Jeremy Gaskins

Computed tomography–planned interstitial brachytherapy for locally advanced gynecologic cancer: Outcomes and dosimetric predictors of urinary toxicity

PURPOSE To identify dosimetric predictors of outcome and toxicity in patients receiving CT-planned interstitial brachytherapy (ISBT) for gynecologic cancers. METHODS AND MATERIALS Patients who received ISBT between 2009 and 2014 were reviewed. Demographic, disease specific, treatment, and toxicity data were collected. Logistic regression was used to model toxicity. A least absolute shrinkage and selection operator penalty was used to identify relevant predictors. Receiver operating characteristic curves were used to analyze the relation between dosimetric factors and urinary toxicity. RESULTS Seventy-three patients received ISBT (21 at time of cancer recurrence and 52 at the first presentation). Thirty-six patients had cervical cancer, 16 had vaginal cancer, 13 had uterine cancer, and 8 had vulvar cancer. ISBT was performed using both high-dose-rate and low-dose-rate 192Ir sources (27 low dose rate and 46 high dose rate). With a median followup of 12 months, Grade 3 vaginal, urinary, and rectal toxicity occurred in 17.8%, 15.1%, and 6.8% of patients, respectively. No patients experienced Grade 4 or 5 toxicity. Dose to 0.1cc of urethra predicted for development of Grade 3 urinary toxicity (area under the curve of 0.81; 95% confidence interval: 0.66, 0.96). A 10% probability of a Grade 3 urinary toxicity associated with a dose of 23.1 equivalent dose in 2 Gy fractions (95% confidence interval: 9.51, 36.27 equivalent dose in 2 Gy fractions). CONCLUSIONS ISBT is a safe treatment for gynecologic malignancies. The dose to 0.1cc significantly predicts for severe urinary toxicity. Our data suggests that dose to a small urethral volume may be the most significant predictor of urinary toxicity in patients receiving ISBT for gynecologic cancer.

Patterns of care and predictors of adjuvant therapies in elderly patients with glioblastoma: An analysis of the National Cancer Data Base

The objectives of this study were to characterize patterns of care and to identify predictors for adjuvant therapy in elderly patients with glioblastoma in the modern era. METHODS. The National Cancer Data Base was queried for patients aged 70 years and older with glioblastoma diagnosed from January 1, 2004 through December 31, 2012. Multinomial logistic regression was used to identify predictors for receiving adjuvant therapy. Survival outcomes were estimated using the Kaplan‐Meier method and were analyzed using Cox regression models and the log‐rank test.

Adipose-Derived Stromal Vascular Fraction Cell Effects on a Rodent Model of Thin Endometrium.

Endometrial dysfunction affects approximately 1% of infertile women, and there is currently no standard therapy for improving fertility treatment outcomes in these patients. In our study, we utilized a rodent model of thin endometrium to test whether intrauterine application of adipose-derived stromal vascular fraction cells (SVF) could improve morphological and physiological markers of endometrial receptivity. Using anhydrous ethanol, endometrial area and gland density were significantly reduced in our model of thin endometrium. Application of SVF was associated with a 29% reduction in endometrial vascular endothelial growth factor (VEGF) expression and significant increases in uterine artery systolic/diastolic velocity ratios and resistance index values, suggesting reduced diastolic microvascular tone. However, no significant improvements in endometrial area or gland density were observed following SVF treatment. 3D confocal imaging demonstrated poor engraftment of SVF cells into recipient tissue, which likely contributed to the negative results of this study. We suspect modified treatment protocols utilizing adjuvant estrogen and/or tail vein cell delivery may improve SVF retention and therapeutic response in subsequent studies. SVF is an easily-obtainable cell product with regenerative capability that may have a future role in the treatment of infertile women with endometrial dysfunction.

Profiling the effects of short time‐course cold ischemia on tumor protein phosphorylation using a Bayesian approach

Phosphorylated proteins provide insight into tumor etiology and are used as diagnostic, prognostic, and therapeutic markers of complex diseases. However, pre-analytic variations, such as freezing delay after biopsy acquisition, often occur in real hospital settings and potentially lead to inaccurate results. The objective of this work is to develop statistical methodology to assess the stability of phosphorylated proteins under short-time cold ischemia. We consider a hierarchical model to determine if phosphorylation abundance of a protein at a particular phosphorylation site remains constant or not during cold ischemia. When phosphorylation levels vary across time, we estimate the direction of the changes in each protein based on the maximum overall posterior probability and on the pairwise posterior probabilities, respectively. We analyze a dataset of ovarian tumor tissues that suffered cold-ischemia shock before the proteomic profiling. Gajadhar et al. (2015) applied independent clusterings for each patient because of the high heterogeneity across patients, while our proposed model shares information allowing conclusions for the entire sample population. Using the proposed model, 15 out of 32 proteins show significant changes during 1-hour cold ischemia. Through simulation studies, we conclude that our proposed methodology has a higher accuracy for detecting changes compared to an order restricted inference method. Our approach provides inference on the stability of these phosphorylated proteins, which is valuable when using these proteins as biomarkers for a disease.

Comparison of Industry-Leading Energy Devices for Use in Gynecologic Laparoscopy: Articulating ENSEAL versus LigaSure Energy Devices

STUDY OBJECTIVE To compare 2 laparoscopic bipolar electrosurgical devices used in total laparoscopic hysterectomy (TLH). An articulating advanced bipolar device (ENSEAL G2; Ethicon Endo-Surgery, Cincinnati, OH) and an electrothermal bipolar vessel sealer (LigaSure; Medtronic, Minneapolis, MN) were analyzed for differences in surgeon perception of ease of instrument use and workload using the NASA Raw Task Load Index (RTLX) scale. A second objective was to examine differences in operative time, estimated blood loss (EBL), and perioperative complication rates between the 2 devices. DESIGN Single-institution, single-blinded, randomized controlled trial (Canadian Task Force classification I). SETTING Division of Minimally Invasive Gynecologic Surgery in a university hospital. PATIENTS Eligibility required planned TLH, over age 18 years, and able to give informed consent; exclusions were stage III or IV endometriosis, known gynecologic malignancy, and early decision for conversion to laparotomy. One hundred seventy-eight patients screened, 142 enrolled, 2 withdrew, and 140 completed the study. Patients were followed 1 month postoperatively. INTERVENTIONS Preoperative randomization to articulating advanced bipolar device or electrothermal bipolar vessel sealer to be used during TLH. MEASUREMENTS AND MAIN RESULTS At the end of each hysterectomy the primary surgeon completed an ergonomic assessment tool, the RTLX. Results were analyzed to detect differences in workload between the 2 devices. For each case the time to ligation of the bilateral uterine arteries, EBL, and complications (including device failure, blood transfusion, or other injury) were recorded. Statistical analysis was performed using the t test for normally distributed data, χ2 test for categorical data, and Mann-Whitney U-test for nonparametric data. There were no differences in age, body mass index, parity, prior surgery, uterine weight, race, indication, pathology, and comorbidities between the 2 groups. A statistically significant increase in RTLX scores (p < .0001), device failures (p = .0031), and time to ligation of bilateral uterine arteries (p = .0281) was noted in the articulating device group. No significant differences in EBL or complication rates were noted between the groups. CONCLUSIONS The articulating advanced bipolar device was shown to have a statistically significant increase in surgeon-perceived workload and rate of device failure when used in TLH; however, clinical and surgical outcomes were equivalent.

A Bayesian approach for analyzing zero‐inflated clustered count data with dispersion

In practice, count data may exhibit varying dispersion patterns and excessive zero values; additionally, they may appear in groups or clusters sharing a common source of variation. We present a novel Bayesian approach for analyzing such data. To model these features, we combine the Conway-Maxwell-Poisson distribution, which allows both overdispersion and underdispersion, with a hurdle component for the zeros and random effects for clustering. We propose an efficient Markov chain Monte Carlo sampling scheme to obtain posterior inference from our model. Through simulation studies, we compare our hurdle Conway-Maxwell-Poisson model with a hurdle Poisson model to demonstrate the effectiveness of our Conway-Maxwell-Poisson approach. Furthermore, we apply our model to analyze an illustrative dataset containing information on the number and types of carious lesions on each tooth in a population of 9-year-olds from the Iowa Fluoride Study, which is an ongoing longitudinal study on a cohort of Iowa children that began in 1991.

A Systematic Assessment of Google Search Queries and Readability of Online Gynecologic Oncology Patient Education Materials

The Internet is a major source of health information for gynecologic cancer patients. In this study, we systematically explore common Google search terms related to gynecologic cancer and calculate readability of top resulting websites. We used Google AdWords Keyword Planner to generate a list of commonly searched keywords related to gynecologic oncology, which were sorted into five groups (cervical cancer, ovarian cancer, uterine cancer, vulvar cancer, vaginal cancer) using five patient education websites from sgo.org. Each keyword was Google searched to create a list of top websites. The Python programming language (version 3.5.1) was used to describe frequencies of keywords, top-level domains (TLDs), domains, and readability of top websites using four validated formulae. Of the estimated 1,846,950 monthly searches resulting in 62,227 websites, the most common was cancer.org. The most common TLD was *.com. Most websites were above the eighth-grade reading level recommended by the American Medical Association (AMA) and the National Institute of Health (NIH). The SMOG Index was the most reliable formula. The mean grade level readability for all sites using SMOG was 9.4 ± 2.3, with 23.9% of sites falling at or below the eighth-grade reading level. The first ten results for each Google keyword were easiest to read with results beyond the first page of Google being consistently more difficult. Keywords related to gynecologic malignancies are Google-searched frequently. Most websites are difficult to read without a high school education. This knowledge may help gynecologic oncology providers adequately meet the needs of their patients.

Minichromosome maintenance complex component 8 and 9 gene expression in the menstrual cycle and unexplained primary ovarian insufficiency

PurposeDNA repair genes Minichromosome maintenance complex component (MCM) 8 and 9 have been linked with gonadal development, primary ovarian insufficiency (POI), and age at menopause. Our objective was to characterize MCM 8 and 9 gene expression in the menstrual cycle, and to compare MCM 8/9 expression in POI vs normo-ovulatory women.MethodsNormo-ovulatory controls (n = 11) and unexplained POI subjects (n = 6) were recruited. Controls provided three blood samples within one menstrual cycle: (1) early follicular phase, (2) ovulation, and (3) mid-luteal phase. Six of 11 controls only provided a follicular phase sample. Amenorrheic POI subjects provided a single, random blood sample. MCM8/9 expression in peripheral blood was assessed with qRTPCR. Analyses were performed using delta-Ct measurements; group differences were transformed to a fold change (FC) and confidence interval (CI). Differences across menstrual cycle phases were compared using random effects ANOVA. Two-sample t tests were used to compare two groups.ResultsMCM8 expression was significantly lower at ovulation and during the luteal phase, when compared to the follicular phase [FC = 0.69 in the luteal vs follicular phase (p = 0.012, CI = 0.53, 0.90); and 0.65 in the ovulatory vs follicular phase (p = 0.0057, CI = 0.50, 0.85)]. No change in MCM9 expression was noted throughout the menstrual cycle. No significant difference was seen in MCM8/9 expression when comparing POI to control subjects.ConclusionsOur study showed greater MCM8 expression in the follicular phase of the menstrual cycle, compared to the ovulatory and luteal phases. No cyclic changes were seen with MCM9. Significant differences in MCM8/9 expression were not detected between POI and controls; however, we recommend further investigation with a larger sample population.

Discovery of the Long Interspersed Nuclear Element-1 activation product [Open Reading Frame-1 (ORF1) protein] in human blood

Long Interspersed Nuclear Element 1 is the only autonomous mobile DNA capable of self-propagation, and is an environmental biomarker that is activated upon an environmental trigger. We have developed an ELISA method to detect and measure Open Reading Frame-1 (ORF1) and have applied it to interrogate serum samples from men with equivocal prostate specific antigen (PSA) results. Polyclonal antibodies were developed using the first 14-amino acid peptide of N-terminal-ORF1 protein. Remnant serum samples from a total of 53 men, ages>50 yr, were analyzed for immunoreactive ORF1 (iORF1) and PSA concentrations; outcomes for the non-biopsied and biopsied groups were also recorded. The dynamic range of the ELISA was between (CV): 2.0 (14%) to 30 ng/mL (1.2%). The total imprecision (within-run/inter-day) was: QC3 = 2.7%/21%, QC6 = 1.1%/18%, and QC20 = 0.33%/11%. The median iORF1 concentration in the non-biopsy group was 14.7 ng/mL (Q1 - Q3: 10.5 - Q3:18.4), which was significantly lower than the Biopsy group at 25.0 ng/mL (Q1 - Q3: 20.0-33.1), P-value = .003. In conclusion, we have developed a competitive ELISA and discovered the presence of iORF1 in serum, which could be used to advance future studies involving ORF1 measurement from blood. In addition, iORF1 may be a complement with the PSA screen to better detect prostate cancer.

A Dose–Volume Response Model for Brain Metastases Treated With Frameless Single-Fraction Robotic Radiosurgery: Seeking to Better Predict Response to Treatment

Purpose/Objective(s): To establish a dose–volume response relationship for brain metastases treated with single-fraction robotic stereotactic radiosurgery and identify predictors of local control. Materials/Methods: We reviewed a prospective institutional database of all patients treated for intact brain metastases with stereotactic radiosurgery alone using the CyberKnife robotic radiosurgery system from 2012 to 2015. Tumor response was determined based on Response Evaluation Criteria In Solid Tumors version 1.1. Survival was estimated using the Kaplan-Meier method. Logistic regression modeling was used to identify predictors of outcome and establish a dose–volume response relationship. Receiver operating characteristic curves were constructed to evaluate the predictive capability of the relationship. Results: There were 357 metastases evaluated in 111 patients with a median diameter of 8.14 mm (2.00-40.77 mm). At 6 and 12 months, local control was 86.9% and 82.2%, respectively. For lesions of similar volumes, higher maximum dose, mean dose, and minimum dose (all P values <.05) predicted for better local control. Tumor volume and diameter were strongly correlated, and a dose–volume response relationship was constructed using mean dose per lesion diameter (Gy/mm) that was predictive of local control (odds ratio: 1.34, 95% confidence interval: 1.06-1.70). Area under the receiver operating characteristic curve for local control and mean dose by volume was 0.6199 with a threshold of 2.05 Gy/mm (local failure 7.6% above and 17.3% below 2.05 Gy/mm). Conclusion: A dose–volume response relationship exists for brain metastases treated with robotic stereotactic radiosurgery. Mean dose per volume is strongly predictive of local control and can be potentially useful during stereotactic radiosurgery plan evaluation while respecting previously established dose constraints.