Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. METHODS: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. RESULTS: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. CONCLUSIONS: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.

Data analytics improves the diagnostic accuracy of serum free light chain results for detecting monoclonal gammopathy.

OBJECTIVES: To evaluate the real-world performance and reference intervals of the Binding Site Freelite serum free light chain (SFLC) assay (Thermo Fisher Scientific), a global standard for diagnosis, prognostication, and response assessment for monoclonal gammopathies. METHODS: An informatics-based approach was used to retrospectively evaluate concordance between SFLC and the orthogonal Sebia HYDRASYS immunofixation assay results in a large clinical data set consecutively reported between 2010 and 2020. RESULTS: Among patients with monoclonal-negative results by both SFLC and Sebia HYDRASYS immunofixation assays, 25% (1226/5057) had κ/λ ratios (KLRs) outside the manufacturer-defined and International Myeloma Working Group-cited normal reference interval of 0.26 to 1.65. These results were consistent over the study period and were not affected by sex, age, impaired kidney function, or assay antisera lot variation. Assay drift, in addition to other potential factors, affected the KLR distribution. Using International Statistical Classification of Diseases (ICD) codes, kidney function data, and the central 95% of KLR values generated on the Optilite platform (Thermo Fisher Scientific), we derived a new reference interval of 0.67 to 2.13, reducing the KLR false-positive rate to 8%. However, normal KLR persisted among 16% (14/85) of samples with free λ chains by immunofixation, warranting caution during interpretation. CONCLUSIONS: Our analysis indicated that revision of Freelite SFLC reference intervals improves assay interpretation and should prompt reconsideration of Freelite reference intervals worldwide.

Anti-Nuclear Antibody Quantitation: Calibration and Harmonization Adjustment via Population Interrogation.

BACKGROUND: The 2019 classification criteria for systemic lupus erythematosus (SLE) includes an initial criterion requiring the presence of an antinuclear antibody (ANA), positive at a titer of at least 1:80 on HEp-2 cells, or equivalent. However, results of ANA tests performed on HEp-2 cells vary when tested in different laboratories. Calibration of ANA assays by achieving a common specificity in healthy control populations offers the possibility of achieving harmonization via population interrogation, but the expected specificity in a healthy control population is not known. METHODS: The studies used to determine the use of ANAs performed by immunofluorescence microscopy on HEp-2 cells as the entry criterion for classification of SLE were reanalyzed by a meta-analysis to determine the expected frequency of positive ANAs in healthy control populations at serum dilutions of 1:40 and 1:80. RESULTS: Our meta-analysis demonstrated that the expected specificity in a healthy control population of ANA performed using serum diluted 1:80 is 91.3% (CI 86.1-94.7%). The expected specificity of ANA performed at 1:40 serum dilution is 79.2% (CI 72.3-84.8%). CONCLUSION: One approach to achieving harmonization of ANA assays from different laboratories with each other and with expected performance would involve adjusting assays so that about 10% of a healthy control population has a positive ANA when tested at 1:80 dilution, and about 20% of the healthy control population has a positive ANA when tested at 1:40 dilution. This pragmatic approach to calibration and harmonization adjustment via population interrogation offers an opportunity for individual laboratories to be aligned with each other and with ANA performance expected for consistent categorization of patients with SLE.

The psychosocial effects of cleft lip and palate in non-Anglo populations: a cross-cultural meta-analysis.

OBJECTIVE: A meta-analytic study was conducted to examine the cross-cultural psychosocial impact of cleft lip and/or palate in non-Anglo populations. DESIGN: A total of 333 citations were initially identified for review using electronic and hand-search strategies. Of the six studies that met inclusion criteria, two were later excluded due to insufficient data. The four remaining studies represented a combined sample size of 2276 adolescents and adults with cleft lip and/or palate from China, Hong Kong, Taiwan, and Norway. MAIN OUTCOME MEASURES: Effect size using Cohen's d and confidence intervals were estimated using data from four studies of empirical, controlled study designs. RESULTS: The magnitude of effect sizes indicated that men (d = -0.75) with cleft lip and/or palate in non-Anglo cultures are more prone to psychosocial issues than women (d = -0.33). Adults (d = -0.50) are more impacted than adolescents (d = -0.04). Overall, regardless of age, gender, or culture, individuals with cleft lip and/or palate have lower psychosocial development than individuals without cleft lip and/or palate (d = -0.42). CONCLUSION: The effects for the cross-cultural comparisons were moderated by the age group and gender of the participants; however, most studies resulted in negative effect sizes. Health care teams for cleft lip and/or palate should recognize the importance of psychological intervention and family support in the treatment of all patients with cleft lip and/or palate throughout the life span.

The use of tympanometry and pneumatic otoscopy for predicting middle ear disease.

PURPOSE: Otitis media is the most common condition diagnosed by pediatricians and is estimated to affect approximately 70% of the pediatric population. The goal of this study was to evaluate the effectiveness of otoscopy and multifrequency tympanometry (MFT) for diagnosis of otitis media in children. METHOD: Twenty-one children, age 1 to 10 years, who were seeking medical treatment for suspected middle ear disease were selected to participate. Data were collected prior to myringotomy to determine the sensitivity and specificity rates of the following otologic and audiologic measures: (a) pneumatic otoscopy, (b) conventional tympanometry, and (c) MFT. For this study, the "gold standard," myringotomy, was used along with pneumatic otoscopy to determine the effectiveness, sensitivity, and specificity of conventional 226-Hz tympanometry, 678-Hz tympanometry, and 1000-Hz tympanometry to predict middle ear disease. RESULTS: The diagnoses provided with pneumatic otoscopy and tympanometry were both similar, agreeing in diagnosis 80%-100% of the time. The diagnoses from 678-Hz and 1000-Hz tympanometry were nearly equal and proved to detect abnormality at a higher rate. CONCLUSIONS: MFT is recommended on a routine basis with children having a history of otitis media, or else abnormal or notched 226-Hz tympanograms. Further research with a larger sample size will illuminate the possible predictive potential of MFT in otitis media.

Association between cardiovascular health and hearing function: pure-tone and distortion product otoacoustic emission measures.

PURPOSE: A reduction in hearing sensitivity is often considered to be a normal age-related change. Recent studies have revisited prior ways of thinking about sensory changes over time, uncovering health variables other than age that play a significant role in sensory changes. METHOD: In this cross-sectional study, cardiovascular (CV) health, pure-tone thresholds at 1000 to 4000 Hz, and distortion product otoacoustic emissions (DPOAEs), with and without contralateral noise, were measured in 101 participants age 10-78 years. RESULTS: Persons in the "old" age category (49-78 years) had worse pure-tone hearing sensitivity and DPOAEs than persons in the younger age categories (p < .05), affirming an age effect. Although hearing decline occurred in all persons in all CV fitness categories of every age group, those with low CV fitness in the old age group had significantly worse pure-tone hearing at 2000 and 4000 Hz (p <.05). Otoacoustic emission measurements were better for the old high-fit group but not significantly influenced by CV fitness level across age groups. CONCLUSIONS: Results of the current study elucidate the potentially positive impact of CV health on hearing sensitivity over time. This finding was particularly robust among older adults.

Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia.

OBJECTIVE: To determine if antibodies to cyclic citrullinated peptide (anti-CCP) are found in chronic hepatitis C virus (HCV) infection. METHODS: Rheumatoid factor (RF) and anti-CCP were measured in sera from 50 patients with HCV infection but without cryoglobulinemia, sera from 29 patients with mixed cryoglobulinemia (including 13 with rheumatic symptoms and 5 with arthritis), and sera from 20 normal blood donors. Anti-CCP was measured by second-generation enzyme-linked immunosorbent assay (ELISA). RESULTS: No sera with elevated anti-CCP were found in patients with HCV infection without cryoglobulinemia, and in that population, the maximum anti-CCP was 10 units, well below the positive cutoff of 20 units. Positive findings on RF testing >13 IU/ml were present in 22 (44%) of the HCV patients, with RF >50 IU/ml in 8 (16%) and a maximum RF of 526 IU/ml. Of the cryoglobulinemia patients, 22 (76%) had positive results on tests for RF, including 18 (62%) with RF >50 IU/ml and a maximum RF of 5,540 IU/ml. Two (6.9%) of the cryoglobulinemia patients had borderline-positive findings on tests for anti-CCP (25 units and 37 units), which were false-positive results caused by nonspecific binding in the ELISA. No association between the RF and the anti-CCP concentrations was found. CONCLUSION: Whereas RF was frequent in patients with HCV infection with and without cryoglobulinemia, anti-CCP was not observed in patients with uncomplicated HCV infection. Borderline-positive anti-CCP results were observed infrequently in patients with mixed cryoglobulinemia and were caused by nonspecific binding to plastic. Measurement of anti-CCP may help in diagnosing RA in patients with chronic HCV infection.