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In this study involving 1655 men who had been treated for localized prostate cancer, differences between prostatectomy and radiotherapy were noted in the first 5 years after treatment, but these differences tended to disappear after 15 years of follow-up. Patients with clinically localized prostate cancer have a favorable long-term overall and cancer-specific rate of survival regardless of treatment choice. 1 – 3 There are currently no completed prospective, randomized trials that evaluate differences in survival outcomes between radical prostatectomy and external-beam radiation therapy. Consequently, predicted functional outcomes have become essential components of treatment decision making. 4 , 5 Although studies with short-term follow-up (1 to 3 years) and intermediate-term follow-up (4 to 5 years) have identified incremental differences in functional outcomes between patients undergoing prostatectomy and those undergoing radiotherapy, longer-term outcomes remain largely unknown. Since the median life expectancy after treatment for prostate . . .

BPH is a common disease associated with age and obesity. However, the biological pathways between obesity and BPH are unknown. Our objective was to investigate biomarkers of systemic and prostate tissue inflammation as potential mediators of the obesity and BPH association. Participants included 191 men without prostate cancer at prostate biopsy. Trained staff measured weight, height, waist and hip circumferences, and body composition by bioelectric impedance analysis. Systemic inflammation was estimated by serum IL-6, IL-1β, IL-8, and TNF-α; and by urinary prostaglandin E2 metabolite (PGE-M), F2-isoprostane (F2iP), and F2-isoprostane metabolite (F2iP-M) levels. Prostate tissue was scored for grade, aggressiveness, extent, and location of inflammatory regions, and also stained for CD3 and CD20 positive lymphocytes. Analyses investigated the association between multiple body composition scales, systemic inflammation, and prostate tissue inflammation against BPH outcomes, including prostate size at ultrasound and LUTS severity by the AUA-symptom index (AUA-SI). Prostate size was significantly associated with all obesity measures. For example, prostate volume was 5.5 to 9.0 mls larger comparing men in the 25th vs. 75th percentile of % body fat, fat mass (kg) or lean mass (kg). However, prostate size was not associated with proinflammatory cytokines, PGE-M, F2iP, F2iP-M, prostate tissue inflammation scores or immune cell infiltration. In contrast, the severity of prostate tissue inflammation was significantly associated with LUTS, such that there was a 7 point difference in AUA-SI between men with mild vs. severe inflammation (p = 0.004). Additionally, men with a greater waist-hip ratio (WHR) were significantly more likely to have severe prostate tissue inflammation (p = 0.02), and a high WHR was significantly associated with moderate/severe LUTS (OR = 2.56, p = 0.03) among those participants with prostate tissue inflammation. The WHR, an estimate of centralized obesity, was associated with the severity of inflammatory regions in prostate tissue and with LUTS severity among men with inflammation. Our results suggest centralized obesity advances prostate tissue inflammation to increase LUTS severity. Clinically targeting centralized fat deposition may reduce LUTS severity. Mechanistically, the lack of a clear relationship between systemic inflammatory or oxidative stress markers in blood or urine with prostate size or LUTS suggests pathways other than systemic inflammatory signaling may link body adiposity to BPH outcomes.

Objective To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). Background Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. Methods This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16–64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. Results Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (− 5.4, 5.8), p  = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p  = 0.012), there were no between-group differences in the secondary outcomes. Conclusion Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Approximately half of esophageal biopsies from patients with eosinophilic esophagitis (EoE) contain inadequate lamina propria, making it impossible to determine the lamina propria fibrosis (LPF). This study aimed to develop and validate a web-based tool to predict LPF in esophageal biopsies with inadequate lamina propria. Prospectively collected demographic and clinical data and scores for 7 relevant EoE histology scoring system epithelial features from patients with EoE participating in the Consortium of Eosinophilic Gastrointestinal Disease Researchers observational study were used to build the models. Using the least absolute shrinkage and selection operator method, variables strongly associated with LPF were identified. Logistic regression was used to develop models to predict grade and stage of LPF. The grade model was validated using an independent data set. Of 284 patients in the discovery data set, median age (quartiles) was 16 (8-31) years, 68.7% were male patients, and 93.4% were White. Age of the patient, basal zone hyperplasia, dyskeratotic epithelial cells, and surface epithelial alteration were associated with presence of LPF. The area under the receiver operating characteristic curve for the grade model was 0.84 (95% confidence interval: 0.80-0.89) and for stage model was 0.79 (95% confidence interval: 0.74-0.84). Our grade model had 82% accuracy in predicting the presence of LPF in an external validation data set. We developed parsimonious models (grade and stage) to predict presence of LPF in esophageal biopsies with inadequate lamina propria and validated our grade model. Our predictive models can be easily used in the clinical setting to include LPF in clinical decisions and determine its effect on treatment outcomes.

Although tumor metastases remain significant drivers of mortality, the genetic factors that increase the risks of metastases are not fully identified. Interleukin 6 (IL-6) has emerged as an important factor in breast cancer progression with IL-6 single nucleotide polymorphism (SNP) variants shown to affect survival. We hypothesized that SNPs of the IL-6 promoter at rs1800795 in breast cancer patients are associated with distant metastases. We performed an initial case-control study using Vanderbilt University Medical Center's BioVU, a genomic biobank linked to de-identified electronic medical records in the Synthetic Derivative database, to identify germline SNPs that may predict the development of metastatic disease to any site from any solid tumor including breast cancer. We identified a SNP in IL-6: rs1800795 to be of significance and evaluated this finding using a separate, matched-pair cohort of breast cancer patients with and without metastases from The Ohio State University Wexner Medical Center. The initial study suggested that GG relative to CG at rs1800795 (OR 1.52; 95% CI 1.14-2.02; p = 0.004) was significantly associated with the development of metastases. This association was also observed in the Ohio State University cohort (OR 2.23; 95% CI 1.06-4.71; p = 0.001). There were no significant relationships between rs1800795 status and any patient or tumor characteristics, including estrogen receptor status. These findings suggest that GG SNP at IL-6: rs1800795 may indicate an increased risk of metastasis of primary breast cancer. Further studies in larger population sets are warranted as advanced screening and prophylactic intervention might be employed in GG carriers.

Background Despite lower cancer incidence rates, cancer mortality is higher among rural compared to urban dwellers. Patient, provider, and institutional level factors contribute to these disparities. The overarching objective of this study is to leverage the multidisciplinary, multispecialty oncology team from an academic cancer center in order to provide comprehensive cancer care at both the patient and provider levels in rural healthcare centers. Our specific aims are to: 1) evaluate the clinical effectiveness of a multi-level telehealth-based intervention consisting of provider access to molecular tumor board expertise along with patient access to a supportive care intervention to improve cancer care delivery; and 2) identify the facilitators and barriers to future larger scale dissemination and implementation of the multi-level intervention. Methods Coordinated by a National Cancer Institute-designated comprehensive cancer center, this study will include providers and patients across several clinics in two large healthcare systems serving rural communities. Using a telehealth-based molecular tumor board, sequencing results are reviewed, predictive and prognostic markers are discussed, and treatment plans are formulated between expert oncologists and rural providers. Simultaneously, the rural patients will be randomized to receive an evidence-based 6-week self-management supportive care program, Cancer Thriving and Surviving, versus an education attention control. Primary outcomes will be provider uptake of the molecular tumor board recommendation and patient treatment adherence. A mixed methods approach guided by the Consolidated Framework for Implementation Research that combines qualitative key informant interviews and quantitative surveys will be collected from both the patient and provider in order to identify facilitators and barriers to implementing the multi-level intervention. Discussion The proposed study will leverage information technology-enabled, team-based care delivery models in order to deliver comprehensive, coordinated, and high-quality cancer care to rural and/or underserved populations. Simultaneous attention to institutional, provider, and patient level barriers to quality care will afford the opportunity for us to broadly share oncology expertise and develop dissemination and implementation strategies that will enhance the cancer care delivered to patients residing within underserved rural communities. Trial registration Clinicaltrials.gov , NCT04758338 . Registered 17 February 2021 – Retrospectively registered, http://www.clinicaltrials.gov/

Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition. Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile -infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4 + cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. IMPORTANCE Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.

To evaluate the relative efficacy of novel retinoblastoma treatments, eye classification-specific success rates for current standard-of-care intravenous chemotherapy regimens must be known. This meta-analysis included studies if: (1) patients received intravenous chemotherapy for retinoblastoma, (2) globe salvage data was reported, (3) only intravenous chemoreduction (with/without local consolidation) was used. The outcome measure was globe salvage success without need for salvage radiotherapy, subdivided by disease classification and chemotherapy regimen. Data from 27 studies (1483 eyes) were pooled. By Reese–Ellsworth classification, globe salvage rates were 85% (95%CI:73–92%) for Group I, 78% (95%CI:70–85%) for Group II, 68% (95%CI:56–78%) for Group III, 47% (95%CI:34–60%) for Group IV, and 35% (95%CI:26–45%) for Group V (Va: 35% [95%CI:21–54%]; Vb: 42% [95%CI:29–56%]; those without sub-classification: 31% [95%CI:19–47%]). By International Classification, globe salvage rates were 93% (95%CI:80–97%) for Group A, 83% (95%CI:73–89%) for Group B, 73% (95%CI:54–86%) for Group C, 40% (95%CI:31–51%) for Group D, and 19% (95%CI:5–50%) for Group E. Standard carboplatin-etoposide-vincristine out-performed two-drug regimens (odds ratio (OR) = 1.9 (95%CI:1.3–3.0) for Groups I-IV and OR = 2.1 (95%CI:1.3–3.4) for Group V; p = 0.002 for each). For eyes with diffuse vitreous seeds (Vb), an enhanced regimen out-performed standard chemotherapy (OR = 2.4 [95%CI:1.3–4.7]; p = 0.004). In conclusion, two-drug regimens were less effective for all eyes, whereas enhanced regimens were more effective for eyes with vitreous seeds. Novel therapies can now be compared to these baseline globe salvage rates.

Clinical decision for primary treatment for prostate cancer is dictated by variables with insufficient specificity. Early detection of prostate cancer likely to develop rapid recurrence could support neo-adjuvant therapeutics and adjuvant options prior to frank biochemical recurrence. This study compared markers in serum and urine of patients with rapidly recurrent prostate cancer to recurrence-free patients after radical prostatectomy. Based on previous identification of urinary sarcosine as a metastatic marker, we tested whether methionine metabolites in urine and serum could serve as pre-surgical markers for aggressive disease. Urine and serum samples (n = 54 and 58, respectively), collected at the time of prostatectomy were divided into subjects who developed biochemical recurrence within 2 years and those who remained recurrence-free after 5 years. Multiple methionine metabolites were measured in urine and serum by GC-MS. The role of serum metabolites and clinical variables (biopsy Gleason grade, clinical stage, serum prostate specific antigen [PSA]) on biochemical recurrence prediction were evaluated. Urinary sarcosine and cysteine levels were significantly higher (p = 0.03 and p = 0.007 respectively) in the recurrent group. However, in serum, concentrations of homocysteine (p = 0.003), cystathionine (p = 0.007) and cysteine (p<0.001) were more abundant in the recurrent population. The inclusion of serum cysteine to a model with PSA and biopsy Gleason grade improved prediction over the clinical variables alone (p<0.001). Higher serum homocysteine, cystathionine, and cysteine concentrations independently predicted risk of early biochemical recurrence and aggressiveness of disease in a nested case control study. The methionine metabolites further supplemented known clinical variables to provide superior sensitivity and specificity in multivariable prediction models for rapid biochemical recurrence following prostatectomy.

Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17. We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls. In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A. Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.