Citations

Abstract We developed rapid 24-h immunoblot assays for detecting autoantibodies to Scl 70 and Jo 1 antigens in serum. In comparative studies, we evaluated the analytical sensitivity of the immunoblot assays and commercial immunodiffusion assays for anti-Scl 70 and anti-Jo 1 autoantibodies with the use of positive control sera, and compared the frequencies of positive and negative results in a group of 116 sera, including specimens from 34 healthy controls and 82 patients with various connective-tissue diseases. The immunoblot assays were greater than 100-fold more sensitive than immunodiffusion for detecting both autoantibodies. Despite greater analytical sensitivity, there were no false-positive results by the immunoblot assay for anti-Scl 70 or anti-Jo 1 autoantibodies in sera from either the controls or the patients. The diagnostic sensitivity of the immunoblot assay for anti-Scl 70 autoantibodies in patients with scleroderma was greater than that of the immunodiffusion assay, 70% vs 20%, and was equivalent in patients with polymyositis, 43%. We conclude that rapid immunoblot assays for anti-Scl 70 and anti-Jo 1 autoantibodies are superior to immunodiffusion assays for clinical use and are suitable for routine use in the clinical laboratory.

Objectives This proposed systematic review will identify the existing evidence on medication‐overuse headache in children and adolescents. Background A number of medications have been shown to be effective for acute treatment of migraine in children and adolescents. However, patients may find they need to use their acute medications more frequently when migraine frequency is high. This has led to concern about their potential to develop medication‐overuse headache. Methods We will search PubMed, Embase, Web of Science, PsycINFO, and Cochrane databases from their inception to present time. We will also search conference proceedings of the last 4 scientific meetings of relevant societies and scan the reference lists of studies identified through the search. Study designs will include case series, cross‐sectional, cohort, case‐control, and interventional studies. Participants will include children and adolescents under 18 years of age with primary headache disorders. We aim to determine whether frequency of acute medication use is associated with headache frequency in children and adolescents. Outcomes of interest include: (1) headache frequency; (2) change in headache frequency, with time and in relationship to use of acute medications; and (3) headache‐related disability. We will also review data addressing treatment/management of medication overuse or medication‐overuse headache in children and adolescents. Relevant comparators will be withdrawal vs reduction of acute medication, initiation of preventive therapy vs no initiation with or without withdrawal of acute medication, and initiation of preventive therapy early vs late. Outcomes of interest include (1) days of acute medication use; (2) headache frequency; (3) change in headache frequency; and (4) headache‐related disability. After screening for inclusion, 2 team members will independently review and extract relevant data, and any discrepancies will be resolved through discussion and arbitration. We will assess risk of bias using appropriate tools (Cochrane Risk of Bias for randomized controlled trials (RCT) and Newcastle‐Ottawa Score for observational studies). Data will be summarized descriptively in text and tables. Results This systematic review will provide an overview of the available evidence on medication‐overuse headache in children and adolescents. Conclusions Findings from this review will aid clinicians by clarifying for them the current state of the evidence base, and will inform design of future research on this topic.

PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.METHODSWe analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.RESULTSWe found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.CONCLUSIONThese results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

INTRODUCTION: Primary plasma cell leukemia (pPCL) is the most aggressive form of multiple myeloma (MM). Recently, pPCL has been defined by as few as >5% circulating plasma cells (cPCs) detected morphologically on a peripheral blood smear. However, this technique may not be sufficiently sensitive and is dependent on inter-observer bias to properly identify and quantify cPCs. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs. However, an optimal quantitative cutoff for cPCs by MFC to define the presence of pPCL has not been established to date. Thus, this is the first study to date that determines an optimal cutoff of cPCs/ microliter that could identity patients with pPCL at diagnosis. METHODS: We retrospectively evaluated all newly diagnosed MM patients seen at the Mayo Clinic, Rochester from January 2007 to December 2017 who had their peripheral blood samples evaluated morphologically by peripheral blood smear and immunophenotypically by MFC prior to beginning therapy. Patients with a peripheral blood smear detecting >5% cPCs were classified as having pPCL. Six-color MFC was performed on peripheral blood mononuclear cells by isolated by Ficoll gradient, and stained with antibodies to CD45, CD19, CD38, CD138 and cytoplasmic Kappa and Lambda immunoglobulin light chains. The data was collected using Becton Dickinson FacsCanto II instruments collecting 150,000 events and analyzed using the BDFacs DIVA Software. The gating strategy employed first used the expression of CD38, CD138, and cytoplasmic immunoglobulin light chains to identify all plasma cells in the specimen. The cPCs were then discriminated from polyclonal/normal plasma cells based on differential CD19 and CD45 expression. The cPCs detected were reported as the number of clonal events/150,000 collected total events and converted to the absolute number of cPCs/microliter using their absolute lymphocyte count and monocyte count determined at the time of the blood draw for cPC MFC assessment. A receiver operator curve (ROC) was performed to determine the absolute cPCs/microliter by MFC that best identified those patients with >5% cPC on their peripheral blood smear. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. RESULTS: A total of 591 patients were included in this analysis of which 59% were male and the median age was 66 years (range: 27 - 95) with 22% being 75 years of age or older. From this cohort, 133 (24%) patients had high risk FISH cytogenetics, 172 (30%) were classified as ISS 3 at diagnosis, 83 (15%) had an elevated LDH level and 61 (17%) had a plasma cell labeling index (PCLI) of 2% or greater. There were 65 (11%) patients with any amount of cPCs detectable by peripheral blood smear of which only 22 (4% of the total population) met criteria for pPCL with >5% cPCs. With MFC, 403 (68%) patients had detectable cPCs. The median number of cPCs per microliter was 0.81 (0 - 10,455) with 273 (46%) having >1 cPC/microliter. A ROC analysis determined that the presence of >50 cPCs/microliter by MFC was the optimal cutoff to identify patients with >5% cPCs by blood smear with approximately a specificity of 94% and a sensitivity of 86%. The presence of >50 cPCs/microliter by MFC was associated with higher presence of high risk FISH cytogenetics, ISS 3 classification, elevated LDH and PCLI > 2%. The median time to next treatment (TTNT) for patients with and without >5% cPCs by peripheral blood smear was 18 months vs. 30 months (P < 0.001). The median TTNT for patients with and without >50 cPCs/microliter by MFC was 19 months vs. 30 months (P < 0.01). The median overall survival (OS) for patients with and without >5% cPCs by peripheral blood smear was 25 months vs. 71 months (P < 0.001; Fig 1A). The median OS for patients with and without >50 cPCs/microliter by MFC was 38 months vs. 71 months (P < 0.01; Fig 1B). CONCLUSION: This is the largest study that attempts to identify an optimal cutoff of cPCs/microliter by MFC for diagnosing pPCL patients. The presence of >50 cPCs/microliter is an optimal cutoff by MFC that best predicts for the presence of >5% cPCs by peripheral blood smear. However, there remains discordance in the OS outcomes between the two cutoffs by different methodologies for pPCL. This could signify the presence of biological processes associated with the presence of >5% cPCs when detected by peripheral blood smear that are not captured by MFC. Disclosures Dispenzieri: Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lacy:Celgene: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Celgene: Honoraria. Leung:Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Russell:Imanis: Equity Ownership. Gertz:DAVA oncology: Speakers Bureau; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Introduction: Several patient and disease biology characteristics that impact overall survival (OS) outcomes of patients with newly diagnosed multiple myeloma (NDMM) have been well described. However, several prior population-based registry studies in the US such as SEER and NCDB databases have demonstrated the negative prognostic impact of socio-economic (SE) factors such as low median household income based on US national census bureau data for zip code of residence as well as absence of marital support on the OS of NDMM patients. Whether such SE factors are independent of established host and disease biology related factors remains unknown due to the absence of detailed patient-level data in population-based cancer registries. Thus, we evaluated whether such SE factors independently affected the OS of NDMM patients in our institution when accounting for patient and disease biology related factors. Methods: We analyzed a retrospective cohort of consecutive NDMM patients seen at the Mayo Clinic from January 2005 to December 2015. Median household income for each patient's area of residence was estimated by matching their home zip code at diagnosis with data available through the US National Census Bureau. Median household income < $63,000 for a zip code were used to classify patients as having low income based on the National Cancer Database classification of the bottom three quartiles. Absence of marital support was considered in patients divorced, single or widowed at the time of diagnosis. Survival estimates were calculated using the Kaplan-Meier method. Patient and disease biology related factors taken into consideration included age, FISH cytogenetics, ISS stage and LDH levels. Survival estimates were compared between groups using the log-rank test. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Results: A total of 2,621 MM patients were analyzed from the Mayo Clinic cohort of which 60% were male and the median age was 64 (22 - 96) years with 14% being 75 years of age or older. In this cohort, 541 (33%) patients had ISS 3 disease and 370 (22%) had high risk cytogenetics by FISH. The median OS based on estimated average household income was 65 months for the group of patients with low household income (N = 32%) and 80 months for the remainder (P = 0.001) (Fig 1A). The median OS based on marital support was 59 months for those without marital support at diagnosis (N = 21%) versus 76 months for remainder (P = 0.003) (Fig 1B). However, in a multivariable analysis that included the aforementioned SE factors and patient and disease biology characteristics , only age of 75 years or older (p < 0.001), the presence of high-risk FISH cytogenetics (p < 0.001), presence of ISS 3 disease (p < 0.001) and elevated LDH (p = 0.005) retained independent statistical significance in predicting for worse OS. Lower household income (p = 0.264) and absence of marital support (p = 0.054) were not independent predictors of worse OS. Conclusions: With the caveat of patient selection bias in a tertiary academic center, SE factors such as estimated average household income and marital support at diagnosis do not appear to impact OS of NDMM patients when considered in the context of traditional host and disease biology risk factors. These findings are in contrast to those suggested by population based registry studies; nevertheless, similar patient-level assessments should be considered in patient cohorts from non-tertiary medical centers as these results may likely be different. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Lacy:Celgene: Research Funding. Kapoor:Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding. Russell:Imanis: Equity Ownership. Gertz:Medscape: Consultancy, Speakers Bureau; Research to Practice: Consultancy; Springer Publishing: Patents & Royalties; Ionis/Akcea: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Background Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)–cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission. Methods We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex. Results A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%. Conclusions This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis. Clinical Trials Registration NCT02870101.