Citations

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.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.

Background Women electing endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) report higher symptom burden but have lower computed tomography (CT) scores. Gender‐specific analysis of outcomes from ESS therefore merits further study. The objective of this work was to study gender‐specific differences in outcomes from ESS for CRS by analyzing preoperative and postoperative 22‐item Sino‐Nasal Outcome Test (SNOT‐22) scores. Methods Data from adult CRS patients electing ESS (2011‐2013) were retrospectively collected. SNOT‐22 total, rhinologic/nonrhinologic subdomain, and individual item scores were analyzed for gender‐specific differences. Results Two hundred and forty‐eight patients met study criteria (mean age 55.4 years; 49.6% female). Preoperatively, mean Lund‐Mackay CT score was 11.1; average total SNOT‐22 score was 41.9. Compared to men, women had lower CT score (10.2 vs 12.0; p = 0.004) but higher total SNOT‐22 score (44.7 vs 39.1; p = 0.02). Both genders showed significant improvement in total SNOT‐22 scores at 3, 6, 12, and 24 months following ESS ( p < 0.001), with largely similar slopes of improvement. The greatest improvement occurred at 3 months (SNOT‐22 decreased by 25.4 points), with stable improvement after 12 months (SNOT‐22 decreased by 21.3 points). Higher total SNOT‐22 scores in females were noted preoperatively and until 6 months post‐ESS; these were driven by rhinologic and nonrhinologic‐otolaryngic subdomain items. No gender differences in anxiety/depression prevalence or psychological subdomain scores were noted preoperatively or postoperatively. Conclusion Both male and female CRS patients showed significant and durable symptom relief following ESS. Women reported higher symptom burden prior to surgery, and in the early postoperative period. However, after 1‐year post‐ESS, both genders showed similar symptom scores. The trend and magnitude of improvement were similar in both genders.

Introduction Vertebral artery injury is a rare but serious complication of cervical spine surgery with an overall incidence rate of 1.4% (Rampersaud, 2006). Iatrogenic injury of the vertebral artery can lead to serious complications including lateral medullary (Wallenberg) syndrome, quadriparesis, and mortality. The high rate of vertebral artery anomalies in the general population mandates assessment via advanced imaging modalities in the preoperative period (Schroeder, 2013). The rarity of this complication makes it difficult to set expectations after an injury is encountered. This study utilized a multi-center database to compile outcomes data after vertebral artery injury during a cervical spine procedure. Materials and Methods A multi-center retrospective case series was compiled involving 23 medical institutions. Inclusion criteria included patients who underwent cervical spine surgery between 2005–2011 and who sustained a vertebral artery injury. IRBs were obtained from all institutions and data was sent to a private research organization that collected and collated all of the data. Patients were evaluated on the basis of condition-specific functional status using the Neck Disability Index (NDI), modified Japanese Orthopaedic Association (mJOA) score, the Nurick scale, and the 36-Item Short-Form Health Survey (SF-36). Results Vertebral artery injuries were identified in a total of 14 of 16,582 total patients screened (8.4 per 10,000). The mean age of patients with vertebral artery injury was 59 years (+/− 10) with a female predominance (78.6%). Diagnoses of affected patients included 7 with myelopathy, 3 with radiculopathy, 1 with cervical instability, and 2 with metastatic disease. The mean duration of operative time for cases was 4.7 hours (+/− 1.8). Vertebral artery injury was also associated with substantial blood loss (770 mL), although only 3 cases required transfusion. Of the 14 cases, 7 occurred with an anterior only approach, 3 cases with posterior only approach, and 4 during circumferential approach. Average length of hospital stay for these patients was 10 days (+/− 8). Notably, 13 of the 14 (92.86%) cases reportedly resolved without residual deficits. Compared with preoperative baseline NDI, Nurick, and SF-36 physical and mental component scores for these patients, there were no observed changes after surgery ( p = 0.20 Ð 0.94). Conclusion Vertebral artery injuries are potentially catastrophic complications that can be sustained from either anterior or posterior cervical spine approaches. This adverse event is associated with an increase in hospital stay and functional disability measured on NDI score. However, the data from this study suggests that with proper steps to ensure hemostasis, patients recover function at a high rate and do not exhibit residual deficits (13 out of 14). Preoperative imaging studies may provide insight into VA anomalies and anatomic variations and are vital to the preoperative assessment. Furthermore, although surgeons should expect increased blood loss once a vertebral artery injury is encountered, patients do not often require a blood transfusion.

AbstractThe Patient‐Centered Outcomes Research Institute (PCORI) was established by Congress in 2010 to promote the conduct of research that could better inform patients in making decisions that reflect their desired health outcomes. PCORI has established five national priorities for research around which specific funding opportunities are issued: 1) assessment of prevention, diagnosis, and treatment options; 2) improving healthcare systems; 3) communication and dissemination research; 4) addressing disparities; and 5) improving methods for conducting patient‐centered outcomes research. To date, implementation of patient‐centered research in the emergency care setting has been limited, in part because of perceived challenges in meeting PCORI priorities such as the need to focus on a specific disease state or to have planned follow up. We suggest that these same factors that have been seen as challenges to performing patient‐centered research within the emergency setting are also potential strengths to be leveraged to conduct PCORI research. This paper explores factors unique to patient‐centered emergency care research and highlights specific areas of potential alignment within each PCORI priority.

Abstract Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E−6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E−6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446–54. ©2016 AACR.

ObjectiveInfantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status.MethodsThe National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of infantile spasms. Children were considered responders if there was clinical remission and resolution of hypsarrhythmia that was sustained at 3 months after first treatment initiation. Standard treatments of adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin were considered individually, and all other nonstandard therapies were analyzed collectively. Developmental status and etiology were assessed. We compared response rates by treatment group using chi‐square tests and multivariate logistic regression models.ResultsTwo hundred thirty infants were enrolled from 22 centers. Overall, 46% of children receiving standard therapy responded, compared to only 9% who responded to nonstandard therapy (p < 0.001). Fifty‐five percent of infants receiving ACTH as initial treatment responded, compared to 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other (p < 0.001). Neither etiology nor development significantly modified the response pattern by treatment group.InterpretationResponse rate varies by treatment choice. Standard therapies should be considered as initial treatment for infantile spasms, including those with impaired development or known structural or genetic/metabolic etiology. ACTH appeared to be more effective than other standard therapies. ANN NEUROL 2016;79:475–484

Abstract Background. Transforaminal epidural steroid injections (TFESI) have demonstrated efficacy and effectiveness in treatment of radicular pain. Despite little evidence of efficacy/effectiveness, interlaminar epidural steroid injections (ILESI) are advocated by some as primary therapy for radicular pain due to purported greater safety. Objective. To assess immediate and delayed adverse event rates of TFESI and ILESI injections at three academic medical centers utilizing International Spine Intervention Society practice guidelines. Methods. Quality assurance databases from a Radiology and two physical medicine and rehabilitation (PM&R) practices were interrogated. Medical records were reviewed, verifying immediate and delayed adverse events. Results. There were no immediate major adverse events of neurologic injury or hemorrhage in 16,638 consecutive procedures in all spine segments (14,956 TFESI; 1,682 ILESI). Vasovagal reactions occurred in 1.2% of procedures, more frequently ( P = 0.004) in TFESI (1.3%) than ILESI (0.5%). Dural punctures occurred in 0.06% of procedures, more commonly after ILESI (0.2% vs 0.04%, P = 0.006). Delayed follow up on PM&R patients (92.5% and 78.5, next business day) and radiology patients (63.1%, 2 weeks) identified no major adverse events of neurologic injury, hemorrhage, or infection. There were no significant differences in delayed minor adverse event rates. Central steroid response (sleeplessness, flushing, nonpositional headache) was seen in 2.6% of both TFESI and ILESI patients. 2.1% of TFESI and 1.8% of ILESI patients reported increased pain. No long-term sequelae were seen from any immediate or delayed minor adverse event. Conclusions. Both transforaminal and ILESI are safely performed with low immediate and delayed adverse event rates when informed by evidence-based procedural guidelines. By demonstrating comparable safety, this study suggests that the choice between ILESI and TFESIs can be based on documented efficacy and effectiveness and not driven by safety concerns.

AbstractDiagnostic imaging is integral to the evaluation of many emergency department (ED) patients. However, relatively little effort has been devoted to patient‐centered outcomes research (PCOR) in emergency diagnostic imaging. This article provides background on this topic and the conclusions of the 2015 Academic Emergency Medicine consensus conference PCOR work group regarding “Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization.” The goal was to determine a prioritized research agenda to establish which outcomes related to emergency diagnostic imaging are most important to patients, caregivers, and other key stakeholders and which methods will most optimally engage patients in the decision to undergo imaging. Case vignettes are used to emphasize these concepts as they relate to a patient's decision to seek care at an ED and the care received there. The authors discuss applicable research methods and approaches such as shared decision‐making that could facilitate better integration of patient‐centered outcomes and patient‐reported outcomes into decisions regarding emergency diagnostic imaging. Finally, based on a modified Delphi process involving members of the PCOR work group, prioritized research questions are proposed to advance the science of patient‐centered outcomes in ED diagnostic imaging.