Citations

ObjectivesPrior analysis at our institution found that patients with hypertrophic cardiomyopathy (HCM) who experience postprandial symptoms (PPS) are more likely to have resting left ventricular outflow tract (LVOT) obstruction and reduced quality of life. Our objective was to determine whether PPS in patients with HCM vs healthy subjects occur as a result of measurable hemodynamic alterations in the postprandial hemodynamic response.MethodsWe conducted a prospective cross‐sectional study examining 45 patients with HCM and 10 controls who underwent fasting and postprandial 2‐dimensional Doppler echocardiography. Postprandial echocardiographic measurements were obtained at symptom onset or 30 minutes after consumption of a standardized meal, whichever occurred first.ResultsThe HCM population included 18 (40%) patients with PPS and 27 (60%) without PPS. Compared to controls, mean resting peak LVOT gradient was 23.4 ± 17.6 mmHg in HCM patients with PPS and 25.1 ± 33.1 mmHg in those without PPS (P = 0.10). The mean change in peak LVOT gradient after a meal was 0.7 ± 1.1 mmHg for controls, 5.0 ± 8.3 mmHg for HCM patients with PPS, and 1.5 ± 18.2 mmHg for HCM patients without PPS (P = 0.64).ConclusionAlthough the ability to provoke an increased LVOT gradient with a postprandial, upright exercise study protocol was recently reported, the current study suggests that a resting, supine, postprandial protocol does not elicit evidence of LVOT obstruction. Therefore, future investigations should consider whether simply performing an upright postprandial study in HCM patients with PPS will provide evidence of dynamic LVOT or if the addition of an exercise component is necessary.

Abstract The incidence of multiple myeloma (MM) is twice as high in blacks compared with whites. MM consists of several different cytogenetic subtypes, with differing presentations, response to therapy, and prognosis. The studies that have characterized the distribution of the primary cytogenetic abnormalities by fluorescence in-situ hybridization (FISH) testing have been primarily conducted in white populations, and more data are needed on whether the distribution of these cytogenetic abnormalities differs in black compared with white MM patients, and to determine if the increased prevalence of MM in blacks is related to specific subtypes of the disease. In this multi-center study, we examined four common clinically assessed cytogenetic subtypes (t(11;14), t(4;14), del13q, and del17p) at time of MM diagnosis in 245 black patients from 3 clinics who had prior FISH testing available in medical records. We compared the prevalence of these subtypes with our previously characterized Mayo Clinic cohort which was all Caucasian (n=484). The t(11;14) translocation was seen in 9 of 245 (4%) black patients with MM; this was significantly lower than the rate of t(11;14) translocations seen in white patients from Mayo Clinic (18%), p < 0.0001). In contrast to t(11;14), the prevalence of the t(4;14) translocation across the two groups was similar (p= 0.92). We conclude that the prevalence of t(11;14) translocation is significantly lower in blacks with myeloma compared with whites. Our findings suggest that the distribution of cytogenetic subtypes found in MM may differ significantly by race, and further studies assessing differences in the prevalence of other primary cytogenetic abnormalities such as trisomies, t(6;14), t(14;16), and t(14;20) are needed. Furthermore, these results support the hypothesis previously put forth that there are several different subtypes of multiple myeloma that may be defined by the major cytogenetic translocations. Since these results differ from those previously reported (Baker et al 2013, Blood), we are conducting further analyses of these data to examine possible factors that could account for the differential association of translocation by race, including probes used. Citation Format: Alexandra Joelle Greenberg, Sunita Philip, Agne Paner, Sylvia Velinova, Ashraf Badros, Rosalind Catchatorian, Dirk Larson, Rhett Ketterling, Robert A. Kyle, Shaji Kumar, Celine M. Vachon, S. Vincent Rajkumar. Evidence of decreased prevalence of the t(11;14) translocation in black patients with multiple myeloma: A multi-center study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 272. doi:10.1158/1538-7445.AM2014-272

Abstract Immunotherapy has proven to be a successful treatment approach for some cancer patients. One promising paradigm in immunotherapy is targeting pathogen-associated molecule pattern receptors (PAMPS) such as the toll-like receptors (TLRs) to activate the innate immune system and enhance the development of tumor-directed adaptive immune responses. However, an ongoing concern in the application of immunotherapeutics is the potential for the immune response in cancer patients to be less robust than in healthy individuals, due to the underlying advanced neoplastic disease or due to previous regimens of cytotoxic drugs. To address this concern in relation to the response to TLR8 stimulation, we compared the pharmacokinetic and pharmacodynamic (PK/PD) relationship defined in a phase 1 clinical trial of the selective small molecule TLR8 agonist VTX-2337 in oncology patients to the response in healthy volunteers. A phase 1 dose-escalation clinical trial (A101) in subjects with advanced solid tumors (n=33) demonstrated that plasma levels of multiple biomarkers of immune activation, including G-CSF, MCP-1, MIP1-β and TNFα, increased in a dose-dependent manner and correlated with increasing plasma levels of VTX-2337. The PK/PD relationship defined in the initial clinical trial was closely aligned with predictions from both in vitro assays and preclinical studies conducted in cynomolgus monkeys. A subsequent phase 1 trial (A105) was conducted as a single-center, open-label, two-period, randomized, crossover, phase 1 study in normal volunteers (n=10). The objective of this study was to compare the PK/PD profiles and local tolerance of two formulations of VTX-2337. In this study, the two preparations of VTX-2337 demonstrated comparable PK profiles and PD responses. At comparable dose levels, the PK profile and overall exposure (AUC) to VTX-2337 was similar for oncology patients and healthy volunteers. VTX-2337 induced the same repertoire of circulating cytokines and chemokines, indicative of TLR8 activation, in both populations. The magnitude of the mediator response in oncology patients was also highly comparable to the response in healthy volunteers that received a similar dose. This comparison demonstrates that the immune system of cancer patients with advanced disease remains highly responsive to TLR8 activation by VTX-2337. In summary, advanced neoplastic disease or a prior treatment history with cytotoxic agents that can negatively impact immune cell function did not appear to moderate the response to VTX-2337 based on the PK/PD relationship using predictive biomarkers. Citation Format: Greg Dietsch, Donald Northfelt, Ramesh Ramanathan, Peter Cohen, Kristi Manjarrez, Mona Newkirk, James Kyle Bryan, Robert Hershberg. Immune modulation by the TLR8 agonist VTX-2337; a comparison of the pharmacodynamic response in cancer patients and healthy volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2540. doi:10.1158/1538-7445.AM2014-2540

The Food and Drug Administration recently approved topiramate for migraine prevention in adolescents. Given the well-established appetite-suppressant side effects of topiramate, as well as data suggesting a potential comorbidity between migraine and eating disorders, susceptible young migraine patients may be at a greater risk for the development or worsening of eating disorder symptoms with topiramate therapy. This case series comprises 7 adolescent patients in whom serious eating disorders developed or were exacerbated after the initiation of topiramate therapy. Clinical characteristics of these patients are highlighted. In addition, this case series provides guidelines for providers to use in assessing eating disorders before prescribing topiramate for migraine prevention in adolescents.

The use of soluble cardiac biomarkers such as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and troponin has revolutionized prognostication for patients with AL amyloidosis. Soluble ST2 (sST2) and galectin‐3 have also been reported to have prognostic value in other cardiac patient populations. We identified 502 patients with AL amyloidosis, who provided a research sample and consent to review their medical records between 1/1/2006‐12/31/2010 within 90 days of their diagnosis. Samples were assayed for sST2 and galectin‐3. Within this AL amyloidosis population, overall survival (OS) was 25.5 months (95% CI 18, 35.7 months). Receiver operating curve analyses were done to detect the best cut‐points for sST2 and galectin‐3 to predict both 1‐ and 5‐year OS. The respective cut points for sST2 were 30 and 29.7 ng/mL, while the median sST2 for the entire population was 31 ng/mL (IQR 19.8, 53.6). The respective cut points for galectin‐3 were 11 and 10.4 ng/mL while the median for the entire population was 16.6 ng/mL (IQR 11.5, 24.0). Although on univariate analysis, both sST2 and galectin‐3 were prognostic, upon multivariate analysis, only sST2 was independent of troponin, NT‐proBNP, serum immunoglobulin free light chain, and blood pressure. Not only did sST2 add to previously reported prognostication systems, but a novel prognostication 5‐point system including sST2 was possible. The addition of sST2 – but not galectin‐3 – to existing prognostication systems for patients with AL amyloidosis strengthens the ability to predict for death. Am. J. Hematol. 90:524–528, 2015. © 2015 Wiley Periodicals, Inc.

AL amyloidosis (AL) is rare and frequently remains undiagnosed until organ function is compromised, even among patients with known pre‐existing untreated plasma cell dyscrasias (PCD). We identified 168 patients with AL amyloidosis who had a prior untreated PCD. The earliest symptom or sign (s/s) was defined as the first symptom reported by the patient that could be attributed to organ dysfunction caused by AL. The interval from the time of development of s/s to the establishment of diagnosis of AL (Interval‐SA) was calculated. PCD diagnosis preceded recorded onset of s/s in 75% (114/152) of patients, with a median interval‐SA for this group of 10 months. PCD was diagnosed after s/s in 25% (38/152) of patients, with a median interval‐SA of 20 months. Overall survival (OS) from diagnosis of AL was not different between the two groups. AL amyloidosis patients with an identified pre‐existing PCD had less advanced cardiac disease at AL diagnosis when compared to a control group of AL patients without preidentified PCD. Long‐term OS was not significantly superior among patients with a pre‐identified PCD. In patients with “asymptomatic” PCD, symptoms and signs of AL amyloidosis should be solicited, since timely diagnosis is important in AL amyloidosis. Am. J. Hematol. 89:1051–1054, 2014. © 2014 Wiley Periodicals, Inc.

Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low-grade (World Health Organization [WHO] Grade II) glioma. Low-grade glioma (LGG) is a uniformly fatal disease of young adults (mean age 41 years), with survival averaging approximately 7 years. Although LGG patients have better survival than patients with high-grade (WHO Grade III or IV) glioma, all LGGs eventually progress to high-grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of LGG patients, overall survival has not significantly improved over the past 3 decades, highlighting the need for intensified study of this tumor. Recently published research suggests that historically used clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g., 1p/19q deletion and IDH1 or IDH2 mutation status), tumor expression profiles (e.g., the proneural profile) and/or constitutive genotype (e.g., rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as identify patients more sensitive to current treatments and targets for improved treatment in the future. This article reports on survival trends for patients diagnosed with LGG within the United States from 1973 through 2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients.