Citations

Background/aims: Some of the most promising avenues of cancer clinical investigation center on immunotherapeutic approaches. These approaches have provided notable gains in cancer therapeutics with recent Food and Drug Administration approvals of agents of this class in several types of cancers, although gains for ovarian cancer lag behind. This study examined perceptions of therapeutic trials including immunotherapy and virotherapy among ovarian cancer patients and their family members. Methods: A total of 72 semi-structured qualitative interviews were conducted with 33 patients and 39 family members at two National Cancer Institute–designated comprehensive cancer centers. Eligible patients were diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube carcinoma and had experience with clinical trial conversations; family members were nominated by patients and interviewed separately. Applied thematic analysis was used to understand and interpret the data. Results: More participants were aware of vaccine trials than virus trials, although more than half had heard of at least one of them. Initial reactions to vaccine trials were generally favorable. For many, childhood experience with vaccines lent a familiar frame of reference. Virus trials elicited more negative initial reactions, including the use of adjectives such as “scary” and “dreadful.” Viruses seemed contagious or difficult to control. Increased receptivity to these trials occurred in the context of limited therapeutic options and cancer recurrence. Most participants, including those not immediately drawn to these types of trials, indicated openness to learning more. Conclusion: Although vaccine and viral trials are both immunologically based therapeutic approaches, patients who are offered these trials may perceive their potential benefit and safety quite differently. There is a need to consider terminology, solicit and address “gut reactions,” and provide information that enables patients and their family members to better understand the science behind these trials.

Abstract Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of T-cell malignancies that generally demonstrate aggressive clinical behavior, often are refractory to standard therapy, and remain significantly understudied. The most common World Health Organization subtype is PTCL, not otherwise specified (NOS), essentially a “wastebasket” category because of inadequate understanding to assign cases to a more specific diagnostic entity. Identification of novel fusion genes has contributed significantly to improving the classification, biologic understanding, and therapeutic targeting of PTCLs. Here, we integrated mate-pair DNA and RNA next-generation sequencing to identify chromosomal rearrangements encoding expressed fusion transcripts in PTCL, NOS. Two of 11 cases had novel fusions involving VAV1, encoding a truncated form of the VAV1 guanine nucleotide exchange factor important in T-cell receptor signaling. Fluorescence in situ hybridization studies identified VAV1 rearrangements in 10 of 148 PTCLs (7%). These were observed exclusively in PTCL, NOS (11%) and anaplastic large cell lymphoma (11%). In vitro, ectopic expression of a VAV1 fusion promoted cell growth and migration in a RAC1-dependent manner. This growth was inhibited by azathioprine, a clinically available RAC1 inhibitor. We also identified novel kinase gene fusions, ITK-FER and IKZF2-ERBB4, as candidate therapeutic targets that show similarities to known recurrent oncogenic ITK-SYK fusions and ERBB4 transcript variants in PTCLs, respectively. Additional novel and potentially clinically relevant fusions also were discovered. Together, these findings identify VAV1 fusions as recurrent and targetable events in PTCLs and highlight the potential for clinical sequencing to guide individualized therapy approaches for this group of aggressive malignancies.

Abstract Background Therapeutic options for management of diabetic gastroparesis are limited. Failure to maintain upregulation of heme oxygenase ( HO 1) leads to loss of interstitial cells of Cajal and delayed gastric emptying ( GE ) in non‐obese diabetic mice. Our hypothesis was that hemin upregulation of HO 1 would restore normal GE in humans with gastroparesis. Aims To compare effects of hemin and placebo infusions on HO 1 activity and protein, GE , autonomic function, and gastrointestinal symptoms in diabetic gastroparesis. Methods In a single‐center, double‐blind, placebo‐controlled, randomized clinical trial, we compared intravenous hemin, prepared in albumin, or albumin alone (placebo) in 20 patients, aged 41 ± 5 ( SEM ) years with diabetic gastroparesis. After infusions on days 1, 3, and 7, weekly infusions were administered for 7 additional weeks. Assessments included blood tests for HO 1 protein and enzyme activity levels, GE with 13 C‐spirulina breath test, autonomic functions (baseline and end), and gastrointestinal symptoms every 2 weeks. Key Results Nine of 11 patients randomized to hemin completed all study procedures. Compared to placebo, hemin increased HO 1 protein on days 3 ( p = 0.0002) and 7 ( p = 0.008) and HO 1 activity on day 3 ( p = 0.0003) but not after. Gastric emptying, autonomic functions, and symptoms did not differ significantly in the hemin group relative to placebo. Conclusions & Inferences Hemin failed to sustain increased HO 1 levels beyond a week and did not improve GE or symptoms in diabetic gastroparesis. Further studies are necessary to ascertain whether more frequent hemin infusions or other drugs would have a more sustained effect on HO 1 and improve GE .

Endovascular Stimulation for Treatment of HypotensionBackgroundWe have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure.MethodsThe pre‐study protocol for endovascular stimulations included 2 minutes of stimulation (1–150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation.ResultsIn 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P < 0.0001), renal vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15–150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings.ConclusionsStimulation of intra‐abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research.

Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Abstract Background/Purpose: Cancer registry data suggests that Duval County (greater Jacksonville, FL) has the highest breast cancer mortality rate for African American (AA) women in the southeastern US. Recent research revealed that race, residence, and insurance were associated with significantly poorer breast cancer outcomes in this area. Therefore we conducted a series of focus groups with AA breast cancer survivors from the urban core of Jacksonville, FL to directly address the disparities observed in our quantitative data. Methods: A series of focus groups were conducted to obtain qualitative data topics that included: breast cancer beliefs; delays to diagnosis and treatment; disparities; and health behaviors. Results: A total of 56 AA breast cancer survivors living in the urban core, with either Medicaid or who were uninsured, participated in the focus groups. Mean age was 62 years, with an average of 3.4 years since diagnosis. Only 21% of women were employed. Participants reported their mean time to see a doctor initially for their breast cancer was 39 days, and mean time to first treatment was 178 days. Participants responded that fear, financial limitations, and personal beliefs played the biggest roles in delays to diagnosis and treatment. Participants responded that poor health behaviors, genetics, lack of education, and personal beliefs accounted for both causing breast cancer, and the disparities observed in breast cancer mortality, and felt that environmental factors from living in the urban core also contribute. Conclusions: Our findings highlight several areas for potential intervention to reduce disparities in breast cancer. Citation Format: Sarah Osian, Monica Albertie, David Monticalvo, Steven Ames, Laila Samiian, Gerardo Colon-Otero. Examining reasons for breast cancer disparities in African American women in Duval County, FL. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C06.