Citations

Abstract The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (P < 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P < 0.0001). Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805–12. ©2018 AACR.

604 Background: Renal cell carcinoma (RCC) is the third most common urologic malignancy worldwide, with clear cell subtype being the most common. In this study, we sought to investigate RCC incidence and mortality trends by demographic and tumor characteristics using data from the surveillance, epidemiology and end results (SEER) database. Methods: We used SEER database to study RCC cases between 1973 and 2014. Incidence and mortality rates were calculated by sex, age, race, state, stage, size, and histological subtype of RCC. Annual percent change (APC) was calculated using joinpoint regression software. Results: A total of 96,058 RCC cases were identified, with 54,000 RCC deaths between 1973 and 2014. Overall incidence was 9.712 per 100,000 persons-years, being highest among males (13.698), blacks (11.886), and people older than 65 years (38.693). Incidence rates of localized cases (5.845) and tumors smaller than 7 cm (6.550) were higher than other tumor subgroups with distant disease incidence of 1.773 per 100,000 persons-years. Overall incidence rates increased by 2.709% (95% CI, 2.544-2.875, p < .001) per year over the study period, but rates became stable since 2007 with only an increase in the incidence of clear-cell subtype (2.538%; 95% CI, 1.300-3.791, p < .001). Overall RCC mortality rates have been declining since 2000, and distant disease mortality have been decreasing since 2008 with most profound decline in the period between 2012 and 2014 with APC of -22.635% (-37.419- -4.359, P = .019) Conclusions: Despite overall increase in rates over the last 40 years, recent years have shown stable incidence and decrease in mortality rates of RCC. The significant decline in mortality over the last 10 years since the approval of the first Vascular Endothelial Growth Factor ‘VEGF’ inhibitor highlights the impact of this class of medications along with other subsequent agents such as mTOR inhibitors and checkpoint inhibitors on the prognosis of renal cell carcinoma.

AbstractBackgroundCatheter ablation is widely accepted intervention for atrial fibrillation (AF) refractory to antiarrhythmic drugs, but limited data are available regarding contemporary trends in major complications and in‐hospital mortality due to the procedure. This study was aimed at exploring the temporal trends of in‐hospital mortality, major complications, and impact of hospital volume on frequency of AF ablation–related outcomes.MethodsThe Nationwide Inpatient Sample database was utilized to identify the AF patients treated with catheter ablation. In‐hospital death and common complications including vascular access complications, cardiac perforation and/or tamponade, pneumothorax, stroke, and transient ischemic attack, were identified using International Classification of Disease (ICD‐9‐CM) codes.ResultIn‐hospital mortality rate of 0.15% and overall complication rate of 5.46% were noted among AF ablation recipients (n = 50,969). Significant increase in complications during study period (relative increase 56.37%, P‐trend < 0.001) was observed. Cardiac (2.65%), vascular (1.33%), and neurological (1.05%) complications were most common. On multivariate analysis (odds ratio [OR]; 95% confidence interval [95% CI]; P value), significant predictors of complications were female sex (OR = 1.40; CI = 1.17–1.68; P value < 0.001), high burden of comorbidity as indicated by Charlson Comorbidity Index ≥2 (OR = 2.84; CI = 2.29–3.52; P value < 0.001), and low hospital volume (< 50 procedures).ConclusionOur study noted a decline in AF ablation–related hospitalizations and complications associated with the procedure. These findings largely reflect shifting trends of outpatient performance of the procedure and increasing safety profile due to improved institutional expertise and catheter techniques.

Background For many indications, the negative chronotropic effect of β‐blockers is important to their efficacy, yet the heart rate ( HR ) response to β‐blockers varies. Herein, we sought to use a genome‐wide association approach to identify novel single nucleotide polymorphisms ( SNP s) associated with HR response to β‐blockers. Methods and Results We first performed 4 genome‐wide association analyses for HR response to atenolol (a β1‐adrenergic receptor blocker) as: (1) monotherapy or (2) add‐on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta‐analysis was then performed between the genome‐wide association analysis performed in PEAR atenolol monotherapy and add‐on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNP s associated with HR response to atenolol at a P <1E‐05 were tested for replication in whites (n=200) and blacks (n=168) treated with metoprolol (a β1‐adrenergic receptor blocker). From the genome‐wide association meta‐analyses, SNP rs17117817 near olfactory receptor family10 subfamily‐p‐member1 ( OR 10P1 ), and SNP rs2364349 in sorting nexin‐9 ( SNX 9 ) replicated in blacks. The combined studies meta‐analysis P values for the rs17117817 and rs2364349 reached genome‐wide significance (rs17117817G‐allele; Meta‐β=5.53 beats per minute, Meta‐ P =2E‐09 and rs2364349 A‐allele; Meta‐β=3.5 beats per minute, Meta‐ P =1E‐08). Additionally, SNP s in the OR 10P1 and SNX 9 gene regions were also associated with HR response in whites. Conclusions This study highlights OR 10P1 and SNX 9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.

AbstractBackgroundCoagulopathy can delay or complicate surgical diseases that require emergent surgical treatment. Prothrombin complex concentrates (PCC) provide concentrated coagulation factors which may reverse coagulopathy more quickly than plasma (FFP) alone. We aimed to determine the time to operative intervention in coagulopathic emergency general surgery patients receiving either PCC or FFP. We hypothesize that PCC administration more rapidly normalizes coagulopathy and that the time to operation is diminished compared to FFP alone.MethodsSingle institution retrospective review was performed for coagulopathic EGS patients during 2/1/2008 to 8/1/2016. Patients were divided into three groups (1) PCC alone (2) FFP alone and (3) PCC and FFP. The primary outcome was the duration from clinical decision to operate to the time of incision. Summary and univariate analyses were performed.ResultsCoagulopathic EGS patients (n = 183) received the following blood products: PCC (n = 20, 11%), FFP alone (n = 119, 65%) and PCC/FFP (n = 44, 24%). The mean (± SD) patient age was 71 ± 13 years; 60% were male. The median (IQR) Charlson comorbidity index was similar in all three groups (PCC = 5(4–6), FFP = 5(4–7), PCC/FFP = 5(4–6), p = 0.33). The mean (± SD) dose of PCC administered was similar in the PCC/FFP group and the PCC alone group (2539 ± 1454 units vs. 3232 ± 1684, p =. 09). The mean (±SD) time to incision in the PCC alone group was significantly lower than the FFP alone group (6.0 ± 3.6 vs. 8.8 ± 5.0 h, p = 0.01). The mean time to incision in the PCC + FFP group was also significantly lower than the FFP alone group (7.1 ± 3.6 vs. 8.8 ± 5.0, p = 0.03). The incidence of thromboembolic complications was similar in all three groups.ConclusionsPCC, alone or in combination with FFP, reduced INR and time to surgery effectively and safely in coagulopathic EGS patients without an apparent increased risk of thromboembolic events, when compared to FFP use alone.Level of evidenceIV single institutional retrospective review.

Online health information should meet the reading level for the general public (set at sixth-grade level). Readability is a key requirement for information to be helpful and improve quality of care. The authors conducted a systematic review to evaluate the readability of online health information in the United States and Canada. Out of 3743 references, the authors included 157 cross-sectional studies evaluating 7891 websites using 13 readability scales. The mean readability grade level across websites ranged from grade 10 to 15 based on the different scales. Stratification by specialty, health condition, and type of organization producing information revealed the same findings. In conclusion, online health information in the United States and Canada has a readability level that is inappropriate for general public use. Poor readability can lead to misinformation and may have a detrimental effect on health. Efforts are needed to improve readability and the content of online health information.

Background Although hydrochlorothiazide ( HCTZ ) is a well‐established first‐line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure ( BP ) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. Methods and Results First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway ( P =5.8E‐05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC 3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C‐allele carriers had a better BP response to HCTZ versus noncarriers (∆ SBP /∆ DBP : −11.4/−6.9 versus −6.8/−3.5 mm Hg; ∆ SBP P =6.7E‐04; ∆ DBP P =4.8E‐04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC 3 genomic region significantly associated with the BP response to HCTZ ( P <0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP ‐response ( r =−0.42; P =7E‐03) and SBP ‐response ( r =−0.36; P =2E‐02). Conclusions This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC 3 is a potential determinant of the BP response to HCTZ . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.