Showing papers by "Beaumont Health published in 2018"

A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology

Abstract: The critical nature of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician/advanced practice provider and the microbiologists who provide enormous value to the healthcare team. This document, developed by experts in laboratory and adult and pediatric clinical medicine, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. This document presents a system-based approach rather than specimen-based approach, and includes bloodstream and cardiovascular system infections, central nervous system infections, ocular infections, soft tissue infections of the head and neck, upper and lower respiratory infections, infections of the gastrointestinal tract, intra-abdominal infections, bone and joint infections, urinary tract infections, genital infections, and other skin and soft tissue infections; or into etiologic agent groups, including arthropod-borne infections, viral syndromes, and blood and tissue parasite infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. In addition, the pediatric needs of specimen management are also emphasized. There is intentional redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a guidance for physicians in choosing tests that will aid them to quickly and accurately diagnose infectious diseases in their patients.

Autosegmentation for thoracic radiation treatment planning: A grand challenge at AAPM 2017.

Abstract: Purpose This report presents the methods and results of the Thoracic Auto-Segmentation Challenge organized at the 2017 Annual Meeting of American Association of Physicists in Medicine. The purpose of the challenge was to provide a benchmark dataset and platform for evaluating performance of autosegmentation methods of organs at risk (OARs) in thoracic CT images. Methods Sixty thoracic CT scans provided by three different institutions were separated into 36 training, 12 offline testing, and 12 online testing scans. Eleven participants completed the offline challenge, and seven completed the online challenge. The OARs were left and right lungs, heart, esophagus, and spinal cord. Clinical contours used for treatment planning were quality checked and edited to adhere to the RTOG 1106 contouring guidelines. Algorithms were evaluated using the Dice coefficient, Hausdorff distance, and mean surface distance. A consolidated score was computed by normalizing the metrics against interrater variability and averaging over all patients and structures. Results The interrater study revealed highest variability in Dice for the esophagus and spinal cord, and in surface distances for lungs and heart. Five out of seven algorithms that participated in the online challenge employed deep-learning methods. Although the top three participants using deep learning produced the best segmentation for all structures, there was no significant difference in the performance among them. The fourth place participant used a multi-atlas-based approach. The highest Dice scores were produced for lungs, with averages ranging from 0.95 to 0.98, while the lowest Dice scores were produced for esophagus, with a range of 0.55-0.72. Conclusion The results of the challenge showed that the lungs and heart can be segmented fairly accurately by various algorithms, while deep-learning methods performed better on the esophagus. Our dataset together with the manual contours for all training cases continues to be available publicly as an ongoing benchmarking resource.

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial.

Abstract: Importance Low-grade non–muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non–muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non–muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90;P Conclusions and Relevance Among patients with suspected low-grade non–muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration clinicaltrials.gov Identifier:NCT00445601

Current Trends in Patient-Reported Outcome Measures in Total Joint Arthroplasty: A Study of 4 Major Orthopaedic Journals

Abstract: Background More emphasis is being placed on patient-reported outcome measures (PROMs), but the myriad of PROMs makes standardization and cross-study comparison difficult. As the era of big data and massive total joint registries matures, it will be critical to identify and implement the best PROMs. Methods All abstracts published in the years 2004, 2009, 2014, and 2016 in the Journal of Bone and Joint Surgery—American volume, the Bone and Joint Journal, Clinical Orthopedics and Related Research, and the Journal of Arthroplasty were reviewed. A PubMed search was performed with filters limiting results only to total knee, total hip, and unicompartmental knee arthroplasty articles with available abstracts. Each abstract was reviewed to identify all PROMs. Trends over time were evaluated using the Cochran-Armitage test. In the non-trend analysis, Pearson chi-square tests and one-way analysis of variance were performed. Results A total of 42 unique PROMs were used 1073 times across 644 studies. The number of PROMs in these 4 journals increased from 97 in 2004 to 228 in 2016 (P Conclusion Providers and registries should consider the relative prevalence of published outcome measures when selecting which PROMs to use, to better facilitate future cross-study comparison.

IFNγ PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy.

Abstract: IFNγ is an attractive target for imaging active antitumor immunity due to its function in the T-cell signaling axis. Here, we test an IFNγ immuno-PET (immunoPET) probe for its capacity to identify adaptive immunotherapy response after HER2/neu vaccination in both spontaneous salivary and orthotopic neu + mouse mammary tumors. IFNγ immunoPET detected elevated cytokine levels in situ after vaccination, which inversely correlated with tumor growth rate, an indicator of response to therapy. In a model of induced T-cell anergy where CD8 T cells infiltrate the tumor, but upregulate PD-1, IFNγ tracer uptake was equivalent to isotype control, illustrating a lack of antitumor T-cell activity. The IFNγ immunoPET tracer detected IFNγ protein sequestered on the surface of tumor cells, likely in complex with the IFNγ receptor, which may explain imaging localization of this soluble factor in vivo . Collectively, we find that the activation status of cytotoxic T cells is annotated by IFNγ immunoPET, with reduced off-target binding to secondary lymphoid tissues compared with imaging total CD3 + tumor-infiltrating lymphocytes. Targeting of soluble cytokines such as IFNγ by PET imaging may provide valuable noninvasive insight into the function of immune cells in situ . Significance: This study presents a novel approach to monitor therapeutic outcomes via IFNγ-targeted positron emission tomography. Cancer Res; 78(19); 5706–17. ©2018 AACR .

Biochemical Profiling of the Brain and Blood Metabolome in a Mouse Model of Prodromal Parkinson's Disease Reveals Distinct Metabolic Profiles

Abstract: Parkinson’s disease is the second most common neurodegenerative disease. In the vast majority of cases the origin is not genetic and the cause is not well understood, although progressive accumulation of α-synuclein aggregates appears central to the pathogenesis. Currently, treatments that slow disease progression are lacking, and there are no robust biomarkers that can facilitate the development of such treatments or act as aids in early diagnosis. Therefore, we have defined metabolomic changes in the brain and serum in an animal model of prodromal Parkinson’s disease. We biochemically profiled the brain tissue and serum in a mouse model with progressive synucleinopathy propagation in the brain triggered by unilateral injection of preformed α-synuclein fibrils in the olfactory bulb. In total, we accurately identified and quantified 71 metabolites in the brain and 182 in serum using 1H NMR and targeted mass spectrometry, respectively. Using multivariate analysis, we accurately identified which metabolites...

Rapid Detection of Zika Virus in Urine Samples and Infected Mosquitos by Reverse Transcription-Loop-Mediated Isothermal Amplification.

Abstract: Infection with Zika virus (ZIKV) is of growing concern since infection is associated with the development of congenital neurological disease. Quantitative reverse transcription PCR (qRT-PCR) has been the standard for ZIKV detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper testing. Studies have suggested that ZIKV detection in urine is more sensitive and has a longer window of detection compared to serum and saliva. The objective of this study was to develop a urine diagnostic test that could be completed in under 30 minutes. Urine samples spiked with ZIKV or dengue virus were tested using RT-LAMP as well as by conventional quantitative qRT-PCR. These techniques were then validated using crude lysates made from ZIKV infected mosquitoes in addition to urine and serum samples from ZIKV infected patients. RT-LAMP specifically detected ZIKV in urine and serum for ZIKV infected patients and crude mosquito lysates. This test was performed in under 30 minutes and did not require RNA extraction from urine nor mosquitos. This approach could be used for monitoring of exposed individuals, especially pregnant women, couples wanting to conceive, or individuals with suspicious symptoms as well as surveillance of mosquito populations.

Male BRCA mutation carriers: clinical characteristics and cancer spectrum.

Abstract: Mutations in BRCA1 and BRCA2 (BRCA1/2) genes are associated with an increased risk of breast and ovarian cancers in women. The cancer characteristics of men with BRCA1/2 mutations are less well studied. This study describes the unique cancer characteristics of male BRCA1/2 mutation carriers at our institution. We performed a retrospective chart review on male patients who were seen between January 2004 and December 2014 and tested positive for a BRCA1/2 mutation. We evaluated clinical characteristics, pathology findings, treatment selection and survival. A total of 102 male patients were identified who tested positive for a BRCA1/2 deleterious mutation. Of these 102 patients, 33 (32%) had a diagnosis of cancer. Of these 33 patients with cancer, the majority (20 patients) were found to carry a BRCA2 mutation. Median age of cancer diagnosis was 65 years (Range: 35-75 years). Of the 33 patients diagnosed with cancer, 8 had two or more cancers, including 1 patient who had 4 cancers. Prostate cancer was the most commonly diagnosed cancer, seen in 13 patients, 11 of whom were BRCA2 positive. These cancers tended to have higher Gleason scores and elevated PSA levels. The majority of these prostate cancer patients were alive and disease free at a median follow-up of 7.4 years. Male breast cancer was the second most common cancer seen in 9 patients, all of whom were BRCA2 positive. The majority of these cancers were high grade, hormone receptor positive and associated with lymph node metastases. There were no breast cancer related deaths. Other cancers included bladder cancer, pancreatic cancer, melanoma and other skin cancers. This study describes the cancer characteristics and outcomes of male BRCA1/2 mutation carriers. A third of male BRCA1/2 mutation carriers had a diagnosis of cancer. A significant number of patients (mostly BRCA2 mutation positive) developed multiple cancers, which may have important implications for cancer screening and prevention. Despite having high grade histology and advanced stage at diagnosis, male BRCA1/2 mutation carriers with breast and prostate cancer demonstrated a favorable 5-year survival.

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Abstract: Importance The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, −6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, −3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, −1.8 days [95% CI, −3.1 to −0.6]). Conclusions and Relevance Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration ClinicalTrials.gov Identifier:NCT01191840

Five-Year Outcomes of a Single-Institution Prospective Trial of 19-Gy Single-Fraction High-Dose-Rate Brachytherapy for Low- and Intermediate-Risk Prostate Cancer.

Abstract: Purpose To update outcome and toxicity results of a prospective trial of 19-Gy single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer. Methods and Materials Patients were treated on a prospective study of single-fraction HDR brachytherapy. All patients had low- or intermediate-risk prostate cancer. Patients with prostate volumes >50 cm3, taking alpha-blockers for urinary symptoms, or with baseline American Urologic Association symptom scores >12 were ineligible. Patients underwent transrectal ultrasound–guided interstitial implant of the prostate followed by single-fraction HDR brachytherapy to a prescription dose of 19 Gy. Results Sixty-eight patients were enrolled with a median follow-up of 3.9 years. Median age was 62 years. Median gland volume at the time of treatment was 35 cm3, 92.6% of patients had T1 disease, 63.2% had a Gleason score of 6, and median pretreatment prostate-specific antigen was 5.0 ng/mL. Chronic grade 2 genitourinary toxicity was 14.7%. No grade 3 urinary toxicity occurred. A single patient experienced grade 2+ rectal toxicity (grade 3 diarrhea) that was transient and resolved with medical management. The 5-year estimated disease-free survival was 77.2% with no significant difference between low- and intermediate-risk patients. A single patient developed distant metastases during the follow-up period. Biopsy-proven local failure at 5 years was 18.8%, occurring at a median interval of 4.0 years posttreatment. No deaths occurred during follow-up. Conclusions With extended follow-up, toxicity rates after single-fraction 19-Gy HDR brachytherapy remain low. Higher-than-expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment currently should not be offered outside the context of a clinical trial.

Multidrug-Resistant Organisms in the Setting of Periprosthetic Joint Infection-Diagnosis, Prevention, and Treatment.

Abstract: Background Periprosthetic joint infection (PJI) is a rare yet challenging problem in total hip and knee arthroplasties. The management of PJI remains difficult primarily due to the evolution of resistance by the infecting organisms. Methods This review profiles acquired mechanisms of bacterial resistance and summarizes established and emerging techniques in PJI diagnosis, prevention, and treatment. Results New techniques in PJI diagnosis and prevention continue to be explored. Antibiotics combined with 1 or 2-stage revision are associated with the higher success rates and remain the mainstay of treatment. Conclusion With higher prevalence of antibiotic-resistant organisms, novel antibiotic implant and wound care materials, improved methods for organism identification, and well-defined organism-specific treatment algorithms are needed to optimize outcomes of PJI.

Improve dosimetric outcome in stage III non-small-cell lung cancer treatment using spot-scanning proton arc (SPArc) therapy.

Abstract: To evaluate spot-scanning proton arc therapy (SPArc) and multi-field robust optimized intensity modulated proton therapy (RO-IMPT) in treating stage III non-small-cell lung cancer (NSCLC) patients. Two groups of stage IIIA or IIIB NSCLC patients (group 1: eight patients with tumor motion less than 5 mm; group 2: six patients with tumor motion equal to or more than 5 mm) were re-planned with SPArc and RO-IMPT. Both plans were generated using robust optimization to achieve an optimal coverage with 99% of internal target volume (ITV) receiving 66 Gy (RBE) in 33 fractions. The dosimetric results and plan robustness were compared for both groups. The interplay effect was evaluated based on the ITV coverage by single-fraction 4D dynamic dose. Total delivery time was simulated based on a full gantry rotation with energy-layer-switching-time (ELST) from 0.2 to 4 s. Statistical analysis was also evaluated via Wilcoxon signed rank test. Both SPArc and RO-IMPT plans achieved similar robust target volume coverage for all patients, while SPArc significantly reduced the doses to critical structures as well as the interplay effect. Specifically, compared to RO-IMPT, SPArc reduced the average integral dose by 7.4% (p = 0.001), V20, and mean lung dose by an average of 3.2% (p = 0.001) and 1.6 Gy (RBE) (p = 0.001), the max dose to cord by 4.6 Gy (RBE) (p = 0.04), and the mean dose to heart and esophagus by 0.7 Gy (RBE) (p = 0.01) and 1.7 Gy (RBE) (p = 0.003) respectively. The average total estimated delivery time was 160.1 s, 213.8 s, 303.4 s, 840.8 s based on ELST of 0.2 s, 0.5 s, 1 s, and 4 s for SPArc plans, compared with the respective values of 182.0 s (p = 0.001), 207.9 s (p = 0.22), 250.9 s (p = 0.001), 509.4 s (p = 0.001) for RO-IMPT plans. Hence, SPArc plans could be clinically feasible when using a shorter ELST. This study has indicated that SPArc could further improve the dosimetric results in patients with locally advanced stage NSCLC and potentially be implemented into routine clinical practice.

Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots.

Abstract: Mouse urinary behavior is quantifiable and is used to pinpoint mechanisms of voiding dysfunction and evaluate potential human therapies. Approaches to evaluate mouse urinary function vary widely am...

Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma

Abstract: Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT).Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments.Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood-brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation.Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. Clin Cancer Res; 24(15); 3632-43. ©2018 AACR.

Current best practice management of interstitial cystitis/bladder pain syndrome.

Abstract: Introduction:Over the last 100 years, the terminology and diagnosis criteria for interstitial cystitis have evolved. Many therapeutic options have changed, but others have endured. This article wil...

Implementation of surgical debriefing programs in large health systems: an exploratory qualitative analysis.

Abstract: The role of the “debrief” to address issues related to patient safety and systematic flaws in care is frequently overlooked. In our study, we interview surgical leaders who have developed successful strategies of debriefing within a comprehensive program of quality improvement. Semi-structured interviews of four implementation leaders were performed. The observations, beliefs and strategies of surgical leaders are compared and contrasted. Common themes are identified related to program success and failure. Quality and safety researchers performed, coded and categorized the interviews and coordinated the analysis and interpretation of the results. The authors from the four institutions aided in interpretation and framing of the results. The debriefing programs evaluated were part of comprehensive quality improvement projects. Seven high-level themes and 24 subthemes were identified from the interviews. Themes related to leadership included early engagement, visible ongoing commitment and enforcement. Success appeared to depend upon meaningful and early debriefing feedback. The culture of safety that promoted success included a commitment to open and fair communication and continuous improvement. There were many challenges to the success of debriefing programs. The loss of institutional commitment of resources and personnel was the instigating factor behind the collapse of the program at Michigan. Other areas of potential failure included communication issues and loss of early and meaningful feedback. Leaders of four surgical systems with strong debriefing programs report success using debriefing to improve system performance. These findings are consistent with previously published studies. Success requires commitment of resources, and leadership engagement. The greatest gains may be best achieved by programs that provide meaningful debriefing feedback in an atmosphere dedicated to open communication.

Metabolomic Profiling of Bile Acids in an Experimental Model of Prodromal Parkinson's Disease.

Abstract: For people with Parkinson’s disease (PD), considered the most common neurodegenerative disease behind Alzheimer’s disease, accurate diagnosis is dependent on many factors; however, misdiagnosis is extremely common in the prodromal phases of the disease, when treatment is thought to be most effective. Currently, there are no robust biomarkers that aid in the early diagnosis of PD. Following previously reported work by our group, we accurately measured the concentrations of 18 bile acids in the serum of a prodromal mouse model of PD. We identified three bile acids at significantly different concentrations (p < 0.05) when mice representing a prodromal PD model were compared with controls. These include ω-murichoclic acid (MCAo), tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA). All were down-regulated in prodromal PD mice with TUDCA and UDCA at significantly lower levels (17-fold and 14-fold decrease, respectively). Using the concentration of three bile acids combined with logistic regression, we can discriminate between prodromal PD mice from control mice with high accuracy (AUC (95% CI) = 0.906 (0.777–1.000)) following cross validation. Our study highlights the need to investigate bile acids as potential biomarkers that predict PD and possibly reflect the progression of manifest PD.

Mitochondrial Respiration in Outer Retina Contributes to Light-Evoked Increase in Hydration In Vivo.

Abstract: Purpose To test the hypothesis that mitochondrial respiration contributes to local changes in hydration involved in phototransduction-driven expansion of outer retina, as measured by structural responses on optical coherence tomography (OCT) and diffusion magnetic resonance imaging (MRI). Methods Oxygen consumption rate and mitochondrial reserve capacity of freshly isolated C57BL/6 and 129S6/SvEvTac mouse retina were measured using a Seahorse Extracellular Flux Analyzer. Light-stimulated outer retina layer water content was determined by proton density MRI, structure and thickness by ultrahigh-resolution OCT, and water mobility by diffusion MRI. Results Compared with C57BL/6 mice, 129S6/SvEvTac retina demonstrated a less robust mitochondrial respiratory basal level, with a higher reserve capacity and lower oxygen consumption in the light, suggesting a relatively lower production of water. C57BL/6 mice showed a light-triggered surge in water content of outer retina in vivo as well as an increase in hyporeflective bands, thickness, and water mobility. In contrast, light did not evoke augmented hydration in this region or an increase in hyporeflective bands or water mobility in the 129S6/SvEvTac outer retina. Nonetheless, we observed a significant but small increase in outer retinal thickness. Conclusions These studies suggest that respiratory-controlled hydration in healthy retina is linked with a localized light-evoked expansion of the posterior retina in vivo and may serve as a useful biomarker of the function of photoreceptor/retinal pigment epithelium complex.

Polyethylene in total knee arthroplasty: Where are we now?

Abstract: Polyethylene (PE) remains the gold standard for the articulating surface in hip and knee arthroplasty. To increase arthroplasty longevity and improve wear resistance, newer versions of PE have been designed with resultantly different wear properties. Highly cross-linked polyethylene (HXLPE) is used in total hip arthroplasty with excellent outcomes; however, its use in total knee arthroplasty (TKA) remains conflicting. This review summarizes biomechanical and wear properties, clinical outcomes, and cost of polyethylene inserts in TKA. Simulation studies have convincingly shown decreased wear and oxidation rates with HXLPE when compared to conventional polyethylene (CPE). Registry results have been conflicting, and short- to midterm clinical studies have not demonstrated a significant difference between HXLPE and CPE. The cost of HXLPE inserts is higher than CPE. Long-term clinical data are lacking and further studies are warranted to evaluate the role of HXLPE in TKA.

Interim Analysis of a Two-Institution, Prospective Clinical Trial of 4DCT-Ventilation-based Functional Avoidance Radiation Therapy.

Abstract: Purpose Functional imaging has been proposed that uses 4DCT images to calculate 4DCT-based lung ventilation (4DCT-ventilation). We have started a 2-institution, phase 2 prospective trial evaluating the feasibility, safety, and preliminary efficacy of 4DCT-ventilation functional avoidance. The trial hypothesis is that the rate of grade ≥2 radiation pneumonitis could be reduced to 12% with functional avoidance, compared with a 25% rate of pneumonitis with a historical control. The trial employed a Simon 2-stage design with a planned futility analysis after 17 evaluable patients. The purpose of this work is to present the trial design and implementation, dosimetric data, and clinical results for the planned futility analysis. Methods and Materials Eligible patients were patients with lung cancer who were prescribed doses of 45 to 75 Gy. For each patient, the 4DCT data were used to generate a 4DCT-ventilation image using the Hounsfield unit technique along with a compressible flow-based image registration algorithm. Two intensity modulated radiation therapy treatment plans were generated: (1) a standard lung plan and (2) a functional avoidance treatment plan that aimed to reduce dose to functional lung while meeting target and normal tissue constraints. Patients were treated with the functional avoidance plan and evaluated for thoracic toxicity (presented as rate and 95% confidence intervals [CI]) with a 1-year follow-up. Results The V20 to functional lung was 21.6% ± 9.5% (mean ± standard deviation) with functional avoidance, representing a decrease of 3.2% (P Conclusions Dosimetrically, functional avoidance achieved reduction in doses to functional lung while meeting target and organ at risk constraints. On the basis of Simon's 2-stage design and the 17.6% grade ≥2 pneumonitis rate, the trial met its futility criteria and has continued accrual.

A multi-institutional phase 2 trial of prostate stereotactic body radiation therapy (SBRT) using continuous real-time evaluation of prostate motion with patient-reported quality of life.

Abstract: Purpose The use of stereotactic body radiation therapy (SBRT) for prostate cancer has been reported predominantly from single institutional studies, although concerns for broader adoption exist. Methods and materials From 2011 through 2013, 66 men were accrued to a phase 2 trial at 5 centers. SBRT consisted of 5 fractions of 7.4 Gy to a total dose of 37 Gy using conventional linear accelerators. Electromagnetic transponders were used for motion management. Health-related quality of life (HRQOL) was evaluated via the Expanded Prostate Cancer Index Composite 26 questionnaire. Acute and late toxicities were collected according to Common Terminology Criteria for Adverse Events, version 4.0. Linear mixed modeling was performed to assess changes in HRQOL over time. Results Median follow-up was 36 months. All men had low- or intermediate-risk disease. There have been 0 biochemical recurrences. No grade 3 urinary or bowel toxicity was reported. Twenty-three percent of patients had acute grade 2 urinary toxicity, with 9% late grade 2 urinary toxicity. Four percent and 5% experienced acute or late grade 2+ bowel toxicity, respectively. Urinary bother and bowel HRQOL transiently decreased during the first 6 to 12 months post-SBRT, and then returned to baseline. In men with good erectile function at baseline, sexual HRQOL declined during the first 6 months and stabilized thereafter. On linear mixed modeling, the strongest predictor of sustained bowel and sexual HRQOL was baseline HRQOL. Conclusions In this multi-institutional phase 2 clinical trial using continuous real-time evaluation of prostate motion, prostate SBRT has excellent intermediate-term tumor control with mild and expected treatment-related side effects.

Patterns and Predictors of Short-Term Peripherally Inserted Central Catheter Use: A Multicenter Prospective Cohort Study.

Abstract: Background The guidelines for peripherally inserted central catheters (PICCs) recommend avoiding insertion if the anticipated duration of use is =5 days. However, short-term PICC use is common in hospitals. We sought to identify patient, provider, and device characteristics and the clinical outcomes associated with short-term PICCs. Methods Between January 2014 and June 2016, trained abstractors at 52 Michigan Hospital Medicine Safety (HMS) Consortium sites collected data from medical records of adults that received PICCs during hospitalization. Patients were prospectively followed until PICC removal, death, or 70 days after insertion. Multivariable logistic regression models were fit to identify factors associated with short-term PICCs, defined as dwell time of =5 days. Complications associated with short-term use, including major (eg, venous thromboembolism [VTE] or central lineassociated bloodstream infection [CLABSI]) or minor (eg, catheter occlusion, tip migration) events were assessed. Results Of the 15,397 PICCs placed, 3902 (25.3%) had a dwell time of =5 days. Most (95.5%) short-term PICCs were removed during hospitalization. Compared to PICCs placed for >5 days, variables associated with short-term PICCs included difficult venous access (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.40-1.69), multilumen devices (OR, 1.53; 95% CI, 1.39-1.69), and teaching hospitals (OR, 1.25; 95% CI, 1.04-1.52). Among those with short-term PICCs, 374 (9.6%) experienced a complication, including 99 (2.5%) experiencing VTE and 17 (0.4%) experiencing CLABSI events. The most common minor complications were catheter occlusion (4%) and tip migration (2.2%). Conclusion Short-term use of PICCs is common and associated with patient, provider, and device factors. As PICC placement, even for brief periods, is associated with complications, efforts targeted at factors underlying such use appear necessary.

Adjuvant androgen deprivation therapy for prostate cancer treated with radiation therapy.

Abstract: Radiation therapy is a commonly used curative modality for prostate cancer. The addition of androgen deprivation therapy (ADT) increases the curative potential of prostate radiotherapy (RT) in multiple subsets of patients. In addition to having an independent cytotoxic effect, current evidence suggests that androgen deprivation synergistically works with radiation therapy by preventing DNA repair. Given the wide-ranging toxicities of this therapy, clinicians must judiciously choose which patients may benefit from ADT and also consider the appropriate length of treatment. With recent advances in RT delivery, higher doses of radiation are currently used when compared with the dose used in historic trials, leading to the unanswered question of how RT dose interacts with ADT. Current and future clinical studies are attempting to further define the appropriate indications and patient populations for which ADT represents a clinically appropriate addition to prostate RT.

Trends in Medicare Reimbursement and Work Relative Value Unit Production in Radiation Oncology.

Abstract: Purpose Medicare payments to individual physicians are released annually by the CMS. The purpose of this study is to analyze trends in Medicare reimbursement and work relative value unit (wRVU) production to radiation oncologists. Materials and Methods The Medicare Physician Supplier and Other Provider Public Use File and the CMS Physician Fee Schedule Relative Value Files (to calculate wRVUs) for the calendar years 2012 to 2015 were used in this analysis. Medicare reimbursement was aggregated for each calendar year. Using the CMS Physician Fee Schedule Relative Value Files, the number of Medicare wRVUs was calculated for each radiation oncologist. Results In 2015, 4,323 radiation oncologists produced 12,895,298 wRVUs compared with 11,352,286 wRVUs produced in 2012. These datasets include only Medicare reimbursements and do not include wRVUs from private insurance or other payers. In 2015, radiation oncologists produced a median of 2,486 wRVUs from Medicare (range 3 to 24,349). Billing to Healthcare Common Procedure Coding System Code 77427 (radiation treatment management, five treatments), a proxy for total radiation treatments, fell from 1,111,670 in 2012 to 1,039,403 in 2015, a decline of 7%. Conclusion The total number of wRVUs produced by radiation oncologists has risen by 14% from 2012 to 2015. However, the number of external beam radiation fractions has declined by approximately 7% over this same period, likely due to a trend toward hypofractionated courses of treatment and use of special treatment modalities such as proton beam therapy or stereotactic body radiation therapy.

Integrative cross-platform analyses identify enhanced heterotrophy as a metabolic hallmark in glioblastoma.

Abstract: Background Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing to the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis. Methods Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n = 28] and glioblastoma [n = 80]) were performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models. Results Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide, and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that O6-methylguanine-DNA methyltransferase methylation and isocitrate dehydrogenase mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing to a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models. Conclusion Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes to a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy.

Erectile Function after Stereotactic Body Radiotherapy for Localized Prostate Cancer

Abstract: Objective To elucidate the functional erection rate after prostate stereotactic body radiotherapy (SBRT) and to develop a comprehensive prognostic model of outcomes after treatment. Patients and Methods Between 2008 and 2013, 373 consecutive men with localized prostate cancer were treated with SBRT at a single academic institution as part of a prospective clinical trial or prospective registry. Prospective longitudinal patient-reported health-related quality of life (HRQoL) data was collected using the Expanded Prostate Cancer Index Composite (EPIC)-26 instrument. Functional erections were strictly defined as ‘firm enough for intercourse’ according to EPIC-26. Detailed comorbidity data were also collected. Logistic regression models were used to predict 24- and 60-month functional erection rates. Observed erection rates after SBRT were compared with those after other radiation therapies (external beam radiation therapy [EBRT] and brachytherapy) using prospectively validated models. Results The median (interquartile range) follow-up was 56 (37–73) months and the response rate at 2 years was 84%. For those with functional erections at baseline, 57% and 45% retained function at 24 and 60 months, respectively. On multivariable analysis for 24-month erectile function, significant variables included higher baseline sexual HRQoL (adjusted odds ratio [aOR] 1.55 per 10 points, 95% confidence interval [CI] 1.37–1.74; P < 0.001) and older age (aOR 0.66 per 10 years, 95% CI 0.43–1.00; P = 0.05). At 60 months, baseline HRQoL and age remained associated with erectile function, along with body mass index (aOR 0.45, 95% CI 0.26–0.78; P < 0.001). The 24- and 60-month models had excellent discrimination (c-index 0.81 and 0.84, respectively). Erection rates after SBRT were not statistically different from model-predicted rates after EBRT or brachytherapy for the whole cohort and the cohort with baseline erectile function. Conclusions Intermediate- to long-term post-SBRT erectile function results are promising and not significantly different from other radiotherapy techniques. Clinicians can use our prognostic model to counsel patients regarding expected erectile function after SBRT.

Stereotactic Radiosurgery for Pediatric Versus Adult Brain Arteriovenous Malformations.

Abstract: Background and Purpose- The aim of this international, multicenter, retrospective matched cohort study is to directly compare the outcomes after stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVM) in pediatric versus adult patients Methods- We performed a retrospective review of patients with AVM who underwent SRS at 8 institutions participating in the International Gamma Knife Research Foundation from 1987 to 2014 Patients were categorized into pediatric (<18 years of age) and adult (≥18 years of age) cohorts and matched in a 1:1 ratio using propensity scores Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes Results- From a total of 2191 patients who were eligible for inclusion in the overall study cohort, 315 were selected for each of the matched cohorts There were no significant differences between matched pediatric versus adult cohorts with respect to the rates of favorable outcome (59% versus 58%; P=0936), AVM obliteration (62% versus 63%; P=0934), post-SRS hemorrhage (9% versus 7%; P=0298), radiological radiation-induced changes (26% versus 26%; P=0837), symptomatic radiation-induced changes (7% versus 9%; P=0383), or permanent radiation-induced changes (2% versus 3%; P=0589) The all-cause mortality rate was significantly lower in the matched pediatric cohort (3% versus 10%; P=0003) Conclusions- The outcomes after SRS for comparable AVMs in pediatric versus adult patients were not found to be appreciably different SRS remains a reasonable treatment option for appropriately selected pediatric patients with AVM, who harbor a high cumulative lifetime hemorrhage risk Age seems to be a poor predictor of AVM outcomes after SRS