Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

INTRODUCTION: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance. METHODS: A Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability. RESULTS: Seventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; P<0.001). Internal consistency of the items was high (Cronbach α=0.88). CONCLUSION: Specific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Validating the Team Emergency Assessment Measure (TEAM) in obstetric and gynaecologic resuscitation teams.

BACKGROUND: Simulation-based training is an effective method of enhancing the knowledge, skill, and technical abilities of individuals and teams encountering obstetric and gynaecologic emergencies. Simulation may also enhance the non-technical performance of teams resulting in improved patient outcomes. Although simulation-based training is widely recognised as an effective educational approach, issues around feasibility - the lack of simulation experts and malleable outcome measures of team performance - remain critical barriers to their implementation. AIM: To evaluate the psychometric properties of the Team Emergency Assessment Measure (TEAM) when used by medical professionals in simulated obstetric and gynaecological emergencies. METHODS: There were 151 participants (63% female; 60% consultants; 69% no previous simulation-based training) who observed three live high-fidelity obstetric and gynaecological resuscitation simulations and completed the TEAM. RESULTS: Confirmatory factor analysis evaluated the construct validity of the TEAM, yielding a second-order structure identified by 'leadership', 'teamwork', and 'team management'. Convergent validity was supported by the average item-to-scale total correlation which was 0.75, P < 0.001 and the average analysis of variance extracted (AVE) 0.88. The individual factors also yielded high factor-to-scale total correlations (mean [M] = 0.87), and AVE (M = 0.89). The internal reliability was high for the whole scale (average alpha = 0.92) and across the sub-factors (average alpha = 0.80). The inter-rater reliability was excellent (inter-class correlation coefficient 1 = 0.98). Participants with differing levels of simulation training experience did not significantly differ. CONCLUSION: The TEAM is a viable instrument for the assessment of non-technical performance during simulated obstetric and gynaecologic emergencies, thus enhancing the feasibility of simulation-based training.

Predictors of endometrial carcinoma in patients with atypical endometrial hyperplasia at a tertiary gynaecological cancer centre in Western Australia.

AIM: Our objective was to assess clinical and pathological factors associated with a final diagnosis of endometrial carcinoma in patients with atypical endometrial hyperplasia with a particular emphasis on the grading of atypia. MATERIALS AND METHODS: A retrospective review over five years on patients (N = 97) who underwent hysterectomy for a diagnosis of atypical endometrial hyperplasia at a statewide public tertiary gynaecologic oncology centre. Clinical and pathological characteristics were obtained. RESULTS: The rate of concurrent endometrial carcinoma was 34% (n = 33) with most being stage 1A endometrioid. A significant group difference was reported for age at diagnosis (t = -2.20 P = 0.031 d = 0.43) with carcinoma patients on average older (Mage  = 60.2 (8.9) years) than patients without carcinoma (Mage  = 55.5 (12.3) years). No significant group differences were found for body mass index, endometrial thickness or time between diagnosis and treatment. Significantly higher rates of carcinoma were reported in patients with moderate atypical hyperplasia (27.6%) and severe atypical hyperplasia (66.7%), compared to mild atypical hyperplasia (7.1%). Only severe atypical hyperplasia (odds ratio (OR) = 21.5, 95% CI 2.8-163.1, P = 0.003) and postmenopausal status (OR = 13.2, 95% CI 1.3-139.0, P = 0.032) significantly increased the risk of carcinoma in a multivariate model. CONCLUSION: Severe atypical hyperplasia and postmenopausal status were significant predictors of concurrent endometrial carcinoma in patients with atypical endometrial hyperplasia. The grading of atypical hyperplasia may be utilised by gynaecologic oncologists in the triage and referral process of managing these patients; however, the grading system requires external validation in larger prospective studies.

Evaluation of Optimized Procedures for High-Precision Lead Isotope Analyses of Seawater by Multiple Collector Inductively Coupled Plasma Mass Spectrometry.

The application of Pb isotopes to marine geochemistry is currently hindered by challenges associated with the analysis of Pb isotopes in seawater. The current study evaluates the performance of multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS) measurements of seawater Pb isotope compositions following Pb separation by either solid-phase extraction with Nobias Chelate PA-1 resin or coprecipitation with Mg(OH)2 and using either a Pb double spike or external normalization to Tl for mass bias correction. The four analytical combinations achieve results of similar quality when measuring 1-7 ng of seawater Pb, with reproducibilities (two standard deviations, 2SD) of 100-1200 ppm for 206Pb/207Pb and 208Pb/207Pb and 300-1700 ppm for ratios involving the minor 204Pb isotope. All four procedures enable significantly improved sample throughput compared to an established thermal ionization mass spectrometry (TIMS) double-spike method and produce unbiased seawater Pb isotope compositions with similar or improved precision. Nobias extraction is preferable to coprecipitation due to its greater analytical throughput and suitability for analyses of large seawater samples with high Si(OH)4 contents. The most accurate Pb isotope data are produced following Nobias extraction and double-spike correction as such analyses are least susceptible to matrix effects. However, Nobias extraction with Tl normalization constitutes an attractive alternative as, unlike the double-spike procedure, only a single mass spectrometric measurement is required, which improves analytical throughput and optimizes Pb consumption for analysis. Despite the advantages of solid-phase extraction, coprecipitation represents a useful Pb separation technique for samples with low to moderate Si contents as it is inexpensive, simple to implement, and the data are only marginally less accurate, especially when combined with a Pb double spike for mass bias correction.

Classical scoring functions for docking are unable to exploit large volumes of structural and interaction data.

MOTIVATION: Studies have shown that the accuracy of random forest (RF)-based scoring functions (SFs), such as RF-Score-v3, increases with more training samples, whereas that of classical SFs, such as X-Score, does not. Nevertheless, the impact of the similarity between training and test samples on this matter has not been studied in a systematic manner. It is therefore unclear how these SFs would perform when only trained on protein-ligand complexes that are highly dissimilar or highly similar to the test set. It is also unclear whether SFs based on machine learning algorithms other than RF can also improve accuracy with increasing training set size and to what extent they learn from dissimilar or similar training complexes. RESULTS: We present a systematic study to investigate how the accuracy of classical and machine-learning SFs varies with protein-ligand complex similarities between training and test sets. We considered three types of similarity metrics, based on the comparison of either protein structures, protein sequences or ligand structures. Regardless of the similarity metric, we found that incorporating a larger proportion of similar complexes to the training set did not make classical SFs more accurate. In contrast, RF-Score-v3 was able to outperform X-Score even when trained on just 32% of the most dissimilar complexes, showing that its superior performance owes considerably to learning from dissimilar training complexes to those in the test set. In addition, we generated the first SF employing Extreme Gradient Boosting (XGBoost), XGB-Score, and observed that it also improves with training set size while outperforming the rest of SFs. Given the continuous growth of training datasets, the development of machine-learning SFs has become very appealing. AVAILABILITY AND IMPLEMENTATION: https://github.com/HongjianLi/MLSF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Excisional treatment comparison for in situ endocervical adenocarcinoma (EXCISE): A phase 2 pilot randomized controlled trial to compare histopathological margin status, specimen size and fragmentation after loop electrosurgical excision procedure and cold knife cone biopsy.

OBJECTIVE: Adenocarcinoma in situ (AIS) of the cervix is a precursor to cervical adenocarcinoma. When AIS is detected by cervical screening an excision biopsy is mandatory to exclude invasion. We aimed to compare margins status, specimen size and fragmentation after loop electrosurgical excision procedure (LEEP) and 'cold knife cone biopsy' (CKC). METHODS: The EXCISE Trial was an investigator-initiated, multicenter, open-label, parallel-group, phase 2, randomized study. Patients were enrolled at seven hospitals in Australia and New Zealand. We randomly assigned women aged ≥18 to ≤45 years with screen detected AIS to LEEP or CKC. Co-primary endpoints were margin status, specimen size and fragmentation. Analysis was by intention-to-treat. RESULTS: Between August 2, 2017 and September 6, 2019, 40 patients were randomly assigned 2:1 to LEEP or CKC. Margin status was evaluable in 36 cases. The proportion of patients with involved margins did not differ between groups. 25 of 26 LEEP and all 14 CKC biopsies were excised as single specimens (p = 1·00). There were no differences in specimen dimensions. Patients in the CKC group had more post-operative complications (64.3% compared to 15.4% for LEEP p = ·00). There were no differences in grade three complications (p = ·65). CONCLUSIONS: LEEP was not associated with a greater likelihood of positive margins, specimen fragmentation or smaller excision compared to CKC when performed according to a standardized protocol. However, the study was not powered to establish non-inferiority of LEEP and a definitive phase 3 trial to compare margin status and rates of treatment failure after LEEP and CKC is warranted.

Fractal analysis of recurrence networks constructed from the two-dimensional fractional Brownian motions.

In this study, we focus on the fractal property of recurrence networks constructed from the two-dimensional fractional Brownian motion (2D fBm), i.e., the inter-system recurrence network, the joint recurrence network, the cross-joint recurrence network, and the multidimensional recurrence network, which are the variants of classic recurrence networks extended for multiple time series. Generally, the fractal dimension of these recurrence networks can only be estimated numerically. The numerical analysis identifies the existence of fractality in these constructed recurrence networks. Furthermore, it is found that the numerically estimated fractal dimension of these networks can be connected to the theoretical fractal dimension of the 2D fBm graphs, because both fractal dimensions are piecewisely associated with the Hurst exponent H in a highly similar pattern, i.e., a linear decrease (if H varies from 0 to 0.5) followed by an inversely proportional-like decay (if H changes from 0.5 to 1). Although their fractal dimensions are not exactly identical, their difference can actually be deciphered by one single parameter with the value around 1. Therefore, it can be concluded that these recurrence networks constructed from the 2D fBms must inherit some fractal properties of its associated 2D fBms with respect to the fBm graphs.

Designing meditation for doctor well-being: can 'Om' help obstetrics and gynaecology doctors?

OBJECTIVE: The study aimed to measure the impact of meditation on participants' ability to regulate brain wave activity in high-stress situations, control physiological stress responses and improve subjective wellbeing. METHODS: Twelve obstetrics and gynaecology (O&G) doctors meditated for 20 minutes daily for 21 days utilising a portable EEG (electroencephalogram) providing instantaneous audio feedback. Their brain activity levels and salivary cortisol were measured before and after performing three surgical procedures. Participants were interviewed about their experiences and completed self-ratings of distress (e.g. DASS-21, Depression, Anxiety and Depression Scale). Data were analysed statistically and thematically. RESULTS: (a) Measures of pre- and post-operative brain activity showed no significantly higher levels of alpha waves. (b) Pre- and post-operative salivary cortisol levels did not significantly decrease. (c) DASS-21 scores showed significant decreases in levels of anxiety and stress. CONCLUSION: Results suggest that, with biofeedback meditation, O&G doctors can learn to reduce situational stress and improve mood overall through a focussed intervention.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Cervical carcinomas with a micropapillary component: a clinicopathological study of eight cases.

AIMS: Micropapillary carcinomas, or carcinomas with a micropapillary component, are well recognised in the breast and other anatomical sites. However, they have seldom been described in the cervix. In this article, we present a clinicopathological analysis of eight cervical tumours that showed at least a focal (≥5%) component of micropapillary carcinoma. METHODS AND RESULTS: The study group comprised eight cervical carcinomas (four adenocarcinomas and four adenosquamous carcinomas) with a micropapillary component. The median patient age was 41.5 years (range 27-65 years). At presentation, five patients were stage IB, two were stage IIB, and one was stage IV. The micropapillary component accounted for ≤25% of the tumour on initial biopsy or resection specimens in all but one case. Immunohistochemistry showed 'inside-out' (reverse polarity) mucin 1 staining along the cell membrane abutting the stroma. Four patients developed metastasis, all of whom showed a pure micropapillary pattern; this led to a misdiagnosis of an apparently independent peritoneal serous carcinoma in one case. All tumours showed diffuse p16 expression, and all three cases that were tested were positive for human papillomavirus (HPV) 18. Three of the six patients with at least 12 months of follow-up died of disease, and one is alive with distant metastasis. CONCLUSIONS: Usual-type (HPV-related) cervical carcinomas may show micropapillary differentiation, usually as a focal finding, and the cells show reverse polarity like similar tumours arising in other sites. Micropapillary cervical carcinoma appears to be a clinically aggressive malignancy, although this needs to be confirmed in larger studies.

Do Groin Drains Reduce Postoperative Morbidity in Women Undergoing Inguinofemoral Lymphadenectomy for Vulvar Cancer?

OBJECTIVE: Sentinel lymph node biopsy has been widely adopted in the surgical management of women with early-stage vulvar cancer, but many patients require inguinofemoral lymphadenectomy (IFL). Following IFL, many surgeons drain the groin to prevent lymphocyst formation despite a lack of evidence to support this practice. Our objective was to investigate whether groin drains after IFL are associated with reduced postoperative morbidity in women undergoing surgery for vulvar cancer. METHODS: A retrospective cohort study of women diagnosed as having primary vulvar cancer who underwent vulvectomy/radical local excision and unilateral or bilateral IFL was conducted. Cases were ascertained from the weekly outcome reports of a statewide tertiary gynecologic oncology tumor board. Data including postoperative outcomes were abstracted from medical records. Patients were stratified into 1 of 2 groups according to whether a groin drain had been used. RESULTS: Seventy-one patients were included. Inguinal drains were used in 48 patients (67.6%) and 23 patients (32.4%) did not have their groin wound(s) drained. The most common postoperative complications recorded were wound infection (59.2%), groin lymphocyst (32.4%), and cellulitis (25.4%). The mean length of hospital admission was 11.5 days (2-40 days). Compared with patients in whom inguinal drains were placed, those in the "no drain" group had a significantly lower incidence of postoperative groin cellulitis (8.7% vs 25.4% P = 0.039). No significant differences were observed between patients in the "drain" and "no drain" groups in lymphocyst formation, wound infection, return to the operating room, duration of hospital stay, readmission post-discharge, and lower-limb lymphedema. CONCLUSIONS: In this study of patients undergoing inguinofemoral dissection for primary vulvar cancer, postoperative cellulitis occurred less frequently in patients without an inguinal drain. The incidence of other postoperative complications was no different whether or not a groin drain was used. Prospective studies may be warranted.

Annexin A2 and alpha actinin 4 expression correlates with metastatic potential of primary endometrial cancer.

The prediction of lymph node metastasis using clinic-pathological data and molecular information from endometrial cancers lacks accuracy and is therefore currently not routinely used in patient management. Consequently, although only a small percentage of patients with endometrial cancers suffer from metastasis, the majority undergo radical surgery including removal of pelvic lymph nodes. Upon analysis of publically available data and published research, we compiled a list of 60 proteins having the potential to display differential abundance between primary endometrial cancers with versus those without lymph node metastasis. Using data dependent acquisition LC-ESI-MS/MS we were able to detect 23 of these proteins in endometrial cancers, and using data independent LC-ESI-MS/MS the differential abundance of five of those proteins was observed. The localization of the differentially expressed proteins, was visualized using peptide MALDI MSI in whole tissue sections as well as tissue microarrays of 43 patients. The proteins identified were further validated by immunohistochemistry. Our data indicate that annexin A2 protein level is upregulated, whereas annexin A1 and α actinin 4 expression are downregulated in tumours with lymph node metastasis compared to those without lymphatic spread. Moreover, our analysis confirmed the potential of these markers, to be included in a statistical model for prediction of lymph node metastasis. The predictive model using highly ranked m/z values identified by MALDI MSI showed significantly higher predictive accuracy than the model using immunohistochemistry data. In summary, using publicly available data and complementary proteomics approaches, we were able to improve the prediction model for lymph node metastasis in EC.

Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma.

AIMS: Gynaecological cancer patients with germline mutations appear to have a better prognosis than those with sporadic malignancies. Following the observation of long-term survival in a patient with stage III ovarian clear cell carcinoma (CCC) and possible Lynch syndrome (LS), DNA mismatch repair (MMR) protein immunohistochemistry was performed in a series of high-stage CCC and correlated with patient outcomes. METHODS AND RESULTS: Thirty-two consecutive cases of stage III/IV ovarian CCCs accessioned between 1992 and 2015 were examined. The tumours from two patients (6%), including the index case, showed loss of MSH2/MSH6 expression while MLH1/PMS2 staining was retained. The index patient subsequently developed colonic and rectal carcinomas that were also MSH2/MSH6-deficient, while the second patient had a genetically confirmed germline MSH2 mutation. All other tumours showed retained expression of the four MMR proteins. The two patients with MMR protein-deficient tumours were alive 160 months and 124 months following surgery, whereas the median survival of patients with MMR protein-intact CCCs was 11.8 months (75th and 25th percentiles of 8.1 months and 39.3 months, respectively), with 21 patients deceased due to tumour. CONCLUSIONS: Larger studies are required but high-stage, MMR protein-deficient CCCs may have a relatively favourable prognosis.

Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

OBJECTIVE: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. METHODS: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. RESULTS: Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10-7), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (PTrend=4.43×10-6), and with increasing numbers of Lynch cancers in relatives (PTrend≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). CONCLUSION: The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.

Risk of persistent and recurrent cervical neoplasia following incidentally detected adenocarcinoma in situ.

BACKGROUND: Adenocarcinoma in situ of the uterine cervix is a precursor to cervical adenocarcinoma and may coexist with both adenocarcinoma and high-grade squamous dysplasia (cervical intraepithelial neoplasia 2 and 3). Up to 60% of adenocarcinoma in situ lesions are detected incidentally following excisional biopsies performed for the treatment of cervical intraepithelial neoplasia 2/3. To date there are no data regarding risk factors for persisting or progressive cervical neoplasia in these patients. OBJECTIVE: We sought to investigate patient outcomes following incidentally detected cervical adenocarcinoma in situ after loop electrosurgical excision procedure or cold knife cone biopsy performed for the treatment of high-grade cervical intraepithelial neoplasia. STUDY DESIGN: We conducted a retrospective, population-based cohort study of Western Australian patients with an incidental diagnosis of adenocarcinoma in situ from 2001 through 2012. Primary outcomes were persistent or recurrent cervical intraepithelial neoplasia 2/3 and or adenocarcinoma in situ, and invasive adenocarcinoma during follow-up (<12 months) and surveillance (≥12 months) periods. RESULTS: The cohort comprised 298 patients, with 228 (76.5%) treated initially by loop electrosurgical excision procedure and 70 (23.5%) treated by cold knife cone biopsy. The mean age was 31.2 (range 18-68) years and the median length of follow-up was 2.4 (range 0.3-12.2) years. Overall, 11 (3.7%) patients had cervical intraepithelial neoplasia 2/3, 23 (7.7%) had adenocarcinoma in situ, and 3 (1.0%) had adenocarcinoma diagnosed during the follow-up and surveillance periods. Age >30 years, pure adenocarcinoma in situ lesions, and larger lesions (>8 mm) were associated with a greater risk of disease persistence or recurrence. CONCLUSION: Following the incidental detection of adenocarcinoma in situ, age >30 years, pure adenocarcinoma in situ lesions, and lesions >8 mm were significantly associated with disease persistence/recurrence. In younger women, incidentally detected adenocarcinoma in situ that coexists with cervical intraepithelial neoplasia 2/3 and is <8 mm extent with clear margins may not require reexcision.

Value of Specialist Pathology Review in a Single Statewide Gynecologic Cancer Service.

OBJECTIVE: A case review by specialist diagnostic pathologists as part of a Gynecologic Oncology Multi-disciplinary Tumor group has the potential to influence the management of patients with cancer. The primary aim of this study was to determine the frequency of diagnostic discrepancies between the initial (nonspecialist) and final pathological diagnoses in cases referred to the Gynecologic Oncology Tumor Conference (TC) in Western Australia and the impact of such revised diagnosis on clinical management. A secondary aim was to assess the evolving workload encountered by the TC during a 5-year interval. METHODS: The records of the weekly TC for the 2 calendar years 2008 and 2013 were examined, and histological and cytological specimens that had been initially assessed by "outside" (nonspecialist) pathology departments, and subsequently reviewed by specialist pathologists, were assessed. The initial and final diagnoses were compared, and where the pathological findings were amended upon review, it was determined whether the change affected clinical management. Diagnostic discrepancies that resulted in a change in patient management were classified as major, whereas discrepancies that did not affect patient management were classified as minor. RESULTS: A total of 481 outside cases were included among 2387 cases presented for histological review at the TC during the 2 years. For outside cases alone, the incidence of major diagnostic discrepancies was 3.4% in 2008, 5.5% in 2013 (no significant difference, P = 0.3787), and 4.6% for the 2 years combined. A recommendation for surgery was the most common change in clinical management as a result of major discrepancy. The minor discrepancy rate was 4.4% of outside cases for both years combined. Pathological discrepancies (major and minor) of the uterine corpus and cervix were most frequent, followed by those of the vulva and ovary. There was a 48.4% increase in total case discussions at the TC during the interval period with a significant rise in nonmalignant cases, 29.8% of the total cases in 2008 compared with 36.8% in 2013 (P = 0.0004). CONCLUSIONS: Nonspecialist pathology departments maintained a high level of reporting accuracy during the interval period, with the major discrepancy rate not changing significantly between 2008 and 2013. Specimens from the uterine corpus and cervix in particular may prove diagnostically challenging on occasion. A pathology review of outside cases by a tertiary-based laboratory in conjunction with a TC can identify a small but clinically significant number of cases that lead to a change in clinical management. It is uncertain whether this affects patient outcomes.