Citations

Objectives/HypothesisTo highlight the phenomenon of cholesteatoma arising from the vascular strip following tympanoplasty and tympanomastoidectomy.Study DesignMulti‐institutional retrospective chart review.MethodsConsecutive adult and pediatric patients evaluated between 2000 and 2015 with acquired cholesteatoma arising from the skin of a prior vascular strip were identified. Patients with evidence of residual or recurrent cholesteatoma elsewhere in the middle ear, mastoid, or ear canal were excluded.ResultsSeventeen cases (71% female, 53% right‐sided) were identified, and the mean age at presentation was 39.2 years. Patients presented on average 12.9 years following prior otologic surgery, which was most commonly tympanoplasty without mastoidectomy (59%). However, younger patients presented with symptoms sooner following prior surgery (r = 0.61, r2 = 0.37, P = 0.0095). The most common presenting symptom was otorrhea (76%). All patients were found to have mastoid cholesteatoma with bony erosion, and three patients exhibited additional tegmen or posterior fossa bone defects. The middle ear was not involved with cholesteatoma in any case. A canal wall down procedure was performed due to extensive bony canal erosion in 29% of cases.ConclusionThe vascular strip is an uncommon source of iatrogenic cholesteatoma that can present years following an otherwise uncomplicated otologic surgery. The findings presented herein highlight the importance of careful vascular strip orientation at the conclusion of otologic surgery.Level of Evidence4. Laryngoscope, 127:698–701, 2017

Purpose To (1) evaluate long‐term outcomes of osteochondral allograft (OCA) with regard to clinical outcome scores, reoperation and failure rates, and (2) examine if certain factors predispose patients to worse outcomes. Methods A comprehensive review was performed with specific inclusion criteria for studies with long‐term outcomes after OCA. Studies reported on patient clinical scores such as Hospital for Special Surgery score, Knee Society Score (knee and function score), and Lysholm score. Reoperation and failure rates were recorded for each study. Modified Coleman Methodology Scores assessed study methodological quality. Results Five studies with a total of 291 patients (55% male, 45% female) and average age of 34.8 years (range, 15 to 69 years) were included. Of all lesions, 67% were on the femoral condyles, 29% on the tibial plateau, and 4% were patellofemoral. All scores (Knee Society Function Score, Knee Society Knee Score, and Lysholm score) have significant mean improvement from preoperative to final follow‐up. The mean postoperative Hospital for Special Surgery score was 84.1. The mean failure rate was 25% at 12.3 years with a reoperation rate of 36%. A total of 72% of the failures were conversion to total (68%) or unicompartmental (4%) knee arthroplasty and 28% involved graft removal, graft fixation, and graft revision. Patellofemoral lesions (83%) had a significantly higher reoperation rate than lesions involving the tibial plateau or the femoral condyles (34%, P = .01). Conclusions Overall, OCA demonstrated significant improvements in clinical outcome scores and good durability with successful outcomes in 75% of the patients at 12.3 years after surgery. Patellofemoral lesions are associated with decreased clinical improvement and more frequent reoperations. The orthopaedic literature is limited by heterogeneity in surgical technique, lesion and patient characteristics, and reporting of nonstandardized outcome measures. Level of Evidence Level IV, systematic review of Level II and IV studies.

Abstract Prostate cancer is a biologically heterogeneous disease with variable molecular alterations underlying cancer initiation and progression. Despite recent advances in understanding prostate cancer heterogeneity, better methods for classification of prostate cancer are still needed to improve prognostic accuracy and therapeutic outcomes. In this study, we computationally assembled a large virtual cohort (n = 1,321) of human prostate cancer transcriptome profiles from 38 distinct cohorts and, using pathway activation signatures of known relevance to prostate cancer, developed a novel classification system consisting of three distinct subtypes (named PCS1–3). We validated this subtyping scheme in 10 independent patient cohorts and 19 laboratory models of prostate cancer, including cell lines and genetically engineered mouse models. Analysis of subtype-specific gene expression patterns in independent datasets derived from luminal and basal cell models provides evidence that PCS1 and PCS2 tumors reflect luminal subtypes, while PCS3 represents a basal subtype. We show that PCS1 tumors progress more rapidly to metastatic disease in comparison with PCS2 or PCS3, including PSC1 tumors of low Gleason grade. To apply this finding clinically, we developed a 37-gene panel that accurately assigns individual tumors to one of the three PCS subtypes. This panel was also applied to circulating tumor cells (CTC) and provided evidence that PCS1 CTCs may reflect enzalutamide resistance. In summary, PCS subtyping may improve accuracy in predicting the likelihood of clinical progression and permit treatment stratification at early and late disease stages. Cancer Res; 76(17); 4948–58. ©2016 AACR.

Background— Approximately one third of patients with symptomatic aortic stenosis have reduced left ventricular ejection fraction (LVEF) before transcatheter aortic valve replacement. The incidence, predictors, and significance of early LVEF recovery after CoreValve transcatheter aortic valve replacement have not been described. Methods and Results— We studied 156 patients from the CoreValve Extreme and High-Risk trials with LVEF ≤40% at baseline who had 30-day LVEF data. All patients underwent core laboratory echocardiographic assessment of LVEF at baseline, post procedure, discharge, 30 days, 6 months, and 1 year. Early LVEF recovery was defined as an absolute increase of ≥10% in EF at 30 days. One-year outcomes were compared between patients with and without early recovery. Multivariable analysis was performed to determine independent predictors of early recovery. Early LVEF recovery occurred in 62% of patients, generally before discharge. By 30 days LVEF increased >17% compared with baseline in the early recovery group with minimal increase in the no–early recovery group (48.9±8.8% versus 31.5±6.9%; P <0.001). One-year all-cause mortality was numerically (but not statistically) higher in the no–early recovery group (24% versus 12%; P =0.07). Absence of previous myocardial infarction (odds ratio, 0.44; 95% confidence interval, 0.19–1.03) and baseline mean gradient ≥40 mm Hg (odds ratio, 4.59; 95% confidence interval, 1.76–11.96) were identified as predictors of early LVEF recovery. Conclusions— Nearly two thirds of patients with reduced LVEF will have a marked early improvement after transcatheter aortic valve replacement. Early LVEF recovery is associated with improved clinical outcomes and is most likely among patients with higher baseline aortic valve gradients and no previous myocardial infarction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01240902.

BACKGROUND Activating, nonamplification ERBB2 mutations ( ERBB2 mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)‐targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2 mut genomic alterations. Clinical responses to anti‐HER2 therapeutics were identified. METHODS DNA was extracted from 40 µm of formalin‐fixed paraffin‐embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications ( ERBB2 amp) and 138 (2.4%) ERBB2 mut; 38 cases (0.7%) had co‐occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2 mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 ( TP53 ) (49%); phosphatidylinositol 3‐kinase catalytic subunit alpha ( PIK3CA ) (42%); cadherin 1, type 1 ( CDH1 ) (37%); MYC (17%); and cyclin D1 protein ( CCND1 ) (16%). CDH1 mutations were enriched in ERBB2 mut mBC ( P <0.0006) and associated with recurrent mBC. Selected patients with ERBB2 mut, without ERBB2 amp, who responded to anti‐HER2 targeted therapies are presented herein. CONCLUSIONS Within this large series, 1.8% of cases harbored ERBB2 mut, which are undetectable by standard‐of‐care IHC or FISH tests. Metastatic BC driven by ERBB2 mut respond to anti‐HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2 mut by CGP and optimize targeted treatments are warranted. Cancer 2016 . © 2016 American Cancer Society . Cancer 2016;122:2654–2662. © 2016 American Cancer Society.

Objectives/HypothesisRadiation plays a prominent role in advanced stage head and neck tumors. Often, the radiated area includes adjacent nonmalignant mesenchymal tissue, which contains a mixture of cells that has been shown to accelerate wound healing. The purpose of this study is to determine the long‐term effect of radiation on the expansion potential of adipose‐derived stromal/stem cell (ADSC) tissue and on the ability of resident stem cells in this fraction to undergo phenotypic differentiation.Study Design/Methods: After institutional review board approval, 12 patients with a history of head and neck radiation and pending surgery were enrolled. Adipose tissue was collected from irradiated tissue (XRT) and nonirradiated tissue (NRT) sites. Mesenchymal stem cells were isolated from these populations, with subsequent assessment of cellular kinetics and differentiation potential between harvest sites.ResultsAdipose‐derived stromal/stem cells could not be isolated from XRT in six patients due to lack of in vitro cell proliferation. For the remaining six patients, overall cumulative population‐doubling time was longer for XRT relative to NRT (29.3 vs. 11.5 days; P = 0.02). However, no significant differences were observed in cell generation time or viability. When XRT and NRT ADSC fractions were grown to standardized concentrations and incubated under conditions that induce phenotypic differentiation of resident stem cells, no significant changes in chondrogenic, adipogenic, or osteogenic differentiation were observed.ConclusionThese preliminary observations suggest that irradiated ADSCs close to the surgical site undergo long‐term changes in proliferative capacity. The potential for phenotypic differentiation is retained, however, in ADSCs that survive the irradiation process.Level of Evidence2b.

AbstractBackgroundThis study compared prucalopride, a selective, prokinetic, 5‐HT4 receptor agonist, with polyethylene glycol 3350 + electrolytes (PEG3350), an osmotic laxative, on colonic motility parameters, primarily high‐amplitude propagating contractions (HAPCs) in patients with chronic constipation.MethodsThis randomized, cross‐over, reader‐blinded study was conducted at a single site in the USA. The study was open to men and women aged 18–75 years who met study inclusion criteria. Colonic manometry catheters were inserted the day before investigation. On the investigation days, patients received oral 2 mg prucalopride or 2 × 13.8 g PEG3350 in solution. The primary endpoint was HAPC count (threshold: mean amplitude ≥100 mmHg, propagation ≥20 cm [HAPC1]) in the 12 h after treatment administration. Analyses were also conducted at two co‐primary thresholds: mean amplitude ≥75 mmHg, propagation ≥20 cm (HAPC2); and mean amplitude ≥75 mmHg, propagation ≥10 cm (HAPC3). Secondary endpoints included HAPC area under the curve (AUC), contraction force, amplitude, duration, and propagation velocity.Key ResultsThirteen women were enrolled, with 12 completing the study. Significantly more HAPC1 (8.7 ± 2.06 vs 2.9 ± 2.06; p = 0.012) and HAPC2 (9.0 ± 2.11 vs 3.3 ± 2.11; p = 0.017) were observed in the 12‐h periods with prucalopride than with PEG3350. Prucalopride significantly increased mean propagation distance and velocity (HAPC2) and mean AUC, force, and amplitude (HAPC3) compared with PEG3350. Adverse events were mild or moderate.Conclusions & InferencesPrucalopride was superior to PEG3350 in inducing HAPCs in patients with chronic constipation.ClinicalTrials.gov number NCT01707667.

Objective: We describe health care simulation, designed primarily for training, and provide examples of how human factors experts can collaborate with health care professionals and simulationists—experts in the design and implementation of simulation—to use contemporary simulation to improve health care delivery. Background: The need—and the opportunity—to apply human factors expertise in efforts to achieve improved health outcomes has never been greater. Health care is a complex adaptive system, and simulation is an effective and flexible tool that can be used by human factors experts to better understand and improve individual, team, and system performance within health care. Method: Expert opinion is presented, based on a panel delivered during the 2014 Human Factors and Ergonomics Society Health Care Symposium. Results: Diverse simulators, physically or virtually representing humans or human organs, and simulation applications in education, research, and systems analysis that may be of use to human factors experts are presented. Examples of simulation designed to improve individual, team, and system performance are provided, as are applications in computational modeling, research, and lifelong learning. Conclusion: The adoption or adaptation of current and future training and assessment simulation technologies and facilities provides opportunities for human factors research and engineering, with benefits for health care safety, quality, resilience, and efficiency. Application: Human factors experts, health care providers, and simulationists can use contemporary simulation equipment and techniques to study and improve health care delivery.

Educators, policy makers, and health systems leaders are calling for significant reform of undergraduate medical education (UME) and graduate medical education (GME) programs to meet the evolving needs of the health care system. Nationally, several schools have initiated innovative curricula in both classroom and workplace learning experiences to promote education in health systems science (HSS), which includes topics such as value-based care, health system improvement, and population and public health. However, the successful implementation of HSS curricula across schools is challenged by issues of curriculum design, assessment, culture, and accreditation, among others. In this report of a working conference using thematic analysis of workshop recommendations and experiences from 11 U.S. medical schools, the authors describe seven priority areas for the successful integration and sustainment of HSS in educational programs, and associated challenges and potential solutions. In 2015, following regular HSS workgroup phone calls and an Accelerating Change in Medical Education consortium-wide meeting, the authors identified the priority areas: partner with licensing, certifying, and accrediting bodies; develop comprehensive, standardized, and integrated curricula; develop, standardize, and align assessments; improve the UME to GME transition; enhance teachers’ knowledge and skills, and incentives for teachers; demonstrate value added to the health system; and address the hidden curriculum. These priority areas and their potential solutions can be used by individual schools and HSS education collaboratives to further outline and delineate the steps needed to create, deliver, study, and sustain effective HSS curricula with an eye toward integration with the basic and clinical sciences curricula.

Abstract Introduction. For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. Materials and Methods. Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. Results. A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. Conclusion. Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.