Timing of High-Dose-Rate Brachytherapy With External Beam Radiation Therapy in Patients With Intermediate- and High-Risk Localized Prostate Cancer and Its Effects on Toxicity and Quality of Life: A Randomized Controlled Trial (THEPCA).

PURPOSE: High-dose-rate brachytherapy (HDR-BT) and external beam radiation therapy (EBRT) are effective treatments for prostate cancer but cause genitourinary (GU) and gastrointestinal (GI) toxicities. There is no consensus on the timing of HDR-BT in relation to EBRT and the effect of sequencing on patients. The primary objective was to assess differences, if any, in the incidence of grade (G) 3 or higher GU toxicities from treatment. We also aimed to explore the incidence of G1 to G4 GI toxicities, quality of life (QOL), and patient satisfaction. Suppression of prostate-specific antigen (PSA) and signals for survival differences were also analyzed. METHODS AND MATERIALS: This was a single-center randomized trial in patients with intermediate- and high-risk localized prostate cancer who received HDR-BT before (Arm A) or after (Arm B) EBRT. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE). The International Prostate Symptom Score (IPSS) was used to assess lower urinary tract symptoms. The International Index of Erectile Function scale (IIEF) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) were used to assess erectile dysfunction and QOL at 0, 3, 9, and 12 months. RESULTS: Fifty patients were recruited to each arm, with 48 and 46 patients completing treatment and follow-up in each arm, 81.5% of whom had high-risk disease. There were no G3 or G4 GU or GI toxicities. G1 urinary frequency was the most common adverse event experienced in both arms, peaking in incidence 3 months after treatment commenced (45.7% and 42.2% in Arm A and B, respectively). Up to 11% of patients reported G1 urinary frequency at 12 months. Other G1 GU toxicities experienced by >10% of patients were urinary tract obstruction, tract pain, and urgency. These symptoms also peaked in incidence at 3 months. G2 GU toxicities were uncommon and experienced in a maximum of 2 patients within each arm at any time point. Over 30% of patients had G1 flatulence at baseline, and this remained the most frequently occurring G1 GI toxicity throughout the study, peaking at 12 months (21.4% and 25.6% in Arm A and B, respectively). Other GI toxicities experienced by more than 10% of patients were GI pain, proctitis, and rectal mucositis, most of which demonstrated a peak incidence at 3 or 9 months. G2 GI toxicities were uncommon except for G2 flatulence. No significant difference was found in CTCAE, IPSS, IIEF, FACT-P, and QOL scores between the arms. Median prostate-specific antigen (PSA) follow-up was 5 years. Seven patients had treatment failure in each arm. Disease Free Survival (DFS) was 93.3% and 90.7% at 5 years in Arm A and B, respectively, with median failure time of 60 and 48 months in Arm A and B, respectively. There were no statistically significant differences between arms. CONCLUSIONS: The sequencing of HDR-BT and EBRT did not affect the incidence of G3 or G4 toxicities, and no significant differences were seen in other patient-reported outcomes. Treatment was well tolerated with maintained QOL scores. Treatment failure was low in both arms in a high-risk cohort; however, a larger study with longer follow-up is underway to establish whether the difference in median time to failure between the 2 arms is a signal of superiority.

Implementation of a Colorectal Surgical Site Infection Prevention Bundle and Checklist: A Quality Improvement Project.

After noting an elevated surgical site infection rate in 2019 associated with colorectal surgeries, leaders at two Central Virginia health system hospitals convened an interdisciplinary team to audit current practices and research infection prevention strategies. After identifying a lack of standardization in care processes for colorectal surgery patients and reviewing the literature on colorectal bundles, the team created a bundle focusing on the use of antibiotics, chlorhexidine gluconate wipes or baths, separate closing instrument trays, nasal decolonization, bowel preparation, and maintaining patient normothermia. After synthesis and stakeholder input, the team implemented the colorectal bundle along with a checklist for all users to complete to ensure compliance and standardization of practice and for auditing purposes. Implementation results were positive: the total number of colorectal infections decreased from nine in 2020 to three in 2021. Education was critical to securing staff member engagement for successful implementation of and compliance with the bundle.

Association of red and processed meat consumption with cardiovascular morbidity and mortality in participants with and without obesity: A prospective cohort study.

OBJECTIVE: There is increasing evidence that red and processed meat consumption is associated with increased risk of cardiovascular (CV) disease. However, little literature reported the association among people with obesity versus those without obesity. We sought to investigate this using the UK Biobank data. METHODS: In this large prospective population-based cohort study, the red and processed meat consumption was assessed through the UK Biobank touch-screen questionnaire at baseline. The estimated hazards ratios (HRs) with 95% confidence intervals (CIs) were obtained from the Cox proportional hazard models to assess the association between red and processed meat consumption and the risk of CV death, cerebrovascular, and ischemic heart diseases in participants with and without obesity. RESULTS: Of 428,070 participants, 100,175 (23.4%) were obese with the mean age of 56 (SD: 7.9) years old and 54% were female. Participants without obesity, the mean age was 56 (SD: 5.2) years old and 55% were female. The overall median follow-up was 7.2 (IQR: 6.5-7.8) years. red and processed meat consumption had increased risk of CV death (HR (95%CI):1.04 (1.01-1.08) per week serve for participants with obesity and 1.04 (1.02-1.07) for those without obesity) after adjusted for age, sex, ethnicity, education, smoking and alcohol status and overall health. The moderate positive association between red and processed meat consumption and ischemic heart disease was only observed in participants without obesity (HR (95%CI): 1.15 (1.00-1.31) for the highest versus lowest terciles of red and processed meat consumption). No association was found with cerebrovascular disease in the participants regardless of obesity. CONCLUSIONS: Consumption frequency of red and processed meat is associated with higher risk of CV death regardless of obesity. The risk of ischemic heart disease associated with red and processed meat consumption may be higher in participants without obesity. Further studies are needed to understand the full extent of the mechanism of the association.

Associations of weight changes with all-cause, cancer and cardiovascular mortality: A prospective cohort study.

Objectives: Previous studies suggest that changes in body weight can lead to an increased risk of mortality in the general population, although the results are controversial. The current study sought to investigate this association further using data from the UK Biobank. Study design: This is a large prospective population-based cohort study. Data were derived from the UK Biobank, with the initial assessments commencing between 2006 and 2010. Methods: Proportional hazard models were used to assess the association between self-reported weight change and risk of all-cause, cancer and cardiovascular mortality. The effect of gender was also investigated. Results: Of 433,829 participants with data for self-reported weight change, the mean age was 56 (standard deviation [SD]: 8.1) years and 55% were female. In total, 55% of participants reported no weight change, 28% gained weight, 15% lost weight, 2% did not know and 0.1% preferred not to give an answer. The median follow-up was 7.1 (interquartile range [IQR]: 6.4-7.8) years. Compared with participants with no weight change, those with weight loss had an increased risk of all-cause mortality (adjusted hazard ratio [HR] 1.25, 95% confident interval [CI] 1.18-1.32), cancer death (HR 1.17, 95% CI 1.08-1.27) and cardiovascular death (HR 1.26, 95% CI 1.12-1.43). Similarly, participants reporting weight gain also had an increased risk of all-cause mortality (HR 1.08, 95% CI 1.02-1.13), cancer death (HR 1.14, 95% CI 1.07-1.22) and cardiovascular death (HR 1.27, 95% CI 1.14-1.42). Participants who had a response 'do not know' or 'prefer not to answer' showed an increased risk of all-cause and cardiovascular mortality, particularly in men. Conclusions: The results of this study highlight the importance of maintaining a stable weight in middle-aged adults. Further studies are needed to understand the pathophysiology of weight change and its effects on mortality.

The feasibility of finger prick autologous blood (FAB) as a novel treatment for severe dry eye disease (DED): protocol for a randomised controlled trial.

INTRODUCTION: Patients with severe dry eye disease (DED) often have limited treatment options with standard non-surgical management focused on the use of artificial tears for lubrication and anti-inflammatory drugs. However, artificial tears do not address the extraordinary complexity of human tears. Crudely, human tears with its vast constituents is essentially filtered blood. Blood and several blood-derived products including autologous serum, have been studied as tear substitutes. This study proposes to test the use of whole, fresh, autologous blood obtained from a finger prick for treatment of severe DED. METHODS AND ANALYSIS: The research team at the two participating sites will approach patients with severe DED for this study. Recruitment will take place over 12 months and we expect to recruit 60 patients in total. The primary outcome of this feasibility study is to estimate the proportion of eligible patients approached who consent to and comply with study procedures including treatment regimen and completion of required questionnaires. The secondary outcome measures, although not powered for in this feasibility, include corneal inflammation (assessed by the Oxford corneal staining guide), patient pain and symptoms scores (assessed by the Ocular Surface Disease Index Score), and objective signs of DED as indicated by visual acuity (assessed by Schirmer's test, tear break-up time, lower and/or upper tear meniscus height measurement). Other secondary outcomes include patients' quality of life (assessed using the validated EQ-5D-5L Questionnaire), cost to the National Health Service (NHS) and patient (assessed via use of NHS services and privately purchased over-the-counter treatment related to DED) and safety measure of pressure within the eye (assessed by the Intraocular Pressure (IOP) Score). ETHICS AND DISSEMINATION: This protocol and any subsequent amendments, along with any accompanying material provided to the participant in addition to any advertising material used in this trial have been approved by the East of England - Cambridgeshire and Hertfordshire Research Ethics Committee (REC reference: 17/EE/0508). Written approval from the committee was obtained and subsequently submitted to the respective Trust's Research and Development (R&D) office with final NHS R&D approval obtained. Data obtained from this study will be published in a suitable peer-review journal and will also presented at international ophthalmic conferences including the American Academy of Ophthalmology, the Royal College of Ophthalmology Annual Congress, the Association for Research and Vision and Ophthalmology, and the European Society of Cataract and Refractive Surgery. Information will be provided to patient groups and charities such as the Sjogren's Society and the Royal National Institute of Blind People. This will also be shared with the study participants as well as with relevant patient groups and charities. TRIAL REGISTRATION NUMBER: NCT03395431; Pre-results.

Timing of High-Dose Rate Brachytherapy With External Beam Radiotherapy in Intermediate and High-Risk Localized Prostate CAncer (THEPCA) Patients and Its Effects on Toxicity and Quality of Life: Protocol of a Randomized Feasibility Trial.

BACKGROUND: Prostate cancer is the most common cancer in males in the UK and affects around 105 men for every 100,000. The role of radiotherapy in the management of prostate cancer significantly changed over the last few decades with developments in brachytherapy, external beam radiotherapy (EBRT), intensity-modulated radiotherapy (IMRT), and image-guided radiotherapy (IGRT). One of the challenging factors of radiotherapy treatment of localized prostate cancer is the development of acute and late genitourinary and gastrointestinal toxicities. The recent European guidelines suggest that there is no consensus regarding the timing of high-dose rate (HDR) brachytherapy and EBRT. The schedules vary in different institutions where an HDR boost can be given either before or after EBRT. Few centers deliver HDR in between the fractions of EBRT. OBJECTIVE: Assessment of acute genitourinary and gastrointestinal toxicities at various time points to better understand if the order in which treatment modality is delivered (ie, HDR brachytherapy or EBRT first) has an effect on the toxicity profile. METHODS: Timing of HDR brachytherapy with EBRT in Prostate CAncer (THEPCA) is a single-center, open, randomized controlled feasibility trial in patients with intermediate and high-risk localized prostate cancer. A group of 50 patients aged 18 years old and over with histological diagnosis of prostate cancer (stages T1b-T3BNOMO), will be randomized to one of two treatment arms (ratio 1:1), following explanation of the study and informed consent. Patients in both arms of the study will be treated with HDR brachytherapy and EBRT, however, the order in which they receive the treatments will vary. In Arm A, patients will receive HDR brachytherapy before EBRT. In Arm B (control arm), patients will receive EBRT before HDR brachytherapy. Study outcomes will look at prospective assessment of genitourinary and gastrointestinal toxicities. The primary endpoint will be grade 3 genitourinary toxicity and the secondary endpoints will be all other grades of genitourinary toxicities (grades 1 and 2), gastrointestinal toxicities (grades 1 to 4), prostate-specific antigen (PSA) recurrence-free survival, overall survival, and quality of life. RESULTS: Results from this feasibility trial will be available in mid-2016. CONCLUSIONS: If the results from this feasibility trial show evidence that the sequence of treatment modality does affect the patients' toxicity profiles, then funding would be sought to conduct a large, multicenter, randomized controlled trial. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 15835424; http://www.isrctn.com/ISRCTN15835424 (Archived by WebCite at http://www.webcitation.org/6Xz7jfg1u).

Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis.

Psoriasis is a complex disease with an expanding definition of its pathological features. We sought to expand/refine the psoriasis transcriptome using 85 paired lesional and non-lesional samples from a cohort of patients with moderate-to-severe psoriasis vulgaris who were not receiving active psoriasis therapy. This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05. These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified. In addition, we profiled the serum of moderate-to-severe psoriatics compared with healthy controls to assess the overlap of overexpressed lesional genes with overexpressed systemic proteins. We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

Simultaneous detection of eight analytes in human serum by two commercially available platforms for multiplex cytokine analysis.

The accurate detection and quantitation of cytokines in serum are important in the study of disease mechanisms, pathogenesis, and treatment. Serum cytokines can reflect processes that are occurring at the cellular or tissue level and thus provide a means of indirectly monitoring these processes. Multiplex detection of cytokines allows the simultaneous measurement of multiple cytokines in a sample, increasing the efficiency of measuring the cytokines while reducing the serum sample volumes required for the testing. Two commercially available multiplex platforms were evaluated (Pierce SearchLight and Meso Scale Discovery), using multiplexes capable of simultaneously detecting eight cytokines. The cytokines analyzed in this study were gamma interferon, vascular endothelial growth factor, tumor necrosis factor alpha, interleukin-6 (IL-6), macrophage inflammatory protein 1beta, monocyte chemoattractant protein 1, IL-12p40, and IL-4. The range of quantitation of the platforms, the recovery of spiked cytokines, and the detection of the cytokines in serum samples from subjects with ulcerative colitis, Crohn's disease, rheumatoid arthritis, and psoriasis were examined. The findings showed that the detection of the cytokines was highly dependent upon the platform, with the consistency of the detection of cytokines across platforms being dependent upon the cytokine being analyzed. A careful examination of platform assay performance must be made prior to utilizing multiplex platforms in a study. While some cytokines will give similar patterns of results across platforms, others will be highly variable. The use of the same platform within a study or across studies where data will be compared is advised.

Perceived and objective risk in children of patients with peripheral arterial disease.

This study examined perceived and objective health risks, health promotive behavior, risk perception, and knowledge of risk factors for peripheral arterial disease (PAD) in children of patients with PAD. Children of patients who had lower extremity distal arterial reconstructive surgery or amputation for complications of PAD completed an investigator-developed questionnaire. Risk factor and behavioral measures were self-reported. Data were collected by telephone interview. The sample consisted of 15 children of 6 patients. Subjects displayed optimistic bias regarding their risk for developing PAD, with 67% reporting their parent's illness had no impact on their health behaviors. Fifty-three percent felt their comparative risk was "about the same" as same-age, same-sex peers. Risk factor knowledge varied and none mentioned hypertension, age, obesity, or gender; the most commonly cited risk factor was diabetes mellitus. Forty-seven percent of the offspring never smoked, less than half exercised regularly, most were overweight or had class I or class II obesity, and most were unaware of their blood pressure or cholesterol levels. Despite frequent interactions with their affected parent, these children exhibited poor understanding of risk factors and personal risk of developing PAD and most did not participate in health promotive behaviors. Educational efforts by national societies promoting an understanding of modifiable risk factors must be improved. Future studies need to explore interventions designed to improve risk perception and health promotive behaviors.