Citations

Background. Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. Methods. Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. Results. Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. Conclusions. Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.

3528 Background: CALGB 80405 is a phase III clinical trial of FOLFOX and FOLFIRI w/ randomly assigned cetuximab or bevacizumab. Novel machine learning approaches to the study dataset provide valuable insights into CRC prognosis and management of CRC progression. Methods: Using a Monte Carlo Bayesian Generalized Linear Model analytical platform, we built an ensemble of models for overall survival (OS). We used 99 baseline and demographic variables, including 1904 patients w/ 1o side and 949 w/ KRAS wild-type status. Building an ensemble of predictive models reduces risk of overfitting, estimates model uncertainty and identifies key variables by model consensus as measured by ensemble frequency (freq). We fit gender and 1o side (L vs R) stratum-specific models to examine differences in drivers of disease in those strata. Results: 1o side (avg Cox hazard ratio = 0.89, R side reference), ECOG performance status (1.30, reference level 0), AST concentration (1.01), peripheral neutrophil percentage (1.01) and local primary and abdominal site of disease indicators (1.22; 1.26) were key variables predictive of OS ( > 75% freq). In 1o side stratum-specific models, urine protein level (1.61), treatment intent (0.75, nonpalliative as reference) and hemoglobin concentration (0.85) were more associated w/ L side progression (freq > 85% in L stratum model, < 20% in R), while liver and lung sites of disease (2.3; 1.09) were more associated w/ R side progression (freq > 65% in R stratum model, < 20% in L). Predictors of 1o left-sidedness included age (avg log odds ratio = 0.02), hemoglobin (0.41), and abdominal (3.79) and liver (0.68) sites of disease. Modest differences in disease prognostic factors existed between genders: women more influenced by metastatic status, age, liver site of disease and creatinine level; men more influenced by urine protein level and prior diabetes. Conclusions: 1o side plays a central role in potentially explaining both variation in OS and differences in drivers of OS. Availability of these measures at baseline enables better sense of disease course at initiation of treatment. Support: U10CA180821, U10CA180882, Eli Lilly & Co., Genentech, Pfizer Clinical trial information: NCT00265850.

Abstract Background: Bioluminescence imaging (BLI) of firefly luciferase expressing cells is widely used for analysis of growth, metastasis and drug response in tumor xenografts. D-luciferin, a commonly used luciferase substrate, has limited brain distribution that may undermine BLI for intracranial xenografts. The synthetic luciferin cyclic alkylamino-luciferin (CycLuc1) is a purported brain penetrant luciferase substrate not yet tested in intracranial xenografts. We compared BLI with CycLuc1 and D-luciferin in a glioblastoma (GBM) xenograft model. Methods: GBM6 cells were lentivirally transduced to express LUC2=tdTomato fusion protein. In vivo BLI were performed in orthotopic and heterotopic xenografts established in athymic nude mice. Concentrations of D-luciferin and CycLuc1 were measured by LC-MS/MS. Results: In a dose-response analysis, CycLuc1 at 5 mg/kg provided robust and reproducible imaging; however, an increased photon flux was observed with 10 mg/kg, while escalation to 15 or 20 mg/kg provided marginal additional gains in photon flux. In comparison of CycLuc1 (5 or 25 mg/kg) and D-luciferin (30 or 150 mg/kg, respectively) with serial, crossover BLI at both dose levels, CycLuc1 resulted in less variability and significantly higher photon flux as compared to D-luciferin in GBM6 intracranial xenografts (15 days after implantation). On average BLI with 25 mg/kg CycLuc1 resulted in ~8 fold greater photon flux from these early-stage xenografts as compared to 150 mg/kg D-luciferin (2.9±0.6x106 vs. 3.3±2.8x105 p/sec/cm2, p&lt;0.001). Interestingly, bioluminescence emission with CycLuc1 and D-luciferin was comparable in xenografts imaged 28 days after implantation. In samples harvested after last imaging session, there was no significant difference in substrate distribution in intracranial tumors (tumor to plasma ratios for CycLuc1 and D-luciferin were 0.012 ± 0.020 and 0.012 ± 0.015, respectively; p=0.89). These results suggest that intracranial tumors at early stage may comprise relatively intact blood-brain barrier, which is disrupted at later stage. Consistent with notion that suboptimal delivery may interfere with D-luciferin mediated BLI in intracranial xenografts, photon flux in heterotopic tumors with D-luciferin or CycLuc1 was comparable (4.9±4.6x108 vs. 1.3±0.8x108 p/sec/cm2, p=0.10). Conclusions: These findings demonstrate that CycLuc1 may be a superior BLI substrate as compared to D-luciferin for monitoring tumor growth of intracranial GBM xenografts. Citation Format: Shiv K. Gupta, Minjee Kim, Bianca-Maria Marin, Lihong He, Katelyn Swanson, Tuma Tuma, Brett L. Carlson, Mark A. Schroeder, William F. Elmquist, Jann N. Sarkaria. Synthetic luciferin, CycLuc1, improves bioluminescence imaging for intracranial glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4112.

Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3‐bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen‐sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL , BPGM, EPOR , EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests. Review of our experience confirms a wide spectrum of alterations associated with erythrocytosis which we have correlated with phenotypic and clinical features. Through generic hemoglobinopathy testing, we have identified 762 patients with 81 distinct HOA Hb variants (61 β, 20 α), including 12 that were first identified by our laboratory. Of the 1192 cases received for an evaluation specific for hereditary erythrocytosis, approximately 12% had reportable alterations: 85 pathogenic/likely pathogenic mutations and 58 variants of unknown significance. Many have not been previously reported. Correlation with clinical and phenotypic data supports an algorithmic approach to guide economical evaluation; although, testing is expanded if the suspected causes are negative or of uncertain significance. Clinical features are similar and range from asymptomatic to recurrent headaches, fatigue, restless legs, chest pain, exertional dyspnea and thrombotic episodes. Many patients were chronically phlebotomized with reported relief of symptoms.

PurposeDespite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype—growth before treatment and during each treatment to recurrence —has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK.Patients and MethodsFrom our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment.ResultsThere was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%).ConclusionDichotomizing the heterogeneity of GBMs into two populations—one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival—suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Microglia are a major cellular component of gliomas, and abundant in the centre of the tumour and at the infiltrative margins. While glioma is a notoriously infiltrative disease, the dynamics of microglia and glioma migratory patterns have not been well characterized. To investigate the migratory behaviour of microglia and glioma cells at the infiltrative edge, we performed two-colour time-lapse fluorescence microscopy of brain slices generated from a platelet-derived growth factor-B (PDGFB)-driven rat model of glioma, in which glioma cells and microglia were each labelled with one of two different fluorescent markers. We used mathematical techniques to analyse glioma cells and microglia motility with both single cell tracking and particle image velocimetry (PIV). Our results show microglia motility is strongly correlated with the presence of glioma, while the correlation of the speeds of glioma cells and microglia was variable and weak. Additionally, we showed that microglia and glioma cells exhibit different types of diffusive migratory behaviour. Microglia movement fit a simple random walk, while glioma cell movement fits a super diffusion pattern. These results show that glioma cells stimulate microglia motility at the infiltrative margins, creating a correlation between the spatial distribution of glioma cells and the pattern of microglia motility.

Background. There is little published literature regarding the impact of age on outcomes amongst hospitalized HHT (hereditary hemorrhagic telangiectasia) patients. Methods. The Nationwide Inpatient Sample (NIS) was used to obtain data on all hospital discharges occurring in HHT patients from 2000 to 2012. The association between admission age and HHT-related complications and outcomes were studied. Results. 10293 hospitalizations in HHT patients from 2000 to 2012 were included. Patients > 50 accounted for 77% of all admissions with 30% of admissions occurring in the 51–65 age group. Bleeding related complications were the most frequent (62.7%, n=6455 hospitalizations), followed by cardiovascular (41%, n=4216), neurological (12.4%, n=1276), and hepatobiliary (6.4%, n=660) complications. Patients older than 50 accounted for 83% of bleeding events, 90% of cardiovascular events, 58% of neurologic events, and 81% of hepatobiliary events. The vast majority (83%) of medical and surgical procedures were performed in those older than 50 years of age. Older patients also experienced higher rates of death. Conclusion. Aging has significant adverse impacts on rates of hospitalization, complications, and outcomes amongst HHT patients in the United States. Except for neurologic complications, the vast majority of this disease burden is borne by patients older than 50 years.

AbstractBackground and AimOptimal rectal cancer (RC) outcomes depend on accurate locoregional staging. The study sought to describe the impact of endoscopic ultrasound (EUS) on RC treatment patterns and survival.MethodsUsing the Surveillance, Epidemiology, and End Results‐Medicare database, the study identified patients with RC between 2005 and 2007. The study excluded patients with stage IV disease, those not enrolled in Medicare parts A and B, those enrolled in managed care, and those staged with pelvic magnetic resonance imaging (because of low numbers). The study then compared outcomes between patients who received EUS and computed tomography of the abdomen and pelvis (CTAP) to those staged with CTAP alone after propensity score matching.ResultsBetween 2005 and 2007, we identified 3,408 nonmetastatic RC patients. Compared with patients staged with CTAP alone, those who received EUS and CTAP were younger (median age: 75 vs 76 years, P < 0.0001), more likely men (57.6% vs 48.7%, P < 0.0001), with a lower Charlson comorbidity index (P < 0.0001). Predictors of EUS included socioeconomic status (highest vs lowest) (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.4–2.5), care by a gastroenterologist (OR 1.713, 95% CI 1.38–2.13), and care in a teaching hospital (OR 1.68, 95% CI 1.35–2.08). Receipt of neoadjuvant chemoradiation was higher in EUS‐staged patients (50.3% vs 16.0%, P < 0.0001). EUS‐staged patients had longer overall survival compared with those staged with CTAP alone (60 vs 57 months), but this was not statistically significant (P = 0.24).ConclusionEndoscopic ultrasound in RC staging is associated with higher utilization of neoadjuvant chemoradiation without a significant difference in overall survival.