Citations

Background Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM. Methods ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3β gold-standard clinician diagnosis. Results Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 ( n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%). Discussion ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.

Objective The purpose of this study was to evaluate the frequency of migraine headache in a large cohort of patients with fibromyalgia using a brief migraine headache‐screening tool. Background Several studies report a high prevalence of fibromyalgia among patients with migraine headaches, but there is a dearth of research evaluating the frequency of migraine headaches in patients with fibromyalgia, despite clinical observations suggesting that migraine headaches are common in patients with fibromyalgia. Design and Methods This was a cross‐sectional survey study. Patients (N = 3717) with a previous diagnosis of fibromyalgia who were members of the M ayo C linic F ibromyalgia R egistry were contacted by electronic survey and asked to complete a brief demographic and medical history questionnaire and the validated ID ‐ M igraine screener. Results A total of 1730 patients (46.5%) completed the electronic survey. The majority of participants were white (97.2%), female (92.5%), with a mean age of 56.2 (±13.1) years. Of the respondents, 966 (55.8%) met criteria for migraine headaches. Hypertension (309 [32.3%] vs 294 [40.1%], P = .004), asthma (312 [32.5%] vs 189 [25.9%], P = .011), irritable bowel syndrome (520 [54.6%] vs 348 [47.6], P = .017), chronic fatigue syndrome (486 [50.7%] vs 271 [37.1], P < .0001), depression (634 [66.5%] vs 413 [56.7%], P = .0002), anxiety (415 [43.5%] vs 252 [34.7%], P = .0011), and post‐traumatic stress disorder (172 [18.0%] vs 96 [13.2%], P = .006) were all significantly more common in those who met criteria for migraine headaches than those who did not. Conclusion The results of this study suggest that migraine headaches are common in patients with fibromyalgia. Clinicians who care for either population must be aware that these conditions commonly overlap and can significantly increase a patient's cumulative disease burden.

Abstract Background: Genome wide association studies (GWAS) have recently identified 8 loci identified with multiple myeloma (MM) susceptibility. We hypothesized that germ line genetic variants may also affect MM progression. We performed the first GWAS of MM survival, by conducting a meta-analysis of two existing studies at University of California San Francisco (UCSF) and the Mayo Clinic, and replicating findings in the International Multiple Myeloma rESEarch (IMMEnSE) consortium. Methods: The UCSF study included 353 MM patients genotyped on an Illumina Omni5 and Illumina 660 array. The Mayo clinic study included 239 MM patients genotyped on an Affymetrix 6.0 array. We imputed missing genotypes using the 1000 Genomes dataset and performed a GWAS for survival using proportional hazards models adjusting for age and gender and genetic ancestry using principal components analysis. We conducted a meta-analysis of the results from the two GWAS. We replicated the top SNPs in the IMMEnSE cohort which included 772 patients with survival data from 7 European countries and one North American site. We used the dataset from Grundberg et al (Nat Genetics 2012) to test for an association between SNPs associated with survival and gene expression in immortalized lymphocytes. We used gene expression data from Zhan et al (Blood 2006) to analyze the association between expression and survival. Results: In meta-analysis, we found a genome wide significant association between SNPs on a region at 16p13 and survival (rs72773978; p=2.9x10e-10). Patients with the minor allele were at increased risk for mortality (HR 2.73; 95% CI: 1.99 - 3.73). The top associated SNPs were all in strong linkage disequilibrium and were centered over the gene FOPNL. We replicated the association in the IMMEnSE cohort and found a significant association between the top SNP from the discovery dataset (rs72773978 p=0.037). We used previously published data to determine the association between gene expression and the top associated SNPs from the GWAS. The top SNP (rs72773978) was not in previously published eQTL databases, so we used rs7201759 which was also associated with survival in our data (p=3.8x10e-10) as a proxy. The minor allele for this SNP was associated with increased levels of expression of FOPNL (p=9x10e-5), but not with expression of any other genes within a 1 megabase region. Finally, we also observed an association between increased expression of FOPNL and shorter survival (HR: 2.62 per standard deviation.; 95% CI: 1.08 - 6.32). Conclusion: Germ line variants at 16p13 near the FOPNL gene are associated with survival among MM patients. FOPNL is thought to be involved in centrosomal function, and centrosomal activity has previously been associated with survival in MM patients. Our results support this previous observation. Furthermore, they suggest that germ line variants could also be useful in assessing prognosis for patients with MM. Citation Format: Elad Ziv, Eric Dean, Donglei Hu, Alessandro Martino, Daniel Serie, Daniele Campa, Blake Aftab, Paige Bracci, Gabriele Buda, Jennifer Caswell, Charles Dumontet, Marek Dudziński, Laura Fejerman, Alexandra Greenberg, Scott Hunstman, Artur Jurczyszyn, Krzysztof Jamroziak, Shaji Kumar, Herlander Marques, Thomas Martin, Joaquin Martinez-Lopez, Vincent Rajkumar, Juan Sainz, Annette Juul Vangsted, Marzena Watek, Jeffrey Wolf, Susan Slager, Federico Canzian, Celine Vachon. Genome wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. [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 5078. doi:10.1158/1538-7445.AM2014-5078

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 &lt; 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 Background: Previous data on the relationship between PD-L1 expression and activity of anti-PD-1 and anti-PD-L1 antibodies have been conflicting. MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated tumor PD-L1 expression and its relationship with outcomes in a phase I clinical trial of MK-3475. We also evaluated T cell activation as a pharmacodynamic marker of MK-3475 activity. Methods: 135 MEL pts received MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W. Tumor response was assessed by RECIST 1.1 per independent central review, including requirement for a confirmatory CT scan. Pretreatment biopsy was required. Serial blood samples were collected before infusion at the start of cycles 1-5 (Q2W dosing) or 1-4 (Q3W dosing). Tumor PD-L1 expression was assessed by IHC. A preliminary cutoff of 1% of stained cells was used to define PD-L1 positivity. Absolute CD4+ and CD8+ T cell counts and the percentage of activated (HLA-DR as marker) CD4+ and CD8+ T cells in peripheral blood were assessed by multiplex flow cytometry (n = 101). Results: Median PFS was 36 weeks, 6-month overall survival (OS) rate was 89%, and 12-month OS rate was 81%. Median duration of response and OS were not reached. In the 116 pts with measurable disease, ORR was 41%. PFS and response rate were significantly associated with tumor PD-L1 expression (Table). At week 6, a statistically significant percent increase from baseline in the percentage of activated (HLA-DR+) CD4+ and CD8+ T cells was observed at all doses (pooled mean percent change [SE], +24.0% [4.7%] for HLA-DR+/CD8+, +17.5% [2.7%] for HLA-DR+/CD4+). Conclusions: Tumor PD-L1 expression levels were associated with tumor response and PFS in MEL pts treated with MK-3475; activity was also observed in pts with low PD-L1 expression. As assessed by HLA-DR expression, post-treatment T cell activation in the circulating pool was increased at all doses tested. Patients WithMeasurable Disease and Interpretable PD-L1 IHC ResultsPatients With InterpretablePD-L1 IHC Results and PFS and OS Data PD-L1 TumorExpressionNORR, n (%)NPFS at 6 months, % (95% CI)Median PFSOS at 6 months, % (95% CI)Median OSPositive (membrane staining in ≥1% of cells)5529 (53)6058 (47-72)10.6 mo93(87-100)Not reachedNegative (membrane staining in &lt;1% of cells)161* (6)2232 (16-64)2.9 mo75(58-97)Not reachedHR (95% CI) for PD-L1-positive vs negative____0.54(0.28-1.05)_0.67(0.25-1.83)One-sidedP value(PD-L1 association test)_&lt;0.004 (logistic regression)__0.034(Cox regression)_0.220(Cox regression)*IPI-pretreated patient who received MK-3475 10 mg/kg Q2W. Citation Format: Adil I. Daud, Omid Hamid, Antoni Ribas, F. Stephen Hodi, Wen-Jen Hwu, Richard Kefford, Jedd Wolchok, Peter Hersey, Jeffrey S. Weber, Richard Joseph, Tara C. Gangadhar, Roxana S. Dronca, Amita Patnaik, Hassane Zarour, Anthony M. Joshua, Kevin Gergich, Dianna Wu, Jared K. Lunceford, Kenneth Emancipator, Marisa Dolled-Filhart, Nicole Li, Scot Ebbinghaus, S. Peter Kang, Caroline Robert. Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): Correlation of tumor PD-L1 expression with outcome. [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 CT104. doi:10.1158/1538-7445.AM2014-CT104

Abstract Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM.

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.

Objectives The objective of this study was to evaluate the problem of multiple chronic conditions and polypharmacy in patients with fibromyalgia. Design Retrospective medical record review. Setting Olmsted County, Minnesota. Participants 1111 adults with fibromyalgia. Primary and secondary outcome measures Number and type of chronic medical and psychiatric conditions, medication use. Results Medical record review demonstrated that greater than 50% of the sample had seven or more chronic conditions. Chronic joint pain/degenerative arthritis was the most frequent comorbidity (88.7%), followed by depression (75.1%), migraines/chronic headaches (62.4%) and anxiety (56.5%). Approximately, 40% of patients were taking three or more medications for symptoms of fibromyalgia. Sleep aids were the most commonly prescribed medications in our sample (33.3%) followed by selective serotonin reuptake inhibitors (28.7%), opioids (22.4%) and serotonin norepinephrine reuptake inhibitors (21.0%). Conclusions The results of our study highlight the problem of multiple chronic conditions and high prevalence of polypharmacy in fibromyalgia. Clinicians who care for patients with fibromyalgia should take into consideration the presence of multiple chronic conditions when recommending medications.