Citations

Purpose To identify clinical variables that affect a surgeon's decision to recommend arthroscopic partial meniscectomy (APM). Methods Members of 2 orthopaedic specialty societies were invited to participate in an online survey by e‐mail. The survey consisted of surgeon demographics and case scenarios to evaluate clinical decision making for APM. Posterior probabilities were calculated to determine the effect of clinical factors on the likelihood of recommending APM. Results Of the respondents with valid e‐mail addresses, 733 (19.3%) returned a completed survey, but only 533 (14.1%) met the eligibility criteria (treated or referred an APM candidate within the past year). Respondents were aged 46.7 ± 9.4 and had performed a mean of 115 APMs in the previous year. Posterior probabilities for a combination of 6 clinical indicators identified 3 factors that most influenced a surgeon's decision to recommend APM: radiographic findings, McMurray test, and failure of nonoperative management. Conclusions Significant variation exists among practicing orthopaedic surgeons with regard to decision making for APM. The 3 clinical factors that most influenced a surgeon's decision to recommend APM were normal radiographic findings, failed nonoperative treatment, and the presence of positive physical examination findings (i.e., positive McMurray test, joint line tenderness, and effusion). Level of Evidence Level III, decision analysis.

Abstract Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case–control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%–10% representing 5,222–50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08–1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants. Cancer Res; 72(6); 1478–84. ©2012 AACR.

Abstract We are in the midst of a rapidly evolving era of technology-assisted medicine. The field of telemedicine provides the opportunity for highly individualized medical management in a way that has never been possible before. Evolving medical technologies using cardiac implantable devices (CIEDs) with capabilities for remote monitoring permit evaluation of multiple parameters of cardiovascular physiology and risk, including cardiac rhythm, device function, blood pressure values, the presence of myocardial ischaemia, and the degree of compensation of congestive heart failure. Cardiac risk, device status, and response to therapies can now be assessed with these electronic systems of detection and reporting. This document reflects the extensive experience from investigators and innovators around the world who are shaping the evolution of this rapidly expanding field, focusing in particular on implantable pacemakers (IPGs), implantable cardioverter-defibrillators (ICDs), devices for cardiac resynchronization therapy (CRT) (both, with and without defibrillation properties), loop recorders, and haemodynamic monitoring devices. This document covers the basic methodologies, guidelines for their use, experience with existing applications, and the legal and reimbursement aspects associated with their use. To adequately cover this important emerging topic, the International Society for Holter and Noninvasive Electrocardiology (ISHNE) and the European Heart Rhythm Association (EHRA) combined their expertise in this field. We hope that the development of this field can contribute to improve care of our cardiovascular patients.

Abstract Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41–6. ©2011 AACR. Read the Commentary on this article by Bakker and de Winter, p. 14 This article is highlighted in the In This Issue feature, p. 1

Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR ( FCAR ) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced ( P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).

Abstract Primary vitreoretinal lymphoma (PVRL), also known as primary intraocular lymphoma, is a rare malignancy typically classified as a diffuse large B-cell lymphoma and most frequently develops in elderly populations. PVRL commonly masquerades as posterior uveitis and has a unique tropism for the retina and central nervous system (CNS). Over 15% of primary CNS lymphoma patients develop intraocular lymphoma, usually occurring in the retina and/or vitreous. Conversely, 65%–90% of PVRL patients develop CNS lymphoma. Consequently, PVRL is often fatal because of ultimate CNS association. Current PVRL animal models are limited and require further development. Typical clinical findings include vitreous cellular infiltration (lymphoma and inflammatory cells) and subretinal tumor infiltration as determined using dilated fundoscopy, fluorescent angiography, and optical coherent tomography. Currently, PVRL is most often diagnosed using both histology to identify lymphoma cells in the vitreous or retina and immunohistochemistry to indicate monoclonality. Additional adjuncts in diagnosing PVRL exist, including elevation of interleukin-10 levels in ocular fluids and detection of IgH or T-cell receptor gene rearrangements in malignant cells. The optimal therapy for PVRL is not defined and requires the combined effort of oncologists and ophthalmologists. PVRL is sensitive to radiation therapy and exhibits high responsiveness to intravitreal methotrexate or rituximab. Although systemic chemotherapy alone can result in high response rates in patients with PVRL, there is a high relapse rate. Because of the disease rarity, international, multicenter, collaborative efforts are required to better understand the biology and pathogenesis of PVRL as well as to define both diagnostic markers and optimal therapies.

Abstract Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2′-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC. Cancer Res; 71(24); 7608–16. ©2011 AACR.

The optimal regimen of the anticoagulant and antiplatelet therapies in patients with atrial fibrillation who have had a coronary stent is unclear. It is well recognized that “triple therapy” with aspirin, clopidogrel, and warfarin is associated with an increased risk of bleeding. National guidelines have not made specific recommendations, given the lack of adequate data. In choosing the best antithrombotic options for a patient, consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding. This executive summary describes these risks, provides specific recommendations concerning vascular access, stent choice, concomitant use of proton pump inhibitors, and the use and duration of triple therapy after stent placement, based on the risk assessment.