyzed for the overall study population and for germline testing (period I) and tumor-first testing (period II) separately. Characteristics of tested and untested patients were compared and predictors for receiving testing were assessed with multivariable logistic regression.ResultsMedian age was 67.0 years (IQR 59.0–73.0) and 173 (69.2%) patients were diagnosed with high-grade serous carcinoma. Overall, 201 (80.4%) patients were tested. In period I, 137/171 (80.1%) patients were tested and in period II this was 64/79 (81.0%). Patients with non-high-grade serous carcinoma were significantly less likely to receive BRCA1/2 testing than patients with high-grade serous carcinoma (OR=0.23, 95% CI 0.11 to 0.46, p<0.001).ConclusionsThe results show that BRCA1/2 testing rates are suboptimal and suggest that clinicians may not be choosing to test patients with epithelial ovarian cancer with non-high-grade serous ovarian carcinoma, although guidelines recommend BRCA1/2 testing in all patients with epithelial ovarian cancer. Suboptimal testing rates limit optimization of care for patients with epithelial ovarian cancer and counseling of potentially affected relatives.

ObjectivesTo evaluate BRCA1/2 testing rates in epithelial ovarian cancer (EOC) patients and to compare rates of germline testing (performed until mid 2018) versus tumor-first testing with germline testing only in those with a positive tumor test (implemented mid 2018). Additionally, we aimed to delineate characteristics of patients who were less likely to receive BRCA1/2 testing.MethodsA consecutive series of 250 patients diagnosed with EOC between 2016 and 2019 was included from the OncoLifeS Databiobank of the University Medical Center Groningen. Testing rates were analyzed for the overall study population and by period of diagnosis to evaluate rates of germline testing (period I) and tumor-first testing (period II) separately. Characteristics of tested and untested patients were compared using the appropriate test.ResultsMedian age was 67.0 years (IQR 59.0–73.0) and 69.2% was diagnosed with high-grade serous carcinoma (HGSC). Overall, 80.0% of all patients had a known germline pathogenic variant (GPV) status. In period I, 79.5% had a known GPV status and in period II this was 81.0%. Overall, as well as in period I and II separately, the proportion of patients diagnosed with non-HGSC was significantly greater in the untested group compared to the tested group (overall: 51.0% versus 23.5%; P<0.001).ConclusionsThe results show that BRCA1/2 testing rates are suboptimal and suggest that clinicians may deliberately choose not to test EOC patients with non-HGSC, although guidelines recommend BRCA1/2 testing in all EOC patients. Suboptimal testing rates limit the optimization of care for EOC patients and counseling of potentially affected relatives.