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.

Background: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. Methods: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation Results: There were 11 529 participants in the preimplementation phase (range, 284–3465) and 19 803 in the postimplementation phase (range, 395–5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%–37.7%) to 18.4% (6.8%–43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3–2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4–3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P =0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. Conclusions: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. Clinical Trial Registration: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

Introduction: Although 80% of patients endorse an advance directive (AD), less than 35% of American adults have a documented AD. Much research has been done on barriers to creating ADs; however, there is a paucity of research addressing motivations for creating ADs. Previous research has identified 4 categories of influence for engaging in advance care planning (ACP). This study aimed to quantify the influence of these 4 motivating categories in creating an AD. Methods: Participants included 238 adults with documented ADs. Participants completed an 11-item questionnaire addressing 1 of the 4 hypothesized categories of influence in addressing ACP: concern for self; concern for others; expectations about the impact of ACP; and anecdotes, stories, and experiences. Results: Principle component analysis yielded 2 factors representing dignity and personal control (intrinsic factors) and societal and familial influence (extrinsic factors). Intrinsic factors were the primary and most influential motivating factors among participants. A regression analysis of individual motivating factors showed that prior to age 50, the desire to provide guidance about personal preferences for end-of-life care significantly predicted the creation of an AD, whereas after age 50, the urging of family members significantly predicted the creation of an AD. Discussion: Results indicated that intrinsic factors were the most influential motivator among participants of all ages. Extrinsic factors appeared to be less influential in the decision to create an AD. Motivating factors were also found to vary by age. These results may help physicians be more targeted in discussions surrounding ADs, thus saving time, which physicians identify as the main barrier in engaging in such discussions, while meeting patients’ wishes for their physicians to bring up the topic of ADs.

BACKGROUND: This review focuses on the use of peripheral nerve blocks as preoperative analgesia, as postoperative analgesia, or as a supplement to general anesthesia for hip fracture surgery and tries to determine if they offer any benefit in terms of pain on movement at 30 minutes after block placement, acute confusional state, myocardial infarction/ischemia, pneumonia, mortality, time to first mobilization, and cost of analgesic. METHODS: Trials were identified by computerized searches of Cochrane Central Register of Controlled Trials (2016, Issue 8), MEDLINE (Ovid SP, 1966 to 2016 August week 1), Embase (Ovid SP, 1988 to 2016 August week 1), and the Cumulative Index to Nursing and Allied Health Literature (EBSCO, 1982 to 2016 August week 1), trials registers, and reference lists of relevant articles. Randomized controlled trials involving the use of nerve blocks as part of the care for hip fractures in adults aged 16 years and older were included. The quality of the studies was rated according to the Cochrane tool. Two authors independently extracted the data. The quality of evidence was judged according to the Grading of Recommendations, Assessment, Development, and Evaluations Working Group scale. RESULTS: Based on 8 trials with 373 participants, peripheral nerve blocks reduced pain on movement within 30 minutes of block placement: standardized mean difference, −1.41 (95% confidence interval [CI], −2.14 to −0.67; equivalent to −3.4 on a scale from 0 to 10; I 2 statistic = 90%; high quality of evidence). The effect size was proportional to the concentration of local anesthetic used ( P < .00001). Based on 7 trials with 676 participants, no difference was found in the risk of acute confusional state: risk ratio, 0.69 (95% CI, 0.38–1.27; I 2 statistic = 48%; very low quality of evidence). Based on 3 trials with 131 participants, the risk for pneumonia was decreased: risk ratio, 0.41 (95% CI, 0.19–0.89; I 2 statistic = 3%; number needed-to-treat for additional beneficial outcome, 7 [95% CI, 5–72]; moderate quality of evidence). No difference was found for the risk of myocardial ischemia or death within 6 months but the number of participants included was well below the optimum information size for these 2 outcomes. Based on 2 trials with 155 participants, peripheral nerve blocks also reduced the time to first mobilization after surgery: mean difference, −11.25 hours (95% CI, −14.34 to −8.15 hours; I 2 statistic = 52%; moderate quality of evidence). From 1 trial with 75 participants, the cost of analgesic drugs when used as a single-shot block was lower: standardized mean difference, −3.48 (95% CI, −4.23 to −2.74; moderate quality of evidence). CONCLUSIONS: There is high-quality evidence that regional blockade reduces pain on movement within 30 minutes after block placement. There is moderate quality of evidence for a decreased risk of pneumonia, reduced time to first mobilization, and reduced cost of analgesic regimen (single-shot blocks).