Feasibility of outpatient hybrid brachytherapy for cervical cancer with minimal sedation: Results from a single-institutional protocol.

Purpose: Pain control techniques during high-dose-rate hybrid intracavitary-interstitial brachytherapy (HBT) for cervical cancer vary widely, with many centers opting for general anesthesia (GA) or conscious sedation (CS). Here, we describe a single-institutional series of patients treated with HBT and ASA-defined minimal sedation, utilizing oral analgesic and anxiolytic medications in substitution for GA or CS. Material and methods: The charts of patients who underwent HBT treatments for cervical cancer from June 2018 to May 2020 were retrospectively reviewed. Prior to HBT, all patients underwent an exam under anesthesia (EUA), and Smit sleeve placement under general anesthesia or deep sedation. Oral lorazepam and oxycodone/acetaminophen were administered between 30-90 minutes before HBT procedure for minimal sedation. HBT placement was performed on computed tomography (CT) table, with needle advancement under CT-guidance. Results: Treatments with minimal sedation were attempted in 63 patients. A total of 244 interstitial implants with 453 needles were placed via CT-guidance. Sixty-one patients (96.8%) tolerated the procedure without any additional intervention, while two patients (3.2%) required the use of epidural anesthesia. None of the patients in the series required a transition to general anesthesia for the procedure. Bleeding, which resolved with short-term vaginal packing, occurred in 22.1% of insertions. Conclusions: In our series, the treatment of HBT for cervical cancer with minimal sedation was feasible at a high percentage (96.8%). The ability to perform HBT without GA or CS could be a reasonable option to provide image-guided adaptive brachytherapy (IGABT) with limited resources, allowing for more widespread use. Further investigations using this technique are warranted.

Stereotactic body radiation therapy (SBRT) for metastatic renal cell carcinoma: A multi-institutional experience.

Objectives: Examine local control(LC), overall survival(OS), and toxicity following stereotactic body radiation therapy(SBRT) for patients with metastatic renal cell carcinoma(mRCC). Methods: A multi-institutional registry was queried. Potential predictive factors of LC and OS were evaluated with a Cox-proportional hazards model for multivariate analysis(MVA). Results: We identified 115 mRCC patients with 181 lesions. Median biologically effective dose (BED7) was 72.9 Gy7 (range: 42.9-231.4 Gy7) with a median dose/fraction of 10 Gy (range: 5-24 Gy). Utilizing both Karnofsky Performance Score (KPS) and presence of osseous metastatic disease as prognostic indicators, estimated 2-year OS rates were 67.7% (95% CI: 49.9-89.5%), 31.8% (95% CI: 19.0-45.3%), and 20% (95% CI: 1.4-54.7%; p=0.0012). One- and 2-year LC rates were 88.2% and 82.7%, respectively, with no prognostic factors identified. Roughly 13% of patients reported toxicities with one Grade 3-5 toxicity. Conclusion: SBRT was well-tolerated with promising LC. Both KPS and osseous metastatic disease should be considered in determining which patients with mRCC may preferentially benefit from SBRT.

Clinical Outcomes Following Stereotactic Body Radiation Therapy (SBRT) for Stage I Medically Inoperable Small Cell Lung Carcinoma: A Multi-Institutional Analysis From the RSSearch Patient Registry.

OBJECTIVES: To utilize the RSSearch Patient Registry (RSSPR) to examine local control (LC), overall survival (OS), and toxicities following stereotactic body radiation therapy (SBRT) for stage I (T1-T2/N0) medically inoperable small cell lung carcinoma (SCLC). MATERIALS AND METHODS: We searched the RSSPR for medically inoperable stage I SCLC patients treated with definitive SBRT. Potential predictive factors of OS were estimated using the Kaplan-Meier method as well as a Cox proportional hazards model. RESULTS: Twenty-one patients were identified with medically inoperable stage I SCLC that met inclusion criteria. Fourteen patients had stage IA SCLC (T1N0) and 7 patients had stage IB SCLC (T2N0) with a median gross tumor volume of 10.1 cm (range: 0.72 to 41.4 cm). The median number of fractions was 4 (range: 3 to 5), and the median BED10 was 105.6 Gy10 (range: 72 to 239.7 Gy10). Four patients received adjuvant chemotherapy. One- and 2-year actuarial OS rates were 73.1% (95% confidence interval [CI]: 36.8%-90.1%) and 36.6% (95% CI: 9.0%-65.7%), respectively. Factors found to be associated with 1-year OS on univariate analysis included T2 disease (85.5% vs. 33.3%; P=0.03), adjuvant chemotherapy (100% vs. 66.3%; P=0.11), and gross tumor volume ≥10 cm (100% vs. 52.5%; P=0.10). On multivariate analysis, adjuvant chemotherapy was associated with improved OS (hazard ratio=0.07 [95% CI: 0.13-0.37; P=0.002]). The 1-, 2-, and 3-year LC rates were 100%, and 1- and 2-year progression-free survival (PFS) rates were 85.7% (95% CI: 33.4-97.9%) and 42.9% (95% CI: 1.1-85.3%), respectively. Similar to OS, patients with T1N0 disease had superior PFS as compared to T2N0 disease (P=0.01). Toxicities were reported by 3/21 (14.3%) of patients with none ≥ grade 3 and no esophageal toxicities. CONCLUSIONS: SBRT was well-tolerated in the treatment of stage I SCLC with excellent LC achieved. Patients with T1N0 stage IA SCLC were noted to have improved PFS and OS following SBRT as compared with T2N0 Stage IB SCLC. Adjuvant chemotherapy was found to result in improved OS for stage I SCLC patients over SBRT alone.

Stereotactic radiosurgery and fractionated stereotactic radiosurgery for vestibular schwannomas: A comparison of clinical outcomes from the RSSearch patient registry.

PURPOSE: To compare clinical outcomes following stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for vestibular schwannomas (VS). MATERIALS/METHODS: We identified 64 VS patients from the RSSearch Patient Registry (12 treated with SRS and 52 patients treated with fSRS). Potential factors predictive of local control (LC) and toxicity were estimated using the Kaplan-Meier method, Cox proportional hazards model, and binary logistic regressions with propensity score weighting. RESULTS: SRS (100%) and fSRS (94.2%) resulted in similar LC (p = 0.33). fSRS was associated with a higher likelihood of experiencing toxicities (42.3% vs. 8.3%; p = 0.054 on time-to-event analysis) that was maintained following a propensity-score weighted binary logistic regression (p = 0.037) and propensity-score weighted Cox regression (p = 0.039; hazard ratio (HR) = 8.85 (95% CI: 1.1 - 70.1)). CONCLUSION: In a multi-institutional analysis, we note equivalent LC but higher toxicity with fSRS compared to SRS for VS.

Salvage Stereotactic Body Radiation Therapy for Locally Recurrent Previously Irradiated Head and Neck Squamous Cell Carcinoma: An Analysis from the RSSearch® Registry.

Objectives To report on overall survival (OS), local control (LC), dose-outcome relationships, and related toxicities following stereotactic body radiation therapy (SBRT) for locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN). Methods We queried the prospectively-maintained RSSearch® Registry for patients with rSCCHN treated with five-fraction SBRT from January 2008 to November 2016. Patients with non-squamous cell histology, missing registry data regarding prior irradiation, those treated with less than five fractions of SBRT, and those treated with SBRT in primary or boost settings were excluded. LC and OS were estimated using the Kaplan-Meier method with comparisons between groups completed using log-rank t-tests and multivariable Cox regression. Logistic regression analyses were used to examine factors predictive of toxicity. Results Forty-five rSCCHN patients treated with SBRT delivered in five fractions at 12 radiotherapy centers were identified. Prescription doses ≥ 40 Gy were associated with higher one-year rates of OS, LC, and a higher likelihood of experiencing toxicities. Acute and late toxicity rates were low (22.2% and 15.6%, respectively) and were all Grade 1-2 with only one late Grade 3 esophagitis. Conclusion Salvage SBRT for rSCCHN resulted in outcomes comparable to prior single-institutional reports in a multi-institutional cohort across clinical settings with low toxicity, thus supporting more widespread adoption of SBRT with recommended doses ≥ 40 Gy.

Factors Associated with Functional Decline in Elderly Female Breast Cancer Patients in Appalachia.

Background Functional status has been previously shown in the elderly cancer population to predict both mortality as well as treatment tolerance. The goal of this study was to determine if there are certain subsets of the elderly breast cancer population that are at higher risk of experiencing functional decline following treatment. Methods Patient charts from the Edwards Comprehensive Cancer Center in Huntington, West Virginia, from January 2006 - January 2016 were reviewed. Relevant inclusion criteria included patients of 65 years of age and older with a new diagnosis of Stage 0-III breast cancer. Functional decline was defined as an increase of at least one point in Eastern Cooperative Oncology Group (ECOG) scores within one year of diagnosis. ECOG performance status was subjectively determined by the physician. Fisher's exact test and Pearson's Chi-squared test were initially utilized to assess potential factors associated with functional decline such as pretreatment ECOG score, age at diagnosis, stage, hormone receptor status, type of surgery received, whether radiation therapy, chemotherapy, or hormonal therapy was received, medical comorbidities, body mass index (BMI), complaints of weakness at diagnosis, and ambulatory status. Factors that were found to be significant were further assessed via multivariate logistic regressions. Results Three-hundred and fourteen patients were identified as meeting inclusion criteria. At one-year follow-up, 45 patients (14.3% of the cohort) had documented functional decline. On initial analysis, factors associated with functional decline included Stage III disease (p=0.002) and complaints of weakness at diagnosis (p=0.004). Following multivariate analysis, Stage III disease (p = 0.02), complaints of weakness at diagnosis (p = 0.04), and bilateral mastectomy (p = 0.03) were significantly associated with functional decline. Conclusion Patients who were diagnosed with Stage III breast cancer, had complaints of weakness at time of diagnosis, or had bilateral mastectomies were more likely to have a decline in functional status at one-year follow-up. Awareness of factors associated with functional decline in the elderly Appalachian population with Stage 0-III breast cancer will be useful during discussions regarding patient expectations, treatment, and goals of care. Elderly breast cancer patients for whom bilateral prophylactic mastectomies are not indicated may be better served by lumpectomy alone (based on patient age, hormone receptor status, and tumor size), lumpectomy followed by radiation therapy, or unilateral mastectomy to maximize the likelihood of functional preservation following treatment.

Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity.

Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels.

Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.

BACKGROUND: Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox. HYPOTHESIS: We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. METHODS AND RESULTS: We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. CONCLUSION: Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.

Blunted IL-6 and IL-10 response to maximal aerobic exercise in patients with traumatic brain injury.

INTRODUCTION: In healthy individuals, strenuous exercise typically results in a transient increase in the inflammatory cytokine, interleukin-6 (IL-6). This increase in IL-6 is reported to have pleiotropic effects including increased glucose uptake, increased fat oxidation, and anti-inflammatory actions. PURPOSE: The purpose of this study was to determine if patients with a traumatic brain injury (TBI) have a differential cytokine response to exercise compared to healthy control subjects (CON). METHODS: Eight patients with a TBI and eight age- and sex-matched controls completed an exercise test to volitional exhaustion. Metabolic data were collected continuously, and blood was collected at baseline, immediately post-exercise, and every 10 min for an hour post-exercise. Serum was analyzed for IL-6, tumor necrosis factor-alpha, interleukin-10 (IL-10), and cortisol. RESULTS: Peak oxygen consumption (CON 33 ± 2 ml kg(-1) min(-1); TBI 29 ± 2 ml kg(-1) min(-1)) and respiratory exchange ratio during exercise were equivalent between groups. There were no baseline differences between groups for cytokine or cortisol concentrations. Exercise did not increase IL-6 in TBI, whereas IL-6 was elevated from baseline in CON at 0, 40, and 50 min post-exercise (p < 0.05). IL-10 and cortisol increased from baseline in CON at 40 min post-exercise (p < 0.05). CONCLUSIONS: These data indicate that patients recovering from TBI have blunted IL-6, IL-10, and cortisol responses following a peak exercise test compared to non-TBI controls. This lack of an exercise response may represent impaired hypothalamic-pituitary-adrenal axis function.

Comparison of gene and protein expressions in rats residing in standard cages with those having access to an exercise wheel.

Lifelong physical inactivity is associated with morbidity in adulthood, possibly influenced by changes in gene and protein expressions occurring earlier in life. mRNA (Affymetrix gene array) and proteomic (2D-DIGE MALDI-TOF/MS) analyses were determined in cardiac tissue of young (3 months) and old (16 months) Sprague-Dawley rats housed with no access to physical activity (SED) versus an exercise wheel (EX). Unfavorable phenotypes for body weight, dyslipidemia, and tumorogenesis appeared more often in adult SED versus EX. No differentially expressed genes (DEGs) occurred between groups at 3 or 16 months. Within groups, SED and EX shared 215 age-associated DEGs. In SED, ten unique DEGs occurred with age; three had cell adhesion functions (fn1, lgals3, ncam2). In EX, five unique DEGs occurred with age; two involved hypothalamic, pituitary, and gonadal hormone axis (nrob2, xpnpep2). Protein expression involved in binding, sugar metabolic processes, and vascular regulation declined with age in SED (KNT1, ALBU, GPX1, PYGB, LDHB, G3P, PYGM, PGM1, ENOB). Protein expression increased with age in EX for ATP metabolic processes (MYH6, MYH7, ATP5J, ATPA) and vascular function (KNT1, ALBU, GPX1). Differences in select gene and protein expressions within sedentary and active animals occurred with age and contributed to distinct health-related phenotypes in adulthood.