Citations

Abstract Background: Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. Methods: Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. Results: Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12–3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18–4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. Conclusions: In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. Impact: BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.

OBJECTIVES Cardiac troponin T, measured using a high‐sensitive assay (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) are associated with increased stroke risk and perhaps with cognitive decline. However, few well‐designed prospective studies with extended follow‐up have been conducted. We aimed to estimate the association of hs‐cTnT and NT‐proBNP with 15‐year cognitive change in the Atherosclerosis Risk in Communities (ARIC) study. DESIGN Prospective cohort study. SETTING Four US communities. PARTICIPANTS A total of 9114 and 9108 participants from the Atherosclerosis Risk in Communities study for analyses of hs‐cTnT and NT‐proBNP, respectively. MEASUREMENTS We examined association of hs‐cTnT and NT‐proBNP with 15‐year change (1996‐1998 to 2011‐2013) in three cognitive tests of executive function (Digit Symbol Substitution Test), verbal learning memory (Delayed Word Recall Test), and semantic fluency (Word Fluency Test), and an overall score combining the three tests using multivariable linear mixed effect models. We conducted several sensitivity analyses including multiple imputations to address bias due to missing data and attrition, and we compared associations within groups combining hs‐cTnT and NT‐proBNP into a three‐level categorical variable. RESULTS At baseline (1996‐1998), mean age was 63.4 (standard deviation [SD] = 5.7) years; 56.4% were women, and 17.5% were black. The hs‐cTnT at baseline was not associated with cognitive change in any measure. Some evidence indicated accelerated decline in verbal learning and memory when comparing those in the highest with the lowest NT‐proBNP quintiles; however, this association was not replicated when considering clinically relevant cutoffs or deciles of exposure in survivors. Sensitivity analyses were consistent with our primary analyses. There was little evidence to support effect modification by any considered factors. People with highest levels of both biomarkers had excessive decline in global z scores vs people with lowest levels (−.34; 95% confidence interval = −.63 to −.04). CONCLUSION Markers of myocardial injury and stretch were not associated with cognitive decline following 15 years among survivors, but when combined together they were suggestive in post hoc analysis. Whether this represents targets of intervention should be examined in the future. J Am Geriatr Soc 67:2353–2361, 2019

OBJECTIVE We sought to examine associations in older adults among diabetes, glycemic control, diabetes duration, and biomarkers of hyperglycemia with incident mild cognitive impairment (MCI) and incident dementia. RESEARCH DESIGN AND METHODS We conducted a prospective analysis of 5,099 participants from the Atherosclerosis Risk in Communities (ARIC) Study who attended the fifth (2011–2013) exam. Cognitive status was assessed during follow-up via telephone calls, death certificate codes, surveillance, and a follow-up examination (2016–2017). We defined incident cognitive impairment as incident MCI or incident dementia in persons dementia-free at the index examination; we also examined each outcome separately. Diabetes was defined using self-report, medications, or HbA1c ≥6.5%; poor glycemic control in persons with diabetes was defined as HbA1c ≥7%. We examined the following biomarkers of hyperglycemia: HbA1c, fructosamine, glycated albumin, and 1,5-anhydroglucitol. RESULTS Mean age at baseline was 76 years, 59% were female, and 21% were black. Diabetes (hazard ratio [HR] 1.14 [95% CI 1.00, 1.31]), poor glycemic control in persons with diabetes (HR 1.31 [95% CI 1.05, 1.63]), and longer diabetes duration (≥5 vs. <5 years; HR 1.59 [95% CI 1.23, 2.07]) were significantly associated with incident cognitive impairment. We found a J-shaped association between HbA1c and incident dementia. Glycated albumin and fructosamine were also associated with incident dementia, independently of HbA1c. HbA1c and fructosamine were also associated with incident MCI. CONCLUSIONS Diabetes status, poor glycemic control, and longer diabetes duration were associated with worse cognitive outcomes over a median follow-up of 5 years.

Purpose To evaluate for appearance-based discrimination in the selection of radiology residents. Method A deception study simulating the resident selection process examined the impact of attractiveness and obesity on resident selection. Seventy-four core faculty from 5 academic radiology departments reviewed mock residency applications in September and October 2017. Each application included demographic information and a photograph, representing a prespecified distribution of facial attractiveness and obesity, combined with randomized academic and supporting variables. Reviewers independently scored applications for interview desirability. Reviewer scores and application variables were compared using linear mixed fixed- and random-effects models. Results Reviewers evaluated 5,447 applications (mean: 74 applications per reviewer). United States Medical Licensing Examination Step 1 scores were the strongest predictor of reviewer rating (B = 0.35 [standard error (SE) = 0.029]). Applicant facial attractiveness strongly predicted rating (attractive vs unattractive, B = 0.30 [SE = 0.056]; neutral vs unattractive, B = 0.13 [SE = 0.028]). Less influential but still significant predictors included race/ethnicity (B = 0.25 [SE = 0.059]), preclinical class rank (B = 0.25 [SE = 0.040]), clinical clerkship grades (B = 0.23 [SE = 0.034]), Alpha Omega Alpha membership (B = 0.21 [SE = 0.032]), and obesity (vs not obese) (B = −0.14 [SE = 0.024]). Conclusions Findings provide preliminary evidence of discrimination against facially unattractive and obese applicants in radiology resident selection. Obesity and attractiveness were as influential in applicant selection for interview as traditional medical school performance metrics. Selection committees should invoke strategies to detect and manage appearance-based bias.

5518 Background: Platinum resistant ovarian cancer (OC) remains a therapeutic challenge. High grade serous OC (HGSOC) harbors TP53 mutations leading to increased dependency on S- and G2-phase checkpoints. Wee1 inhibition with Adavosertib (AZD 1775) (A) induces G2 checkpoint escape. Gemcitabine (G) is an antimetabolite therapy and blocks the progression of cells through the G1/S phase. We hypothesized that combining G+A would be synergistic and overcome resistance. Methods: We conducted a multicentre double-blind 2:1 randomized phase 2 trial to assess the progression free survival (PFS) in women with recurrent platinum-resistant/refractory HGSOC receiving G+A or G+placebo (P) (NCT02151292). Eligibility required measurable disease and feasibility of paired tumor biopsies; no limitation in prior lines of therapy. Non HGSOC histologic subtypes were enrolled in a separate non-randomized exploratory cohort. A/P was given orally at 175mg QD on D1-2, D8-9 and D15-16 with G 1000mg/m² IV D1, D8 and D15 in a 28-day cycle until progression or unacceptable AE. Tumor staging was scheduled every 8 weeks. TP53 mutations were analyzed on archival tissue with Sanger sequencing, TAm-Seq and IHC. TP53 mutation will be also assessed in circulating tumor DNA (ctDNA). Whole exome and RNA sequencing were performed on paired tumor tissues. Results: 124 patients (pts) with median of 3 prior lines of therapy (range 1-10) from 12 centres across Canada and US were enrolled between Sep 2014 to May 2018, with 99 pts randomized (65 in Arm G+A and 34 in G+P). 5 pts were ineligible; 64 pts have died. The median follow-up was 14.3 months. Main related AE was hematologic toxicity (Anemia G≥3: 31% in G+A vs 18% in G+P; Thrombocytopenia G≥3: 31% vs 6%; Neutropenia G≥3: 62% vs 30%). PFS was significantly improved from 3.0 to 4.6 months (HR 0.56 (95%CI: 0.35-0.90, p=0.015 Log rank). There was a significant improvement in overall survival (OS) from 7.2 to 11.5 months (HR 0.56 (95%CI: 0.34-0.92, P=0.022). Partial response by RECIST 1.1 was observed in 13 (21%) and 1 (3%) pts for Arms G+A and G+P, respectively (p=0.02). From the 25 pts in the exploratory cohort, 3 (12%) partial responses were observed. Final results will be reported at the meeting. Conclusion: Addition of adavosertib to gemcitabine in women with platinum resistant/refractory OC improved response rate, PFS and OS with manageable toxicity. Clinical trial information: NCT02151292.

PURPOSE Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.

AbstractWe describe two patients—both who underwent general anesthesia—in whom we theorize that hydraulic pressure on carotid artery baroreceptors resulted in transient asystolic cardiac arrest (TACA) during diagnostic or therapeutic procedures. Patient #1 was a 58‐year‐old female who experienced TACA in response to rapid injection of radiocontrast material into the carotid artery during diagnostic cerebral angiography. Her history was remarkable for aneurysmal subarachnoid hemorrhage at least 13 hr prior to angiography, radiographic evidence of intracranial hypertension, and baseline bradycardia, collectively suggestive of increases in baseline vagal tone. Potentially contributing to TACA, the patient had a 90° curve in the internal carotid artery, just distal to the carotid bifurcation and tip of the angiography catheter, that likely diminished runoff of injected contrast solution and, in turn, would have exacerbated any intracarotid pressure increases in response to injection. There was no evidence of increased baseline vagal tone in Patient #2, a 79‐year‐old female having carotid endarterectomy surgery. She experienced TACA immediately after full release of an occlusive clamp on the common carotid artery proximal to the now closed carotid arteriotomy, but while the internal carotid was still occluded. Of note, the carotid artery baroreceptors were not treated with local anesthetic in these patients, thus they should have retained much of their normal function. We describe the possible pathomechanisms involved in TACA in these patients, measures to diminish the likelihood of the phenomenon occurring in future patients, and methods for treating the asystole.

Metastatic pheochromocytoma and paraganglioma (PPGL) are incurable neuroendocrine tumors. The goals of treatment include palliating symptoms and reducing tumor burden. Little is known about the use of radiofrequency ablation (RFA), cryoablation (CRYO), and percutaneous ethanol injection (PEI) to treat metastatic PPGL. We performed a retrospective study of patients age 17 years and older with metastatic PPGL who were treated with ablative therapy at Mayo Clinic, USA, between June 14, 1999 and November 14, 2017. Our outcomes measures were radiographic response, procedure-related complications, and symptomatic improvement. Thirty-one patients with metastatic PPGL had 123 lesions treated during 42 RFA, 23 CRYO, and 4 PEI procedures. The median duration of follow-up was 60 months (range, 0–163 months) for non-deceased patients. Radiographic local control was achieved in 69/80 (86%) lesions. Improvement in metastasis-related pain or symptoms of catecholamine excess was achieved in 12/13 (92%) procedures. Thirty-three (67%) procedures had no known complications. Clavien-Dindo Grade I, II, IV, and V complications occurred after 7 (14%), 7 (14%), 1 (2%), and 1 (2%) of the procedures, respectively. In patients with metastatic PPGL, ablative therapy can effectively achieve local control and palliate symptoms.

TPS535 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, possibly because of the high rate of immunosurveillance in baseline small bowel function, and is frequently diagnosed in late stages. Due to these factors, there is no consistent standard of care for metastatic disease beyond first-line where several prospective studies have confirmed activity of FOLFOX/CAPOX. Historically, second-line treatment of SBA has been extrapolated from colon/gastric cancer. Recent studies suggest that SBA has a distinct genomic profile, including higher incidence of microsatellite instability, compared to gastric and colon cancers. Additionally, the tumor microenvironment reflects a greater degree of PD-L1 expression and infiltration by lymphocytes. Immune checkpoint inhibitors have not previously been tested in SBA unselected for MSI status. Methods: The study is a phase 2, multicenter, single-arm clinical trial of pembrolizumab (200 mg IV every 3 weeks) for patients with unresectable or metastatic SBA refractory to first-line chemotherapy. Forty patients with any tumor mismatch repair status will be enrolled at 8 US sites as part of the ACCRU network and International Rare Cancer Initiative (IRCI) with a primary objective to assess the confirmed response rate (H0 p < 10%, HA: p > 30%) to pembrolizumab. Secondary endpoints include PFS, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, MSI-H/MSS status, cfDNA, mutation burden, etc.) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 18 patients become evaluable. The study is open with 16 patients enrolled at time of submission. Clinical trial information: NCT02949219.