Citations

Hepatocellular adenomas (HCAs) often pursue an innocuous clinical course. Recent work has elucidated important subtypes of HCA and biomarkers to identify them, including HCA at an increased risk for malignant transformation. Another key complication of HCAs is the risk of spontaneous tumoral hemorrhage, which may be life-threatening. Identification of a predictive biomarker for this clinical complication would therefore be of clinical value. It has been suggested that Argininosuccinate Synthase 1 (ASS1) immunohistochemistry (IHC) identifies HCA with a high propensity for hemorrhage. The aim of our study was to validate ASS1 IHC as a predictive marker of hemorrhage. Eighty-nine HCAs were collected for ASS1 IHC and subtyped according to published criteria. Clinical records were examined for evidence of tumoral hemorrhage. Twenty-one (23.6%) HCAs were complicated by clinically detected hemorrhage and were more likely to be resected (P=0.0002). Hemorrhage complicated all WHO subtypes of HCA. There was no association between hemorrhage and HCA subtype (P=0.92). Neither the distribution of ASS1 expression nor the intensity of ASS1 expression compared to normal liver showed a significant association with hemorrhage (P=0.051 and 0.34). Interlaboratory comparison of 8 cases showed good agreement regarding the intensity (6/8 and 7/8) and distribution of staining (7/8 and 7/8) across 3 laboratories performing ASS1 IHC. In conclusion, all subtypes of HCA may be complicated by hemorrhage. ASS1 IHC expression did not correlate with hemorrhagic complications. Caution is prudent before routine implementation of ASS1 IHC in clinical practice.

AbstractObjectivesLong-term follow-up is important for determining performance characteristics of thyroid fine-needle aspiration (FNA).MethodsHistologic or 3 or more years of clinical follow-up was used to calculate performance characteristics of thyroid FNA before and after implementation of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) classification was also investigated.ResultsFollow-up was obtained for 1,277/1,134 and 1,616/1,393 aspirates/patients (median clinical follow-up, 9.9 and 4.4 years, pre- and post-TBSRTC, respectively). Nondiagnostic, suspicious for follicular neoplasm, and suspicious for malignancy (SFM) diagnoses decreased and benign diagnoses increased post-TBSRTC, while atypical rate remained less than 1%. Negative predictive value for benign nodules and positive predictive value (PPV) for SFM increased significantly. Eleven nodules were reclassified as NIFTP, slightly decreasing PPV/risk of malignancy (ROM).ConclusionsAppropriate ROM for thyroid FNA can be achieved through application of TBSRTC terminology with minimal use of atypical category.

Background: Aiming at fostering local development of cardiology and cardiovascular surgery centers in developing countries, the nonprofit organization Children’s HeartLink (CHL) encourages centers to participate in the International Quality Improvement Collaborative Database for Congenital Heart Disease (IQIC). The definition of parameters and data to evaluate patient treatment provides an opportunity to improve quality of care, reducing morbidity and mortality. The objective of the study was to analyze the outcomes of the partnership between CHL and IQIC database with a single pediatric cardiology and cardiovascular surgery center for seven years providing continuous follow-up to guide actions aiming at morbidity and mortality reduction in patients with pediatric and congenital heart diseases. Methods: Data were collected from January 2011 to December 2017 independently and with external audits and included preoperative information (demographic data, nutritional status, chromosomal abnormalities), Risk Adjustment for Congenital Heart Surgery (RACHS-1) score, and postoperative information such as infections or complications within the first 30 days or until hospital discharge and/or death. Results: In the preoperative period, there was a trend toward an increase in the number of newborn patients. The postoperative period showed significant surgical procedure variations between groups for RACHS-1 risk category ( P = .003), prevalence of risk categories 2 and 3, and an increase in risk categories 4, 5, and 6, mainly in the last two years. Decreases in surgical site infection ( P = .03), bacterial sepsis, and other infections (both P < .001) were observed. At the 30-day postoperative follow-up, there was a decrease of in-hospital ( P = .16) and 30-day ( P = .14) mortality. Conclusion: The partnership between CHL and this seven-year analysis of IQIC database demonstrated structural and human flaws, whose resolution led to significant decrease in infection and reduction in mortality despite an increase in the complexity of our pediatric and congenital heart disease population.

Abstract Endocrine based therapy is the standard treatment for estrogen receptor positive (ER+) MBC. Agents targeting the ER pathway including aromatase inhibitors (AIs), fulvestrant and tamoxifen along with CDK 4/6 inhibitors are considered standard for first and 2nd line treatment. However, endocrine resistance develops in nearly all patients and the optimal systemic therapy after progression on a CDK 4/6 inhibitor is unknown. Lasofoxifene is a third generation SERM previously investigated for the treatment of osteoporosis and vulvo-vaginal atrophy (VVA). In a large phase 3 trial evaluating the efficacy of lasofoxifene for the postmenopausal treatment of osteoporosis, lasofoxifene significantly reduced the incidence of ER+ breast cancer. Further unpublished preclinical data have demonstrated significant in vitro and in vivo efficacy in non-clinical breast cancer models including models with and without ESR1 mutants. Moreover, lasofoxifene significantly reduced metastases in ESR1 mutated models. These non-clinical and clinical data provide a strong rationale to pursue a phase 2 clinical trial in women with ER+, ESR1 mutated MBC. This open-label, multi-center study will compare the efficacy and tolerability of lasofoxifene (5 mg orally daily) to fulvestrant (IM 500 mg D1,15,29 and then q30 D) in a 1:1 randomization. Inclusion criteria include postmenopausal women with ER+ advanced breast cancer; progression on a non-steroidal AI in combination with a CDK 4/6 inhibitor; and a known ESR1 mutation. Approximately 90 patients with measurable or evaluable disease (i.e. bone only) will be recruited to have at least 40 patients per treatment arm. The primary endpoint will be progression free survival (PFS) with secondary endpoints of objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR) and time to response (TTR). It is assumed that lasofoxifene will double the median PFS compared to fulvestrant in this ESR1 mutation patient population for a hazard ratio 0.5 and a power of 89% to reach a 1-sided p of &lt;0.05. The study will commence in 4Q2018 and will complete recruitment in 1 year. It is anticipated that 25-30 centers in the US will be participating. Citation Format: Plourde PV, Schwartzberg LS, Greene GL, Portman DJ, Komm BS, Jenkins SN, Liu P-Y, Portman MD, Goetz MP. An open-label, randomized, multi-center phase 2 study evaluating the activity of lasofoxifene relative to fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic ER+/HER2 - breast cancer (MBC) with an ESR1 mutation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-02.

In 2011, we initiated a sentinel surveillance network to assess changes in Clostridioides (formerly Clostridium ) difficile antimicrobial susceptibility to fidaxomicin from 6 geographically dispersed medical centers in the United States. This report summarizes data from 2013 to 2016. C. difficile isolates or toxin-positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution. CLSI, EUCAST, or FDA breakpoints were used, where applicable.

Abstract Aim: We aimed to develop a comprehensive Colorectal cancer Risk Prediction Tool (CRiPT). To achieve this, it is necessary to incorporate germline mutations in the DNA mismatch repair genes and MUTYH to account for a proportion of the familial aggregation of colorectal cancer. Population prevalence of these mutations and the genetic and environmental causes of the remaining familial aggregation, however, are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the USA, Canada and Australia, and screened probands for mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and MUTYH. We fitted modified segregation analysis models to the cancer history of first-degree relatives, conditional on the age at diagnosis of the proband, using the software MENDEL. We determined the genetic model that best explained the familial aggregation of colorectal cancer by estimating the prevalence of mutations in the known susceptibility genes, the prevalence of and hazard ratio for unmeasured high-risk gene mutations, and the variance of the unmeasured polygenic component, using a χ2 goodness-of-fit test. Results: The best fitting model was a mixed dominant model with the polygenic standard deviation varying by age. Under that model, we estimated 1 in 279 of the population carry mutations in the mismatch repair genes (MLH = 1 in 1946, MSH2 = 1 in 2841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations in unknown major gene(s) which are associated with on average a 31-fold increased risk of colorectal cancer. The estimated variance of the polygenic component decreased from 1.8 for age &lt;40 years to 0.7 for age ≥70 years (equivalent to a sibling relative risk of 5.1 and 1.3, respectively). There was good internal consistency in the best fitting model; i.e., predicted and observed numbers were close. Conclusion: CRiPT is a comprehensive prediction model that incorporates both known and unknown major genes and polygenes. CRiPT can provide the probabilities of having a mutation in a DNA mismatch repair gene or MUTYH as well as estimate future risk (e.g., 5-year risk) of developing colorectal cancer. This model is similar to the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) that calculates for women the probabilities of carrying a BRCA1 or BRCA2 mutation and their future risk of developing breast and ovarian cancer based on their family history. Further work will include measured environmental factors and genetic variants to CRiPT, and it will be useful for genetic counselling and targeted colorectal cancer screening in clinical practices. This abstract is also being presented as Poster B04. Citation Format: Aung Ko Win, Mark A. Jenkins, James G. Dowty, Antonis C. Antoniou, Andrew Lee, Yingye Zheng, Noralane M. Lindor, Polly A. Newcomb, John L. Hopper, Robert J. MacInnis. Development of a comprehensive colorectal cancer risk prediction tool (CRiPT) incorporating known and unknown major genes and polygenes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR10.

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR10) of the Conference Proceedings. Citation Format: Aung Ko Win, Mark A. Jenkins, James G. Dowty, Antonis C. Antoniou, Andrew Lee, Yingye Zheng, Noralane M. Lindor, Polly A. Newcomb, John L. Hopper, Robert J. MacInnis. Development of a comprehensive colorectal cancer risk prediction tool (CRiPT) incorporating known and unknown major genes and polygenes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B04.

Glioma incidence is highest in non‐Hispanic Whites, and to date, glioma genome‐wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case–Control Study and GliomaSE Case–Control Study previously estimated to have <80% EA, or self‐identify as non‐White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR ≥0.4 ), and ≥15% NAA (AMR ≥0.15 ), genome‐wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10 −4 ; 11p11.12, p = 7.0 × 10 −4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR ≥0.4 . In addition, we identified a peak at rs1620291 ( p = 4.36 × 10 −6 ) in 7q21.3. Among AMR ≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10 −4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10 −4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

AbstractBackgroundThe military use of ketamine is well established. The benefits of prehospital civilian use have not been extensively reported.MethodsA retrospective review was performed of patients with prehospital ketamine use in Mayo One’s air and critical care ground transport.ResultsThe medical records were reviewed from 2014 to 2016 to assess the efficacy of Ketamine. During this time frame, 158 (167 instances) patients were treated with ketamine for analgesia (38%), sedation (44%), or procedural (18%) use. The patient population had a mean age of 49 (range: 1–100), with 105 (67%) male patients. Indications included trauma (69%), which was further broken down into blunt (57%), penetrating (4%), and miscellaneous (8%), and medical illness (31%). The mean ketamine dose was 52.6 mg (range: 5–200 mg) via intravenous route. Ketamine was utilized in 61% of patients after other medications were ineffective. Overall success rate was 98%. Mean pain scale before and after ketamine use was 9/10 and 3/10, respectively. Ketamine use increased yearly from 21 (13%) in 2014, 56 (36%) in 2015, and 81 (51%) in 2016.ConclusionPrehospital ketamine use is effective alone or in conjunction with other medications for analgesia, sedation, and procedural use in trauma and critically ill patients with minimal hemodynamic and respiratory consequences.