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Review of the literature reveals that environmental hazards cause adverse health effects that include sterility, infertility, embryotoxicity, low birth weight, skin lesions, neurodevelopmental defects, immunologic disorders, cancer, and fear of late effects. They have been identified mostly by astute practitioners but also by a bacteriologist, an animal experimentalist, 5 factory workers in childless marriages, and a tipsy bystander in an economically impoverished area of Baltimore. Dust on a parent's work clothes has transported a hazard at work to a hazard at home (lead, asbestos, and chlordecone). Causality is established by showing a dose-response effect and reproducing the effect in studies of other exposed groups or by using another epidemiologic method, eg, prospective instead of retrospective study. Also, the findings should be biologically plausible and not attributable to a concomitant variable such as cigarette smoking. Contrary to front-page newspaper headlines, incidence rates for childhood leukemia are not rising. Preserving specimens for future studies has been valuable: blood from people who were exposed to dioxin in Seveso, Italy; mummified umbilical cords containing methyl mercury at Minamata Bay, Japan; and Guthrie dried blood spots to screen retrospectively for 43 genetic disorders and a specific prenatal cytogenetic abnormality in some children with 1 form of leukemia. Recommendations are given for enhancing interest in environmental hazards and their discovery by clinicians. [ABSTRACT FROM AUTHOR]

Background: High grade gliomas (HGG) are typically treated with a combination of surgery, radiotherapy and chemotherapy. Three dimensional (3D) conformal radiotherapy treatment planning is still the main stay of treatment for these patients. New treatment planning methods suggest better dose distributions and organ sparing but their clinical benefit is unclear. The purpose of the current study was to compare normal tissue sparing and tumor coverage using four different radiotherapy planning methods in patients with high grade glioma.Methods: Three dimensional conformal (3D), sequential boost IMRT, integrated boost (IB) IMRT and Tomotherapy (TOMO) treatment plans were generated for 20 high grade glioma patients. T1 and T2 MRI abnormalities were used to define GTV and CTV with 2 and 2.5 cm margins to define PTV1 and PTV2 respectively.Results: The mean dose to PTV2 but not to PTV1 was less then 95% of the prescribed dose with IB and IMRT plans. The mean doses to the optic chiasm and the ipsilateral globe were highest with 3D plans and least with IB plans. The mean dose to the contralateral globe was highest with TOMO plans. The mean of the integral dose (ID) to the brain was least with the IB plan and was lower with IMRT compared to 3D plans. The TOMO plans had the least mean D10 to the normal brain but higher mean D50 and D90 compared to IB and IMRT plans. The mean D10 and D50 but not D90 were significantly lower with the IMRT plans compared to the 3D plans.Conclusion: No single treatment planning method was found to be superior to all others and a personalized approach is advised for planning and treating high-grade glioma patients with radiotherapy. Integral dose did not reflect accurately the dose volume histogram (DVH) of the normal brain and may not be a good indicator of delayed radiation toxicity. [ABSTRACT FROM AUTHOR]

Background: Prior preclinical studies showed promising antitumor activity and an acceptable safety profile associated with radiopharmaceuticals for patients with metastatic, persistent, or recurrent uterine cervix cancers. Whether the addition of a radiopharmaceutical to chemotherapy would significantly increase progression-free survival in such patients is untested. Our retrospective study sought to associate the line of treatment and progression-free survival as benchmarks for next-generation radiopharmaceutical development. Methods: We grouped metastatic, persistent, or recurrent uterine cervix cancer patients not amenable to curable surgery or radiotherapy between 2002 and 2023 by the line of doublet, triplet, and quadruplet chemotherapy or another intervention. After the first-line treatment, patients were monitored for radiographic progression every three months for up to three years. The primary endpoints were the first and any second or third progression-free survival intervals. Results: A total of 127 patients contributed demographic, tumor, line of treatment, and outcome data with a median follow-up of 18 months (25-75% interquartile range: 9 to 37 months). After the first-line treatment, 113 patients had local or distant progression or died from any cause, most often death from the disease (67%). Median progression-free survivals were 5.5 months (95% confidence interval: 4.8-6.0 months), 5.3 months (95% confidence interval: 4.5-6.3 months), and 3.0 months (95% confidence interval: 2.1-3.7 months) for the first-, second-, and third-line treatments, respectively. For a first-line cisplatin-containing regimen, the median progression-free survival was 6.5 months (95% confidence interval: 5.5-7.7 months). Conclusions: This study highlights the limited efficacy of current treatments for metastatic, persistent, or recurrent uterine cancer patients. A five-month progression-free survival might serve as a benchmark for the development of novel therapies in clinical efficacy trials, such as radiopharmaceuticals.

Purpose: Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs., Methods: Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR)., Results: Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40)., Conclusion: The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.

Purpose: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician., Methods: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing., Results: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1 , BRCA2 , MSH6 , SDHAF2 , SDHB , and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing., Conclusion: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Objective: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers., Methods: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m 2 and adavosertib 100 mg/m 2 on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy., Results: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free., Conclusion: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities., Competing Interests: Competing interests: BRC is on advisory boards for GSK, Merck, Immunogen, Imvax, AstraZeneca and Gilead; research funding from Clovis and Immunogen. JLA reports research support from Pfizer and Amgen. HM has been part of advisory boards for Merck, Essai and GSK. YCL in on an advisory board for GSK. VB has been on advisory boards for GSK and AstraZeneca. AMO is PI and on steering committees with AstraZeneca, GSK and Clovis; advisory boards for AstraZeneca and Morphosys; CEO in Ozmosis Research (uncompensated). SL reports support for grants or contracts to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare, GSK, and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GSK, Eisai, and Shattuck Labs; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Eisai; and participation on a data safety monitoring board or advisory board for AstraZeneca. The rest of the authors declare no potential conflicts of interest., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The purpose of this retrospective study was to determine the relationship between pretherapy hemoglobin levels and progression-free survival among women with uterine cervix cancer undergoing concurrent weekly cisplatin and radiotherapy followed by brachytherapy., Methods: Patients with advanced-stage II-IVA uterine cervix cancer were grouped by hemoglobin level (Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL). Endpoints were progression-free survival, overall survival, and local control., Results: Between 01/2001 and 07/2022, 168 patients contributed demographic, tumor, pretherapy hemoglobin, and outcome data with a median follow-up of 31 months. Progression-free survival at three years was 73% (95% confidence interval: 58%-84%), 71% (95% confidence interval: 56%-82%), and 62% (95% confidence interval: 44%-75%) for the Hgb ≥ 12.0, 11.9-10.0, or < 10.0 g/dL groups, respectfully (P < 0.001). In addition, pretherapy hemoglobin levels were significant with treatment outcome when included in a multivariate analysis of prognostic variables., Discussion: In conclusion, the difference in pretherapy hemoglobin level was prognostic of progression-free survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kunos, Fabian, Fredericks, Baldwin, Dietrich, Miller and Ueland.)

The discovery of X rays in the late 19th century heralded the beginning of a new age in medicine, and the advent of channeling the power of radiation to diagnose and treat human disease. Radiation has been leveraged in medicine in a multitude of ways and is a critical element of cancer care including screening, diagnosis, surveillance, and interventional treatments. Modern radiotherapy techniques include a multitude of methodologies utilizing both externally and internally delivered radiation from a variety of approaches. This review provides a comprehensive overview of contemporary radiotherapy methodologies, the field of radiopharmaceuticals and theranostics, effects of low dose radiation and highlights the phenomena of fear of exposure to radiation and its impact in modern medicine., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

Purpose: The purpose of this study was to assess the impact of implementing a Nurse Navigator (NN) to improve the rate and timeliness of molecular tumor testing., Methods: This is an evaluation of the impact of education sessions, consensus building, and NN implementation for molecular tumor testing in patients with epithelial ovarian cancer. The NNs' responsibilities included attending tumor boards and ensuring Next Generation Sequencing (NGS) is ordered, reviewed, and coordinated for appropriate patients., Results: NNs significantly improved NGS testing rates from 35.29% to 77.27%, p = 0.002. Ordering a targeted panel test (TPT) was the most common reason for not ordering NGS in the pre-NN cohort (13/22, 59%). The total turnaround time for testing was reduced after the introduction of NNs from 145.2 days to 42.8 days, p < 0.0001. The post-NN group had a significantly higher rate of actionable mutations identified for the recurrent setting [67.6% versus 20.8% ( p = 0.0005)] and a trend towards a higher rate of actionable mutations identified in the frontline setting [41.2% versus 33.3% ( p = 0.41)]., Conclusion: NNs significantly improved somatic tumor testing rates and timeliness for patients with ovarian cancer. Discontinuing TPT in favor of NGS revealed a higher rate of actionable tumor mutations that would have been missed with TPT alone.

Introduction: High-risk human epidermal growth factor receptor 2 (HER2)-positive adenocarcinomas associate with early recurrence and death, prompting consideration of novel radiotherapeutic options like a trastuzumab-linked thorium-227 alpha-particle emitting radionuclide., Methods: We conducted a retrospective pilot biomarker study of uterine cervix cancers among patients in Appalachian Kentucky, to characterize an exploitable triage biomarker like HER2 expression before starting a prospective phase 0 trial., Results: Most (60%) adenocarcinomas showed HER2 cell-surface overexpression, whereas squamous cell carcinomas (4%) did not do so., Discussion: Further validation tests of HER2 expression as a triage biomarker for radiopharmaceutical selection are warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kunos, Fabian, Piecoro, Napier, Miller and Ueland.)

Initial assessment of vaginal bleeding in gynecologic malignancies includes a thorough history and physical examination, identification of site and extent of disease, and patient goals of care. Patients who are initially hemodynamically unstable may require critical care services. Choice of treatment is disease site specific. Cervical cancer frequently is treated with chemoradiation. Uterine cancer may be treated surgically, with radiation, or pharmacologically. Gestational trophoblastic disease is treated surgically. Alternative treatment modalities include vascular embolization and topical hemostatic agents. Patients with bleeding gynecologic malignancies should be managed as inpatients in facilities with gynecologic oncology, radiation oncology, and critical care services., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Multidisciplinary molecular tumor boards (MTBs) interpret next-generation sequencing reports and help oncologists determine best therapeutic options; however, there is a paucity of data regarding their clinical utility. The purpose of this study was to determine if MTB-directed therapy improves progression-free survival (PFS) over immediately prior therapy in patients with advanced cancer., Methods: This single-arm, prospective phase II clinical trial enrolled patients with advanced cancer with an actionable mutation who received MTB-recommended targeted therapy between January 1, 2017, and October 31, 2020. MTB-recommended both on-label (level 1 evidence) and off-label (evidence levels 2 and 3) therapies. Of the 93 enrolled patients, 43 were treated frontline and 50 received second-line or greater-line therapy. The primary outcome was the probability of patients treated with second-line or greater-line MTB-directed therapy who achieved a PFS ratio ≥ 1.3 (PFS on MTB-directed therapy divided by PFS on the patient's immediately prior therapy). Secondary outcomes included PFS for patients treated frontline and overall survival and adverse effects for the entire study population., Results: The most common disease sites were lung (35 of 93, 38%), gynecologic (17 of 93, 18%), GI (16 of 93, 17%), and head and neck (7 of 93, 8%). The Kaplan-Meier estimate of the probability of PFS ratio ≥ 1.3 was 0.59 (95% CI, 0.47 to 0.75) for patients treated with second-line or greater-line MTB-directed therapy. The median PFS was 449 (range 42-1,125) days for patients treated frontline. The median overall survival was 768 (range 22-1,240) days. There were four nontreatment-related deaths., Conclusion: When treated with MTB-directed therapy, most patients experienced improved PFS compared with immediately prior treatment. MTB-directed targeted therapy may be a strategy to improve outcomes for patients with advanced cancer.

The primary objective was to examine the role of pelvic fluid observed during transvaginal ultrasonography (TVS) in identifying ovarian malignancy. A single-institution, observational study was conducted within the University of Kentucky Ovarian Cancer Screening trial from January 1987 to September 2019. We analyzed true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) groups for the presence of pelvic fluid during screening encounters. Measured outcomes were the presence and duration of fluid over successive screening encounters. Of the 48,925 women surveyed, 2001 (4.1%) had pelvic fluid present during a TVS exam. The odds ratio (OR) of detecting fluid in the comparison group (TN screen; OR = 1) significantly differed from that of the FP cases (benign pathology; OR: 13.4; 95% confidence interval (CI): 9.1-19.8), the TP cases with a low malignant potential (LMP; OR: 28; 95% CI: 26.5-29.5), TP ovarian cancer cases (OR: 50.4; 95% CI: 27.2-93.2), and FN ovarian cancer cases (OR: 59.3; 95% CI: 19.7-178.1). The mean duration that pelvic fluid was present for women with TN screens was 2.2 ± 0.05 encounters, lasting 38.7 ± 1.3 months. In an asymptomatic screening population, free fluid identified in TVS exams was more associated with ovarian malignancy than in the control group or benign ovarian tumors. While pelvic free fluid may not solely discriminate malignancy from non-malignancy, it appears to be clinically relevant and warrants thoughtful consideration.

Purpose: Large-scale genomic sequencing studies are driving oncology drug development. However, rural populations, like those residing in Appalachian Kentucky, are underrepresented in these efforts. In this study, we determined the frequency of participation, reasons for nonparticipation, and factors predicting the decision to participate in the Total Cancer Care (TCC) prospective genomic cohort study., Methods: A total of 1,188 patients were invited to enroll in the TCC prospective cohort from December 2018 to May 2019. Declining patients were queried for their rationale for nonparticipation and their patient data were obtained from the Kentucky Cancer Registry (KCR). Logistic regression was used to assess the association between characteristics and study participation. The association of study participation with survival was modeled with Cox proportional-hazards regression., Results: 90.9% (1,081) patients consented to participate. In multivariate analysis, factors significantly associated with participation were age, gender, treatment status, and race. Though overall more women participated in the study, men were more likely to participate than women when invited (OR 1.57). Younger, Caucasian individuals who had received chemotherapy, but not surgery, were also more likely to participate. Patients in the Kentucky Appalachian cohort were primarily rural, had less educational attainment, and lower socioeconomic status. Kentucky Appalachian patients were no less likely to enroll in TCC than non-Appalachian patients. Consented individuals had higher overall survival compared to those who declined., Conclusion: Though minorities, those with low socioeconomic status, and rural populations are underrepresented in genomic studies, they were no less likely to participate when given the opportunity, and participation was associated with better clinical outcomes., (© 2020 National Rural Health Association.)

Uterine cervix cancer (UCCx) is clinically and socioeconomically diverse among women in the United States (US), which obscures the discovery of effective radiochemotherapy approaches for this disease. UCCx afflicts 7.5 per 100,000 American women nationally but 11.7 per 100,000 women in Appalachian Kentucky (AppKY), when age-adjusted to the 2000 US standard population. Epidemiological chart review was performed on 212 women with UCCx treated at the University of Kentucky (UKY) between January 2001 and July 2021. Demographics, tumor characteristics, and relative radiochemotherapy dose and schedule intensity were compared among AppKY and non-AppKY cohorts as well as Surveillance, Epidemiology, and End Results (SEER) data. One hundred thirty-eight (65%) of 212 women seeking radiochemotherapy treatment for UCCx resided in AppKY. Most (80%) sought external-beam radiochemotherapy close to their AppKY residence. Brachytherapy was then most frequently (96%) conducted at UKY. Cancer stage at diagnosis was significantly more advanced in AppKY residents. Women residing in AppKY had a median 10-week radiochemotherapy course, longer than an 8-week guideline. Estimated survival in women residing in AppKY was 8% lower than US national averages. In summary, this study identified an increased percentage of advanced-stage UCCx cancer at diagnosis arising in AppKY residents, with a confounding population-specific delay in radiochemotherapy schedule intensity lowering survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kunos, Fabian, Kudrimoti, Miller, Ueland and Randall.)

Background: The COVID-19 pandemic forced cystic fibrosis (CF) care programs to rapidly shift from in-person care delivery to telehealth. Our objective was to provide a qualitative exploration of facilitators and barriers to: 1) implementing high-quality telehealth and 2) navigating reimbursement for telehealth services., Methods: We used data from the 2020 State of Care CF Program Survey (n=286 U.S. care programs) administered in August-September to identify two cohorts of programs, with variation in telehealth quality (n=12 programs) and reimbursement (n=8 programs). We conducted focus groups and semi-structured interviews with CF program directors and coordinators in December 2020, approximately 9 months from onset of the pandemic. We used the Consolidated Framework for Implementation Research to identify facilitators and barriers of implementation, and inductive thematic analysis to identify facilitators and barriers of reimbursement., Results: Factors differentiating programs with greater and lower perceived telehealth quality included telehealth characteristics (perceived advantage over in-person care, cost, platform quality); external influences (needs and resources of those served by the CF program), characteristics of the CF program (compatibility with workflows, relative priority, available resources); characteristics of team members (individual stage of change), and processes for implementation (engaging patients and teams). Reimbursement barriers included documentation to optimize billing; reimbursement of multi-disciplinary team members, remote monitoring, and telephone-only telehealth; and lower volume of patients., Conclusions: A number of factors are associated with successful implementation and reimbursement of telehealth. Future efforts should provide guidance and incentives that support telehealth delivery and infrastructure, share best practices across CF programs, and remove barriers., (Copyright © 2021. Published by Elsevier B.V.)

With the introduction of precision medicine, treatment options for non-small-cell lung cancer have improved dramatically; however, underutilization, especially in disadvantaged patients, like those living in rural Appalachian regions, is associated with poorer survival. Molecular tumor boards (MTBs) represent a strategy to increase precision medicine use. UK HealthCare at the University of Kentucky (UK) implemented a statewide MTB in January 2017. We wanted to test the impact of UK MTB review on overall survival in Appalachian and other regions in Kentucky., Methods: We performed a case-control study of Kentucky patients newly diagnosed with non-small-cell lung cancer between 2017 and 2019. Cases were reviewed by the UK MTB and were compared with controls without UK MTB review. Controls were identified from the Kentucky Cancer Registry and propensity-matched to cases. The primary end point was the association between MTB review and overall patient survival., Results: Overall, 956 patients were included, with 343 (39%) residing in an Appalachian region. Seventy-seven (8.1%) were reviewed by the MTB and classified as cases. Cox regression analysis showed that poorer survival outcome was associated with lack of MTB review (hazard ratio [HR] = 8.61; 95% CI, 3.83 to 19.31; P < .0001) and living in an Appalachian region (hazard ratio = 1.43; 95% CI, 1.17 to 1.75; P = .004). Among individuals with MTB review, survival outcomes were similar regardless of whether they lived in Appalachia or other parts of Kentucky., Conclusion: MTB review is an independent positive predictor of overall survival regardless of residence location. MTBs may help overcome some health disparities for disadvantaged populations., Competing Interests: Susanne M. Arnold Research Funding: AstraZeneca, Genentech, Merck Sharp & Dohme, Nektar, Exelixis, Ohio State University, National Cancer Institute, Regeneron No other potential conflicts of interest were reported. Susanne M. Arnold Research Funding: AstraZeneca, Genentech, Merck Sharp & Dohme, Nektar, Exelixis, Ohio State University, National Cancer Institute, Regeneron No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

The development of patient-derived tumor organoids (TOs) from an epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine. Here, we utilized TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high-grade, serous epithelial ovarian cancer tumor organoid lines from tissue obtained during debulking surgery (two neoadjuvant-carboplatin-exposed and four chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1, and 0.1 µM). Cell viability curves and resultant EC 50 values were determined. One organoid line, UK1254, was predicted to be resistant to carboplatin based on its EC 50 value (50.2 µM) being above clinically achievable Cmax. UK1254 had a significantly shorter PFS than the rest of the subjects ( p = 0.0253) and was treated as a platinum-resistant recurrence. Subsequent gene expression analysis revealed extensively interconnected, differentially expressed pathways related to NF-kB, cellular differentiation (PRDM6 activation), and the linkage of B-cell receptor signaling to the PI3K-Akt signaling pathway (PI3KAP1 activation). This study demonstrates that patient-derived tumor organoids can be developed from patients at the time of primary or interval debulking surgery and may be used to predict clinical platinum sensitivity status or to investigate drivers of carboplatin resistance.

We conducted this systematic review to evaluate the clinical outcomes associated with molecular tumor board (MTB) review in patients with cancer., Methods: A systematic search of PubMed was performed to identify studies reporting clinical outcomes in patients with cancer who were reviewed by an MTB. To be included, studies had to report clinical outcomes, including clinical benefit, response, progression-free survival, or overall survival. Two reviewers independently selected studies and assessed quality with the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group or the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies depending on the type of study being reviewed., Results: Fourteen studies were included with a total of 3,328 patients with cancer. All studies included patients without standard-of-care treatment options and usually with multiple prior lines of therapy. In studies reporting response rates, patients receiving MTB-recommended therapy had overall response rates ranging from 0% to 67%. In the only trial powered on clinical outcome and including a control group, the group receiving MTB-recommended therapy had significantly improved rate of progression-free survival compared with those receiving conventional therapy., Conclusion: Although data quality is limited by a lack of prospective randomized controlled trials, MTBs appear to improve clinical outcomes for patients with cancer. Future research should concentrate on prospective trials and standardization of approach and outcomes., Competing Interests: Jill M. Kolesar Stock and Other Ownership Interests: Helix Diagnostics No other potential conflicts of interest were reported. Jill M. Kolesar Stock and Other Ownership Interests: Helix Diagnostics No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Objective: DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population., Methods: We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB)., Results: Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342)., Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers., Competing Interests: The employment of Dr. Oliver Hampton by M2GEN does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Gliomas are the most common primary tumor of the brain and are classified into grades I-IV of the World Health Organization (WHO), based on their invasively histological appearance. Gliomas grading plays an important role to determine the treatment plan and prognosis prediction. In this study we propose two novel methods for automatic, non-invasively distinguishing low-grade (Grades II and III) glioma (LGG) and high-grade (grade IV) glioma (HGG) on conventional MRI images by using deep convolutional neural networks (CNNs)., Methods: All MRI images have been preprocessed first by rigid image registration and intensity inhomogeneity correction. Both proposed methods consist of two steps: (a) three-dimensional (3D) brain tumor segmentation based on a modification of the popular U-Net model; (b) tumor classification on segmented brain tumor. In the first method, the slice with largest area of tumor is determined and the state-of-the-art mask R-CNN model is employed for tumor grading. To improve the performance of the grading model, a two-dimensional (2D) data augmentation has been implemented to increase both the amount and the diversity of the training images. In the second method, denoted as 3DConvNet, a 3D volumetric CNNs is applied directly on bounding image regions of segmented tumor for classification, which can fully leverage the 3D spatial contextual information of volumetric image data., Results: The proposed schemes were evaluated on The Cancer Imaging Archive (TCIA) low grade glioma (LGG) data, and the Multimodal Brain Tumor Image Segmentation (BraTS) Benchmark 2018 training datasets with fivefold cross validation. All data are divided into training, validation, and test sets. Based on biopsy-proven ground truth, the performance metrics of sensitivity, specificity, and accuracy are measured on the test sets. The results are 0.935 (sensitivity), 0.972 (specificity), and 0.963 (accuracy) for the 2D Mask R-CNN based method, and 0.947 (sensitivity), 0.968 (specificity), and 0.971 (accuracy) for the 3DConvNet method, respectively. In regard to efficiency, for 3D brain tumor segmentation, the program takes around ten and a half hours for training with 300 epochs on BraTS 2018 dataset and takes only around 50 s for testing of a typical image with a size of 160 × 216 × 176. For 2D Mask R-CNN based tumor grading, the program takes around 4 h for training with around 60 000 iterations, and around 1 s for testing of a 2D slice image with size of 128 × 128. For 3DConvNet based tumor grading, the program takes around 2 h for training with 10 000 iterations, and 0.25 s for testing of a 3D cropped image with size of 64 × 64 × 64, using a DELL PRECISION Tower T7910, with two NVIDIA Titan Xp GPUs., Conclusions: Two effective glioma grading methods on conventional MRI images using deep convolutional neural networks have been developed. Our methods are fully automated without manual specification of region-of-interests and selection of slices for model training, which are common in traditional machine learning based brain tumor grading methods. This methodology may play a crucial role in selecting effective treatment options and survival predictions without the need for surgical biopsy., (© 2020 American Association of Physicists in Medicine.)

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC., Competing Interests: Page: 10The authors declare no conflict of interest.

Objectives: Uterine cancer is the nation's most common gynecologic malignancy, but it is understudied in the geographically and socioeconomically diverse state of Kentucky (KY). Our aim was to assess the frequency, distribution, and survival of uterine corpus malignancies in KY, and specifically the differences between Appalachia (AP) and non-Appalachia (NAP) KY., Methods: This population-based cohort study used Surveillance, Epidemiology, and End Results data and the Kentucky Cancer Registry to study uterine corpus malignancy between January 1, 2000 and December 31, 2014. The analysis looked at the incidence between diagnoses in AP and NAP. The evaluation criteria included tumor histology (type I, type II, sarcoma, and mixed uterine malignancy), age, race, smoking status, stage at diagnosis, insurance status, and county of residence at diagnosis., Results: The overall age-adjusted incidence rate and survival are similar for US and KY populations; however, histologic types and distribution differ. Compared with the United States, the incidence of corpus cancers in KY is higher for type I ( P = 0.03), but lower for type II ( P = 0.003), sarcoma ( P = 0.006), and mixed ( P < 0.001). AP KY has a higher incidence of type I ( P < 0.0001) and mixed malignancy ( P = 0.04), younger age at diagnosis ( P < 0.0001), larger non-Hispanic white population ( P < 0.0001), fewer smokers ( P = 0.002), and more uninsured and Medicaid recipients ( P < 0.0001) compared with NAP KY. The hazard ratio for death is similar in AP and NAP KY (0.896; 95% confidence interval 0.795-1.009)., Conclusions: Type I and mixed uterine corpus cancers have a higher age-adjusted incidence and a younger age at diagnosis in AP compared with NAP KY.

Background : Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy and is treated with a combination of cytoreductive surgery and platinum-based chemotherapy. Extended length of stay (LOS) after surgery can affect patient morbidity, overall costs, and hospital resource utilization. The primary objective of this study was to identify factors contributing to prolonged LOS for women undergoing surgery for ovarian cancer. Methods : The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify women from 2012-2016 who underwent hysterectomy for ovarian, fallopian tube and peritoneal cancer. The primary outcome was LOS >50th percentile. Preoperative and intraoperative variables were examined to determine which were associated with prolonged LOS. Results : From 2012-2016, 1771 women underwent elective abdominal surgery for OC and were entered in the ACS-NSQIP database. The mean and median LOS was 4.6 and 4.0 days (IQR 0-38), respectively. On multivariate analysis, factors associated with prolonged LOS included: American Society of Anesthesiologists (ASA) Classification III (aOR 1.71, 95% CI 1.38-2.13) or IV (aOR 1.88, 95% CI 1.44-2.46), presence of ascites (aOR 1.88, 95% CI 1.44-2.46), older age (aOR 1.23, 95% CI 1.13-1.35), platelet count >400,000/mm 3 (aOR 1.74, 95% CI 1.29-2.35), preoperative blood transfusion (aOR 11.00, 95% CI 1.28-94.77), disseminated cancer (aOR 1.28, 95% CI 1.03-1.60), increased length of operation (121-180 min, aOR 1.47, 95% CI 1.13-1.91; >180 min, aOR 2.78, 95% CI 2.13-3.64), and postoperative blood transfusion within 72 h of incision (aOR 2.04, 95% CI 1.59-2.62) ( p < 0.05 for all). Conclusions : Longer length of hospital stay following surgery for OC is associated with many patient, disease, and treatment-related factors. The extent of surgery, as evidenced by perioperative blood transfusion and length of surgical procedure, is a factor that can potentially be modified to shorten LOS, improve patient outcomes, and reduce hospital costs.

Molecularly targeted, genomic-driven, and immunotherapy-based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log-linear model of the GMI. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size. The proposed designs provide sound statistical methods for a single-arm phase II trial with GMI as the primary endpoint., (© 2018 John Wiley & Sons, Ltd.)

Objective: To estimate the effect of ultrasound screening on stage at detection and long-term disease-specific survival of at-risk women with epithelial ovarian cancer., Methods: Eligibility included all asymptomatic women 50 years of age or older and women 25 years of age or older with a documented family history of ovarian cancer. From 1987 to 2017, 46,101 women received annual ultrasound screening in a prospective cohort trial. Women with a persisting abnormal screen underwent tumor morphology indexing, serum biomarker analysis, and surgery., Results: Seventy-one invasive epithelial ovarian cancers and 17 epithelial ovarian tumors of low malignant potential were detected. No women with a low malignant potential tumor experienced recurrent disease. Stage distribution for screen-detected invasive epithelial ovarian cancers was stage I-30 (42%), stage II-15 (21%), stage III-26 (37%), and stage IV-0 (0%). Follow-up varied from 9.2 months to 27 years (mean 7.9 years). Disease-specific survival at 5, 10, and 20 years for women with invasive epithelial ovarian cancer detected by screening was 86±4%, 68±7%, and 65±7%, respectively, vs 45±2%, 31±2%, and 19±3%, respectively, for unscreened women with clinically detected ovarian cancer from the same geographic area who were treated at the same institution by the same treatment protocols (P<.001). Twenty-seven percent of screen-detected malignancies were type I and 73% were type II. The disease-specific survival of women with type I and type II screen-detected tumors was significantly higher than that of women with clinically detected type I and type II tumors and was related directly to earlier stage at detection., Conclusion: Annual ultrasound screening of at-risk asymptomatic women was associated with lower stage at detection and increased 5-, 10-, and 20-year disease-specific survival of women with both type I and type II epithelial ovarian cancer., Clinical Trial Registration: OnCore Clinical Trials Management System, NCI-2013-01954.

Objectives: Adherence to National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer treatment improves patient outcomes. The aim of this study was to assess disparities associated with ovarian cancer treatment in the state of Kentucky and central Appalachia., Methods: Data on patients diagnosed as having ovarian cancer from 2007 through 2011 were extracted from administrative claims-linked Kentucky Cancer Registry data. NCCN compliance was defined by stage, grade, surgical procedure, and chemotherapy. Selection criteria were reviewed carefully to ensure data quality and accuracy. Descriptive analysis, logistic regression, and Cox regression analyses were performed to examine factors associated with guidelines compliance and survival., Results: Most women were aged 65 years or older (62.5%) and had high-grade (65.9%) and advanced-stage (61.0%) ovarian cancer. Two-thirds of cases (65.9%) received NCCN-recommended treatment for ovarian cancer. The hazard ratio of death for women who did not receive NCCN-compliant care was 62% higher compared with the women who did receive NCCN-compliant treatment. Results from the logistic regression showed that NCCN-compliant treatment was more likely for women aged 65 to 74 years compared with women aged 20 to 49 years, late-stage compared with early-stage cancers, receipt of care at tertiary care hospitals, and privately insured compared with Medicaid or Medicare., Conclusions: When the treatment of ovarian cancer did not follow NCCN recommendations, patients had a significantly higher risk of death. Women were less likely to receive NCCN-compliant care if they were younger (20-49 years), had early-stage disease, did not have private insurance, or had care provided at a nontertiary care hospital.

Purpose: Gliomas are rapidly progressive, neurologically devastating, largely fatal brain tumors. Magnetic resonance imaging (MRI) is a widely used technique employed in the diagnosis and management of gliomas in clinical practice. MRI is also the standard imaging modality used to delineate the brain tumor target as part of treatment planning for the administration of radiation therapy. Despite more than 20 yr of research and development, computational brain tumor segmentation in MRI images remains a challenging task. We are presenting a novel method of automatic image segmentation based on holistically nested neural networks that could be employed for brain tumor segmentation of MRI images., Methods: Two preprocessing techniques were applied to MRI images. The N4ITK method was employed for correction of bias field distortion. A novel landmark-based intensity normalization method was developed so that tissue types have a similar intensity scale in images of different subjects for the same MRI protocol. The holistically nested neural networks (HNN), which extend from the convolutional neural networks (CNN) with a deep supervision through an additional weighted-fusion output layer, was trained to learn the multiscale and multilevel hierarchical appearance representation of the brain tumor in MRI images and was subsequently applied to produce a prediction map of the brain tumor on test images. Finally, the brain tumor was obtained through an optimum thresholding on the prediction map., Results: The proposed method was evaluated on both the Multimodal Brain Tumor Image Segmentation (BRATS) Benchmark 2013 training datasets, and clinical data from our institute. A dice similarity coefficient (DSC) and sensitivity of 0.78 and 0.81 were achieved on 20 BRATS 2013 training datasets with high-grade gliomas (HGG), based on a two-fold cross-validation. The HNN model built on the BRATS 2013 training data was applied to ten clinical datasets with HGG from a locally developed database. DSC and sensitivity of 0.83 and 0.85 were achieved. A quantitative comparison indicated that the proposed method outperforms the popular fully convolutional network (FCN) method. In terms of efficiency, the proposed method took around 10 h for training with 50,000 iterations, and approximately 30 s for testing of a typical MRI image in the BRATS 2013 dataset with a size of 160 × 216 × 176, using a DELL PRECISION workstation T7400, with an NVIDIA Tesla K20c GPU., Conclusions: An effective brain tumor segmentation method for MRI images based on a HNN has been developed. The high level of accuracy and efficiency make this method practical in brain tumor segmentation. It may play a crucial role in both brain tumor diagnostic analysis and in the treatment planning of radiation therapy., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Objectives: Prospectively validate an intraoperative surgical staging algorithm to stratify patients with early endometrial cancer by risk of lymph node metastasis., Methods: Subjects with endometrial cancer clinically confined to the uterus were prospectively enrolled at an academic cancer center between Jan 2012 and Jun 2015. Study participants were stratified intraoperatively into two groups based on risk of nodal involvement using cell type, tumor grade, myometrial invasion, and tumor size in accordance with an established protocol from the Mayo Clinic. Low risk (LR) subjects received extrafascial hysterectomy with bilateral salpingo-oophorectomy; high risk (HR) patients received complete surgical staging including bilateral pelvic and para-aortic lymphadenectomy., Results: Of the 200 subjects enrolled, 194 were eligible for analysis. The algorithm identified 132 (68%) HR and 62 (32%) LR cancers. Of the HR subjects, 126 had lymphadenectomy performed with 14 (11%) positive for nodal metastases. Five HR subjects experienced disease recurrence. Of the 62 LR cancers, two patients developed disease recurrence. Ten LR cancers were upgraded to HR on final pathology due to lesion size (6) and grade (4). None of these patients experienced disease recurrence. The algorithm demonstrated 90% sensitivity (18/20) and 36% specificity (62/174) as determined by positive lymph nodes and/or disease recurrence., Conclusions: Intraoperative assessment of early endometrial cancer can be used to determine the extent of surgical staging. The studied algorithm has low specificity and modifications are necessary to better match the surgical procedure to the risk of metastatic cancer., (Published by Elsevier Inc.)

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported.

The aim of this study was to evaluate complications of surgical intervention for participants in the Kentucky Ovarian Cancer Screening Program and compare results to those of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. A retrospective database review included 657 patients who underwent surgery for a positive screen in the Kentucky Ovarian Cancer Screening Program from 1988-2014. Data were abstracted from operative reports, discharge summaries, and office notes for 406 patients. Another 142 patients with incomplete records were interviewed by phone. Complete information was available for 548 patients. Complications were graded using the Clavien-Dindo (C-D) Classification of Surgical Complications and considered minor if assigned Grade I (any deviation from normal course, minor medications) or Grade II (other pharmacological treatment, blood transfusion). C-D Grade III complications (those requiring surgical, endoscopic, or radiologic intervention) and C-D Grade IV complications (those which are life threatening) were considered "major". Statistical analysis was performed using SAS 9.4 software. Complications were documented in 54/548 (10%) subjects. For women with malignancy, 17/90 (19%) had complications compared to 37/458 (8%) with benign pathology ( p < 0.003). For non-cancer surgery, obesity was associated with increased complications ( p = 0.0028). Fifty patients had minor complications classified as C-D Grade II or less. Three of 4 patients with Grade IV complications had malignancy ( p < 0.0004). In the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, 212 women had surgery for ovarian malignancy, and 95 had at least one complication (45%). Of the 1080 women with non-cancer surgery, 163 had at least one complication (15%). Compared to the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, the Kentucky Ovarian Cancer Screening Program had significantly fewer complications from both cancer and non-cancer surgery ( p < 0.0001 and p = 0.002, respectively). Complications resulting from surgery performed as a result of the Kentucky Ovarian Cancer Screening Program were infrequent and significantly fewer than reported in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Complications were mostly minor (93%) and were more common in cancer versus non-cancer surgery.

Functionalized derivatives of the saddle-shaped molecule tetrabenzo[8]circulene were successfully synthesized through a Diels-Alder/oxidative cyclodehydrogenation approach. This methodology improves on our previously reported synthesis, affording products containing both electron-rich and electron-poor functional groups from readily available starting materials in a more efficient manner. The optoelectronic effects that result from the introduction of this functionality are presented and briefly discussed.

Objective: Some ovarian malignancies may originate in the fallopian tube. The feasibility of ultrasonographically visualizing the fallopian tube is presented., Methods: In total, 549 normal women participated in the fallopian tube visualization trial, while ovarian visualization was studied in 43,521. Chi-square analysis, t-tests and multivariate analysis determined significance and interactions., Results: Ovaries were observed in 82.7% while fallopian tubes were detected in 77.2% of women and 85.2% of the time when an ovary was detected. Age, BMI or parity was not significantly different when one or both fallopian tubes were visualized. Elevated BMI had slightly greater influence than age in limiting visualization of the fallopian tubes in multivariate analysis., Conclusion: Fallopian tubes can often be identified sonographically. Ovarian visualization provides the strongest indicator favoring fallopian tube detection. Thus, ultrasonographic examinations for adnexal cancer could include evaluation of fallopian tubes even in women >60 years and in women with BMI ≥25.

The dose measurements of the small field sizes, such as conical collimators used in stereotactic radiosurgery (SRS), are a significant challenge due to many factors including source occlusion, detector size limitation, and lack of lateral electronic equilibrium. One useful tool in dealing with the small field effect is Monte Carlo (MC) simulation. In this study, we report a comparison of Monte Carlo simulations and measurements of output factors for the Varian SRS system with conical collimators for energies of 6 MV flattening filter-free (6 MV) and 10 MV flattening filter-free (10 MV) on the TrueBeam accelerator. Monte Carlo simulations of Varian's SRS system for 6 MV and 10 MV photon energies with cones sizes of 17.5 mm, 15.0 mm, 12.5 mm, 10.0 mm, 7.5 mm, 5.0 mm, and 4.0 mm were performed using EGSnrc (release V4 2.4.0) codes. Varian's version-2 phase-space files for 6 MV and 10 MV of TrueBeam accelerator were utilized in the Monte Carlo simulations. Two small diode detectors Edge (Sun Nuclear) and Small Field Detector (SFD) (IBA Dosimetry) were applied to measure the output factors. Significant errors may result if detector correction factors are not applied to small field dosimetric measurements. Although it lacked the machine-specific kfclin,fmsrQclin,Qmsr correction factors for diode detectors in this study, correction factors were applied utilizing published studies conducted under similar conditions. For cone diameters greater than or equal to 12.5 mm, the differences between output factors for the Edge detector, SFD detector, and MC simulations are within 3.0% for both energies. For cone diameters below 12.5 mm, output factors differences exhibit greater variations.

Data from screening trials indicate that a significant percent of asymptomatic women older than 50 years of age will develop ovarian abnormalities that are detectable by ultrasonography. Most of these abnormalities are benign, and many will resolve spontaneously. However, the risk of ovarian cancer, particularly in postmenopausal women, is of concern. The goal is to use a diagnostic and treatment algorithm that will reliably detect ovarian cancer at the earliest possible stage while limiting the number of women undergoing surgery for benign disease. The combination of morphology indexing and serum biomarker analysis can accurately predict the risk of malignancy in most ovarian tumors. Ovarian tumors with cystic or septate morphology are at minimal risk of malignancy and can be followed with serial ultrasonography evaluations, thereby avoiding the morbidity and cost of surgery. Complex or solid ovarian tumors with a high morphology index score, or those with increasing biomarker production, are at a high risk of malignancy, and patients with these tumors should be referred to a gynecologic oncologist for further evaluation and treatment.

Objective: Transvaginal ultrasonography with tumor morphology index (MI) has been used to predict the risk of ovarian malignancy. Our objective was to analyze changes in serial MI scores for malignant and non-malignant ovarian tumors in a large and asymptomatic population., Methods: Eligible subjects participated in the University of Kentucky Ovarian Cancer Screening Program and had abnormalities that included cysts, cysts with septations, complex cysts with solid areas, and solid masses. Analysis included: MI, change in MI (delta MI), delta MI per scan and per month, number and duration of scans., Results: From 1987 to 2012, 38,983 women received 218,445 scans. Of the 7104 eligible subjects, 6758 tumors were observed without surgery and 472 were surgically removed. Eighty-six percent (5811) of observed tumors were resolved. There were 74 malignant and 272 non-malignant tumors. Eighty-five percent of malignancies had MI ≥5 at decision for surgery. The risk of malignancy based on MI was: MI=5 (3%), MI=6 (3.7%), MI=7 (12.6%), MI=8 (26.7%), MI=9 (27.8%), MI=10 (33.3%). The mean delta MI per month decreased for tumors that resolved (delta MI -1.0, p<0.001) or persisted without surgery (delta MI -0.7, p<0.001). For abnormalities surgically removed, the mean delta MI per month increased significantly more for malignancies than for benign tumors (delta MI +1.6 vs. +0.3, p<0.001)., Conclusions: The mean MI for malignant ovarian tumors increases over time, while non-malignant tumors have a decreasing or stable MI. Serial MI analysis can improve the prediction of ovarian malignancy by reducing false-positive results, thereby decreasing the number of operations performed for benign abnormalities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to investigate the relationship between imaging and the multivariate index assay (MIA) in the prediction of the likelihood of ovarian malignancy before surgery., Study Design: Subjects were recruited in 2 related prospective, multiinstitutional trials that involved 44 sites across the United States. Women had ovarian imaging, biomarker analysis, and surgery for an adnexal mass. Ovarian tumors were classified as high risk for solid or papillary morphologic condition on imaging study. Biomarker and imaging results were correlated with surgical findings., Results: Of the 1110 women who were enrolled with an adnexal mass on imaging, 1024 cases were evaluable. There were 255 malignant and 769 benign tumors. High-risk findings were present in 46% of 1232 imaging tests and 61% of 1024 MIA tests. The risk of malignancy increased with rising MIA scores; similarly, the likelihood of malignancy was higher for high-risk, compared with low-risk, imaging. Sensitivity and specificity for the prediction of malignancy were 98% (95% CI, 92-99) and 31% (95% CI, 27-34) for ultrasound or MIA; 68% (95% CI, 58-77) and 75% (95% CI, 72-78) for ultrasound and MIA, respectively. For computed tomography scan or MIA, sensitivity was 97% (95% CI, 92-99) and specificity was 22% (95% CI, 16-28); the sensitivity and specificity for computed tomography scan and MIA were 71% (95% CI, 62-79) and 70% (95% CI, 63-76). Only 1.6% of ovarian tumors were malignant when both tests indicated low risk. A logistic regression model to predict risk of malignancy is presented., Conclusion: An understanding of how pelvic imaging influences the MIA score can help clinicians better interpret the malignant risk of an ovarian tumor., (Copyright © 2014 Mosby, Inc. All rights reserved.)