The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

10.1371/journal.pone.0075483PLoS ONE810-POLN

Prospective Multicenter Study of Surgical Correction of Pectus Excavatum: Design, Perioperative Complications, Pain, and Baseline Pulmonary Function Facilitated by Internet-Based Data Collection

Background: Given widespread adoption of the Nuss procedure, prospective multicenter study of management of pectus excavatum by both the open and Nuss procedures was thought desirable. Although surgical repair has been performed for more than 50 years, there are no prospective multicenter studies of its management. Study Design: This observational study followed pectus excavatum patients treated surgically at 11 centers in North America, according to the method of choice of the patient and surgeon. Before operation, all underwent evaluation with CT scan, pulmonary function tests, and body image survey. Data were collected about associated conditions, hospital complications, and perioperative pain. One year after completion of treatment, patients will repeat the preoperative evaluations. This article addresses early results only. Results: Of 416 patients screened, 327 were enrolled; 284 underwent the Nuss procedure and 43 had the open procedure. Median preoperative CT index was 4.4. Pulmonary function testing before operation showed mean forced vital capacity of 90% of predicted values; forced expiratory volume in 1 second (FEV1), 89% of predicted; and forced expiratory flow during the middle half of the forced vital capacity (FEF25% to 75%), 85% of predicted. Early postcorrection results showed that operations were performed without mortality and with minimal morbidity at 30 days postoperatively. Median hospital stay was 4 days. Postoperative pain was a median of 3 on a scale of 10 at time of discharge; the worst pain experienced was the same as was expected by the patients (median 8), and by 30 days after correction or operation, the median pain score was 1. Because of disproportionate enrollment and similar early complication rates, statistical comparison between operation types was limited. Conclusions: Anatomically severe pectus excavatum is associated with abnormal pulmonary function. Initial operative correction performed at a variety of centers can be completed safely. Perioperative pain is successfully managed by current techniques

SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma

Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors

Increasing Severity of Pectus Excavatum Is Associated with Reduced Pulmonary Function

Objective To determine whether pulmonary function decreases as a function of severity of pectus excavatum, and whether reduced function is restrictive or obstructive in nature in a large multicenter study. Study design We evaluated preoperative spirometry data in 310 patients and lung volumes in 218 patients aged 6 to 21 years at 11 North American centers. We modeled the impact of the severity of deformity (based on the Haller index) on pulmonary function. Results The percentages of patients with abnormal forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow from 25% exhalation to 75% exhalation, and total lung capacity findings increased with increasing Haller index score. Less than 2% of patients demonstrated an obstructive pattern (FEV1/FVC \u3c67%), and 14.5% demonstrated a restrictive pattern (FVC and FEV1 \u3c80% predicted; FEV1/FVC \u3e80%). Patients with a Haller index of 7 are \u3e4 times more likely to have an FVC of ≤80% than those with a Haller index of 4, and are also 4 times more likely to exhibit a restrictive pulmonary pattern. Conclusions Among patients presenting for surgical repair of pectus excavatum, those with more severe deformities have a much higher likelihood of decreased pulmonary function with a restrictive pulmonary pattern

Multicenter study of pectus excavatum, final report: complications, static/exercise pulmonary function, and anatomic outcomes.

BackgroundA multicenter study of pectus excavatum was described previously. This report presents our final results.Study designPatients treated surgically at 11 centers were followed prospectively. Each underwent a preoperative evaluation with CT scan, pulmonary function tests, and body image survey. Data were collected about associated conditions, complications, and perioperative pain. One year after treatment, patients underwent repeat chest CT scan, pulmonary function tests, and body image survey. A subset of 50 underwent exercise pulmonary function testing.ResultsOf 327 patients, 284 underwent Nuss procedure and 43 underwent open procedure without mortality. Of 182 patients with complete follow-up (56%), 18% had late complications, similarly distributed, including substernal bar displacement in 7% and wound infection in 2%. Mean initial CT scan index of 4.4 improved to 3.0 post operation (severe >3.2, normal = 2.5). Computed tomography index improved at the deepest point (xiphoid) and also upper and middle sternum. Pulmonary function tests improved (forced vital capacity from 88% to 93%, forced expiratory volume in 1 second from 87% to 90%, and total lung capacity from 94% to 100% of predicted (p < 0.001 for each). VO2 max during peak exercise increased by 10.1% (p = 0.015) and O2 pulse by 19% (p = 0.007) in 20 subjects who completed both pre- and postoperative exercise tests.ConclusionsThere is significant improvement in lung function at rest and in VO2 max and O2 pulse after surgical correction of pectus excavatum, with CT index >3.2. Operative correction significantly reduces CT index and markedly improves the shape of the entire chest, and can be performed safely in a variety of centers

Surgical Repair of Pectus Excavatum Markedly Improves Body Image and Perceived Ability for Physical Activity: Multicenter Study

Article Surgical Repair of Pectus Excavatum Markedly Improves Body Image and Perceived Ability for Physical Activity: Multicenter Study Robert E. Kelly Jr, MDa,b, Thomas F. Cash, PhDc, Robert C. Shamberger, MDd, Karen K. Mitchell, RNb, Robert B. Mellins, MDe, M. Louise Lawson, PhDb,f, Keith Oldham, MDg, Richard G. Azizkhan, MDh, Andre V. Hebra, MDi, Donald Nuss, MBChBa,b, Michael J. Goretsky, MDa,b, Ronald J. Sharp, MDj, George W. Holcomb III, MDj, Walton K. T. Shim, MDk, Stephen M. Megison, MDl, R. Lawrence Moss, MDm, Annie H. Fecteau, MDn, Paul M. Colombani, MDo, Traci Bagley, RN, BSNb, Amy Quinn, MSb, Alan B. Moskowitz, MSb + Author Affiliations aDepartments of Surgery bPediatrics, Eastern Virginia Medical School, Norfolk, Virginia cDepartment of Psychology, Old Dominion University, Norfolk, Virginia dDepartment of Surgery, Harvard Medical School, Boston, Massachusetts eDepartment of Pediatrics, Columbia University, New York, New York fDepartment of Mathematics and Statistics, Kennesaw State University, Kennesaw, Georgia gDepartment of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin hDepartment of Surgery, University of Cincinnati, Cincinnati, Ohio iDepartment of Surgery, Medical University of South Carolina, Charleston, South Carolina jDepartment of Surgery, University of Missouri at Kansas City, Kansas City, Missouri kDepartment of Surgery, Kapiolani Medical Center for Women and Children, Honolulu, Hawaii lDepartment of Surgery, University of Texas Southwestern Medical School, Dallas, Texas mDepartment of Surgery, Yale University, New Haven, Connecticut nDepartment of Surgery, University of Toronto, Toronto, Ontario, Canada oDepartment of Surgery, Johns Hopkins University, Baltimore, Maryland Abstract OBJECTIVE. This study evaluated changes in both physical and psychosocial quality of life reported by the parent and child after surgical repair of pectus excavatum. METHODS. As part of a multicenter study of pectus excavatum, a previously validated tool called the Pectus Excavatum Evaluation Questionnaire was administered by the research coordinator, via telephone, to parents and patients (8–21 years of age) before and 1 year after surgery. Eleven North American children\u27s hospitals participated. From 2001 to 2006, 264 patients and 291 parents completed the initial questionnaire, and 247 patients and 274 parents completed the postoperative questionnaire. Responses used a Likert-type scale of 1 to 4, reflecting the extent or frequency of a particular experience, with higher values conveying less-desirable experience. RESULTS. Preoperative psychosocial functioning was unrelated to objective pectus excavatum severity (computed tomographic index). Patients and their parents reported significant positive postoperative changes. Improvements occurred in both physical and psychosocial functioning, including less social self-consciousness and a more-favorable body image. For children, the body image component improved from 2.30 ± 0.62 (mean ± SD) to 1.40 ± 0.42 after surgery and the physical difficulties component improved from 2.11 ± 0.82 to 1.37 ± 0.44. For the parent questionnaire, the child\u27s emotional difficulties improved from 1.81 ± 0.70 to 1.24 ± 0.36, social self-consciousness improved from 2.86 ± 1.03 to 1.33 ± 0.68, and physical difficulties improved from 2.14 ± 0.75 to 1.32 ± 0.39. Ninety-seven percent of patients thought that surgery improved how their chest looked. CONCLUSIONS. Surgical repair of pectus excavatum can significantly improve the body image difficulties and limitations on physical activity experienced by patients. These results should prompt physicians to consider the physiologic and psychological implications of pectus excavatum just as they would any other physical deformity known to have such consequences