Distinct Genomic Profiles Are Associated with Treatment Response and Survival in Ovarian Cancer.

The majority of patients with ovarian cancer ultimately develop recurrent chemotherapy-resistant disease. Treatment stratification is mainly based on histological subtype and stage, prior response to platinum-based chemotherapy, and time to recurrent disease. Here, we integrated clinical treatment, treatment response, and survival data with whole-genome sequencing profiles of 132 solid tumor biopsies of metastatic epithelial ovarian cancer to explore genome-informed stratification opportunities. Samples from primary and recurrent disease harbored comparable numbers of single nucleotide variants and structural variants. Mutational signatures represented platinum exposure, homologous recombination deficiency, and aging. Unsupervised hierarchical clustering based on genomic input data identified specific ovarian cancer subgroups, characterized by homologous recombination deficiency, genome stability, and duplications. The clusters exhibited distinct response rates and survival probabilities which could thus potentially be used for genome-informed therapy stratification for more personalized ovarian cancer treatment.

Optimizing Nanopore sequencing-based detection of structural variants enables individualized circulating tumor DNA-based disease monitoring in cancer patients.

Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons. These SVs could be quantified in ctDNA samples of patients with metastatic prostate cancer using a digital PCR assay. The results suggest that SV dynamics correlate with and may improve existing treatment-response biomarkers such as PSA. https://github.com/UMCUGenetics/SHARC .

INTER-RATER AND TEST-RETEST RELIABILITY OF TWO NEW SINGLE LEG SIT-TO-STAND TESTS.

BACKGROUND: The single leg sit-to-stand test (SLSTST) is a functional test that assesses quadriceps strength. The original SLSTST was used to diagnose lumbar nerve root impingement/radiculopathy - specifically at the L3 and L4 level. The original SLSTST used one repetition as the requirement for a successful test, therefore it may not identify quadriceps weakness in highly functional individuals with or recovering from an athletic injury. PURPOSE/HYPOTHESIS: The purpose of this study was to determine the interrater and test-retest reliability of two new SLSTSTs, one for maximum number of repetitions over 30 seconds and one for time to complete five repetitions. STUDY DESIGN: Cross-sectional, reliability study. METHODS: Twenty healthy college-aged individuals (12 males, age: 22.5 years ± 1.37, height: 1.72 m ± 0.09; weight: 70.2 kg ± 11.0) participated in the study. Two testing sessions were held three to seven days apart, and two second-year physical therapy students served as examiners. The objective of the 30-second SLSTST was for the participant to perform as many single leg sit-to-stand repetitions they could in thirty seconds, while the five repetitions SLSTST measured how quickly the subjects could perform five single leg sit to stand repetitions. Both lower extremities were tested and Intraclass Correlation Coefficients (ICC) were calculated to determine reliability. RESULTS: Both SLSTSTs were found to have excellent interrater and good to excellent test-retest reliability. The 30-second SLSTSTs had inter-rater ICC = 0.99 on the right and 0.98 on the left while the test-retest ICCs ranged from 0.92 to 0.94. The five repetition SLSTSTs had an inter-rater ICC = .99 on both legs while the test-retest ICC ranged from 0.87 to 0.94. CONCLUSIONS: The results of the current study indicate that the two new SLSTSTs had good to excellent test-retest and excellent inter-rater reliability. However, more research is needed to determine if SLSTSTs can be used to identify quadriceps weakness in individuals with recovering from an athletic injury or to be used as a return-to-sport (RTS) assessment. LEVELS OF EVIDENCE: Level 2.

Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses.

There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories. OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity.

An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity.

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.

Prairie strips improve biodiversity and the delivery of multiple ecosystem services from corn-soybean croplands.

Loss of biodiversity and degradation of ecosystem services from agricultural lands remain important challenges in the United States despite decades of spending on natural resource management. To date, conservation investment has emphasized engineering practices or vegetative strategies centered on monocultural plantings of nonnative plants, largely excluding native species from cropland. In a catchment-scale experiment, we quantified the multiple effects of integrating strips of native prairie species amid corn and soybean crops, with prairie strips arranged to arrest run-off on slopes. Replacing 10% of cropland with prairie strips increased biodiversity and ecosystem services with minimal impacts on crop production. Compared with catchments containing only crops, integrating prairie strips into cropland led to greater catchment-level insect taxa richness (2.6-fold), pollinator abundance (3.5-fold), native bird species richness (2.1-fold), and abundance of bird species of greatest conservation need (2.1-fold). Use of prairie strips also reduced total water runoff from catchments by 37%, resulting in retention of 20 times more soil and 4.3 times more phosphorus. Corn and soybean yields for catchments with prairie strips decreased only by the amount of the area taken out of crop production. Social survey results indicated demand among both farming and nonfarming populations for the environmental outcomes produced by prairie strips. If federal and state policies were aligned to promote prairie strips, the practice would be applicable to 3.9 million ha of cropland in Iowa alone.

Robot-Assisted Sacrocolporectopexy for Multicompartment Prolapse of the Pelvic Floor: A Prospective Cohort Study Evaluating Functional and Sexual Outcome.

BACKGROUND: Pelvic floor disorders are a major public health issue. For female genital prolapse, sacrocolpopexy is the gold standard. Laparoscopic ventral mesh rectopexy is a relatively new and promising technique correcting rectal prolapse. There is no literature combining the 2 robotically assisted techniques. OBJECTIVE: This study was designed to evaluate the safety, quality of life, and functional and sexual outcomes of robot-assisted sacrocolporectopexy for multicompartment prolapse of the pelvic floor. DESIGN: This was a prospective, observational cohort study. SETTINGS: The study was conducted in a tertiary care setting. PATIENTS: All sexually active patients undergoing robot-assisted sacrocolporectopexy at our institution between 2012 and 2014 were included. INTERVENTION: Robot-assisted sacrocolporectopexy was the study intervention. MAIN OUTCOME MEASURES: Preoperative and postoperative (12 months) questionnaires using the Urinary Distress Inventory, Pescatori Incontinence Scale, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, and Pelvic Floor Impact Questionnaire were completed. In addition Wexner and Vaizey incontinence scores and the Wexner constipation score were recorded postoperatively. RESULTS: Fifty-one patients underwent robot-assisted sacrocolporectopexy (median follow-up, 12.5 months). The simplified Pelvic Organ Prolapse Quantification improved significantly (p < 0.0005) for all 4 of the anatomic landmarks. Both median fecal (preoperative and postoperative Pescatori 4 vs 3, p = 0.002) and urinary incontinence scores (Urinary Distress Inventory, 27.8 vs 22.2; p < 0.0005) improved significantly at 12 months. Postoperatively median Wexner (3) and Vaizey incontinence (6) and Wexner Constipation (7) scores were noted. A positive effect on sexual function (Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire score 31.8 vs 35.9; p = 0.002) and quality of life for each compartment (p < 0.0005) was observed. One patient (2%) developed mesh erosion. No multicompartment recurrences were detected. LIMITATIONS: This was a observational study with a limited follow-up, no control group, and no preoperatively validated constipation score. CONCLUSIONS: Robot-assisted sacrocolporectopexy is a safe and effective technique for multicompartment prolapse in terms of functional outcome, quality of life, and sexual function.