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Lung cancer is the most common cause of cancer-related deaths worldwide. In advanced stages, the overall prognosis is poor, with a median survival rate of 12 to 15 months. The [...], * Context.--The immune microenvironment is involved in fundamental aspects of tumorigenesis, and immune scores are now being developed for clinical diagnostics. Objective.--To evaluate how well small diagnostic biopsies and tissue microarrays (TMAs) reflect immune cell infiltration compared to the whole tumor slide, in tissue from patients with non-small cell lung cancer. Design.--A TMA was constructed comprising tissue from surgical resection specimens of 58 patients with non-small cell lung cancer, with available preoperative biopsy material. Whole sections, biopsies, and TMA were stained for the pan-T lymphocyte marker CD3 to determine densities of tumor-infiltrating lymphocytes. Immune cell infiltration was assessed semiquantitatively as well as objectively with a microscopic grid count. For 19 of the cases, RNA sequencing data were available. Results.--The semiquantitative comparison of immune cell infiltration between the whole section and the biopsy displayed fair agreement (intraclass correlation coefficient [ICC], 0.29; P =.01; CI, 0.03-0.51). In contrast, the TMA showed substantial agreement compared with the whole slide (ICC, 0.64; P Conclusions.--Although overall lymphocyte infiltration is relatively well represented on TMAs, the representativity in diagnostic lung cancer biopsies is poor. This finding challenges the concept of using biopsies to establish immune scores as prognostic or predictive biomarkers for diagnostic applications. doi: 10.5858/arpa.2022-0327-OA

Antibody titration in transfusion medicine is a commonly used clinical assay to detect the strength of reactivity of red cell antibodies present in a patient's plasma. (1) There are a [...], * Context.--Substantial variability between different antibody titration methods has been identified since the development and introduction of the uniform procedure in 2008. Objective.--To determine whether more recent methods or techniques decrease interlaboratory and intralaboratory variation measured using proficiency testing. Design.--Proficiency test data for antibody titration between 2014 and 2018 were obtained from the College of American Pathologists. Interlaboratory and intralaboratory variations were compared by analyzing the distribution of titer results by method and phase, comparing the results against the supplier's quality control titer, and by evaluating the distribution of paired titer results when each laboratory received a sample with the same titer twice. Results.--A total of 1337 laboratories participated in the antibody titer proficiency test during the study period. Only 54.1 % (5874 of 10 852) of anti-D and 63.4% (3603 of 5680) of anti-A reported responses were within 1 titer of the supplier's intended result. Review of the agreement between laboratories of the same methodology found that 78.4% (3139 of 4004) for anti-A and 89.0% (9655 of 10 852) of laboratory responses for anti-D fell within 1 titer of the mode response. When provided with 2 consecutive samples of the same titer (anti-D titer: 16), 85% (367 of 434) of laboratories using the uniform procedure and 80% (458 of 576) using the other method reported a titer difference of 1 or less. Conclusions.--Despite advances, interlaboratory and intralaboratory variance for this assay remains high in comparison with the strong reliance on titer results in clinical practice. There needs to be a reevaluation of the role of this test in clinical decision-making. (Arch Pathol Lab Med. 2023;147:1351-1359; doi: 10.5858/arpa.2022-0248-CP)

Multiple myeloma (MM) is a plasma-cell dyscrasia characterized by the accumulation of plasma cells in the bone marrow that produces an excess of clonal immunoglobulins (M-protein or monoclonal component). (1) [...], Context.-Minimal residual disease (MRD) is a major prognostic factor in multiple myeloma, although validated technologies are limited. Objective.-To standardize the performance of the LymphoTrack next-generation sequencing (NGS) assays (Invivoscribe), targeting clonal immunoglobulin rearrangements, in order to reproduce the detection of tumor clonotypes and MRD quantitation in myeloma. Design.-The quantification ability of the assay was evaluated through serial dilution experiments. Paired samples from 101 patients were tested by LymphoTrack, using Sanger sequencing and EuroFlow's next-generation flow (NGF) assay as validated references for diagnostic and follow-up evaluation, respectively. MRD studies using LymphoTrack were performed in parallel at 2 laboratories to evaluate reproducibility. Results.-Sensitivity was set as 1.3 tumor cells per total number of input cells. Clonality was confirmed in 99% and 100% of cases with Sanger and NGS, respectively, showing great concordance (97.9%), although several samples had minor discordances in the nucleotide sequence of rearrangements. Parallel NGS was performed in 82 follow-up cases, achieving a median sensitivity of 0.001%, while for NGF, median sensitivity was 0.0002%. Reproducibility of LymphoTrack-based MRD studies (85.4%) and correlation with NGF ([R.sup.2] > 0.800) were high. Bland-Altman tests showed highly significant levels of agreement between flow and sequencing. Conclusions.-Taken together, we have shown that LymphoTrack is a suitable strategy for clonality detection and MRD evaluation, with results comparable to gold standard procedures.

SARS-CoV-2 is a highly transmissible and pathogenic virus that has caused serious harm to human health and public safety during the ongoing COVID-19 global pandemic. (1,2) Global COVID-19 cases now [...], Context.--Neutralizing antibody detection can assess the incidence of COVID-19 and the effectiveness of vaccines. However, commercial reagents for neutralizing antibodies were developed after the anti-SARS-CoV-2 immunoglobulin (Ig) G and IgM antibodies. Therefore, some laboratories did not perform neutralizing antibody testing services because of multiple factors. Objective.--To find a fast, accurate, and economic alternative for the detection of neutralizing antibodies for the development of COVID-19 screening programs. Design.--The response and correlation of 3 antibodies (anti-spike protein neutralizing antibody, total anti-receptor-binding domain [RBD] antibody, and anti-RBD IgG) were determined by observing the dynamics in 61 participants for 160 days after vaccination. Results.--The levels of neutralizing and anti-RBD IgG antibodies reached their peak values on day 42 after vaccination (120.75 IU/mL and 14.38 signal-to-cutoff ratio [S/CO], respectively). The total antibody levels peaked at 138.47 S/CO on day 35 after vaccination. The strongest correlation was found between neutralizing and anti-RBD IgG antibody levels (r = 0.894, P Conclusions.--Neutralizing and anti-RBD IgG antibody levels were strongly correlated, and thus anti-RBD IgG antibody levels can be used for the accurate assessment of immunity following SARS-CoV-2 infection or vaccination.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is histologically characterized by the presence of relatively rare lymphocyte-predominant (LP) cells (originally termed lymphocytic and histiocytic cells) that are surrounded by an abundance of [...], * Context.--Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is characterized by neoplastic lymphocyte-predominant cells frequently rimmed by [CD3.sup.+]/ [CD57.sup.+]/programmed death receptor-1 [(PD-1).sup.+] T cells. Because of the rarity of lymphocyte-predominant cells in most cases, flow cytometric studies on NLPHL often fail to show evidence of malignancy. Objective.--To evaluate the diagnostic utility of PD-1 in detecting NLPHL by flow cytometry, in conjunction with the CD4:CD8 ratio and the percentage of T cells doubly positive for CD4 and CD8. Design.--Flow cytometric data obtained from cases of NLPHL (n = 10), classic Hodgkin lymphoma (n = 20), B-cell non-Hodgkin lymphoma (n = 22), T-cell non-Hodgkin lymphoma (n = 5), benign lymphoid lesions (n = 20), angioimmunoblastic T-cell lymphomas (n = 6) and T-cell/ histiocyte-rich large B-cell lymphomas (n = 2) were analyzed and compared. Results.--Compared with the other groups, NLPHL showed significantly higher values in the following parameters: CD4:CD8 ratio, percentage of T cells doubly positive for CD4 and CD8, percentage of PD-1-positive T cells, and median fluorescence intensity of PD-1 expression in the doubly positive for CD4 and CD8 subset. Using a scoring system (0-4) based on arbitrary cutoffs for these 4 parameters, all 10 NLPHL cases scored 3 or higher, as compared with only 3 cases from the other groups, producing an overall sensitivity of 100% and a specificity of 96% (72 of 75). Two of the 3 outliers were non-Hodgkin lymphoma, and both showed definitive immunophenotypic abnormalities leading to the correct diagnosis. The remaining outlier was a case of T-cell/histiocyte-rich large B-cell lymphoma. Conclusions.--The inclusion of anti-PD-1 in flow cytometry is useful for detecting NLPHL in fresh tissue samples, most of which would have otherwise been labeled as nondiagnostic or reactive lymphoid processes.

Deaths associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have raised concerns that contact with the corpses of deceased persons might pose a risk for transmitting infection (1). Nasopharyngeal [...]

Accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for patient management and infection control (1). Molecular diagnostics are highly sensitive in the acute phase of [...]

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the virus that causes COVID-19, was first detected in Wuhan, China in December 2019 and has quickly led to a global pandemic on [...], * Context.--The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited a surge in demand for serologic testing to identify previously infected individuals. In particular, antibody testing is crucial in identifying COVID-19 convalescent plasma, which has been approved by the Food and Drug Administration under the Emergency Use Authorization for use as passive immunotherapy for hospitalized patients infected with COVID-19. Currently, high-titer COVID-19 convalescent plasma can be qualified by Ortho&apos;s Vitros COVID-19 IgG antibody test. Objective.--To explore the use of an efficient testing method to identify high-titer COVID-19 convalescent plasma for use in treating COVID-19-infected patients and track COVID-19 positivity over time. Design.--We evaluated an enzyme-linked immunosorbent assay (ELISA)-based method that detects antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) with individual and pooled plasma samples and compared its performance against the Vitros COVID-19 IgG antibody test. Using the pooled RBD-ELISA (P-RE) method, we also screened more than 10 000 longitudinal healthy blood donor samples to assess seroprevalence. Results.--P-RE demonstrates 100% sensitivity in detecting Food and Drug Administration-defined high-titer samples when compared with the Vitros COVID-19 IgG antibody test. Overall sensitivity of P-RE when compared with the Vitros COVID-19 IgG antibody test and our individual sample RBD-ELISA (I-RE) were 83% and 56%, respectively. When screening 10 218 healthy blood donor samples by P-RE, we found the seroprevalence correlated with the local infection rates with a correlation coefficient of 0.21 (P < .001). Conclusions.--Pooling plasma samples can be used to efficiently screen large populations for individuals with high-titer anti-RBD antibodies, important for COVID-19 convalescent plasma identification. doi: 10.5858/arpa.2021-0215-SA

With the availability of vaccines against the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and as the pressure to reopen the economy increases, the demand for coronavirus disease [...], * Context.--Emerging evidence shows correlation between the presence of neutralization antibodies (nAbs) and protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently available commercial serology assays lack the ability to specifically identify nAbs. An enzyme-linked immunosorbent assay-based nAb assay (GenScript cPass neutralization antibody assay) has recently received emergency use authorization from the Food and Drug Administration. Objective.--To evaluate the performance characteristics of this assay and compare and correlate it with the commercial assays that detect SARS-CoV-2-specific immunoglobulin G (IgG). Design.--Specimens from SARS-COV-2 infected patients (n = 124), healthy donors obtained prepandemic (n = 100), and patients with non-coronavirus disease 2019 (COVID-19) respiratory infections (n = 92) were analyzed using this assay. Samples with residual volume were also tested on 3 commercial serology platforms (Abbott, Euroimmun, Siemens). Twenty-eight randomly selected specimens from patients with COVID-19 and 10 healthy controls were subjected to a plaque reduction neutralization test. Results.--The cPass assay exhibited 96.1% (95% CI, 94.9%-97.3%) sensitivity (at PCR), 100% (95% CI, 98.0%-100.0%) specificity, and zero cross-reactivity for the presence of non-COVID-19 respiratory infections. When compared with the plaque reduction assay, 97.4% (95% CI, 96.2%-98.5%) qualitative agreement and a positive correlation ([R.sup.2] = 0.76) was observed. Comparison of IgG signals from each of the commercial assays with the nAb results from plaque reduction neutralization test/cPass assays displayed greater than 94.7% qualitative agreement and correlations with [R.sup.2] = 0.43/0.68 (Abbott), [R.sup.2] = 0.57/0.85 (Euroimmun), and [R.sup.2] = 0.39/0.63 (Siemens), respectively. Conclusions.--The combined data support the use of cPass assay for accurate detection of the nAb response. Positive IgG results from commercial assays associated reasonably with nAbs presence and can serve as a substitute. doi: 10.5858/arpa.2021-0213-SA

Tests for antibodies to nuclear antigens (ANAs) are important for clinical diagnosis of several autoimmune rheumatic diseases, are central to epidemiologic classification of systemic lupus erythematosus and subsets of systemic [...], Context.--Presence of antibodies to nuclear antigens (ANAs) above a threshold titer is an important diagnostic feature of several autoimmune diseases, yet titers reported vary between laboratories. Proficiency survey results can help clarify factors contributing to the variability. Objective.--To determine the contribution of HEp-2 ANA kits from different manufacturers to the variation in titers, and assess whether the differences between kits are consistent over the long term. Design.--HEp-2 ANA titers reported by laboratories participating in the external quality assessment proficiency testing surveys conducted by the College of American Pathologists between 2008 and 2018 were analyzed. The ANA titers reported for each specimen were ranked according to the kits being used by testing laboratories, and the statistical significance of the differences was determined. Results.--The ANA titer results were strongly influenced by the HEp-2 ANA kit used (P < .001). During the 11 years studied, the rank order of the ANA titer for each kit relative to the other kits was remarkably consistent. The rank of ANA titer for individual ANA patterns observed for each kit was similar to the overall rank of that kit. Conclusions.--Variability in ANA titers was strongly associated with the kits used, and the differences between kits were quite consistent during the 11 years studied. Because the variability is not random, it has the potential to be managed by harmonizing kits, which could lead to improved consistency in reporting ANA titers. doi: 10.5858/arpa.2020-0419-CP

Rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential to prevent viral dissemination. Rapid antigen tests (RATs) have recently been approved and are now widely used in [...]

The COVID-19 pandemic resulted in a significant expansion of infectious diseases testing technology. (1) As of November 2021, the US Food and Drug Administration (FDA) has conferred emergency use authorization [...]

1 | INTRODUCTION HIV viral load (VL) monitoring is recommended by the World Health Organization (WHO) to confirm viral suppression and to take action if a patient has an elevated [...], Introduction: In many low- and middle-income countries, HIV viral load (VL) testing occurs at centralized laboratories and time-to-result-delivery is lengthy, preventing timely monitoring of HIV treatment adherence. Near point-of-care (POC) devices, which are placed within health facility laboratories rather than clinics themselves (i.e. "true" POC), can offer VL in conjunction with centralized laboratories to expedite clinical decision making and improve outcomes, especially for patients at high risk of treatment failure. We assessed impacts of near-POC VL testing on result receipt and clinical action in public sector programmes in Cameroon, Democratic Republic of Congo, Kenya, Malawi, Senegal, Tanzania and Zimbabwe. Methods: Routine health data were collected retrospectively after introducing near-POC VL testing at 57 public sector health facilities (2017 to 2019, country-dependent). Where possible, key indicators were compared to data from patients receiving centralized laboratory testing using hazard ratios and the Somers&apos; D test. Results: Data were collected from 6795 tests conducted on near-POC and 17614 tests on centralized laboratory-based platforms. Thirty-one percent (2062/6694) of near-POC tests were conducted for high-risk populations: pregnant and breastfeeding women, children and those with suspected failure. Compared to conventional testing, near-POC improved the median time from sample collection to return of results to patient [six vs. sixty-eight days, effect size: -32.2%; 95% CI: -41.0% to -23.4%] and to clinical action for individuals with an elevated HIV VL [three vs. fourty-nine days, effect size: -35.4%; 95% CI: -46.0% to -24.8%]. Near-POC VL results were two times more likely to be returned to the patient within 90 days compared to centralized tests [50% (1781/3594) vs. 27% (4172/15271); aHR: 2.22, 95% CI: 2.05 to 2.39]. Thirty-seven percent (340/925) of patients with an elevated near-POC HIV VL result had documented clinical follow-up actions within 30 days compared to 7% (167/2276) for centralized testing. Conclusions: Near-POC VL testing enabled rapid test result delivery for high-risk populations and led to significant improvements in the timeliness of patient result receipt compared to centralized testing. While there was some improvement in time-to-clinical action with near-POC VL testing, major gaps remained. Strengthening of systems supporting the utilization of results for patient management are needed to truly capitalize on the benefits of decentralized testing. Keywords: point of care; viral load monitoring; Africa; viral suppression

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the cause of the coronavirus disease 2019 (COVID-19) pandemic, is spreading throughout the world. (1) More than 1 699 000 confirmed cases and [...], * Context.--Covert severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections could be seeding new outbreaks. How to identify asymptomatic SARS-CoV2 infections early has become a global focus. Objective.--To explore the roles of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies detection, nucleic acid tests, and computed tomography (CT) scanning to identify asymptomatic SARS-CoV-2 infection. Design.--The clinical data of 389 individuals with close contacts, including in general characteristics, SARS-CoV-2 etiology, serum-specific IgM and IgG antibody detection and CT imaging results, were systematically analyzed. Results.--The present study showed that only 89 of 389 individuals with close contacts were positive after the first nucleic acid test, while 300 individuals were still negative after 2 nucleic acid tests. Among the 300 individuals, 75 did not have pneumonia, and the other 225 individuals had pulmonary imaging changes. A total of 143 individuals were eventually diagnosed as having asymptomatic infection through IgM antibody and IgG antibody detection. The sensitivity, specificity, and false-negative rate of IgM and IgG antibody detection were approximately 97.1% (347 of 357), 95.3% (204 of 214), and 4.67% (10 of 214), respectively. It also indicated that during approximately 2 weeks, most individuals were both IgM positive and IgG positive, accounting for 68.57% (72 of 105). During approximately 3 weeks, the proportion of IgM-positive and IgG-positive individuals decreased to 8.57% (9 of 105), and the proportion of IgM-negative and IgG-positive individuals increased to 76.19% (80 of 105). Conclusions.--There are highlighted prospects of IgM/ IgG antibody detection as a preferred method in identifying the individuals with asymptomatic SARS-CoV-2 infection, especially combined with nucleic acid tests and pulmonary CT scanning. (Arch Pathol Lab Med. 2021;145:39-45; doi: 10.5858/arpa.2020-0310-SA)

Coronavirus disease (COVID-19) emerged in December 2019 (1,2), and by June 2020, [approximately equal to]10 million persons worldwide had acquired the disease. The confirmatory test for severe acute respiratory syndrome [...]

To the Editor.--The number of patients with negative antinuclear antibodies (ANAs) and positive extractable nuclear antigen antibodies (ENAs) appears to be greater than we expected. However, medical colleges (1) and [...]

To the Editor.--The presence of antibodies to nuclear antigens (ANAs) above a threshold titer is a defining criterion for classification of systemic lupus erythematosus (SLE) and participation in clinical trials, [...]

To the Editor.--Alloimmunization from fetomaternal hemorrhage remains an ongoing cause of hemolytic disease of the fetus and newborn. (1) Though failure rates of postnatal prophylaxis have decreased to less than [...]

Prostatic stromal hyperplasia with atypia (PSHA) is a rare lesion that can be mistaken for sarcoma because of the presence of bizarre, degenerative myocyte nuclei. (1-10) The nuclear abnormalities are [...], * Context.--Prostatic stromal hyperplasia with atypia is a rare lesion that can be mistaken for sarcoma because of the presence of atypical, bizarre, degenerative myocyte nuclei. Objective.--To determine the diagnostic criteria and clinical significance of prostatic stromal hyperplasia with atypia. Design.--Eighteen cases of prostatic stromal hyperplasia with atypia were reviewed from the consultation file of one of the authors (D.G.B.). Results.--Prostatic stromal hyperplasia with atypia consists of 1 or more ill-defined, uncircumscribed, hyperplastic stromal nodules, with variable numbers of atypical, bizarre giant cells, with vacuolated nuclei, smudged chromatin, and frequent multinucleation infiltrating around benign acini. There was a hypocellular, loose, myxoid stromal matrix, with ectatic hyalinized vessels and mild to moderate chronic inflammation. Stromal cells displayed intense immunoreactivity for androgen receptors and vimentin, but moderate reactivity for desmin and actin. There were 3 local recurrences, with a mean follow-up of 6.3 years (range, 0.5-14 years), but none developed evidence of sarcomatous transformation or malignancy. Conclusions.--Prostatic stromal hyperplasia with atypia is a rare, benign lesion, composed of degenerative myocytes with atypia that is histologically and clinically reminiscent of benign counterparts in the myometrium, breast, vulva, vagina, and elsewhere. Recognition of this distinctive entity should allow separation from phyllodes tumor and sarcoma of the prostate. The phrase stromal tumor of uncertain malignant potential is inappropriate for this benign tumor, and its use is discouraged.