Citations

Objective Implantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and the combination therapy (CRT-D) have been shown to reduce all-cause mortality compared with medical therapy alone in patients with heart failure and reduced EF. Our aim was to synthesise data from major randomised controlled trials to estimate the comparative mortality effects of these devices and how these vary according to patients’ characteristics. Methods Data from 13 randomised trials (12 638 patients) were provided by medical technology companies. Individual patient data were synthesised using network meta-analysis. Results Unadjusted analyses found CRT-D to be the most effective treatment (reduction in rate of death vs medical therapy: 42% (95% credible interval: 32–50%), followed by ICD (29% (20–37%)) and CRT-P (28% (15–40%)). CRT-D reduced mortality compared with CRT-P (19% (1–33%)) and ICD (18% (7–28%)). QRS duration, left bundle branch block (LBBB) morphology, age and gender were included as predictors of benefit in the final adjusted model. In this model, CRT-D reduced mortality in all subgroups (range: 53% (34–66%) to 28% (−1% to 49%)). Patients with QRS duration ≥150 ms, LBBB morphology and female gender benefited more from CRT-P and CRT-D. Men and those <60 years benefited more from ICD. Conclusions These data provide estimates for the mortality benefits of device therapy conditional upon multiple patient characteristics. They can be used to estimate an individual patient's expected relative benefit and thus inform shared decision making. Clinical guidelines should discuss age and gender as predictors of device benefits.

Abstract Background: Blood-based biopsies can be used as a non-invasive method to recover both Circulating Tumor Cells (CTCs) and Circulating Cancer Associated Macrophage-Like cells (CAMLs) from the blood of cancer patients. CAMLs are a newly-defined circulating immune cell type, described as a subtype of circulating stromal cells, known to engulf tumor cells/debris. CAMLs are identified by their large size, 30-300 microns, and aberrant nuclear structure. We studied the peripheral blood of cancer patients to ascertain the prevalence, specificity and sensitivity of CAMLs in relation to their disease status at presentation, including a variety of benign and malignant diseases. We supply evidence that this previously unidentified circulating cell can be used as a screening tool to detect solid tumors in numerous malignancy subtypes in all disease stages. Methods: CellSieveTM microfilters were used to isolate CAMLs from 7.5 mL of whole peripheral blood. The pore size of CellSieveTM is 7 microns, capable of isolating both CTCs and CAMLs based on size. Collected cells were fixed, permeabilized, and stained with DAPI and antibodies against cytokeratin 8, 18 and 19, CD14, and CD45. CAMLs were defined as enlarged, multinuclear cells with diffuse cytoplasmic cytokeratin staining, and/or CD14+, and/or CD45+. CTCs were defined as filamentous cytokeratin cells that are CD45-. Study 1: Blinded peripheral blood samples from 61 cancer patients were tested, including Stage I-IV breast, pancreatic, lung and prostate cancers, and newly diagnosed, untreated patients. Non-blinded blood samples from 30 healthy volunteers served as controls. Study 2: Double blinded peripheral blood samples from 20 patients with abnormal mammogram results were drawn at time of tissue biopsy and screened. After analysis, unblinding showed a distribution of malignant breast disease (n = 10), benign (n = 8), or atypical hyperplasia (AH) (n = 2). Results: Study 1: CAMLs were found in 94% patients with Stage III/IV cancers, 87% with Stage I/II cancers, and 89% of all patients, regardless of cancer type. Specifically, CAMLs were found in 77% of prostate, 100% of pancreatic, 80% of lung, and 100% of breast patient samples. CAMLs were not found in healthy control samples (sensitivity: 84-96%, Specificity: 100%, PPV: 100%, NPV: 88-97%). Study 2: CAMLs were found in 8 patients with malignant disease, 2 with benign disease, and 2 with AH (sensitivity: 80%, Specificity: 75%, PPV: 80%, NPV: 75%) Conclusions: We present evidence that CAMLs can be used as a non-invasive blood based biopsy, to detect the anatomical presence of solid malignancies and potentially pre-malignant lesions. The presence of CAMLs in newly diagnosed patient samples suggests their use as a blood biomarker for early stage cancer screening in a broad population. Preliminary data from a double blind breast cancer study suggests that CAMLs may differentiate between benign and malignant breast diseases. Citation Format: Daniel Adams, Katherine Alpaugh, Massimo Cristofanilli, Stuart Martin, Saranya Chumsri, Raymond C. Bergen, Susan Tsai, Martin Edelman, Peixuan Zhu, Shuhong Li, Olga V. Makarova, Platte T. Amstutz, Cha-Mei Tang, Jeffrey R. Marks. Cancer associated macrophage-like cells as a blood-based biomarker for the screening of solid tumors. [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 5165. doi:10.1158/1538-7445.AM2015-5165

ABSTRACT In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of Clostridium difficile isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of C. difficile isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC 90 was 0.5 μg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at ≤1.0 μg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of tcdA , tcdB , and cdtA/B positive with a tcdC 18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against C. difficile isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons.

Objectives: Patients with patellar instability and tibial tubercle to trochlear groove (TT-TG) distances ≥ 20 mm are often considered to have pathologic lateralization of the tibial tubercle (TT) relative to the femoral trochlea and may be candidates for TT realignment surgery. Although this variable has proven valuable in predicting risk of recurrent dislocations, the measure is limited in that it is not individualized to the patient and does not consider patient size, bony morphology, or patellofemoral mechanics. The purpose of this study was to develop a Patellar Instability Ratio (PIR) that predicts the risk of recurrent instability based on the TT-TG distance relative to patient specific anatomy. Methods: Fifty-nine patients with a clinical diagnosis of patellar instability were included in the study. A number of measures were calculated on MRI by two observers (one staff orthopedic surgeon and one senior resident) in a blinded and randomized fashion. Variables analyzed included: TT-TG, tibial tubercle to posterior cruciate ligament distance (TT-PCL), sagittal patellar length (PL), sagittal trochlear length (TL), axial patellar width (PW), axial trochlear width (TW), sagittal patellofemoral engagement (SPE; SPE=TL/PL) and axial patellofemoral engagement (APE; APE=PW/TW). Patients were divided into two groups: those with ≤ 1 dislocation and those with ≥ 2 dislocations. Using these groups, the ability of TT-TG, TT-PCL, and 12 different ratios with cut-off values to predict recurrent instability was assessed by calculating odds ratios (OR), C-statistics, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the ratios. P values < 0.05 were considered significant. Results: Mean follow up was 6.6 years. Twelve patients (20%) did not experience recurrent instability while 47 (80%) sustained two or more dislocations during the study period. Pathologic TT-TG (≥ 20 mm) was predictive of recurrent instability with an OR of 5.38 (p=0.29). The highest OR's for recurrent instability were noted for TT-TG/PW ≥ 0.40 (OR > 7.37, p=0.02) and TT-TG/TW ≥ 0.5 (OR 8.88, p=0.04)(Table 1). PW was defined as the largest medial to lateral width of the articular surface of the patella. TW is defined as the largest articular width of the trochlea that is articulating with the patella and can be conceptualized as the “jump distance” that must be overcome for the patella to dislocate. The sensitivity and specificity of TT-TG/PW ratio ≥ 0.40 was 61% and 83% and that of TT-TG/TW ≥ 0.50 was 59% and 92%, respectively. PPV for TT-TG/PW ≥ 0.40 was 94% while that of TT-TG/TW ≥ 0.49 was 97%. Conclusion: Two distinct PIR (TT-TG/PW and TT-TG/TW) have been identified that predict recurrent patellar instability more accurately than TT-TG ≥ 20 mm with PPV's ≥ 94% and OR's > 7 for both measures. These ratios take into consideration the TT-TG relative to patient specific size and anatomy. Further research is needed to determine if patients with increased PIR benefit from TT osteotomy.

Objectives: Female athletes are an at-risk population for anterior cruciate ligament (ACL) injury, with rates of injury significantly higher than the general population. Few studies have reported on a second ACL injury for female athletes. The purpose of this study was to (1) report the rate of subsequent ACL injury (ACL graft rupture or contralateral ACL tear) in competitive female soccer players, (2) compare these rates to those of other female athletes of similar competitive level, and (3) determine risk factors for second ACL injury in this athletic population. Methods: The medical record at our institution was reviewed for patients treated with primary ACL reconstruction between 1998 and 2013. Female patients injured during a competitive athletic event were included for further review, and followed for an average of 7.1 years postoperatively (range 1.0 - 17.7 years). Chi-square analysis was used to compare rate of graft rupture and contralateral ACL injury based on pre-operative Tegner score, graft type, and injury side for soccer players vs. other female athletes. Wilcoxon rank-sum test was used to compare rate of subsequent ACL injury to patient age. Results: 337 patients met our inclusion/exclusion criteria (90 soccer players; 247 non-soccer playing athletes) with a mean age of 24.0 years. Of the 337 athletes, 6 were injured during professional competition, 43 were injured during collegiate athletics, 184 during high school play, and 136 during recreational athletics. No patient demographical differences were found at baseline between the soccer group and non-soccer group, including Tegner scores. Overall, 21 soccer players (23.3%) sustained a second ACL injury compared to 21 (8.5%) non-soccer athletes (P < 0.001). Soccer players had significantly more graft ruptures (10.0% vs. 2.0%, P = 0.003) and more contralateral ACL tears (13.3% vs. 6.5%, P = 0.04). Risk factors for ACL graft tear included young age (mean 16.0 vs 24.3 years; P < 0.0001) and higher Tegner Activity Level scores (mean 8.1 vs. 7.4, P = 0.049), but were not risk factors for contralateral ACL injury. Graft selection and injury side showed no statistical significance on graft rupture or contralateral injury. Conclusion: Female soccer players treated with ACL reconstruction had an increased rate of second ACL injury, including graft tear and contralateral ACL injury, compared to a similar group of non-soccer female athletes (23.3% vs. 8.5%, P < 0.001). In addition, young age and higher activity level were risk factors for graft rupture in this population.

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Epigenetic drugs can overcome resistance to monoclonal antibodies in T-PLL and activate therapeutic targets for antibody-drug conjugates.

Purpose To (1) determine the incidence of symptomatic venous thromboembolic events (VTEs) after knee arthroscopy and arthroscopy‐assisted procedures at a single institution and (2) determine associated risk factors for VTEs in these patients. Methods The records of patients who underwent knee arthroscopy at a single institution between 1988 and 2008 were reviewed. Chemoprophylaxis was not routinely used. Confirmed VTEs occurring within 4 weeks after the index arthroscopy procedure were included. A 2:1 matched control group was generated to include patients in whom knee arthroscopy was performed by the same surgeon either on the same day or immediately before each case resulting in a VTE. Preoperative and perioperative data were collected with respect to demographic data, medical history, medications, and surgical and anesthesia data. Univariate and multivariate analyses were performed. Results During the study period, 12,595 patients underwent knee arthroscopy. Among these patients, 43 cases of VTEs (35 deep venous thromboses [DVTs], 5 pulmonary embolisms [PEs], and 3 DVTs that progressed to PEs) occurred, resulting in an incidence of 0.30% (95% confidence interval [CI], 0.22% to 0.41%) for DVT, 0.06% (95% CI, 0.03% to 0.12%) for PE, and 0.34% (95% CI, 0.25% to 0.46%) for VTEs overall. Factors associated with an elevated risk of symptomatic postoperative VTEs included a history of malignancy ( P = .01; odds ratio [OR], 6.3), a history of VTEs ( P = .02; OR, 5.2), or the presence of more than 2 classic risk factors for VTEs ( P = .01; OR, 13.6). Conclusions In this study, symptomatic VTEs were rare and occurred infrequently, with an incidence of 0.34% (95% CI, 0.25% to 0.46%), after knee arthroscopy and arthroscopy‐assisted cases in the absence of routine chemoprophylaxis. Patients with a history of VTEs, a history of malignancy, or 2 or more classic risk factors are at increased risk of VTEs after knee arthroscopy, and chemoprophylaxis should be considered in these select patients. Level of Evidence Level III, case‐control study.

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org ).