Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

Fluctuations in populations of subsurface methane oxidizers in coordination with changes in electron acceptor availability.

The concentrations of electron donors and acceptors in the terrestrial subsurface biosphere fluctuate due to migration and mixing of subsurface fluids, but the mechanisms and rates at which microbial communities respond to these changes are largely unknown. Subsurface microbial communities exhibit long cellular turnover times and are often considered relatively static-generating just enough ATP for cellular maintenance. Here, we investigated how subsurface populations of CH4 oxidizers respond to changes in electron acceptor availability by monitoring the biological and geochemical composition in a 1339 m-below-land-surface (mbls) fluid-filled fracture over the course of both longer (2.5 year) and shorter (2-week) time scales. Using a combination of metagenomic, metatranscriptomic, and metaproteomic analyses, we observe that the CH4 oxidizers within the subsurface microbial community change in coordination with electron acceptor availability over time. We then validate these findings through a series of 13C-CH4 laboratory incubation experiments, highlighting a connection between composition of subsurface CH4 oxidizing communities and electron acceptor availability.

Understanding the problem of inadequately staging early ovarian cancer.

BACKGROUND: Early ovarian cancer patients are often incompletely staged during initial surgery.(1-3) This omission can have serious adverse consequences for the prognosis of patients as the completeness of surgical staging has been identified as an independent prognostic parameter for survival.(4,5) The reasons for the problem of inadequate staging of early ovarian cancer are largely unknown. We have analysed the data of a large randomised trial in early ovarian cancer in which detailed information of the surgical staging procedure was monitored.(5) METHODS: Data of the EORTC Adjuvant ChemoTherapy In Ovarian Neoplasm (ACTION) Trial were used in which 448 early ovarian cancer patients were randomised between postoperative chemotherapy in one arm and observation following surgery in the other. In this trial strict criteria for surgical staging were advised but optimal, complete staging was performed in only 1/3 of patients. Staging characteristics of the incompletely staged patients were analysed and factors that could explain the failure to perform a complete staging were studied. RESULTS: Sampling of para-aortic nodes was omitted in 78% of the incompletely staged patients, while 52% of these patients had no pelvic lymph node dissection. Taking blind biopsies from different peritoneal sites was not performed in more than 1/3 of the incompletely staged group. Omission of the staging steps ranged from 3% (infracolic omentectomy) to 55% (biopsy of the right hemi-diaphragm). A significant difference (p=0.04) between the fraction of completely staged patients was found when comparing institutes who entered less than 5 patients (21%) versus those who included more than 20 patients (37%) in the trial. CONCLUSIONS: Even in a randomised trial in which comprehensive surgical staging was strongly advised in the study protocol the majority of patients (66%) were incompletely staged. Factors relating to a lack of surgical skills attributed most to the number of incompletely staged patients, but insufficient knowledge of the tumour behaviour and routes of spread of ovarian cancer also contributed substantially to this problem. Multicentre trials recruiting patients from many institutes with small volume contribution to the study, run the risk of inadequate adherence to the study protocol.

Clear cell carcinoma compared to serous carcinoma in early ovarian cancer: same prognosis in a large randomized trial.

BACKGROUND: An analysis was performed comparing survival of patients with clear cell carcinoma (CCC) to patients with serous adenocarcinoma (SAC) in early ovarian cancer. Furthermore, a literature search was done to clarify the clinical and histopathological features of clear cell tumors of the ovary. METHODS: Between November 1990 and March 2000, 448 patients with ovarian cancer International Federation of Gynecology and Obstetrics stages I to IIa were enrolled in the European Organisation for Research and Treatment of Cancer-Adjuvant Chemotherapy in Ovarian Neoplasm Trial, a randomized study comparing adjuvant platinum-based chemotherapy to observation after surgical treatment in patients with early ovarian cancer. RESULTS: Sixty-three patients (14.1%) with CCC were compared with 156 patients (34.8%) with serous tumors. A significant difference was found in the International Federation of Gynecology and Obstetrics stage Ic with capsule rupture, 28 (44.4%) of 63 patients with CCC and 29 (18.6%) of 156 patients with SAC (P < 0.001). Recurrences occurred in 25% of the patients, and this was similar in the CCC and SAC groups. No significant difference was found in overall survival between patients with CCC and patients with SAC in both treatment arms together. In the observation arm, the 5-year disease-free survival was 71% in the CCC group versus 61% in the SAC group, whereas in the chemotherapy arm, the 5-year disease-free survival was higher in the SAC group compared with the CCC group (78% vs 60%). Both differences were not statistically significant. CONCLUSIONS: The present study showed no worse prognosis in patients with CCC as compared with patients with serous carcinoma in early ovarian cancer.

Long-term follow-up confirms a survival advantage of the paclitaxel-cisplatin regimen over the cyclophosphamide-cisplatin combination in advanced ovarian cancer.

Two independent and consecutive randomized clinical trials, conducted by the American Gynecological Oncology Group and by an European-Canadian Intergroup, have shown superiority, in clinical response rate, progression-free survival, and overall survival, of a cisplatin-paclitaxel regimen over cisplatin-cyclophosphamide given as first-line chemotherapy for women with advanced epithelial ovarian cancer. The results of these studies, published with a median follow-up of about 3 years, have been updated with a 6.5-year follow-up: In each case, an 11% absolute gain in survival favoring the paclitaxel arm is shown; this advantage remains both statistically and clinically significant and supports a role for paclitaxel in frontline chemotherapy for advanced ovarian cancer.

Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results.

BACKGROUND: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial. METHODS: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided. RESULTS: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen. CONCLUSIONS: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer.

Human papillomavirus infection in squamous cell carcinoma of the vulva, in various synchronous epithelial changes and in normal vulvar skin.

OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV) infection in various vulvar lesions. METHODS: HPV infection using consensus primer-PCR was studied in 66 patients with vulvar carcinoma and in the synchronous epithelial lesions. RESULTS: HPV infection was present in 13/66 carcinoma, in 1/33 VIN I, in 3/11 VIN II, in 8/16 VIN III, in 2/30 lichen sclerosus, in 1/37 squamous cell hyperplasia, and in 2/55 normal skin specimens. Normal skin from healthy controls showed HPV-negative specimens only. Patients with HPV-positive carcinomas were younger, presented in lower stages, and had high-grade VIN more often than those with HPV-negative carcinomas. CONCLUSIONS: In sum we found that all types of epithelial changes synchronous with carcinoma of the vulva showed HPV infection, indicating that they all might have malignant potential.

[Care in stillbirth; mothers' opinion]. / Hulpverlening bij doodgeboorte; het oordeel van de moeders.

Semi-structured interviews were conducted with 49 women who had experienced stillbirth in 1987-1989. Only 55% were satisfied with the manner in which the first suspicion had been communicated to them, while 85% were satisfied with the communication at the time of the diagnosis. Opinions about care in the labour ward, while largely positive, indicate that lack of tact from an individual may cloud the entire perception of care. Although only 40% had expressed a desire to see the baby, the others were happy to have been persuaded to do so and all were positive about the contact with the dead baby. Of 42 women (86%) who gave consent for autopsy, only one regretted this decision. Support received post partum was considered to be inadequate or insufficient by 10%. Despite the short hospital stay (average 1 day), most women afterwards felt that they would have preferred to return home earlier; only 9% felt that they would have preferred to stay longer.