Citations

Percutaneous image-guided ablation is an increasingly common treatment for a multitude of solid organ malignancies. While historically these techniques have been restricted to the management of small, unresectable tumors, there is an expanding appreciation for the systemic effects these locoregional interventions can cause. In this review, we summarize the mechanisms of action for the most common thermal ablation modalities and highlight the key advances in knowledge regarding the interactions between thermal ablation and the immune system.

Background: Reconstruction of anterior cruciate ligament (ACL) tears may potentially prevent the development of secondary meniscal injuries and arthritis. Purpose/Hypothesis: The purpose of this study was to (1) evaluate the protective benefit of ACL reconstruction (ACLR) in preventing subsequent meniscal tears or arthritis, (2) determine if earlier ACLR (<1 year after injury) offers greater protective benefits than delayed reconstruction (≥1 year after injury), and (3) evaluate factors predictive of long-term sequelae after ACLR. The hypothesis was that the incidence of secondary meniscal tears, arthritis, and total knee arthroplasty (TKA) would be higher in patients treated nonoperatively after ACL tears than patients treated with surgical reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: This retrospective study included a population-based incidence cohort of 964 patients with new-onset, isolated ACL tears between 1990 and 2000 as well as an age- and sex-matched cohort of 964 patients without ACL tears. A chart review was performed to collect information related to the initial injury, treatment, and outcomes. A total of 509 patients were treated with early ACLR, 91 with delayed ACLR, and 364 nonoperatively. All patients were retrospectively followed (range, 2 months to 25 years) to determine the development of subsequent meniscal tears, arthritis, or TKA. Results: At a mean follow-up of 13.7 years, patients treated nonoperatively after ACL tears had a significantly higher likelihood of developing a secondary meniscal tear (hazard ratio [HR], 5.4; 95% CI, 3.8-7.6), being diagnosed with arthritis (HR, 6.0; 95% CI, 4.3-8.4), and undergoing TKA (HR, 16.7; 95% CI, 5.0-55.2) compared with patients treated with ACLR. Similarly, patients treated with delayed ACLR had a higher likelihood of developing a secondary meniscal tear (HR, 3.9; 95% CI, 2.2-6.9) and being diagnosed with arthritis (HR, 6.2; 95% CI, 3.4-11.4) compared with patients treated with early ACLR. Age >21 years at the time of injury, articular cartilage damage, and medial/lateral meniscal tears were predictive of arthritis after ACLR. Conclusion: Patients treated with ACLR have a significantly lower risk of secondary meniscal tears, symptomatic arthritis, and TKA when compared with patients treated nonoperatively after ACL tears. Similarly, early ACLR significantly reduces the risk of subsequent meniscal tears and arthritis compared with delayed ACLR.

Engineered protein therapeutics offer advantages, including strong target affinity, selectivity and low toxicity, but like natural proteins can be susceptible to proteolytic degradation, thereby limiting their effectiveness. A compelling therapeutic target is mesotrypsin, a protease up-regulated with tumour progression, associated with poor prognosis, and implicated in tumour growth and progression of many cancers. However, with its unique capability for cleavage and inactivation of proteinaceous inhibitors, mesotrypsin presents a formidable challenge to the development of biological inhibitors. We used a powerful yeast display platform for directed evolution, employing a novel multi-modal library screening strategy, to engineer the human amyloid precursor protein Kunitz protease inhibitor domain (APPI) simultaneously for increased proteolytic stability, stronger binding affinity and improved selectivity for mesotrypsin inhibition. We identified a triple mutant APPIM17G/I18F/F34V, with a mesotrypsin inhibition constant (Ki) of 89 pM, as the strongest mesotrypsin inhibitor yet reported; this variant displays 1459-fold improved affinity, up to 350 000-fold greater specificity and 83-fold improved proteolytic stability compared with wild-type APPI. We demonstrated that APPIM17G/I18F/F34V acts as a functional inhibitor in cell-based models of mesotrypsin-dependent prostate cancer cellular invasiveness. Additionally, by solving the crystal structure of the APPIM17G/I18F/F34V–mesotrypsin complex, we obtained new insights into the structural and mechanistic basis for improved binding and proteolytic resistance. Our study identifies a promising mesotrypsin inhibitor as a starting point for development of anticancer protein therapeutics and establishes proof-of-principle for a novel library screening approach that will be widely applicable for simultaneously evolving proteolytic stability in tandem with desired functionality for diverse protein scaffolds.

Abstract Rationale Hospital readmission for chronic obstructive pulmonary disease (COPD) has attracted attention owing to the burden to patients and the health care system. There is a knowledge gap on approaches to reducing COPD readmissions. Objectives To determine the effect of comprehensive health coaching on the rate of COPD readmissions. Methods A total of 215 patients hospitalized for a COPD exacerbation were randomized at hospital discharge to receive either (1) motivational interviewing–based health coaching plus a written action plan for exacerbations (the use of antibiotics and oral steroids) and brief exercise advice or (2) usual care. Measurements and Main Results We evaluated the rate of COPD-related hospitalizations during 1 year of follow-up. The absolute risk reductions of COPD-related rehospitalization in the health coaching group were 7.5% (P = 0.01), 11.0% (P = 0.02), 11.6% (P = 0.03), 11.4% (P = 0.05), and 5.4% (P = 0.24) at 1, 3, 6, 9, and 12 months, respectively, compared with the control group. The odds ratios for COPD hospitalization in the intervention arm compared with the control arm were 0.09 (95% confidence interval [CI], 0.01–0.77) at 1 month postdischarge, 0.37 (95% CI, 0.15–0.91) at 3 months postdischarge, 0.43 (95% CI, 0.20–0.94) at 6 months postdischarge, and 0.60 (95% CI, 0.30–1.20) at 1 year postdischarge. The missing value rate for the primary outcome was 0.4% (one patient). Disease-specific quality of life improved significantly in the health coaching group compared with the control group at 6 and 12 months, based on the Chronic Respiratory Disease Questionnaire emotional score (emotion and mastery domains) and physical score (dyspnea and fatigue domains) (P &lt; 0.05). There were no differences between groups in measured physical activity at any time point. Conclusions Health coaching may represent a feasible and possibly effective intervention designed to reduce COPD readmissions. Clinical trial registered with www.clinicaltrials.gov (NCT01058486).

Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). Conclusion Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment.

Although the occurrence of sudden cardiac death (SCD) in a young person is a rare event, it is traumatic and often widely publicized. In recent years, SCD in this population has been increasingly seen as a public health and safety issue. This review presents current knowledge relevant to the epidemiology of SCD and to strategies for prevention, resuscitation, and identification of those at greatest risk. Areas of active research and controversy include the development of best practices in screening, risk stratification approaches and postmortem evaluation, and identification of modifiable barriers to providing better outcomes after resuscitation of young SCD patients. Institution of a national registry of SCD in the young will provide data that will help to answer these questions.

Abstract Background Surgical performance, provider health, and patient safety can be compromised when workload demands exceed individual capability on the surgical team. The purpose of this study is to quantify and compare intraoperative workload among surgical team members. Methods Observations were conducted for an entire surgical day for 33 participating surgeons and their surgical team at one medical institution. Workload (mental, physical, case complexity, distractions, and case difficulty) was measured for each surgical team member using questions from validated questionnaires. Statistical analyses were performed with a mixed effects model. Results A total of 192 surgical team members participated in 78 operative cases, and 344 questionnaires were collected. Procedures with high surgeon mental and physical workload included endovascular and gastric surgeries, respectively. Ratings did not differ significantly among surgeons and residents, but scrub nurses physical demand ratings were 14–22 (out of 100) points lower than the surgeons, residents, and surgical assistants. Residents reported the highest mental workload, averaging 19–24 points higher than surgical assistants, scrub nurses, and circulating nurses. Mental and physical demands exceeded 50 points 28–45 % of the time for surgeons and residents. Workload did not differ between minimally invasive and open techniques. Conclusion The workload questionnaires are an effective tool for quantifying intraoperative workload across the surgical team to ensure mental and physical demands do not exceed thresholds where performance may decrease and injury risk increase. This tool has the potential to measure the safety of current procedures and drive design of workload interventions.

AbstractTraining and credentialing for robotic surgery in otolaryngology ‐ head and neck surgery is currently not standardized, but rather relies heavily on industry guidance. This manuscript represents a comprehensive review of this increasingly important topic and outlines clear recommendations to better standardize the practice. The recommendations provided can be used as a reference by individuals and institutions alike, and are expected to evolve over time. © 2016 Wiley Periodicals, Inc. Head Neck 38: E151–E158,