Citations

Abstract Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Consistent with this carcinogenic exposure, cytogenetic analyses have identified multiple recurrent structural chromosomal abnormalities in this malignancy, but more recent high-throughput sequencing evaluations of point mutations suggest that there is a low mutational burden in mesothelioma. Since tumor mutational burden has been correlated with responses to treatment with immune checkpoint inhibitors such as nivolumab, it was not consistent that patients with mesothelioma and low mutation burdens would have similar response rates in clinical trials with immune checkpoint inhibitors as patients with non-small cell lung cancer which is associated with a high mutation burden. In order to reconcile these differences, and given the potential for an improved understanding of the molecular pathogenesis of mesothelioma to improve therapeutic options, we used mate-pair sequencing (MPseq) and RNA sequencing (RNAseq) to understand how structural variants affect the transcriptome. MPseq differs from standard next generation sequencing approaches by tiling the whole genome with larger fragments (2-5kb) to reliably detect structural variants such as insertions, deletions and rearrangements. Amongst 22 mesothelioma specimens there were 1535 chromosomal rearrangements (median 41, range 3-298 per specimen), that resulted in junctions or novel fusions of non-coding DNA or genes. Six-hundred thirty-seven of these rearrangements (median 22, range 5-103 range per specimen) resulted in novel fusions of genes. Many of these inter- or intra-chromosomal rearrangements were consistent with a pattern of chromoanagesis such as chromoplexy or chromothripsis. Chromosomal rearrangements detected by MPseq were used to guide analysis of RNAseq data and revealed that these chromosomal junctions resulted in the expression of 179 novel amino acid sequences (median 5, 0-51 range per specimen). To determine whether transcription of chromosomal rearrangement-related junctions have neoantigenic potential, we used in silico tools to determine whether any of the expressed junctions contained peptides that could be presented by patient-specific HLA molecules. The top candidate rearrangement-related peptides with neoantigenic potential bound patient-specific HLA molecules nearly as well or as well as a positive control in competitive binding assays. Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel therapeutic strategies, the selection of patients to receive immunotherapy, and blood-based treatment monitoring strategies. Citation Format: Aaron S. Mansfield, Tobias Peikert, James B. Smadbeck, Julia B. Udell, Farhad Kosari, Stephen J. Murphy, Hongzheng Ren, Vishnu V. Serla, Janet L. Schaefer Klein, Giannoula Karagouga, Faye R. Harris, Carlos Sosa, Sarah H. Johnson, Wendy Nevala, Svetomir N. Markovic, Aaron O. Bungum, Eric S. Edell, Haidong Dong, John C. Cheville, Marie Christine Aubry, Jin Jen, George Vasmatzis. Rearrangement-related peptides with neoantigenic potential in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5726.

To quantitatively study platelet deposition on arterial prostheses and the effect of platelet inhibitory therapy with ticlopidine, 14 dogs underwent bilateral femoral artery excision and replacement with one polytetrafluoroethylene (Gore-Tex) and one autologous vein graft. Five dogs received 60 mg/kg/day of ticlopidine orally on four consecutive days prior to surgery. Nine untreated dogs served as controls. Collagen-induced platelet aggregometry studies were performed at the end of day 4. Autologous indium-111-labeled platelets were injected 24 hours prior to surgery to serve as aplatelet marker. All animals received heparin (1 mg/kg I.V.) 5 minutes prior to excision of the arterial segment. Grafts were removed 1 hour following resumption of blood flow and gently flushed with 30 cc normal saline. Radioactivity per unit weight of Gore-Tex, vein and blood was determined with a gamma counter. The relative radioactivity with respect to the internal reference standard, blood, is tabulated below.Ticlopidine treated dogs showed a 15-fold reduction in platelet deposition on Gore-Tex grafts and a 3-fold reduction on venous grafts. Platelet deposition was reduced significantly in Gore-Tex grafts (P<0.001) to a level comparable to that in autologous veins. Platelet inhibitory effect was also observed in collagen-induced platelet aggregometry.According to this “in vivo” data, ticlopidine appears to be a promising platelet inhibiting agent.

Platelet calcium appears to be essential in platelet activation. Accordingly, Verapamil (a channel calcium blocker) was tested “in vivo” as a possible platelet inhibitor agent. Fifteen dogs underwent bilateral femoral artery grafting with one polytetrafluoroethylene (Gore-Tex) and one autologous vein graft. Peroperatively, five dogs were infused continuously with Verapamil (6 μgs/kg/min) and 9 dogs were left untreated and the arterial prostheses were surgically implanted. Using autologous Indium-111-labeled platelets injected 24 hours prior to surgery as a platelet marker, grafts were removed 1 hour following resumption of blood flow. Radioactivity per unit weight of Gore-Tex, vein and blood were determined with a gamma counter and the relative radioactivity with respect to the internal reference standard of blood is tabulated belowVerapamil-treated dogs showed a significant reduction in the “in vivo” platelet deposition on Gore-Tex and autologous venous grafts. Preliminary data indicates that “in vitro” platelet aggregation with soluble calf skin collagen (515 μg/ml) and ADP (2-100 μm) is not different between control and drug-treated dogs.Calcium channel blockers may be promising “in vivo” platelet inhibitor agents; in addition, they may provide further understanding of the different processes involved in “in vivo” and “in vitro” platelet activation.

Abstract Background In the past decade, opioid use in the general population of the US has increased dramatically. Concomitantly, opioid-related morbidity and mortality have also risen steeply. The causes of opioid over-prescribing are multifactorial, with pressure from medical agencies, patients, aggressive patient-directed marketing, and use of patient surveys as an evaluation tool to unduly influence medical providers' decision-making. Providers also have significant concerns regarding scrutiny from their medical board and exposure to medicolegal liability. Content To provide the basis for best practice recommendations, several aspects of modern opioid prescribing practice require review. The practicing clinician should be aware of: (a) the pervasiveness of current opioid prescribing within the US; (b) the availability and applicability of clinical tools used to assess patient risk; (c) the new guidelines designed to facilitate appropriate and safe medical use of opioids; (d) the incorporation of clinical tools and best documentation practices to reduce medicolegal exposure. Summary On completion of this review, the reader should be able to recognize the magnitude of the problem of opioid over-prescribing in the US and identify several patient risk factors for opioid misuse, abuse, and/or diversion. Specifically, better familiarity with the recently published CDC guidelines for opioid prescribing will help ensure the adoption of best-use practices that maximize therapeutic efficacy while attenuating the possibility of harm to patients. A thorough review of the legal principles and risk-mitigation strategies relevant to opioid prescribing will also lessen the clinician's exposure to medicolegal liability.

Background and Purpose/Objective: Few studies have examined the efficacy of fall risk assessment tools for patients undergoing hematopoietic cell transplant (HCT). The purpose of this study was to determine whether the Hendrich II Fall Risk Model (HFRM II) can distinguish patients who fell from those who did not fall in the inpatient HCT population. Methods: Observational study. Design: Retrospective chart review. Setting: Academic medical center. Patients: Patients undergoing HCT who fell during the first 100 days posttransplant. Intervention: None. Measurements: Independent-sample t tests were performed to determine differences in HFRM II score, age, pulse, systolic and diastolic blood pressure, platelet count, hemoglobin concentration, and hematocrit for fallers compared with nonfallers. Chi-square tests of independence determined differences regarding sex, assistive device used on the day of fall, transplant type, and physical therapy. Logistic regression analysis detected odds of falling dependent on transplant type, pulse rate, and HFRM II score. Results: Forty-seven patients who fell within 100 days after HCT were control matched by transplant date with 2 nonfallers each. Significant differences included HFRM II mean score (5.36 for fallers vs 3.41 for nonfallers; t = 4.510, P < .001) and mean pulse rates (100.09 vs 88.70 bpm; t = 3.398, P = .001). Patients with allogeneic HCT were 3.46 times more likely to have fallen than those with autologous HCT (P = .007). Limitations: Potential selection bias of retrospective review. Conclusions: HCT patients with higher HFRM II scores, greater pulse rate, or allogeneic transplant were more likely to fall.

Abstract Researchers hypothesized that telomere shortening facilitates carcinogenesis. Previous studies found inconsistent associations between blood leukocyte telomere length (LTL) and cancer. Epigenetic reprogramming of telomere maintenance mechanisms may help explain this inconsistency. We examined associations between DNA methylation in telomere-related genes (TRG) and cancer. We analyzed 475 participants providing 889 samples 1 to 3 times (median follow-up, 10.1 years) from 1999 to 2013 in the Normative Aging Study. All participants were cancer-free at each visit and blood leukocytes profiled using the Illumina 450K array. Of 121 participants who developed cancer, 34 had prostate cancer, 10 melanoma, 34 unknown skin malignancies, and 43 another cancer. We examined 2,651 CpGs from 80 TRGs and applied a combination of Cox and mixed models to identify CpGs prospectively associated with cancer (at FDR &lt; 0.05). We also explored trajectories of DNA methylation, logistic regression stratified by time to diagnosis/censoring, and cross-sectional models of LTL at first blood draw. We identified 30 CpGs on 23 TRGs whose methylation was positively associated with cancer incidence (β = 1.0–6.93) and one protective CpG in MAD1L1 (β = −0.65), of which 87% were located in TRG promoters. Methylation trajectories of 21 CpGs increased in cancer cases relative to controls; at 4 to 8 years prediagnosis/censoring, 17 CpGs were positively associated with cancer. Three CpGs were cross-sectionally associated with LTL. TRG methylation may be a mechanism through which LTL dynamics reflect cancer risk. Future research should confirm these findings and explore potential mechanisms underlying these findings, including telomere maintenance and DNA repair dysfunction. Cancer Prev Res; 11(8); 511–22. ©2018 AACR.

AbstractBackground: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements.Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry.Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was &lt; + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results.Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine.Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR.

Abstract BACKGROUND A decrease in diastolic blood pressure (DBP) with exercise is considered normal, but the significance of an increase in DBP has not been validated. Our aim was to determine the relationship of DBP increasing on a stress test regarding comorbidities and mortality. METHODS Our database was reviewed from 1993 to 2010 using the first stress test of a patient. Non-Minnesota residence, baseline cardiovascular (CV) disease, rest DBP &lt;60 or &gt;100 mm Hg, and age &lt;30 or ≥80 were exclusion criteria. DBP response was classified: normal if peak DBP–rest DBP &lt; 0, borderline 0–9, and abnormal ≥10 mm Hg. Mortality was determined from Mayo Clinic records and Minnesota Death Index. Logistic regression was used to determine the relationship of DBP response to the presence of comorbidities. Cox regression was used to determine total and CV mortality risk by DBP response. All analyses were adjusted for age, sex, and resting DBP. RESULTS Twenty thousand seven hundred sixty patients were included (51 ± 11 years, female n = 7,314). Rest/peak averaged DBP 82 ± 8/69 ± 15 mm Hg in normal vs. 79 ± 9/82 ± 9 mm Hg in borderline vs. 76 ± 9/92 ± 11 mm Hg in abnormal DBP response. There were 1,582 deaths (8%) with 557 (3%) CV deaths over 12 ± 5 years of follow-up. In patients with borderline and abnormal DBP response, odds ratios for obesity, hypertension, diabetes, and current smoking were significant, while hazard ratios for total and CV death were not significant compared with patients with normal DBP response. CONCLUSIONS DBP response to exercise is significantly associated with important comorbidities at the time of the stress test but does not add to the prognostic yield of stress test.