Retrospective study of a 16 year cohort of BRCA1 and BRCA2 carriers presenting for RRSO: Prevalence of invasive and in-situ carcinoma, with follow-up.

OBJECTIVES: Carriers of BRCA1 and BRCA2 mutations are at increased risk of high grade serous carcinoma and are therefore offered risk-reducing salpingo-oophorectomy (RRSO) by 40-45 years. Most of these carcinomas are believed to arise in the fallopian tube from serous tubal intraepithelial carcinoma (STIC). We conducted a retrospective study on the prevalence of high grade serous carcinoma and STIC in BRCA1/2 carriers presenting for RRSO, and their follow-up. METHODS: Consecutive BRCA1/2 carriers presenting for an RRSO at Erasmus MC (2000-2016) were studied. SEE-FIM pathology protocol was followed from 2010 onwards. For the cases with carcinoma and/or STIC, the histology was reviewed and immunohistochemistry (p53 & MIB-1) was performed. Next Generation Targeted Sequencing (NGTS) for TP53 mutation was used to establish clonality in 2 cases. RESULTS: Of the 527 included patients, 68% were BRCA1, 31.6% were BRCA2, and 0.4% carried both mutations. The prevalence of high grade serous carcinoma was 2.3% (12/527); 59% of these were of tubal origin. High grade serous carcinoma was more common in patients operated on after the recommended age (p = 0.03). Isolated STIC was present in 0.8% (4/527). Two BRCA1 carriers with isolated STIC at RRSO developed peritoneal serous carcinoma >7 years later. Identical TP53 mutations in the peritoneal serous carcinoma and the preceding STIC established their clonal origin. CONCLUSIONS: High grade serous carcinoma is more common in BRCA1/2 carriers presenting for RRSO after the recommended age, and is more often of tubal origin. Longer follow up of patients with STIC at RRSO should be considered.

Treatment and outcome of elderly patients with advanced stage ovarian cancer: A nationwide analysis.

OBJECTIVE: To provide an overview of treatment strategies for elderly patients with advanced stage epithelial ovarian cancer (EOC) in daily practice, evaluate changes over time and relate this to surgical mortality and survival. METHODS: All women diagnosed with advanced stage (FIGO IIB and higher) EOC between 2002 and 2013 were selected from the Netherlands Cancer Registry (n=10,440) and stratified by age, stage and period of diagnosis. Elderly patients were defined as aged ≥70years. Time trends in treatment patterns and postoperative mortality were described by age category and tested using multivariable logistic regression. Relative survival was calculated. RESULTS: With advancing age, less patients received ((neo-)adjuvant) treatment. Over time, elderly patients were less often treated (OR 2002-2004 versus 2011-2013: 0.73; 95%CI:0.58-0.92). But if treated, more often standard treatment was provided and 30-day postoperative mortality decreased from 4.5% to 1.9% between 2005 and 2007 and 2011-2013. In all age categories treatment shifted from primary surgery towards primary chemotherapy, in patients aged 70-79years combination therapy increased (+5%) between 2002 and 2004 and 2011-2013. Five-year relative survival for patients diagnosed in 2008-2010 aged <70years was 34% compared to 18% for elderly patients. CONCLUSION: Large treatment differences exist between younger and elderly patients. Over time, selection of elderly patients eligible for curative surgical treatment may have improved. More elderly patients were treated with neoadjuvant chemotherapy while less patients underwent surgery and simultaneously postoperative mortality decreased. However, the large and increasing number of elderly patients without treatment and the large survival gap suggests opportunities for further improvements in the care for elderly EOC patients.

The lack of clinical value of peritoneal washing cytology in high risk patients undergoing risk-reducing salpingo-oophorectomy: a retrospective study and review.

BACKGROUND: To assess the clinical value of peritoneal washing cytology (PWC) in women with BRCA1 or BRCA2 mutations and women from a family with hereditary breast and/or ovarian cancer (HBOC) undergoing risk-reducing salpingo-oophorectomy (RRSO) in detecting primary peritoneal cancer (PPC) or occult ovarian/fallopian tube cancer. METHODS: A retrospective study of patients with known BRCA1 or BRCA2 mutation or HBOC who underwent RRSO at the Erasmus Medical Centre, Rotterdam, The Netherlands between January 2000-2014. Patients with an elevated risk of malignancy prior to the procedure were excluded from primary analysis (elevated CA-125, an ovarian mass, abdominal pain or another gynecological malignancy). A review of the literature was conducted. RESULTS: Of the 471 patients who underwent RRSO, a total of 267 cytology samples were available for analysis. Four samples showed malignant cells, all four patients were diagnosed with ovarian and/or fallopian tube cancer at histologic examination. A fifth patient, of whom no cytology sample was obtained during RRSO, developed primary peritoneal cancer 80 months post RRSO. CONCLUSIONS: This study failed to show that cytology is of value during RRSO in detecting primary peritoneal cancer, however 36% of patients with concomitant ovarian or fallopian tube cancer had positive cytology. Therefore, the routine sampling of peritoneal washings during RRSO is not found to be useful to detect subsequent PPC.

Ovarian neuroendocrine tumor metastases can induce estrogen production in postmenopausal patients.

Neuroendocrine tumors (NET) are malignant neoplasms that can be associated with specific hormonal syndromes. We describe a novel syndrome of postmenopausal vaginal bleeding and ovarian estradiol overproduction due to ovarian NET localizations. An extensive workup was performed for two index patients with ovarian metastases of small bowel neuroendocrine tumors and symptoms of postmenopausal vaginal bleeding. Clinically significant ovarian estrogen production was demonstrated by a combination of ovarian vein sampling and normalization of circulating estrogen levels after oophorectomy. Immunohistochemical analyses revealed marked aromatase immunoactivity in the ovarian NET cells, while CYP17A1 and SF-1 were detected in the adjacent ovarian stromal cells but not the NET cells. Ex vivo and in vivo endocrine tests were unable to identify a paracrine mechanism of ovarian estradiol overproduction by NET cells. A retrospective search of electronic medical records revealed that 21% (14/66) of postmenopausal patients with an ovarian NET localization reported symptoms of vaginal blood loss. Together, these findings support the presence of a novel NET-associated hormonal syndrome.

Unfavorable biological behavior and treatment response of neuroendocrine ovarian metastases of midgut neuroendocrine tumors.

Neuroendocrine ovarian metastases (NOM) predominantly derive from midgut neuroendocrine tumors (NETs) and develop in about 25% of women with advanced stage of this malignancy. Little is known of the growth rate and treatment response of NOM. We therefore evaluated the efficacy of different management options for patients with NOM, including peptide receptor radionuclide therapy (PRRT), somatostatin analogues (SSAs) and oophorectomy. Records were screened for patients with well-differentiated NOM of midgut origin that presented in our NET referral center between 1991 and 2022. Progression-free survival (PFS) and tumor growth rate (TGR) of ovarian and extra-ovarian metastases were determined using RECIST (response evaluation criteria in solid tumors) 1.1. In 12 available patients undergoing PRRT, NOM were associated with a shorter PFS than extra-ovarian metastases (P = 0.003). While PRRT induced a similar decrease in TGR for ovarian and extra-ovarian lesions in nine patients with available data (-2.3 vs -1.4, P > 0.05), only the TGR of NOM remained positive after PRRT. In 16 patients treated with SSAs, the TGR of NOM was almost three times that of extra-ovarian lesions during treatment (2.2 vs 0.8, P = 0.011). Oophorectomy was performed in 46 of the 61 included patients and was significantly associated with a prolonged OS (115 vs 38 months, P < 0.001). This association persisted after propensity score matching and correction for tumor grade and simultaneous tumor debulking. In conclusion, NOM have a higher TGR compared to extra-ovarian metastases, resulting in a shorter PFS after PRRT. Bilateral salpingo-oophorectomy should be considered for postmenopausal women with NOM undergoing surgery for metastatic midgut NETs.

Outcome of surgery in advanced ovarian cancer varies between geographical regions; opportunities for improvement in The Netherlands.

INTRODUCTION: The care for patients with epithelial ovarian cancer(EOC) is organised in eight different geographical regions in the Netherlands. This situation allows us to study differences in practice patterns and outcomes between geographical regions for patients with FIGO stage IIIC and IV. METHODS: We identified all EOC patients who were diagnosed with FIGO stage IIIC or IV between 01.01.2008 and 31.12.2015 from the Netherlands Cancer Registry. Descriptive statistics were used to summarize treatment and treatment sequence(primary cytoreductive surgery(PCS) or neoadjuvant chemotherapy and interval cytoreductive surgery(NACT-ICS)). Moreover, outcome of surgery was compared between geographical regions. Multilevel logistic regression was used to assess whether existing variation is explained by geographical region and case-mix factors. RESULTS: Overall, 6,741 patients were diagnosed with FIGO IIIC or IV disease. There were no differences in the percentage of patients that received any form of treatment between the geographical regions(range 80-86%, P = 0.162). In patients that received cytoreductive surgery and chemotherapy, a significant variation between the geographical regions was observed in the use of PCS and NACT-ICS(PCS: 24-48%, P < 0.001). The percentage of complete cytoreductive surgeries after PCS ranged from 10 to 59%(P < 0.001) and after NACT-ICS from 37 to 70%(P < 0.001). Moreover, geographical region was independently associated with the outcome of surgery, also when adjusted for treatment sequence(P < 0.001). CONCLUSION: We observed a significant variation in treatment approach for advanced EOC between geographical regions in the Netherlands. Furthermore, the probability to achieve no residual disease differed significantly between regions, regardless of treatment sequence. This may suggest that surgical outcomes can be improved across geographical regions.

Urinary GSTP1-1 excretion is markedly increased in normotensive pregnancy as well as in preeclampsia.

BACKGROUND: Glutathione S-transferases (GSTs) are present in large amounts in the human kidney, where they demonstrate a specific distribution. The assessment of urinary excretion of GST alpha (proximal tubules) and pi (distal and collecting tubules) could be helpful in determining if, and to what degree renal tubular damage is present in preeclampsia and whether this damage is in the proximal or distal region. METHODS: Urine samples were collected from 22 women with severe preeclampsia and/or HELLP syndrome (PE), from 30 non-pregnant women with a history of severe preeclampsia (HPE), from 18 women with uncomplicated pregnancies (PC) and from 30 non-pregnant women with a history of uncomplicated pregnancies (HPC). GSTA1-1 and GSTP1-1 were assayed by ELISA and were expressed as nanograms per 10 mmol creatinine (Cr). RESULTS: Median urinary GSTP1-1 concentrations were significantly (p<0.001) higher in women with preeclampsia [62.2 (4.3-291.2) ng/10 mmol Cr] compared to non-pregnant women with a history of preeclampsia [22.3 (0-142.6) ng/10 mmol Cr]). In addition, in normotensive pregnant women, urinary GSTP1-1 concentrations were significantly (p<0.01) higher [82.6 (8.3-206.7) ng/10 mmol Cr]) compared to non-pregnant controls [5.1 (0-66.7) ng/10 mmol Cr]. No difference in GSTP1-1 concentrations was found between women with preeclampsia and normotensive pregnant women. GSTA1-1 concentrations were not significantly different between the four groups of women investigated. There were no correlations between the degree of proteinuria and urinary GSTP1-1 or GSTA1-1 concentrations. CONCLUSION: GSTP1-1 metabolism in the distal tubule changes during normotensive as well as preeclamptic pregnancy. Whether this is due to tubular cell damage, disturbed resorption or an increase in cellular levels cannot be determined as yet.

Severe preeclampsia is associated with a positive family history of hypertension and hypercholesterolemia.

OBJECTIVE: To investigate an association between a family history of cardiovascular disease and severe preeclampsia and/or HELLP syndrome (Haemolysis, Elevated Liver enzymes, Low Platelets). METHODS: One hundred twenty-eight women with a history of severe preeclampsia and/or HELLP syndrome and 123 women with previous uncomplicated pregnancies only were included in the study. All participants completed questionnaires about diagnoses of cardiovascular diseases, hypertension, and hypercholesterolemia among their first-degree relatives, which were subsequently confirmed by the relatives' general practitioners. The main outcome measures were the prevalence of cardiovascular diseases, hypertension, and hypercholesterolemia among first-degree relatives of both groups. Statistical analysis was done using chi(2)-analysis. RESULTS: The prevalence of familial cardiovascular disease among women with a history of severe preeclampsia and/or HELLP syndrome (23%) compared to controls (19%) was not significantly different (OR 1.3, 95%CI 0.7-2.5). However, women with a history of severe preeclampsia and/or HELLP syndrome more often had one or more first-degree relatives with hypertension and/or hypercholesterolemia before the age of 60 years compared to controls (54% vs. 32%, respectively; OR 2.6, 95%CI 1.5-4.3). The prevalence of hypertension and hypercholesterolemia among first-degree relatives, irrespective of age, also was significantly higher among women with a history of severe preeclampsia and/or HELLP syndrome as compared to controls (60% vs. 42%, respectively; OR 2.0, 95%CI 1.2-3.4). CONCLUSION: Severe preeclampsia is associated with a positive family history of hypertension and/or hypercholesterolemia.

Oxidized and free whole blood thiols in preeclampsia.

OBJECTIVE: To measure levels of oxidized and free thiols in whole blood of normotensive pregnant and preeclamptic women and evaluate the role of oxidative stress. METHODS: We measured whole blood oxidized and free levels of cysteine, homocysteine, cysteinylglycine, and glutathione by high performance liquid chromatography in women with normotensive pregnancies (n = 50), preeclampsia (n = 29), and preeclampsia complicated by the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 16). RESULTS: Oxidized and free levels (median [range], micromol/L) of cysteine and homocysteine were higher in women with preeclampsia than normotensive pregnancies (45 [27-81] versus 29 [9-91], P <.001, and 98 [57-193] versus 69 [33-215], P <.001; 0.8 [0.2-4.4] versus 0.4 [0.01-1.6], P <.001, and 2.1 [0.7-9.4] versus 1.2 [0.2-21.2], P <.01; respectively). The ratios of free to oxidized cysteine, homocysteine, and cysteinylglycine were lower in preeclampsia than normotensive pregnancy (2.2 [1.3-3.0] versus 2.4 [1.7-4.3], P <.001; 2.3 [0.5-5.4] versus 2.9 [1.1-24], P <.001; 4.1 [2.3-11.6] versus 5.4 [2.6-24.3], P <.02, respectively), indicating a shift in favor of the oxidized form of those thiols. In HELLP syndrome, levels of oxidized and free cysteine and levels of oxidized homocysteine were higher than normal (44 [33-63] versus 29 [9-91], P <.001, and 102 [82-133] versus 69 [33-215], P <.001; 1.0 [0.3-2.9] versus 0.4 [0.01-1.6], P <.001, respectively). No significant differences were found in oxidized glutathione levels in women with preeclampsia (22 [5-49] versus 17 [2- 60], P =.06) or free levels in preeclamptic women with HELLP syndrome (757 [624-993] versus 842 [539-1516], P =.09) as compared with normotensive pregnant women. The ratios of free to oxidized cysteinylglycine and glutathione were higher in women with HELLP syndrome than in those with preeclampsia (5.4 [3.3-12.7] versus 4.1 [2.3-11.6], P =.02, and 56 [28-124] versus 45 [16-166], P =.02, respectively). CONCLUSION: Significantly lower ratios of free to oxidized cysteine, homocysteine, and cysteinylglycine in preeclampsia might indicate oxidative stress.

The C242T-polymorphism of the NADPH/NADH oxidase gene p22phox subunit is not associated with pre-eclampsia.

Pre-eclampsia is a pregnancy-related multisystem disorder characterised by elevation of blood pressure and proteinuria, in which oxidative stress may play an important role. Blood pressure is partly controlled by O(-)(2) production by NADPH/NADH oxidase and recently it was shown that a C242T substitution in the p22phox gene was associated with coronary artery disease, in which elevated blood pressure and oxidative stress are also important pathophysiologic features. Therefore we studied the prevalence of the C242T polymorphism in the NADPH/NADH oxidase gene in women with pre-eclampsia and/or haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome as compared with women with a normotensive pregnancy. DNA from control women (n = 78), women with pre-eclampsia (n = 40), HELLP syndrome (n = 9) or women with HELLP complicated by pregnancy-induced hypertension or pre-eclampsia (n = 46) were tested for the presence of the C242T polymorphism by polymerase chain reaction followed by restriction fragment-length polymorphism. The prevalence of the homozygous CC-genotype was similar in the patient groups compared with controls. The allele frequency of the T-allele was 31% in both control and patient groups. In conclusion the C242T polymorphism in the p22phox subunit of the NADPH/NADH oxidase gene is not associated with pre-eclampsia. Therefore, oxidative stress generated by NADPH/NADH oxidase probably does not play a role in the development of pre-eclampsia.

High levels of urinary vascular endothelial growth factor in women with severe preeclampsia.

Elevated plasma VEGF concentrations in preeclampsia are associated with local placental ischemia and endothelial dysfunction. We investigated the urinary VEGF excretion in women with severe preeclampsia (n=37) and its relation with proteinuria compared to that in healthy pregnant (n=32) and non-pregnant women (n=30). In women with severe preeclampsia VEGF levels were 54.0 (19.9-192.4) ng/mmol creatinine, significantly (p<0.0001) higher than levels in pregnant controls (28.2 (6.7-63.0) ng/mmol creatinine) and non-pregnant controls (29.5 (10.1-59.1) ng/mmol creatinine). Proteinuria was not significantly correlated with urinary VEGF levels. In conclusion, high urinary VEGF concentrations in severe preeclampsia might reflect increased renal production of VEGF rather than elevated VEGF levels in the systemic circulation.

Deficient detoxifying capacity in the pathophysiology of preeclampsia.

An imbalance between oxidative stress and maternal detoxification or antioxidant capacity may explain the symptoms of preeclampsia and the haemolysis-elevated liver enzymes-low platelets (HELLP) syndrome. Oxidative stress is known to induce damage of the endothelium, which is one of the pathophysiological features of preeclampsia and the HELLP syndrome. Administration of N-acetylcysteine, an antioxidant itself and a precursor of the endogenous antioxidant glutathione, might stabilize or even partly recover the process of endothelial damage and may lead to prolongation of pregnancy.

Serum anti-müllerian hormone levels in healthy females: a nomogram ranging from infancy to adulthood.

CONTEXT: Anti-müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce. OBJECTIVE: This study was an assessment of serum AMH levels in healthy females. SUBJECTS: In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion. RESULTS: In the total cohort, AMH was inversely correlated with age (r = -0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = -0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = -0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed. CONCLUSION: During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.

Glutathione S-transferase alpha levels in epileptic and healthy women preconceptionally and throughout pregnancy.

We studied plasma GSTA1-1 concentrations in preconceptionally recruited epileptic women who received antiepileptic drugs (n = 99) and a control group of healthy women (n = 106). Mean plasma GSTA1-1 concentrations in the control group did not show significant changes preconceptionally and throughout pregnancy. Six weeks postpartum, however, a significant increase in the mean plasma GSTA1-1 concentration (p < 0.001) was found as compared to preconceptional levels and levels during pregnancy. The mean plasma GSTA1-1 concentration in epileptic women was significantly higher in the 4th gestational week compared to those determined in healthy pregnant women (1.68 versus 1.08 microg/l, p < 0.001). Values between the groups in the second and third trimester and postpartum period showed no significant differences.