Citations

93 Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.

AbstractBackgroundConflicting data have been published on whether an association exists between atopic dermatitis (AD) and nonmelanoma skin cancer. This study aimed to determine whether individuals with AD had an increased risk of squamous cell carcinoma (SCC) development.MethodsWe conducted a retrospective, case–control study of patients residing in Olmsted County, Minnesota. Cases were selected from patients seen at Mayo Clinic (Rochester, Minnesota) who had an initial SCC diagnosis (either invasive SCC or SCC in situ) from January 1, 1996, through December 23, 2010. Age‐ and sex‐matched controls were selected from patients seen at Mayo Clinic with no history of SCC before the case event date.ResultsThree hundred ninety‐nine individuals with a documented history of SCC were identified and matched with 780 controls who did not have a history of SCC. After adjusting for race, smoking history, ionizing radiation exposure, corticosteroid and cyclosporine use, and non‐SCC skin cancers, the odds ratio for SCC development between patients with history of AD versus patients without history of AD was 1.75 (95% CI, 1.05–2.93).ConclusionsOur findings support an increased risk of SCC development in the setting of AD.

AbstractBackground/ObjectivesPediatricians manage skin conditions such as atopic dermatitis (AD) but report that their dermatologic training is inadequate. Online modules may enhance medical education when sufficient didactic or clinical teaching experiences are lacking. We assessed whether an online module about AD improved pediatric residents’ knowledge and changed their clinical management of AD.MethodsTarget and control cohorts of pediatric residents from two institutions were recruited. Target subjects took a 30‐question test about AD early in their residency, reviewed the online module, and repeated the test 6 months and 1 year later. The control subjects, who had 1 year of clinical experience but had not reviewed the online module, also took the test. The mean percentage of correct answers was calculated and compared using two‐sided, two‐sample independent t tests and repeated‐measures analysis of variance. For a subset of participants, clinical documentation from AD encounters was reviewed and 13 practice behaviors were compared using the Fisher exact test.ResultsTwenty‐five subjects in the target cohort and 29 subjects in the control cohort completed the study. The target cohort improved from 18.0 ± 3.2 to 23.4 ± 3.4 correctly answered questions over 1 year (P < .001). This final value was greater than that of the control cohort (20.7 ± 4.5; P = .01). Meaningful differences in practice behaviors were not seen.ConclusionPediatric residents who reviewed an online module about AD demonstrated statistically significant improvement in disease‐specific knowledge over time and had statistically significantly higher scores than controls. Online dermatology education may effectively supplement traditional clinical teaching.

BackgroundIt is widely assumed that the amount of alcohol in the blood reflects the amount of alcohol consumed. However, several factors in addition to amount of alcohol consumed can influence blood alcohol concentration (BAC). This study examines the effect of alcohol dose, concentration, and volume onBACin rats with a high‐alcohol‐drinking (HAD) phenotype.MethodsStudy 1 examined the relationship between the amount of alcohol consumed andBAC. Alcohol‐naïve, male,HADrats (N = 7) were given access to alcohol for 2 h/d for 9 consecutive days with food and water ad libitum. Alcohol intake andBACwere measured at 30, 60, and 90 minutes after onset of access. Study 2 examined the effects of altering alcohol dose, concentration, and volume onBAC(as measured by area under the curve). Alcohol‐naïve, male,HADrats (N = 39) were infused, via an intragastric cannulus, with 1.16, 2.44, or 3.38 g alcohol/kg body weight (BW), produced by varying alcohol volume while holding concentration constant or by holding volume constant while varying concentration. Other rats were infused with 10, 15, or 20% v/v alcohol solutions while holding dose constant.ResultsBACwas more strongly correlated with the ratio of alcohol intake (g/kgBW) to total fluid intake (mls) (R = 0.85 to 0.97,p < 0.05 top < 0.001) than it was with the amount of alcohol consumed (g/kgBW) (R = 0.70 to 0.81,p < 0.05). No effect of alcohol dose was seen during the first hour following the onset of an alcohol infusion regardless of whether dose was achieved by altering alcohol volume or concentration. After 1 hour, higher alcohol doses were predictive of greaterBACs.ConclusionsThe fact that a 3‐fold difference in alcohol dose did not result in significant differences inBACs during the first 30 minutes after ingestion of alcohol has potentially important implications for interpretation of studies that measure alcohol‐sensitive end points during this time.

The Institute of Medicine and US Food and Drug Administration (FDA) recognize that activating clinical trials in the United States is lengthy and inefficient. Downstream consequences include increased expense, suboptimal accrual, move of clinical trials overseas, and delayed availability of treatments for patients. An in‐tandem processing initiative is here highlighted that transformed the activation of clinical trials (TACT), reduced the activation time by 70%, and offers a paradigm for enhanced translational readiness.

Objectives: To characterize the burden of seizure clusters (SC) on patients and caregivers, a large internet-based survey was conducted. Methods: The Seizure Cluster Burden of Illness US Survey was conducted online by Harris Poll on behalf of The Epilepsy Foundation in September 2014. Respondents included adult patients 18 years and above with epilepsy or a seizure disorder who had experienced SC in the past year (defined as ≥2 seizures within 24 h outside the patient’s typical seizure pattern), caregivers providing current care for a patient with SC (adult or child), and clinicians (neurologists, epileptologists) who treat adult or pediatric patients. Responses to a wide range of topics, including emotional well-being, daily function, productivity, and approach to clinical practice, were collected. Results: There were 861 respondents (259 adult SC patients, 263 caregivers, and 339 clinicians). A majority of all respondent groups felt SC have a moderate/major negative impact on patient and caregiver quality of life, including emotional, financial, and social components. Responses indicated possible overutilization of emergency room services and underutilization of rescue treatment. Only 30% of patients reported having a seizure emergency plan. Some responses showed discrepancies between clinicians and patients/caregivers in the perceived degree of negative impact of SC and management practices for SC. Conclusions: These results suggest the need for increased education on managing SC. Clinicians need to develop seizure emergency plans and discuss rescue therapies, whereas patients and caregivers need to ask for and utilize these management strategies.