Citations

14118 Background: Triapine is a small molecule iron chelator that has been shown to inhibit ribonucleotide reductase (RR) at the M2 subunit. Early trials suggested activity in pancreatic cancer. The P2C initiated a study of single agent Triapine as both first-line therapy and for pts with gemcitabine-refractory disease. Correlatives included: pharmacokinetics, MDR polymorphisms, and the effects of Triapine on cell cycle and electron paramagnetic resonance spectroscopy (EPR). Methods: Standard eligibility criteria were used, however, pts with G6PD deficiency were excluded. Triapine was given 96 mg/m2 IV over 2 hours, days 1–4 and 15–18, repeated q 28 days. Primary goals - evaluate survival (S) at 6 mos (previously untreated pts) and 4 mos (refractory pts). Interim analyses were planned when 28 previously untreated and 20 refractory pts were enrolled. Results: 14 eligible pts were enrolled in 10 mos (13 refractory, 9 male). The previously untreated pt received only 1 cycle secondary to progressive disease. Of the 13 refractory pts, 7 pts received at most 2 cycles; 6 received 1. Disease progression precluded further treatment in 11 pts. 6 pts had Gr 4 toxicities at least possibly related to drug, including: neutropenia-4, hyperkalemia-1, hyponatremia-1, leukopenia-1, thrombocytopenia-1, hypophosphatemia-1. 6 pts had a Gr 3 fatigue. One refractory patient expired on study. No responses were seen. Estimated 4 mos S in refractory pts is 16% (95% CI 3–94). EPR studies showed that Triapine led to a loss of the RR tyrosine radical EPR signal. Conclusions: Enrollment was suspended due to excess toxicity and lack of activity in pts refractory to gemcitabine. Correlative studies confirm the mechanism of action of Triapine as a chelating agent on RR. Supported by NCI Grant N01 CM17104 and the NCI Translational Research Fund. No significant financial relationships to disclose.

5534 Purpose: A number of patients with advanced/recurrent cervical cancer do not respond to cisplatin-based chemotherapy. A pool analysis of three published phase III GOG studies was undertaken to identify the predictive factors and develop a model predictive of (non-) response to chemotherapy. Methods: The study population consisted of patients who received single-agent cisplatin or a cisplatin-containing combination in GOG protocols 110, 169 and 179. Prognostic variables (age, race, performance status, stage, histology, grade, disease site, prior chemotherapy—with primary radiation, time to recurrence, single-agent versus combination) were analyzed and multivariate analysis was conducted to identify factors independently predictive of response and survival. These analyses were used to establish a predictive model. Results: 816 patients were evaluable for response. In addition to single-agent treatment, multivariate analysis identified six factors (age, African-American, PS > 0, pelvic disease, prior radiosensitizer, recurrence ≤ one year) independently predictive of poor response. Those factors, but not age and African-American, were also independently associated with increased risk of death. 428 patients treated with a cisplatin- containing combination were classified into three risk groups based on the total number of risk factors (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors). Patients with 4–5 of risk factors were predicted to have a treatment response of only 13% (observed 10%), and median progression-free and overall survival of PFS of 2.8 months and 5.5 months, respectively. This subgroup of patients consist ∼14% of the target population in clinical practice. The predictive model was externally validated using GOG protocol 149 data that were not used for model development and further supported the predictive accuracy. Conclusions: High risk patients should be directed to non-cisplatin chemotherapy or investigational trials. No significant financial relationships to disclose.

Abstract Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line. Conclusions: This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

Moyamoya angiopathy is a rare cerebral vasculopathy characterized by a progressive stenosis of the terminal portion of the internal carotid arteries and the development of abnormal collateral vessels. Children with moyamoya angiopathy become symptomatic because of cerebral ischemic complications, and many patients eventually need revascularization. In most pediatric patients with this disease, the etiology is likely genetic. We aim to report clinical characteristics of a single-center cohort of pediatric patients with moyamoya. We performed a retrospective chart review of patients <18 years with angiographically confirmed moyamoya disease evaluated at our institution. An in-house text search tool, Advanced Cohort Explorer, was used to filter electronic medical records for patients with a diagnosis of moyamoya angiopathy from January 1999 to December 2018. The inclusion criteria were age <18 years at the time of onset of disease and a diagnosis confirmed at Mayo clinic. Fifty-one patients met the inclusion criteria. Fifty-five percent of our cohort were male, and the median age was 9 years. Three patients had a family history of moyamoya disease. Approximately half of our patients had bilateral disease. Sixteen patients had a genetic or chromosomal diagnosis (Down syndrome and NF1 being most common). Congenital anomalies like heart defects and renal dysplasia were also noted. This study is unique in that it was a large study on pediatric patients with moyamoya angiopathy. It also highlights the importance of considering genetic syndromes as an underlying cause when moyamoya angiopathy starts early in life.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

Abstract Aims To determine the prevalence and in vitro electrophysiological (EP) phenotype of ultra-rare SCN5A variants of uncertain significance (VUS) identified in unexplained sudden cardiac arrest (SCA) survivors. Methods and results Retrospective review of 73 unexplained SCA survivors was used to identify all patients that underwent a form of genetic testing that included comprehensive SCN5A analysis. Ultra-rare SCN5A variants (minor allele frequency &lt; 0.005) were adjudicated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Variants designated as VUS were expressed heterologously and characterized using the whole-cell patch clamp technique. Overall, 60/73 (82%; the average age at SCA 28 ± 12 years) unexplained SCA survivors had received SCN5A genetic testing. Of these, 5/60 (8.3%) had an ultra-rare SCN5A variant. All SCN5A variants were classified as VUS. Whereas the single SCN5A VUS (p.Asp872Asn-SCN5A) identified in an unexplained SCA survivor with PR interval prolongation and inferior early repolarization conferred a loss-of-function phenotype (46.2% reduction in peak current density; 16 ms slower recovery from inactivation), the four other SCN5A VUS (p.Glu30Gly-SCN5A, p.Gln245Lys-SCN5A, p.Pro648Leu-SCN5A, and p.Glu1240Gln-SCN5A) identified in unexplained SCA survivors without early repolarization/conduction delay were indistinguishable from wild-type Nav1.5 channels. Conclusion In the absence of a phenotype(s) potentially attributable to sodium channel dysfunction, all SCN5A VUS identified in unexplained SCA survivors conferred a wild-type EP phenotype in vitro. As the background rate of SCN5A genetic variation is not trivial, great care must be taken to avoid prioritizing genotype over phenotype when attempting to ascertain the root cause of an individual's SCA.

AbstractBackgroundThe 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN).MethodsThe summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience.ResultsThe current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence‐based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω‐3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation.ConclusionsThis article provides a set of expert consensus statements to complement formal PN guideline recommendations.

480 Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival >1 year. For surgical patients, treatment response was defined as <50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value <0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p<0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.

Stem cell treatment outside of studied and approved medical indications can have unforeseen adverse consequences. Here, we present a 74-year-old male that underwent such therapy. The patient presented to our institution with progressive lower extremity weakness and urinary incontinence. He had previously undergone intrathecal stem cell therapy in Moscow, Russia for weakness and fatigue. Magnetic resonance imaging of his thoracic and lumbar spine showed marked enlargement of the cauda equina nerve roots and abnormal mass-like soft tissue involving the thoracolumbar thecal sac. Surgical biopsy of the intrathecal soft tissue showed polyclonal lymphocytic and glial cell proliferation. The patient’s symptoms did not improve with medical treatment or radiation, and he is currently under observation after multidisciplinary evaluation. Our patient’s experience illustrates one of the potential risks of “stem cell tourism” and exemplifies the imaging and histopathologic features of this rare entity. We also compare our patient’s treatment with other similar examples of stem cell treatments in our institution and others. These have had a wide spectrum of results. In some instances, intrathecal stem cells have caused abnormal imaging findings without any associated patient symptoms. In extreme examples, however, stem cell treatments have resulted in central nervous system neoplasms. Our patient’s lesion is quite unique, with only one similar lesion having been previously published.