Citations

Purpose Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2–positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). Patients and Methods The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. Results In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. Conclusion These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.

Background— Little is known about the clinical value of stress imaging studies in asymptomatic patients after percutaneous coronary intervention (PCI). Methods and Results— Residents of Olmsted County, MN, who underwent PCI were followed up for the occurrence of stress imaging (stress nuclear or stress echocardiography), coronary angiography, or coronary artery bypass grafting (without angiography) as initial procedures after PCI. Patients whose first follow-up procedure was a stress imaging test were evaluated for their symptom status at the time of the study and whether they underwent angiography or revascularization (PCI or coronary artery bypass grafting) within 90 days. Of 1848 patients who underwent PCI during the study period, 710 (38%) had stress imaging as their initial procedure after PCI, and 241 (13% of the entire cohort) were asymptomatic at the time of testing. The majority (86%) of these 241 patients underwent PCI for acute myocardial infarction or unstable angina. Within 90 days of stress imaging, 16 of the 241 asymptomatic patients underwent angiography, and 2 patients were revascularized. Stratified by timing after PCI, none of 138 asymptomatic patients tested within 2 years of PCI underwent revascularization. Two of 103 asymptomatic patients tested after 2 years from PCI underwent revascularization. Compared with patients who were asymptomatic at the time of stress imaging, patients who did not undergo any follow-up procedures (stress imaging, angiography, or coronary artery bypass grafting) after the index PCI were older, were more likely to have comorbidities, and had significantly greater all-cause mortality ( P <0.001). Conclusions— In a population-based sample of patients undergoing PCI primarily for acute coronary syndromes, 1 in 8 had subsequent stress imaging when they were asymptomatic. These stress imaging tests resulted in further revascularization in <1% of patients. The low rate of downstream revascularization suggests that stress imaging in asymptomatic patients after PCI has low value.

Abstract Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF–wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28–1.80; P &lt; 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P &lt; 0.0001), proximal tumor site (P &lt; 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P &lt; 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. ©2014 AACR.

Background and Purpose— To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. Methods— After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. Results— Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. Conclusions— Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Background Cardiovascular implantable electronic device (CIED) pocket infections are often related to recent CIED placement or manipulation, but these infections are not well characterized. The clinical presentation of CIED pocket infection, based on temporal onset related to last CIED procedure, deserves further study. Methods The MEDIC (Multicenter Electrophysiologic Device Infection Cohort) prospectively enrolled subjects with CIED infection. Subjects were stratified into those whose infection occurred <12 months (early) or ≥12 months (late) since their last CIED‐related procedure. Results There were 132 subjects in the early group and 106 in the late group. There were more females (P = 0.009) and anticoagulation use (P = 0.039) in the early group. Subjects with early infections were more likely to have had a generator change or lead addition as their last procedure (P = 0.03) and had more prior CIED procedures (P = 0.023). Early infections were more likely to present with pocket erythema (P < 0.001), swelling (P < 0.001), and pain (P = 0.007). Late infections were more likely to have pocket erosion (P = 0.005) and valvular vegetations (P = 0.009). In bacteremic subjects, early infections were more likely healthcare‐associated (P < 0.001). In‐hospital and 6‐month mortality were equivalent. Conclusion A total of 45% of patients with CIED pocket infection presented >12 months following their last CIED‐related procedure. Patients with early infection were more likely to be female, on anticoagulation, and present with localized inflammation, whereas those with late infection were more likely to have CIED erosion or valvular endocarditis.

Key Points NK cells and their expression of FcRγIII (CD16) are decreased in MDS and inversely correlate with a substantial increase in MDSCs. CD16xCD33 BiKE potently activates blood and marrow MDS-NK cells at all diseases stages to lyse CD33+ MDS and CD33+ MDSC targets.

A significant issue in research on the epidemiology of injury relates not to the numerator (injury), but to the denominator: exposure time. Most hockey injury studies “assume” equivalent playing time. This assumption is not problematic for large investigations designed to establish differences in concussion rates between levels of participation. However, the assumption is a serious issue when investigators are testing differences in rules, coaching programs, skills training, and behavioral interventions. Because players are at higher risk for injuries when fatigued, individual exposure time is important. Until recently, analyzing individual playing times for ice hockey teams has been a daunting task, as it involved the hand-written recording of times using a grid and check marks. During the 2011–2012 season, a computer-based program, Time on Ice (TOI), was used to expedite the accurate recording of individual exposure, including shorthanded and power-play situations. The purpose of using TOI software in this study was to ensure that its results were in agreement with the exposure times recorded manually using a paper-and-pencil grid. Preliminary results from six games (12 records of data) showed that exposure time ranged from 6.3 to 26.4 min when using manual recording and 8.3 to 33.2 min when using TOI. These methods were concluded to be in agreement. Now that software has been developed exclusively for the task of tracking time on ice, it is recommended that exposure time be measured when injuries such as concussion are being evaluated and causation is being determined. The Sport Performance Analyzer TOI system is commercially available.

Catastrophic injuries in the sport of ice hockey are rare but result in life-altering conditions such as paralysis and cognitive impairment, or even death. Potentially catastrophic injuries without permanent functional disability are also a serious concern. In 2006, Mayo Clinic Sports Medicine Center and USA Hockey established a registry for catastrophic and potentially catastrophic injuries sustained by ice hockey players in the Unites States. Since data collection began in 2008, our research team has acquired 45 database entries obtained from self-reports, Google Alerts (using the term “hockey injury”), and the National Electronic Injury Surveillance System. Cervical fracture and neck laceration were the most common types of injuries, with the spine and head being the most commonly injured body parts. Steps to reduce the aforementioned injury types and locations include USA Hockey's “Heads Up, Do Not Duck” program and increased use and awareness of neck laceration protectors.