Background Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. Objective The objective of ...this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. Methods OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate–dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. Results Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue ( P < .05). OSM levels were also increased in bronchoalveolar lavage fluid of allergic asthmatic patients after segmental allergen challenge and in esophageal biopsy specimens from patients with eosinophilic esophagitis. OSM stimulation of air-liquid interface cultures resulted in reduced barrier function, as measured by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran flux ( P < .05). Alterations in barrier function by OSM were reversible, and the viability of epithelial cells was unaffected. OSM levels in lysates of nasal polyps and uncinate tissue positively correlated with levels of α2 -macroglobulin, a marker of epithelial leak, in localized nasal secretions ( r = 0.4855, P < .05). Conclusions These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases.
Background Frailty is an objective method of quantifying a patient’s fitness for surgery. Its clinical use is limited by the time needed to complete, as well as a lack of evidence-based interventions ...to improve outcomes in identified frail patients. The purpose of this study was to critically analyze the components of the Fried Frailty Criteria, among other preoperative variables, to create a simplified risk assessment amenable to a busy clinical setting, while maintaining prognostic ability for surgical outcomes. Study Design We performed a prospective evaluation of patients that included the 5-component Fried Frailty Criteria, traditional surgical risk assessments, biochemical laboratory values, and clinical and demographic data. Thirty-day postoperative outcomes were the outcomes of interest. Results There were 351 consecutive patients undergoing major intra-abdominal operations enrolled. Analysis demonstrated that shrinking and grip strength alone hold the same prognostic information as the full 5-component Fried Frailty Criteria for 30-day morbidity and mortality. The addition of American Society of Anesthesia (ASA) score and serum hemoglobin creates a composite risk score, which facilitates easy classification of patients into discrete low (ref), intermediate (odds ratio OR 1.974, 95% CI 1.006 to 3.877, p = 0.048), and high (OR 4.889, 95% CI 2.220 to 10.769, p < 0.001) risk categories, with a corresponding stepwise increase in risk for 30-day postoperative complications. Internal validation by bootstrapping confirmed the results. Conclusions This study demonstrated that 2 components of the Fried Frailty Criteria, shrinking and grip strength, hold the same predictive value as the full frailty assessment. When combined with American Society of Anesthesiologists score and serum hemoglobin, they form a straightforward, simple risk classification system with robust prognostic information.
Abstract Context Assessment of cancer-related fatigue is currently based on patient-reported outcomes. We asked whether objective assessments such as muscle strength and nutritional markers can be ...used as surrogate measures of cancer-related fatigue. Objective We examined the association among three fatigue scales, muscle strength, and nutritional markers in patients with advanced cancer. Methods In this prospective study, we enrolled hospitalized cancer patients who had been seen in palliative care consultation at MD Anderson Cancer Center. We assessed fatigue with use of three fatigue scales—the Brief Fatigue Inventory (BFI), the Edmonton Symptom Assessment System (ESAS), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30)—and determined their association with objective assessments, including handgrip strength, maximal inspiratory pressure (MIP), lean body mass, phase angle, and albumin. Spearman’s correlation test was used to assess associations. Results Among 222 patients, the mean age was 55 years; 59% were female. The median overall survival was 106 days. The total BFI score had weak association with handgrip strength (ρ = -0.18, P = 0.007) and no association with the remaining objective measures. ESAS fatigue and EORTC fatigue showed similar findings. Total BFI had moderate to strong association with ESAS (ρ = 0.54, P < 0.0001) and EORTC (ρ = 0.60, P < 0.0001) fatigue. Conclusion Our study showed that subjective assessment of fatigue based on patient-reported outcomes correlates only weakly with muscle strength and nutritional markers; thus, patient-reported outcomes remain the gold standard for fatigue assessment.
Abstract Context Episodic breathlessness is common and debilitating in cancer patients. Objectives In this pilot study, we examined the effect of prophylactic fentanyl pectin nasal spray (FPNS) on ...exercise-induced dyspnea, physiologic function and adverse events. Methods In this parallel, double-blind randomized placebo-controlled trial, opioid-tolerant patients performed three six-minute walk tests (6MWT) to induce dyspnea. They were randomized to receive either FPNS (15-25% of total daily opioid dose each time) or placebo 20 minutes before the second and third 6MWTs. We compared dyspnea numeric rating scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function and adverse events between the first and second 6MWTs (T2-T1) and between the first and third 6MWTs (T3-T1). Results Twenty-four patients enrolled, with 96% completion. FPNS was associated with significant within-arm reduction in dyspnea NRS at rest (T2-T1: -0.9 95% confidence interval CI -1.7,-0.1; T3-T1: -1.3 95% CI -2.0,-0.5) and after six minutes (T2-T1: -2.0 95% CI -3.5,-0.6; T3-T1: -2.3 95% CI -4.0,-0.7), and longer walk distance (T2-T1 +23.8m 95% CI +1.3,+46.2m; T3-T1: +23.3m 95% CI -1.7,+48.2). In the placebo arm, we observed no significant change in walk distance nor dyspnea NRS at rest, but significant reduction in dyspnea NRS at 6 minutes (T2-T1: -1.7 95% CI -3.3,-0.1; T3-T1: -2.5 95% CI -4.2,-0.9). Vital signs, neurocognitive function and adverse effects did not differ significantly. Conclusion FPNS was safe, reduced dyspnea at rest and increased walk distance in before-after comparison. The placebo effect was substantial, which needs to be factored in future study designs.( clinicaltrials.gov registration: NCT01832402)
Background Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have ...shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF 1. Methods We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1–2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). Results Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p = 0.008 and five-fold increase days 1–2, p = 0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA ( p = 0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1–2 ( p = 0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. Conclusion Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.
Hepatic arterial therapy with yttrium-90 microspheres exploits the avenue provided by the neoplastic microvasculature to deliver high-energy, low-penetrating therapeutic doses of radiation. Variant ...hepatic arterial anatomy, collateral vessels, and changes in flow dynamics during treatment can affect particle dispersion and lead to nontarget particle distribution and subsequent gastrointestinal morbidity. Awareness of these variances and techniques to prevent gastrointestinal tract microsphere delivery is essential in mitigating this serious complication. Our aim is to increase the understanding of the role of various imaging and preventative techniques in minimizing this undesired effect.
Background Sevoflurane is one of the most commonly used volatile anesthetic agents with the fastest onset and offset, replacing isoflurane in modern anesthesiology. Preconditioning and ...postconditioning using volatile anesthetics can attenuate ischemia-reperfusion injury (IRI). However, no previous studies have evaluated the effect of sevoflurane in lung transplantation after cold ischemic injury. We aimed to study the effects of donor and recipient treatment with sevoflurane in a rat lung transplantation model. Methods Lewis rats were allocated to four groups: control, PreC (preconditioning), PostC (postconditioning), and PreC + PostC. Donor rats in the PreC and PreC + PostC groups were exposed to 1.5% sevoflurane for 30 minutes before donor operation. Donor lungs were flushed with Perfadex and stored for 12 hours at 4°C before transplantation. Recipients received orthotopic left lung transplantation. In the PostC and PreC + PostC groups, sevoflurane was initiated 2 minutes before reperfusion and maintained for 30 minutes. Two hours after reperfusion, lung function was evaluated, and samples were collected for histologic, inflammatory, and cell death assessment. Results Preconditioning and postconditioning using sevoflurane significantly improved the oxygenation of lung grafts (partial arterial gas pressure of oxygen: 198 mm Hg in control, 406.5 mm Hg in PreC, 472.4 mm Hg in PostC, and 409.7 mm Hg in PreC + PostC, p < 0.0001) and reduced pulmonary edema. Sevoflurane treatment reduced levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α. Moreover, sevoflurane significantly inhibited apoptotic cells by a decrease in cytochrome c release into cytosol and caspase-3 cleavage. Conclusions Preconditioning or postconditioning of lungs using sevoflurane exhibits a significant protective effect against early phase of ischemia-reperfusion injury in a rat lung transplantation model.
We report the first clinical experience and toxicity of multifield optimization (MFO) intensity modulated proton therapy (IMPT) for patients with head and neck tumors.
Fifteen consecutive patients ...with head and neck cancer underwent MFO-IMPT with active scanning beam proton therapy. Patients with squamous cell carcinoma (SCC) had comprehensive treatment extending from the base of the skull to the clavicle. The doses for chemoradiation therapy and radiation therapy alone were 70 Gy and 66 Gy, respectively. The robustness of each treatment plan was also analyzed to evaluate sensitivity to uncertainties associated with variations in patient setup and the effect of uncertainties with proton beam range in patients. Proton beam energies during treatment ranged from 72.5 to 221.8 MeV. Spot sizes varied depending on the beam energy and depth of the target, and the scanning nozzle delivered the spot scanning treatment "spot by spot" and "layer by layer."
Ten patients presented with SCC and 5 with adenoid cystic carcinoma. All 15 patients were able to complete treatment with MFO-IMPT, with no need for treatment breaks and no hospitalizations. There were no treatment-related deaths, and with a median follow-up time of 28 months (range, 20-35 months), the overall clinical complete response rate was 93.3% (95% confidence interval, 68.1%-99.8%). Xerostomia occurred in all 15 patients as follows: grade 1 in 10 patients, grade 2 in 4 patients, and grade 3 in 1 patient. Mucositis within the planning target volumes was seen during the treatment of all patients: grade 1 in 1 patient, grade 2 in 8 patients, and grade 3 in 6 patients. No patient experienced grade 2 or higher anterior oral mucositis.
To our knowledge, this is the first clinical report of MFO-IMPT for head and neck tumors. Early clinical outcomes are encouraging and warrant further investigation of proton therapy in prospective clinical trials.
Abstract Introduction For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays.
Long-term abstinence is rarely achieved; many ...patients relapse and overdose after detoxification.
Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized.
This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies. Methods The National Institute on Drug Abuse
'
s Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients.
Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX. Results The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase.
Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms).
Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness. Conclusions XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance.
Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed. Clinical Trial Registration: NCT02032433.
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