Sentinel Lymph Node Evaluation in Early-Stage Vulvar Cancer.

OPINION STATEMENT: Sentinel lymph node mapping (SLNM) and dissection (SLND) should be used as an alternative to full inguinofemoral lymph node dissection (IFLND) in select patients with early-stage vulvar cancer. IFLND is associated with high postoperative complications such as wound breakdown, lymphedema, lymphocyst formation, and infection. SLND in select patients offers a safe, effective, and less morbid alternative. Candidates for SLND include patients with a unifocal vulvar tumor less than four centimeters, clinically negative lymph nodes, and no prior inguinofemoral surgeries. SLND should ideally be performed by a high-volume SLN surgeon. Most commonly, SLND is performed using both radiocolloid lymphoscintigraphy (e.g., Technetium-99) and a visual tracer such as blue dye; however, near infrared imaging with indocyanine green injection is becoming more widely adopted. Further prospective studies are needed to examine the safety and efficacy of various techniques for SLND. SLND has been demonstrated to be cost-effective, especially when including perioperative complications. Further studies are needed to demonstrate quality of life differences between IFLND and SLND.

Association of hospital-based substance use supports on emergency department revisits: a retrospective cohort study in Sudbury, Canada from 2018 to 2022.

BACKGROUND: This study compares emergency department (ED) revisits for patients receiving hospital-based substance-use support compared to those who did not receive specialized addiction services at Health Sciences North in Sudbury, Ontario, Canada. METHODS: The study is a retrospective observational study using administrative data from all patients presenting with substance use disorder (SUD) at Health Sciences North from January 1, 2018, and August 31, 2022 with ICD-10 codes from the Discharge Abstract Database (DAD) and the National Ambulatory Care Database (NACRS). There were two interventions under study: addiction medicine consult services (AMCS group), and specialized addiction medicine unit (AMU group). The AMCS is a consult service offered for patients in the ED and those who are admitted to the hospital. The AMU is a specialized inpatient medical unit designed to offer addiction support to stabilize patients that operates under a harm-reduction philosophy. The primary outcome was all cause ED revisit within 30 days of the index ED or hospital visit. The secondary outcome was all observed ED revisits in the study period. Kaplan-Meier curves were used to measure the proportion of 30-day revisits by exposure group. Odds ratios and Hazard Ratios were calculated using logistic regression models with random effects and Cox-proportional hazard model respectively. RESULTS: A total of 5,367 patients with 10,871 ED index visits, and 2,127 revisits between 2018 and 2022 are included in the study. 45% (2,340/5,367) of patient were not admitted to hospital. 30-day revisits were less likely among the intervention group: Addiction Medicine Consult Services (AMCS) in the ED significantly reduced the odds of revisits (OR 0.53, 95% CI 0.39-0.71, p < 0.01) and first revisits (OR 0.42, 95% CI 0.33-0.53, p < 0.01). The AMU group was associated with lower revisits odds (OR 0.80, 95% CI 0.66-0.98, p = 0.03). For every additional year of age, the odds of revisits slightly decreased (OR 0.99, 95% CI 0.98-1.00, p = 0.01) and males were found to have an increased risk compared to females (OR 1.50, 95% CI 1.35-1.67, p < 0.01). INTERPRETATION: We observe statistically significant differences in ED revisits for patients receiving hospital-based substance-use support at Health Sciences North. Hospital-based substance-use supports could be applied to other hospitals to reduce 30-day revisits.

Concordance Between Genomic Alterations Detected by Tumor and Germline Sequencing: Results from a Tertiary Care Academic Center Molecular Tumor Board.

OBJECTIVE: The majority of tumor sequencing currently performed on cancer patients does not include a matched normal control, and in cases where germline testing is performed, it is usually run independently of tumor testing. The rates of concordance between variants identified via germline and tumor testing in this context are poorly understood. We compared tumor and germline sequencing results in patients with breast, ovarian, pancreatic, and prostate cancer who were found to harbor alterations in genes associated with homologous recombination deficiency (HRD) and increased hereditary cancer risk. We then evaluated the potential for a computational somatic-germline-zygosity (SGZ) modeling algorithm to predict germline status based on tumor-only comprehensive genomic profiling (CGP) results. METHODS: A retrospective chart review was performed using an academic cancer center's databases of somatic and germline sequencing tests, and concordance between tumor and germline results was assessed. SGZ modeling from tumor-only CGP was compared to germline results to assess this method's accuracy in determining germline mutation status. RESULTS: A total of 115 patients with 146 total alterations were identified. Concordance rates between somatic and germline alterations ranged from 0% to 85.7% depending on the gene and variant classification. After correcting for differences in variant classification and filtering practices, SGZ modeling was found to have 97.2% sensitivity and 90.3% specificity for the prediction of somatic versus germline origin. CONCLUSIONS: Mutations in HRD genes identified by tumor-only sequencing are frequently germline. Providers should be aware that technical differences related to assay design, variant filtering, and variant classification can contribute to discordance between tumor-only and germline sequencing test results. In addition, SGZ modeling had high predictive power to distinguish between mutations of somatic and germline origin without the need for a matched normal control, and could potentially be considered to inform clinical decision-making.

Simplification of soil biota communities impairs nutrient recycling and enhances above- and belowground nitrogen losses.

Agriculture is a major source of nutrient pollution, posing a threat to the earth system functioning. Factors determining the nutrient use efficiency of plant-soil systems need to be identified to develop strategies to reduce nutrient losses while ensuring crop productivity. The potential of soil biota to tighten nutrient cycles by improving plant nutrition and reducing soil nutrient losses is still poorly understood. We manipulated soil biota communities in outdoor lysimeters, planted maize, continuously collected leachates, and measured N2 O- and N2 -gas emissions after a fertilization pulse to test whether differences in soil biota communities affected nutrient recycling and N losses. Lysimeters with strongly simplified soil biota communities showed reduced crop N (-20%) and P (-58%) uptake, strongly increased N leaching losses (+65%), and gaseous emissions (+97%) of N2 O and N2 . Soil metagenomic analyses revealed differences in the abundance of genes responsible for nutrient uptake, nitrate reduction, and denitrification that helped explain the observed nutrient losses. Soil biota are major drivers of nutrient cycling and reductions in the diversity or abundance of certain groups (e.g. through land-use intensification) can disrupt nutrient cycling, reduce agricultural productivity and nutrient use efficiency, and exacerbate environmental pollution and global warming.

Understanding the spectrum of malignant bowel obstructions in gynecologic cancers and the application of the Henry score.

OBJECTIVE: Malignancy-associated bowel obstruction (MBO) is a potential sequela of advanced gynecologic cancers, adversely impacting both quality of life and prognosis. The Henry score (HS) was developed in a gastrointestinal cancer-predominant population to predict 30-day mortality. We aim to characterize MBO in gynecologic cancers and assess the utility of the HS in this population. METHODS: This is a retrospective review of patients with gynecologic cancer and MBO admitted to a single academic institution from 2016 to 2021. The primary outcome is to characterize malignant small and large bowel obstructions in primary and recurrent gynecologic cancer using readmission and mortality rates. Secondary outcomes are to assess the Henry score and inpatient MBO management. RESULTS: 179 patients totaling 269 were admissions identified, most commonly affecting patients with ovarian cancer. The majority (89.4%) were managed non-operatively while 10.6% were managed surgically. No significant differences were observed in survival for medical versus surgical management. Thirty-day mortality increased with increasing HS (0%, 0-1; 14.3%, 2-3; 40.9%, 4-5). Over 1/3 (34.1%) of patients were readmitted for recurrent or persistent MBO. Goals of care conversations were documented for 56.8% of patients with HS 4-5. Mortality rates across the entire cohort were high-20.1% and 60.9% had died by 1 and 6 months, respectively. CONCLUSIONS: Survival rates following an initial MBO admission are poor. The HS has utility in gynecologic cancers for assessing 30-day mortality and may be a useful tool to aid in the management and counseling of patients with gynecologic cancer and MBO.

Exploring Prosodic Features Modelling for Secondary Emotions Needed for Empathetic Speech Synthesis.

A low-resource emotional speech synthesis system for empathetic speech synthesis based on modelling prosody features is presented here. Secondary emotions, identified to be needed for empathetic speech, are modelled and synthesised in this investigation. As secondary emotions are subtle in nature, they are difficult to model compared to primary emotions. This study is one of the few to model secondary emotions in speech as they have not been extensively studied so far. Current speech synthesis research uses large databases and deep learning techniques to develop emotion models. There are many secondary emotions, and hence, developing large databases for each of the secondary emotions is expensive. Hence, this research presents a proof of concept using handcrafted feature extraction and modelling of these features using a low-resource-intensive machine learning approach, thus creating synthetic speech with secondary emotions. Here, a quantitative-model-based transformation is used to shape the emotional speech's fundamental frequency contour. Speech rate and mean intensity are modelled via rule-based approaches. Using these models, an emotional text-to-speech synthesis system to synthesise five secondary emotions-anxious, apologetic, confident, enthusiastic and worried-is developed. A perception test to evaluate the synthesised emotional speech is also conducted. The participants could identify the correct emotion in a forced response test with a hit rate greater than 65%.

A Pilot Study of a Screening Program for Human Papillomavirus-Related Squamous Intraepithelial Lesion and Malignancy in Gynecologic Oncology Patients.

OBJECTIVE: Human papillomavirus (HPV)-related squamous intraepithelial lesion (SIL) or malignancy is associated with a significantly increased risk of second-site SIL or malignancy. The primary objective of this study was to determine the feasibility and acceptability of concurrent anal, cervical, and vulvovaginal screening in patients with a history of HPV-related gynecologic high-grade SIL or malignancy. The secondary objective was to assess subjects' knowledge regarding HPV screening and risks. METHODS: Women with high-grade cervical, vulvar, or vaginal SIL or malignancy were enrolled during a 1-year pilot period. Subjects with cervical SIL or malignancy underwent vulvar examination and anoscopy. Subjects with vulvovaginal SIL or malignancy underwent Pap test if indicated and anoscopy. Appropriate referrals were made for abnormal findings. Feasibility was assessed by compliance using study acceptance rate, screening procedure adherence, and referral adherence. Acceptability was assessed using a Likert-scaled question after completion of screening procedures. RESULTS: One hundred three women with a diagnosis of high-grade vulvovaginal or cervical SIL or carcinoma were approached regarding study enrollment; of these, 74 (71.8%) enrolled. The median score on the HPV knowledge assessment was 8.1 ± 1.6 (max score 10). Seventy-three (98.6%) of 74 patients rated the screening procedures as acceptable (score of 5/5). On examination, 14 (18.9%) subjects had abnormalities noted; 7 (9.5%) were referred for colorectal surgical evaluation, and 6/7 (85.7%) were compliant with their referral appointments. CONCLUSIONS: Screening examinations for other HPV-related SILs and malignancies, including Pap tests, vulvovaginal inspection, and anoscopy, are acceptable to patients, with abnormal findings in almost 1 in 5 women.

Reducing non-surgical readmissions on a gynecologic oncology service.

OBJECTIVE: To assess the effects of a quality improvement (QI) initiative designed to reduce non-surgical readmissions on a gynecologic oncology service. METHODS: A two-phase QI initiative was implemented on an inpatient gynecologic oncology service to reduce non-surgical 30-day readmissions. Phase 1, from July 2018 to June 2020, included trainee education, frequent physical therapy consultation, pharmacy discharge medication review, 72-h post-discharge telephone call, and standardized 10-day clinic follow-up after discharge. Phase 2, from July 2020 to December 2020, incorporated a nurse practitioner to perform discharge navigation and arrange outpatient follow-up. The incidence of non-surgical readmissions during these phases was compared to that of a baseline period (July 2017-June 2018). We also assessed readmissions to identify common indications and evaluate potential demographic and clinical risk factors. RESULTS: Of 390 total non-surgical gynecologic oncology admissions, 100 were readmitted within 30 days (25.6%). Gastrointestinal tract (GI) obstruction, malignancy-associated pain and infection were the most common symptomatic diagnoses at the index admission, and 30% of readmitted patients had an identical indication for readmission. Compared to the baseline period, we observed a reduction in non-surgical readmissions from 34.1% to 22.6% in Phase 1 and to 18.9% in Phase 2 (p < 0.03) based on internal review, and a reduction from 13.9% to 11.9% in Phase 1 and to 4.7% in Phase 2 (p = 0.04) based on healthcare performance tracking data. CONCLUSIONS: 30-day hospital readmission among non-surgical gynecologic oncology patients is common. Implementation of a multifaceted readmissions reduction QI initiative significantly improved readmission rates.

Promoting timely goals of care conversations between gynecologic cancer patients at high-risk of death and their providers.

OBJECTIVE: We designed a multi-faceted intervention to increase the rate of outpatient goals of care (GOC) conversations in women with gynecologic cancers who are at high-risk of death. METHODS AND MATERIALS: A multidisciplinary team developed an educational program around GOC conversations at end-of-life and chose criteria to prospectively identify patients at high-risk of death who might benefit from timely GOC conversations: recurrent or metastatic endometrial, cervical or vulvar cancer or platinum-resistant ovarian cancer. Gynecologic oncology provider consensus was built regarding the need to improve the quality and timing of GOC conversations. Eligible outpatients were prospectively identified and providers alerted pre-encounter; timely GOC documentation within 3 visits of high-risk identification was tracked. Our institution concurrently and subsequently tracked GOC documentation during the last 6 months of life among all established oncology patients. RESULTS: Of 220 pilot period high-risk patients (96 pre- and 124 during pilot period 2017-2018), timely GOC discussion documentation increased from 30.2% to 88.7% (p < 0.001) and this increase was sustained over time. In the post-pilot period (2019-2020), among patients seen by oncologists during last 6 months of life, compared to other cancer types, gynecologic cancer patients had a higher rate of GOC documentation (81% versus 9%; p < 0.001), a lower rate of receiving chemotherapy during the last 14 days of life (2% vs 5%; p = 0.051), and no difference in end-of-life admissions (29% vs 31%; p = NS). CONCLUSIONS: Implementation of systematic outpatient identification of high-risk gynecologic oncology patients is feasible, sustainable, and increases the timely conduct of GOC conversations.

Fatal Respiratory Diphtheria Caused by ß-Lactam-Resistant Corynebacterium diphtheriae.

BACKGROUND: Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, ß-lactam resistance in toxigenic diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other ß-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element. METHODS: Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of ß-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem. RESULTS: BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration [MIC] ≥ 256 µg/ml), ß-lactam/ß-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 µg/mL; ceftriaxone MIC ≥ 8 µg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype. CONCLUSIONS: We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.

Chemotherapy discontinuation processes in a gynecologic oncology population.

OBJECTIVE: We sought to categorize the processes by which gynecologic oncology patients stop chemotherapy and to evaluate associations between these processes and end-of-life outcome metrics. METHODS: A cohort of patients with metastatic or recurrent gynecologic cancer in an outpatient setting from January 2016 to May 2018 was identified. All deceased patients in this cohort were included for analysis. Processes of discontinuing chemotherapy were categorized as: 1) definitive decision inpatient; 2) definitive decision outpatient; 3) delayed decision (eg: treatment break and never resumed chemotherapy); 4) no decision. Associations between patient characteristics and clinical outcomes of those who made a definitive outpatient decision versus those who made any other type of decision were assessed. RESULTS: 220 patients were identified; 205 patients were deceased at time of analysis. Of these, 36.6% made a definitive decision to stop chemotherapy as an outpatient, while 41.5% never made a decision to discontinue chemotherapy. Making a definitive decision as an outpatient, when compared to all other decision types, was associated with significantly lower incidence of death in the hospital (5.6% vs 21.1%, p < 0.004) and hospitalization within 30 days of death (20.8% vs 56.6%, p < 0.001), and significantly increased median time from last chemotherapy to death (135.5 vs 62 days, p < 0.001). CONCLUSION: Only one in three women in this cohort of patients deceased from gynecologic cancer made a definitive decision to discontinue chemotherapy in an outpatient setting, and this process was associated with improved end-of-life outcomes. Future efforts should examine the impact of interventions designed to increase the proportion of patients who transition away from chemotherapy via shared decision making in the outpatient setting.

Facilitated cascade testing (FaCT): a randomized controlled trial.

BACKGROUND: Identifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing. PRIMARY OBJECTIVE: Our primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing. STUDY HYPOTHESIS: We hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care. TRIAL DESIGN: The FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services. MAJOR INCLUSION/EXCLUSION CRITERIA: Adult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included. PRIMARY ENDPOINT: Analyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm. SAMPLE SIZE: One hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: January 2024. TRIAL REGISTRATION: NCT04613440.

Alternative lengthening of telomeres in normal mammalian somatic cells.

Some cancers use alternative lengthening of telomeres (ALT), a mechanism whereby new telomeric DNA is synthesized from a DNA template. To determine whether normal mammalian tissues have ALT activity, we generated a mouse strain containing a DNA tag in a single telomere. We found that the tagged telomere was copied by other telomeres in somatic tissues but not the germline. The tagged telomere was also copied by other telomeres when introgressed into CAST/EiJ mice, which have telomeres more similar in length to those of humans. We conclude that ALT activity occurs in normal mouse somatic tissues.

Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy?

OBJECTIVES: Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/-RAD. METHODS: This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/-lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/-RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/-RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/-RAD (HR = 0.18, 95% CI: 0.09-0.39) and RAD (HR = 0.31, 95% CI: 0.18-0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/-RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12-0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03-0.32). Overall survival did not differ by treatment. CONCLUSIONS: In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone.

Clinical and Economic Outcomes of Genome Sequencing Availability on Containing a Hospital Outbreak of Resistant Escherichia coli in Australia.

OBJECTIVES: To evaluate the outbreak size and hospital cost effects of bacterial whole-genome sequencing availability in managing a large-scale hospital outbreak. METHODS: We built a hybrid discrete event/agent-based simulation model to replicate a serious bacterial outbreak of resistant Escherichia coli in a large metropolitan public hospital during 2017. We tested the 3 strategies of using whole-genome sequencing early, late (actual outbreak), or not using it and assessed their associated outbreak size and hospital cost. The model included ward dynamics, pathogen transmission, and associated hospital costs during a 5-month outbreak. Model parameters were determined using data from the Queensland Hospital Admitted Patient Data Collection (N = 4809 patient admissions) and local clinical knowledge. Sensitivity analyses were performed to address model and parameter uncertainty. RESULTS: An estimated 197 patients were colonized during the outbreak, with 75 patients detected. The total outbreak cost was A$460 137 (US$317 117), with 6.1% spent on sequencing. Without sequencing, the outbreak was estimated to result in 352 colonized patients, costing A$766 921 (US$528 547). With earlier detection from use of routine sequencing, the estimated outbreak size was 3 patients and cost A$65 374 (US$45 054). CONCLUSIONS: Using whole-genome sequencing in hospital outbreak management was associated with smaller outbreaks and cost savings, with sequencing costs as a small fraction of total hospital costs, supporting the further investigation of the use of routine whole-genome sequencing in hospitals.

Management of high, moderate, and low penetrance ovarian cancer susceptibility mutations: an assessment of current risk reduction practices.

OBJECTIVE: Limited information exists regarding risk reduction strategies for women with moderate and low penetrance ovarian cancer susceptibility mutations. We sought to assess current risk reduction practice patterns for carriers of these mutations through a survey of members of the Society of Gynecologic Oncology. METHODS: Society of Gynecologic Oncology members were emailed a survey consisting of two vignettes: (1) a 35-year-old premenopausal woman; (2) a 55-year-old postmenopausal woman with comorbidities. Each vignette contained sub-scenarios in which the patient had either a BRCA1 (relative risk (RR)=30-60), RAD51C (RR=5.0), or ATM (RR=1.5-2.0) mutation. Respondents were queried about their preferred management approach. Summary statistics were performed to describe results of the survey. We used χ2 testing for statistical analyses, comparing results according to mutation type and demographic information. RESULTS: A total of 193 (15%) of 1284 Society of Gynecologic Oncology members responded. For the premenopausal woman, 99%, 80%, and 40% would perform a risk reducing salpingo-oophorectomy prior to menopause in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. For the postmenopausal woman, 98%, 85%, and 42% would proceed with risk reducing salpingo-oophorectomy in the setting of a BRCA1, RAD51C, and ATM mutation, respectively. Response distribution for carriers of RAD51C and ATM mutations were different from BRCA1 in both vignettes (p<0.001). CONCLUSIONS: Respondents were more likely to perform risk reducing salpingo-oophorectomy, in the setting of a BRCA1, RAD51C, and ATM mutation, earlier and more frequently in the setting of a BRCA1 mutation. However, there was a lack of consensus about management of the moderate and low penetrance mutations, suggesting that more data regarding age specific risks and appropriate risk reduction strategies for these alterations are needed.

Adjuvant treatment improves overall survival in women with high-intermediate risk early-stage endometrial cancer with lymphovascular space invasion.

BACKGROUND: Adjuvant therapy in early-stage endometrial cancer has not shown a clear overall survival benefit, and hence, patient selection remains crucial. OBJECTIVE: To determine whether women with high-intermediate risk, early-stage endometrial cancer with lymphovascular space invasion particularly benefit from adjuvant treatment in improving oncologic outcomes. METHODS: A multi-center retrospective study was conducted in women with stage IA, IB, and II endometrial cancer with lymphovascular space invasion who met criteria for high-intermediate risk by Gynecologic Oncology Group (GOG) 99. Patients were stratified by the type of adjuvant treatment received. Clinical and pathologic features were abstracted. Progression-free and overall survival were evaluated using multivariable analysis. RESULTS: 405 patients were included with the median age of 67 years (range 27-92, IQR 59-73). 75.0% of the patients had full staging with lymphadenectomy, and 8.6% had sentinel lymph node biopsy (total 83.6%). After surgery, 24.9% of the patients underwent observation and 75.1% received adjuvant therapy, which included external beam radiation therapy (15.1%), vaginal brachytherapy (45.4%), and combined brachytherapy + chemotherapy (19.1%). Overall, adjuvant treatment resulted in improved oncologic outcomes for both 5-year progression-free survival (77.2% vs 69.6%, HR 0.55, p=0.01) and overall survival (81.5% vs 60.2%, HR 0.42, p<0.001). After adjusting for stage, grade 2/3, and age, improved progression-free survival and overall survival were observed for the following adjuvant subgroups compared with observation: external beam radiation (overall survival HR 0.47, p=0.047, progression-free survival not significant), vaginal brachytherapy (overall survival HR 0.35, p<0.001; progression-free survival HR 0.42, p=0.003), and brachytherapy + chemotherapy (overall survival HR 0.30 p=0.002; progression-free survival HR 0.35, p=0.006). Compared with vaginal brachytherapy alone, external beam radiation or the addition of chemotherapy did not further improve progression-free survival (p=0.80, p=0.65, respectively) or overall survival (p=0.47, p=0.74, respectively). CONCLUSION: Adjuvant therapy improves both progression-free survival and overall survival in women with early-stage endometrial cancer meeting high-intermediate risk criteria with lymphovascular space invasion. External beam radiation or adding chemotherapy did not confer additional survival advantage compared with vaginal brachytherapy alone.

A pilot study of lower extremity lymphedema, lower extremity function, and quality of life in women after minimally invasive endometrial cancer staging surgery.

OBJECTIVE: The primary aim of this study was to pilot the use of an objective measurement technique to prospectively evaluate the incidence of lower extremity lymphedema (LEL) after minimally invasive staging surgery for endometrial cancer. Secondary objectives included observation of changes in lower extremity function and quality of life in this patient population. METHODS: A prospective evaluation of LEL was performed in 97 women who underwent minimally invasive staging surgery for endometrial cancer using comparative circumferential volume measurements. Postoperative changes in lower extremity function and global quality of life were also assessed using patient-reported outcome measures. RESULTS: Ninety-seven patients were included for lymphedema analysis. The rate of LEL was 25% at 4-6 weeks, 19% at 6-9 months, and 27% at 12-18 months postoperatively. The presence of LEL was associated with a significant worsening from baseline Lower Extremity Functional Scale (LEFS) scores at 4-6 weeks (-27.0% vs -3.7%, p = 0.02) and 6-9 months (-13.0% vs 0%, p = 0.01). LEL was not associated with a change in patient-reported global quality of life. CONCLUSIONS: Up to one in four women experience lymphedema following surgical staging for endometrial cancer, and its presence is associated with diminished lower extremity function. Larger, prospective trials using the objective methodology piloted in this study should better clarify risk factors and long-term outcomes of this morbidity.

Non-enzymatic recombination of RNA: Ligation in loops.

BACKGROUND: While the RNA world hypothesis is widely accepted, it is still far from complete: the existence of self-replicating ribozyme, consisting of potentially hundreds of nucleotides, is a core assumption for the majority of RNA world models. The appearance of such long RNA molecules under prebiotic conditions is not self-evident. Recombination seems to be a plausible way of creating RNA diversity, resulting in the appearance of functional RNAs, capable of self-replicating. METHODS: We report here on the study of recombination process modelled with two 96 nts RNA fragments. Detection of recombination products was performed with RT-PCR followed by TA-cloning and Sanger sequencing. RESULTS: A wide range of recombinant products was detected. We found that (i) the most efficient ligation was observed for RNA species forming bulges or internal loops, with ligation partners located within the loop; (ii) a strong preference was observed for formation of a few types of major products with a large variety of minor products; (iii) ligation could occur with participation of either 2',3'-cyclophosphate or 5'-ppp; (iv) the presence of key reaction components, i.e. 5'ppp-RNAs, enabled the formation of additional types of product; (v) molecular dynamics simulations of one of the most abundant products suggests that the ligation results in a preferable formation of 2'-5'- rather than 3'-5'-linkages. CONCLUSIONS: The study demonstrates regularities of new RNA molecules formation with non-enzymatic recombination process. GENERAL SIGNIFICANCE: Our findings provide new data supporting the RNA World hypothesis and show the way of new RNA sequences emergence under prebiotic conditions.

Long-term Changes in Grassland Soil Phosphorus with Fertilizer Application and Withdrawal.

Long-term phosphorus (P) applications can increase soil P concentrations in excess of agronomic optima, posing a risk to water quality. Once fertilization stops, however, it may take time for soil P concentrations to decline. Whereas P fertilization adds orthophosphate, little is known about changes in other soil P forms during P buildup and drawdown. This study examined changes in P pools (total P, Olsen P, Mehlich P, and water-extractable P) and P forms determined by P-nuclear magnetic resonance spectroscopy (P-NMR) in grazed grassland plots from Northern Ireland. Between 1994 and 1999, all plots received 8.3 kg P ha yr with variable rates of nitrogen (100-500 kg N ha yr). From 2000 to 2005, plots received 0, 20, 40, or 80 kg P ha yr and 250 kg N ha yr; from 2005 to 2010, no P fertilizer was applied to any plots. In 2005, soil P pool concentrations at the highest P fertilization rates were significantly elevated compared with those in 2000 but had decreased to 2000 concentrations by 2010. In soils receiving no P, soil P pool concentrations were significantly lower than those in 1994 only in 2010. There were few changes in P forms determined by P-NMR. Orthophosphate followed the same trend observed for the soil P pools; total organic P, total inositol phosphates, and total orthophosphate monoesters and diesters were highest in 2010 in the soil receiving no P fertilizer for 10 yr. For these soils, fertilizer application and cessation influenced inorganic P more than organic P.