Citations

AbstractBackgroundRib fractures are common after chest wall trauma. For patients with flail chest, surgical stabilization is a promising technique for reducing morbidity. Anatomical difficulties often lead to an inability to completely repair the flail chest; thus, the result is partial flail chest stabilization (PFS). We hypothesized that patients with PFS have outcomes similar to those undergoing complete flail chest stabilization (CFS).MethodsA prospectively collected database of all patients who underwent rib fracture stabilization procedures from August 2009 until February 2013 was reviewed. Abstracted data included procedural and complication data, extent of stabilization, and pulmonary function test results.ResultsOf 43 patients who underwent operative stabilization of flail chest, 23 (53 %) had CFS and 20 (47 %) underwent PFS. Anterior location of the fracture was the most common reason for PFS (45 %). Age, sex, operative time, pneumonia, intensive care unit and hospital length of stay, and narcotic use were the same in both groups. Total lung capacity was significantly improved in the CFS group at 3 months. No chest wall deformity was appreciated on follow‐up, and no patients underwent additional stabilization procedures following PFS.ConclusionDespite advances in surgical technique, not all fractures are amenable to repair. There was no difference in chest wall deformity, narcotic use, or clinically significant impairment in pulmonary function tests among patients who underwent PFS compared with CFS. Our data suggest that PFS is an acceptable strategy and that extending or creating additional incisions for CFS is unnecessary.

AbstractBackgroundActinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing.ObjectivesThe goal of these evidence‐ and consensus‐based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus‐based recommendations for the histopathological definition, diagnosis and the assessment of patients.MethodsThe guidelines development followed a pre‐defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.ResultsVarious interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately.ConclusionsInternational guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

SummaryThe International Prognostic Score (IPS‐7) is the most commonly used risk stratification tool for advanced Hodgkin lymphoma (HL), however recent studies suggest the IPS‐7 is less discriminating due to improved outcomes with contemporary therapy. We evaluated the seven variables for IPS‐7 recorded at study entry for 854 patients enrolled on Eastern Cooperative Oncology Group 2496 trial. Univariate and multivariate Cox models were used to assess their prognostic ability for freedom from progression (FFP) and overall survival (OS). The IPS‐7 remained prognostic however its prognostic range has narrowed. On multivariate analysis, two factors (age, stage) remained significant for FFP and three factors (age, stage, haemoglobin level) for OS. An alternative prognostic index, the IPS‐3, was constructed using age, stage and haemoglobin level, which provided four distinct risk groups [FFP (P = 0·0001) and OS (P < 0·0001)]. IPS‐3 outperformed the IPS‐7 on risk prediction for both FFP and OS by model fit and discrimination criteria. Using reclassification calibration, 18% of IPS‐7 low risk patients were re‐classified as intermediate risk and 13% of IPS‐7 intermediate risk patients as low risk. For patients with advanced HL, the IPS‐3 may provide a simpler and more accurate framework for risk assessment in the modern era. Validation of these findings in other large data sets is planned.

Background— Current risk models for predicting long-term mortality after percutaneous coronary intervention are restricted to all-cause mortality. We sought to develop novel risk models for the prediction of cardiac and noncardiac mortality after percutaneous coronary intervention. Methods and Results— We retrospectively evaluated patients who underwent index percutaneous coronary intervention at Mayo Clinic from 2003 to 2008. Long-term deaths were ascertained through scheduled prospective surveillance. Cause of death was determined via telephone interviews, medical records, and autopsy reports. Fine and Gray extension of Cox proportional hazards models was used to model cause-specific cumulative incidence. Candidate variables and interactions were chosen a priori, without variable selection methods. Resulting models were mapped to an integer-based risk score. The study comprised 6636 patients followed up over a median of 62 months (25th, 75th percentiles: 45, 77 months). There were 1488 deaths, 518 (35%) cardiac, 938 (63%) noncardiac, and 32 (2%) unknown. The 5-year predicted cardiac mortality ranged from 0.6% to 97%, with a corrected c -statistic of 0.82. Risk factors for cardiac death included age, body mass index, ejection fraction, and history of congestive heart failure. The integer score for noncardiac death included age, medicine index, body mass index, current smoker, noncardiac Charlson index and cardiac Charlson index, and accommodated significant age-based interactions for smoking and the 2 Charlson indices. Predicted noncardiac mortality at 5 years ranged from 0.2% to 81%, with a corrected c -statistic of 0.77. Conclusions— We report novel risk models to predict cardiac and noncardiac long-term mortality after percutaneous coronary intervention.

Meningiomas are common intracranial tumors categorized as Grades I–III per the current WHO guidelines. A small percentage of meningiomas are Grades II and III, which are likely to recur after initial treatment. Grade III meningiomas are considered to be malignant and warrant aggressive management. If surgery and radiation fail to produce lasting remission, effective treatment options for patients with progressive anaplastic meningiomas are elusive. The authors present the case of a patient with a meningioma that gradually progressed from Grade I to Grade III over 12 years despite repeated surgery and radiation therapy. The patient has been in remission for over 3 years following octreotide therapy.

1. The effect of 1,25-dihydroxyvitamin D [1,25-(OH)2D] on dietary oxalate absorption and postprandial urine supersaturation with calcium oxalate was determined in 11 normal subjects. 2. 1,25-(OH)2D increased the urinary excretion of orally administered [14C]oxalate in the 8 h period after a liquid meal containing 1.875 mmol of calcium and 0.83 mmol of oxalate (P &lt; 0.01), and during a 48 h period when the subjects ingested a diet containing 25 mmol of calcium and 3.3 mmol of oxalate/day (P &lt; 0.01); however, 1,25-(OH)2D administration had no effect on [14C]oxalate excretion when calcium was removed from the liquid meal. 3. 1,25-(OH)2D increased 24 h urinary oxalate excretion from 28.7 ± 2.1 mmol/mol of creatinine to 36.8 ± 2.6 mmol/mol of creatinine (P &lt; 0.05) on the 10 mmol/day calcium diet and from 26.4 ± 2.9 to 33.2 ± 2.2 mmol/mol of creatinine (P &lt; 0.1) on the 25 mmol/day calcium diet. 4. A linear correlation (r = 0.72) was found between plasma 1,25-(OH)2D levels and urinary [14C]oxalate excretion after the liquid meal. 5. 1,25-(OH)2D administration produced postprandial supersaturation of urine with calcium oxalate and calcium oxalate crystalluria. 6. These studies suggest that 1,25-(OH)2D increases oxalate absorption (and urinary excretion) by increasing calcium absorption, which results in less binding of calcium to oxalate in the intestine; therefore more oxalate is available for absorption. The combined effect of increased calcium and oxalate absorption results in postprandial supersaturation of urine with calcium oxalate, with resultant crystalluria.

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC ( r 2 =0.93) than with site-ABC ( r 2 =0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm 3 ; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P <0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Abstract Genome-wide association studies (GWAS) of multiple myeloma (MM) in Northern Europeans have identified seven novel risk loci (2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, 22q13.1). We performed a multiethnic meta-analysis of these regions in 1,274 MM patients and 1,486 controls of European ancestry (EA) and 1,049 MM patients and 7,080 controls of African ancestry (AA), leveraging the differential linkage-disequilibrium of these populations in order to better localize the putative functional variants. We observed directionally consistent effects for all seven index SNPs in both populations, with four significantly associated (p&lt;0.05) with risk in EAs (3p22.1, 7p15.3, 17p11.2, 22q13.1), and two significantly associated with risk in AAs (7p15.3 and 22q13.1). In a fixed effects meta-analysis of six regions (excluding the HLA region on chromosome 6), variation in five of the regions (2p33.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) had statistically significant associations with risk (Table 1). In one region, the index variant had the strongest association [rs4487645 at 7p15.3, (OR = 1.30, p = 8.7×10−8)]. Five of the six most significantly associated variants identified in the multiethnic analyses overlapped with biologically relevant features indicating regulatory activity based on CD20+ (B lymphocyte) cells, showing evidence of potential function; those included a missense variant in (17p11.2, rs34562254, Pro251Leu) in TNFRSF13B, which encodes a lymphocyte-specific protein in the tumor necrosis factor receptor family that interacts with the NF-kb pathway. Our study shows that these regions are important in MM risk across ethnicities and further supports the use of multiple ethnic groups in genetic studies to enhance identification of risk variants. Table 1.Most significant associations for each region in the multiethnic meta-analysis.Individuals of European AncestryIndividuals of African AncestryMulitethnic Metar2 with IndexcCHRSNPRAaFreqbORP-valueFreqbORP-valueORP-valueP-het2rs732075G0.591.222.0×10−30.621.122.0×10−21.162.6×10−40.280.09/0.283rs73069394A0.191.243.0×10−30.621.181.5×10−21.201.3×10−50.550.77/0.963rs12637184G0.761.136.0×10−20.921.192.7×10−11.151.0×10−20.640.94/1.007rs4487645C0.671.237.0×10−40.891.485.5×10−51.308.7×10−80.07-d17rs34562254A0.121.452.4×10−50.131.212.2×10−31.312.5×10−60.120.33/0.9022rs139400T0.491.224.0×10−40.531.172.1×10−31.191.2×10−60.630.63/0.96aRisk allelebFrequency of the risk allele in European and African ancestry studiescr2 metrics based on 1000 Genomes Project AFR/EUR populationsdIndex SNP Citation Format: Kristin A. Rand, Chi Song, Eric Dean, Daniel Serie, Karen Curtin, Dennis Hazelett, Amie E. Hwang, Xin Sheng, Alex Stram, David J. Van Den Berg, Carol Ann Huff, Leon Bernal-Mizrachi, Michael H. Tomasson, Sikander Ailawadhi, Anneclaire De Roos, Seema Singhal, Karen Pawlish, Edward Peters, Catherine Bock, David V. Conti, Graham Colditz, Todd Zimmerman, Scott Huntsman, John Graff, African Ancestry Prostate Cancer GWAS Consortium,African Ancestry Breast Cancer GWAS Consortium, Stephen J. Chanock, Michael Lieber, Jayesh Mehta, Eric A. Klein, Nalini Janakiraman, Richard K. Severson, Angela R. Brooks-Wilson, Vincent Rajkumar, Elizabeth E. Brown, Laurence Kolonel, Susan Slager, Brian E. Henderson, Graham G. Giles, John J. Spinelli, Brian Chiu, Kenneth C. Anderson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola Camp, Celine Vachon, Elad Ziv, Dan O. Stram, Christopher A. Haiman, Wendy Cozen. Multiple myeloma susceptibility loci examined in African and European ancestry populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4629. doi:10.1158/1538-7445.AM2015-4629

OBJECT Neuroophthalmological morbidity is commonly associated with large and giant cavernous and supraclinoid internal carotid artery (ICA) aneurysms. The authors sought to evaluate the neuroophthalmological outcomes after treatment of these aneurysms with the Pipeline Embolization Device (PED). METHODS The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was an international, multicenter prospective trial evaluating the safety and efficacy of the PED. All patients underwent complete neuroophthalmological examinations both before the PED procedure and at a 6-month follow-up. All examinations were performed for the purpose of this study and according to study criteria. RESULTS In total, 108 patients were treated in the PUFS trial, 98 of whom had complete neuroophthalmological follow-up. Of the patients with complete follow-up, 39 (40%) presented with a neuroophthalmological baseline deficit that was presumed to be attributable to the aneurysm, and patients with these baseline deficits had significantly larger aneurysms. In 25 of these patients (64%), the baseline deficit showed at least some improvement 6 months after PED treatment, whereas in 1 patient (2.6%), the deficits only worsened. In 5 patients (5%), new deficits had developed at the 6-month follow-up, while in another 6 patients (6%), deficits that were not originally assumed to be related to the aneurysm had improved by that time. A history of diabetes was associated with failure of the baseline deficits to improve after the treatment. The aneurysm maximum diameter was significantly larger in patients with a new deficit or a worse baseline deficit at 6 months postprocedure. CONCLUSIONS Patients treated with the PED for large and giant ICA aneurysms had excellent neuroophthalmological outcomes 6 months after the procedure, with deficits improving in most of the patients, very few deficits worsening, and few new deficits developing.

Significance Glioblastoma Multiforme (GBM) is the most common and deadliest primary brain tumor in adults. As the median survival is approximately 14 mo there is an urgent need for novel therapies. Epigenetic modulators such as bromodomain and extraterminal (BET) proteins are important therapeutic targets in GBM. Bromodomain inhibitors (including I-BET151) suppress proliferation by repressing oncogenes and inducing tumor suppressor genes through unidentified pathways. Here we demonstrate that HOTAIR (HOX transcript antisense RNA) is overexpressed in GBM, where it is crucial to sustain tumor cell proliferation, and that inhibition of HOTAIR by I-BET151 is necessary to induce cell cycle arrest in GBM cells. Our study outlines the mechanism of action underlying the antiproliferative activity of I-BET151, showing for the first time, to our knowledge, that the oncogenic long noncoding RNA HOTAIR is a major target.