Reply: Familial ovarian screening: how to address abnormal TVU findings and its influence on the efficacy of screening?

Contains fulltext : 50362.pdf (publisher's version ) (Closed access

External validation of serum hCG cutoff levels for prediction of resistance to single-agent chemotherapy in patients with persistent trophoblastic disease

Van Trommel et al have previously shown that serum human chorionic gonadotropin (hCG) cutoff levels can provide early prediction of resistance to first-line methotrexate (MTX) in patients with persistent trophoblastic disease (PTD). In this study, we validate this approach of prediction of resistance to single-agent chemotherapy in an independent and larger cohort of PTD patients using a different hCG assay. Receiver operating characteristics (ROC) curves were constructed to determine hCG cutoff levels and sensitivity between patients cured on single-agent chemotherapy (control group) and patients requiring change to combination chemotherapy (study group). Receiver operating characteristics analysis identified an hCG cutoff value of 737 IU l−1 that enabled us to predict the subsequent development of single-agent chemotherapy resistance in 52% of patients before their fourth MTX course at 97.5% specificity. This would have enabled an earlier switch to combination chemotherapy reducing the MTX exposure by an average of 2.5 courses. The present findings confirm that serum hCG cutoff levels predict resistance to single-agent therapy earlier than traditional methods. Change to combination chemotherapy should be considered for patients whose serum hCG levels exceed these hCG cutoff values. For patients not exceeding the hCG cutoff levels, static or rising hCG levels should still be included in the criteria for change of chemotherapy

Short-term surgical complications after radical hysterectomy - a nationwide cohort study

Introduction: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. Material and methods: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications. Results: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss. Conclusions: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss

The efficacy of ultrasound in the follow up after a negative sentinel lymph node in women with vulvar cancer:a prospective single-centre study

ObjectiveTo determine the efficacy of the addition of an ultrasound of the groins in routine follow up of women with vulvar squamous cell carcinoma (SCC) after a negative sentinel lymph node (SLN). DesignProspective single-centre study. SettingA tertiary expert oncology centre for the treatment of vulvar cancer. PopulationAll women with vulvar SCC with a negative SLN, treated between 2006 and 2014. MethodsWe prospectively collected data of 139 women with vulvar SCC treated with an SLN procedure. We analysed data of 76 patients with a negative SLN. Three-monthly follow-up visits consisted of physical examination combined with an ultrasound of the groins by a radiologist. Main outcome measuresThe diagnostic value of ultrasound in the follow up of women with vulvar SCC with a negative SLN during the first 2 years after treatment. ResultsDuring a routine visit, two asymptomatic isolated groin recurrences were detected. Both patients were treated by inguinofemoral lymphadenectomy and adjuvant radiotherapy and are alive without evidence of disease 39 and 120 months after diagnosis. In total, 348 ultrasounds and 29 fine-needle aspiration were performed. The sensitivity of ultrasound to detect a groin metastasis was 100% (95% CI 16-100%), and specificity was 92% (95% CI 89-95%). ConclusionsRoutine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences. Further research is necessary to determine the exact role of ultrasound in the follow up of patients with vulvar SCC with a negative SLN. Tweetable abstractRoutine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences. Tweetable abstract Routine follow up including ultrasound of the groin led to early detection of asymptomatic isolated groin recurrences

Surveillance of women at high risk for hereditary ovarian cancer is inefficient

To determine the effectiveness of annual gynaecological screening (pelvic examination, transvaginal ultrasound, and CA-125), a prospective cohort study of women at high risk for hereditary ovarian cancer was conducted. Women were offered DNA analysis followed by either annual screening or prophylactic bilateral salpingo-oophorectomy (BSO). Study population consisted of 512 high-risk women (median follow-up 2.07 years, range 0–9.4 years): 265 women (52%) had a BRCA mutation. Persisting abnormalities indicated diagnostic surgery in 24 women resulting in one primary ovarian cancer FIGO stage IIIc was found. The effectiveness of screening was studied by calculating the probability of finding ovarian cancers in the BRCA-1 and BRCA-2 carrier group and comparing this to the identified number of ovarian cancers. The number of ovarian cancer patients found at surveillance was in accordance with the predicted number of ovarian cancers. A total number of 169 women underwent prophylactic BSO: one ovarian cancer stage IIb was found. In conclusion, the surveillance programme for hereditary ovarian cancer does identify patients with ovarian cancer but is very inefficient considering the high number of surveillance visits and the advanced stage of ovarian cancer in the identified patient. For prevention of advanced stage ovarian cancer, prophylactic BSO from age 35–40 years is a more efficient alternative

Survival of Ovarian Cancer Patients Is Independent of the Presence of DC and T Cell Subsets in Ascites

Ascites is a prominent feature of ovarian cancer and could serve as liquid biopsy to assess the immune status of patients. Tumor-infiltrating T lymphocytes are correlated with improved survival in ovarian cancer. To investigate whether immune cells in ascites are associated with patient outcome, we analyzed the amount of dendritic cell (DC) and T cell subsets in ascites from ovarian cancer patients diagnosed with high-grade serous cancer (HGSC). Ascites was collected from 62 HGSC patients prior to chemotherapy. Clinicopathological, histological and follow-up data from patients were collected. Ascites-derived immune cells were isolated using density-gradient centrifugation. The presence of myeloid DCs (BDCA-1+, BDCA-3+, CD16+), pDCs (CD123+BDCA-2+), and T cells (CD4+, CD8+) was analyzed using flow cytometry. Complete cytoreduction, response to primary treatment and chemosensitivity were associated with improved patient outcome. In contrast, immune cells in ascites did not significantly correlate with patient survival. However, we observed a trend toward improved outcome for patients having low percentages of CD4+ T cells. Furthermore, we assessed the expression of co-stimulatory and co-inhibitory molecules on T cells and non-immune cells in 10 ascites samples. PD-1 was expressed by 30% of ascites-derived T cells and PD-L1 by 50% of non-immune cells. However, the percentage of DC and T cell subsets in ascites was not directly correlated to the survival of HGSC patients

Coexisting high-grade glandular and squamous cervical lesions and human papillomavirus infections

Contains fulltext : 144469.pdf (publisher's version ) (Closed access)The frequency of high-risk human papillomavirus (hr-HPV) genotypes in patients with adenocarcinoma in situ (ACIS) with coexisting cervical intraepithelial neoplasia (CIN), ACIS without coexisting CIN, and high-grade CIN (CIN II/III) was studied, in order to gain more insight into the relation between hr-HPV infections and the development of coexisting squamous and glandular lesions. The SPF(10) LiPA PCR was used to detect simultaneously 25 different HPV genotypes in biopsies obtained from 90 patients with CIN II/III, 47 patients with ACIS without coexisting CIN, and 49 patients with ACIS and coexisting CIN. hr-HPV was detected in 84 patients (93%) with CIN II/III, 38 patients (81%) with ACIS without CIN, and in 47 patients (96%) with ACIS and coexisting CIN. A total of 13 different hr-HPV genotypes were detected in patients with CIN II/III, and only five in patients with ACIS with/without coexisting CIN. HPV 31, multiple hr-HPV genotypes, and HPV genotypes other than 16, 18, and 45 were significantly more often detected in patients with CIN II/III, while HPV 18 was significantly more often detected in patients with ACIS with/without CIN. There were no significant differences in the frequency of specific hr-HPV genotypes between patients with ACIS with or without coexisting CIN. In conclusion, the frequency of specific hr-HPV genotypes is similar for patients with ACIS without CIN and patients with ACIS and coexisting CIN, but is significantly different for patients with CIN II/III without ACIS. These findings suggest that squamous lesions, coexisting with high-grade glandular lesions, are aetiologically different from squamous lesions without coexisting glandular lesions

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations