Stereotactic Body Proton Therapy Versus Conventionally Fractionated Proton Therapy for Early Prostate Cancer: A Randomized, Controlled, Phase 3 Trial.

PURPOSE: We aimed to determine if ultra-hypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. MATERIALS AND METHODS: This study was a multicenter, randomized, controlled, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 according to AJCC 7th ed. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Non-inferiority for FFF was determined based on one-sided confidence intervals. Toxicities were compared at different time points using Fisher's Exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual. RESULTS: Between December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR 3.9-5.2). The 2-year FFF was 100% for both groups, with the one-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI: -1.70%-6.96%), favoring the SBRT arm, thus fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. Rates of gastrointestinal (GI) and genitourinary (GU) G2 and G3 toxicities did not differ significantly between groups but the the study was not powered to detect significant toxicity differences. Also, HRQoL metrics did not differ significantly between groups over the study median follow up. CONCLUSIONS: SBPT is non-inferior to CFPT regarding FFF, with similar long-term GU and GI toxicity rates and minimal impact in patient reported HRQoL over time.

Enabling Medical Leaders Through Mentoring.

Mentoring is important to the development and enhancement of the medical profession and to organizational performance. The challenge is to implement a mentoring program within your organization. Leaders can use this article to assist in training both mentors and mentees. This article reminds people that the mindsets and skills necessary to become good mentor and mentee improve with practice, thus engage, learn, and improve. The time invested in mentoring relationships enhances patient care, creates positive work environment within organizations, improves individual and organizational performance, and creates a brighter future for the medical profession.

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain.

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.

Preclinical models of endometriosis and interstitial cystitis/bladder pain syndrome: an Innovative Medicines Initiative-PainCare initiative to improve their value for translational research in pelvic pain.

ABSTRACT: Endometriosis (ENDO) and interstitial cystitis/bladder pain syndrome (IC/BPS) are chronic pain conditions for which better treatments are urgently needed. Development of new therapies with proven clinical benefit has been slow. We have conducted a review of existing preclinical in vivo models for ENDO and IC/BPS in rodents, discussed to what extent they replicate the phenotype and pain experience of patients, as well as their relevance for translational research. In 1009 publications detailing ENDO models, 41% used autologous, 26% syngeneic, 18% xenograft, and 11% allogeneic tissue in transplantation models. Intraperitoneal injection of endometrial tissue was the subcategory with the highest construct validity score for translational research. From 1055 IC/BPS publications, most interventions were bladder centric (85%), followed by complex mechanisms (8%) and stress-induced models (7%). Within these categories, the most frequently used models were instillation of irritants (92%), autoimmune (43%), and water avoidance stress (39%), respectively. Notably, although pelvic pain is a hallmark of both conditions and a key endpoint for development of novel therapies, only a small proportion of the studies (models of ENDO: 0.5%-12% and models of IC/BPS: 20%-44%) examined endpoints associated with pain. Moreover, only 2% and 3% of publications using models of ENDO and IC/BPS investigated nonevoked pain endpoints. This analysis highlights the wide variety of models used, limiting reproducibility and translation of results. We recommend refining models so that they better reflect clinical reality, sharing protocols, and using standardized endpoints to improve reproducibility. We are addressing this in our project Innovative Medicines Initiative-PainCare/Translational Research in Pelvic Pain.

Cognitive disturbances in the cuprizone model of multiple sclerosis.

Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10-week-old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle-treated mice. Cuprizone-treated animals showed multiple deficits in short touchscreen-based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule-learning task. In contextual/cued fear conditioning experiments, cuprizone-treated mice showed significantly lower levels of contextual freezing than vehicle-treated mice. Diffusion tensor imaging showed treatment-dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone-treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.

Acquisition and reversal of visual discrimination learning in APPSwDI/Nos2-/- (CVN) mice.

Studies of cognitive behavior in rodent models of Alzheimer's disease (AD) are the mainstay of academic and industrial efforts to find effective treatments for this disorder. However, in the majority of such studies, the nature of rodent behavioral tests is considerably different from the setting associated with cognitive assessments of individuals with AD. The recently developed touchscreen technique provides a more translational way of rodent cognitive testing because the stimulus (images in different locations on the screen) and reaction (touch) are similar to those employed in human test routines, such as the Cambridge Neuropsychological Test Automated Battery. Here, we used Visual Discrimination and Reversal of Visual Discrimination touchscreen tasks to assess cognitive performance of APPSwDI/Nos2-/- (CVN) mice, which express mutated human APP and have a homozygous deletion of the Nos2 gene. We revealed that CVN mice made more first-time errors and received more correction trials than WT mice across both discrimination and reversal phases, although mutation effect size was larger during the latter phase. These results indicate sensitivity of touchscreen-based measurements to AD-relevant mutations in CVN mice and warrant future touchscreen experiments aimed at evaluating other cognitive and motivational phenotypes in this AD mouse model.

Building Moral Strength: Bridging the Moral Judgment-Action Gap.

This chapter reviews the literature on the moral self and student development and highlights the best practices for enhancing students' moral strength.

Tobacco cessation among low-income smokers: motivational enhancement and nicotine patch treatment.

INTRODUCTION: Despite decades of tobacco use decline among the general population in the United States, tobacco use among low-income populations continues to be a major public health concern. Smoking rates are higher among individuals with less than a high school education, those with no health insurance, and among individuals living below the federal poverty level. Despite these disparities, smoking cessation treatments for low-income populations have not been extensively tested. In the current study, the efficacy of 2 adjunctive smoking cessation interventions was evaluated among low-income smokers who were seen in a primary care setting. METHODS: A total of 846 participants were randomly assigned either to motivational enhancement treatment plus brief physician advice and 8 weeks of nicotine replacement therapy (NRT) or to standard care, which consisted of brief physician advice and 8 weeks of NRT. Tobacco smoking abstinence was at 1, 2, 6, and 12 months following baseline. RESULTS: The use of the nicotine patch, telephone counseling, and positive decisional balance were predictive of increased abstinence rates, and elevated stress levels and temptation to smoke in both social/habit and negative affect situations decreased abstinence rates across time. Analyses showed intervention effects on smoking temptations, length of patch use, and number of telephone contacts. Direct intervention effects on abstinence rates were not significant, after adjusting for model predictors and selection bias due to perirandomization attrition. CONCLUSIONS: Integrating therapeutic approaches that promote use of and adherence to medications for quitting smoking and that target stress management and reducing negative affect may enhance smoking cessation among low-income smokers.

Building spiritual fitness in the Army: an innovative approach to a vital aspect of human development.

This article describes the development of the spiritual fitness component of the Army's Comprehensive Soldier Fitness (CSF) program. Spirituality is defined in the human sense as the journey people take to discover and realize their essential selves and higher order aspirations. Several theoretically and empirically based reasons are articulated for why spirituality is a necessary component of the CSF program: Human spirituality is a significant motivating force, spirituality is a vital resource for human development, and spirituality is a source of struggle that can lead to growth or decline. A conceptual model developed by Sweeney, Hannah, and Snider (2007) is used to identify several psychological structures and processes that facilitate the development of the human spirit. From this model, an educational, computer-based program has been developed to promote spiritual resilience. This program consists of three tiers: (a) building awareness of the self and the human spirit, (b) building awareness of resources to cultivate the human spirit, and (c) building awareness of the human spirit of others. Further research will be needed to evaluate the effectiveness of this innovative and potentially important program.

Intravenous piperacillin/tazobactam plus fluoroquinolone prophylaxis prior to prostate ultrasound biopsy reduces serious infectious complications and is cost effective.

Infectious complications related to prostate ultrasound and biopsy have increased in the past decade with the emergence of increasing fluoroquinolone bacterial resistance. We investigated the addition of intravenous (iv) piperacillin/tazobactam immediately prior to prostate ultrasound and biopsy with standard fluoroquinolone prophylaxis to determine if it would decrease the incidence of serious infectious complications after prostate ultrasound and biopsy. Group 1 patients were a historic control of 197 patients who underwent prostate ultrasound and biopsy with standard fluoroquinolone prophylaxis. Group 2 patients, 104 patients, received standard fluoroquinolone prophylaxis and the addition of a single dose of iv piperacillin/tazobactam 30 minutes prior to prostate ultrasound and biopsy. There were ten serious bacterial infectious complications in group 1 patients. No patients in group 2 developed serious bacterial infections after prostate ultrasound and biopsy. There was approximately a 5% incidence of serious bacterial infection in group 1 patients. Subgroup analysis revealed an almost 2.5 times increased risk of infection in diabetes patients undergoing prostate ultrasound and biopsy. There was a 10% risk of serious bacterial infection in diabetics compared with a 3.8% risk group 1 nondiabetes patients. The addition of a single dose of iv piperacillin/tazobactam along with standard fluoroquinolone prophylaxis substantially reduces the risk of serious bacterial infection after prostate ultrasound and biopsy (P < 0.02).

Predictors of tumor control in patients treated with linac-based stereotactic radiosurgery for metastatic disease to the brain.

OBJECTIVE: The objective of this study was to determine predictive factors for local control (LC) of brain metastases (BM) treated with Linac-based stereotactic radiosurgery (LB-SRS). METHODS: Between January 1994 and July 2001, 80 patients (126 BM) underwent LB-SRS. All patients had follow-up imaging with computed tomography (40%) or magnetic resonance imaging (60%). Most patients had either lung (41%) or renal cell (20%) cancer. The median SRS prescription dose was 18 Gy (range, 10-21 Gy). Most patients (86%) also received whole-brain radiotherapy (WBRT). LC was defined as the absence of enlargement of the BM on follow-up scans. Actuarial LC analyses were performed by the method of Kaplan-Meier and compared with the log-rank test. Factors analyzed included histology, volume, prescription dose, maximum and minimum tumor dose, target volume ratio, number of arcs and isocenters, total degrees, and WBRT. Multivariate analysis was accomplished. RESULTS: At a median follow up of 8.8 months, 11 BM failed (8.7%). The 1-and 2-year actuarial LC rates were 88.6% and 77.2%, respectively. The most significant factors correlated with LC were prescription (P = 0.0004) and minimum tumor (P = 0.002) doses, and tumor volume (P = 0.04). On multivariate analysis, the sole factor correlated with LC was minimum tumor dose (P = 0.03). CONCLUSION: Our results confirm that LB-SRS is associated with excellent LC rates in the majority of patients treated. However, particular attention should be given to minimum target dose to ensure optimal outcome.