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Background: Isatuximab, an IgG-kappa (IgGκ) anti-cluster of differentiation 38 (CD38) monoclonal antibody approved for use in patients with relapsed or refractory multiple myeloma (MM), can potentially interfere with the visualization of endogenous monoclonal protein (M-protein) on standard immunofixation electrophoresis (IFE) and lead to inaccurate classification of a patient's response to therapy. The Hydrashift 2/4 isatuximab IFE assay (Hydrashift isatuximab assay) removes isatuximab interference from IFE. Using samples from patients enrolled in clinical trials of isatuximab-based therapy for MM, we demonstrate how the Hydrashift isatuximab assay improves the ability to detect residual M-protein and offer recommendations for when the assay is most useful., Methods: Samples from 141 patients with a variety of known M-protein isotypes were selected and analyzed by standard IFE and the Hydrashift isatuximab assay. A positive control containing isatuximab was run on every standard IFE and Hydrashift gel., Results: The Hydrashift isatuximab assay reliably shifted the migration of isatuximab in patient samples. Standard IFE was adequate for determining 104 patients' M-protein status, and the Hydrashift isatuximab assay confirmed these results. In samples from 37 patients with a history of IgGκ MM and a single IgGκ band visible on standard IFE near the isatuximab migration site, the Hydrashift isatuximab assay was able to separate isatuximab from endogenous M-protein, identifying residual M-protein in 17 samples and preventing false-positive interpretations of standard IFE in 20 samples., Conclusions: The Hydrashift isatuximab assay is most useful in patients with known IgGκ MM when a single IgGκ band appears near the isatuximab migration site on standard IFE during isatuximab-based therapy., Clinicaltrials.gov Registration Numbers: NCT03275285 and NCT03319667., (© Association for Diagnostics & Laboratory Medicine 2024.)

An elevated risk of myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS), was identified among Fire Department of the City of New York (FDNY) World Trade Center (WTC)-exposed firefighters. Further investigation was needed to determine if these findings were reproducible in a more heterogeneous WTC-exposed rescue/recovery workers cohort, the Stony Brook University-General Responder Cohort GRC (SBU-GRC). MGUS risk was compared between the cohorts and to published general population estimates from Olmsted County, MN, USA. In this observational seroprevalence study, odds ratios (OR) and age-standardized risk ratios (RR) of MGUS (M-spike and light-chain-MGUS combined), M-spike, and light-chain-MGUS were estimated using logistic regression. Age-standardized prevalences were calculated for white males aged 50-79; RRs were estimated by comparing risk in the WTC-exposed cohort with the Olmsted County screened cohort. SBU-GRC had elevated odds of MGUS compared with FDNY (OR = 1.38; 95%CI = 1.00-1.89). The age-standardized prevalence of MGUS was 9.0/100 persons (95%CI = 7.5-10.6), over two-fold higher than the general population (RR = 2.08; 95%CI = 1.72-2.51); the age-standardized prevalence of light-chain-MGUS was 3.5-fold higher (RR = 3.54; 95%CI = 2.52-4.97). This study adds to mounting evidence supporting an association between WTC/environmental exposures and MGUS among rescue/recovery workers. Access to MGUS screenings for the entire WTC-exposed cohort could allow for treatment interventions that improve survival., (© 2022. The Author(s).)

Importance: Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone., Objective: To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant., Design, Setting, and Participants: Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months)., Interventions: Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8])., Main Outcomes and Measures: The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates., Results: Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5 sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths., Conclusions and Relevance: In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS.

Background Lenalidomide maintenance improves progression-free survival for patients with multiple myeloma, although its optimal duration is unknown. Clearance of minimal residual disease (MRD) in the bone marrow results in superior outcomes, although its attainment or sustainment does not alter clinical decision-making. Studies that have evaluated MRD serially are limited in length. We therefore aimed to evaluate longitudinal changes in MRD-status (dynamics) and their association with progression-free survival in patients with multiple myeloma., Methods: In this single-centre, single-arm, phase 2 study, we enrolled patients aged 18 years and older from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) who had newly diagnosed multiple myeloma following unrestricted frontline therapy and an Eastern Cooperative Oncology Group Performance Status of 2 or lower, including patients who started maintenance before study enrolment. All participants received lenalidomide maintenance at 10 mg for 21 days of 28-day cycles until progression or unacceptable toxic effects for up to 5 years on protocol. The primary endpoint was progression-free survival at 60 months per protocol and key secondary endpoints were MRD rates after completion of the 12th, 24th, and 36th cycle of maintenance and the association between progression-free survival and annual measurement of MRD status. MRD was assessed from first-pull bone marrow aspirates at baseline and annually by flow cytometry per International Myeloma Working Group criteria, (limit of detection of at least 1 × 10 -5 ) up to a maximum of 5 years. Patients who completed at least four cycles of treatment were included in the analysis of the primary endpoint, and patients who had completed at least one dose of treatment on protocol were assessable for secondary endpoints. The study was registered at ClinicalTrials.gov, NCT02538198, and is now closed to accrual., Findings: Between Sept 8, 2015, and Jan 25, 2019, 108 patients (100 evaluable for the primary endpoint) were enrolled. Median follow-up was 40·7 months (95% CI 38·7-45·0). At 60 months, progression-free survival was 64% (95% CI 52-79). Median progression-free survival was unreached (95% CI unreached-unreached). MRD dynamics were assessed using 340 MRD assessments done over 5 years for 103 evaluable patients. Patients who sustained MRD negativity for 2 years (n=34) had no recorded disease progression at median 19·8 months (95% CI 15·8-22·3) past the 2-year maintenance landmark. By contrast, patients who lost their MRD-negative responses (n=10) were more likely to progress than those with sustained MRD negativity (HR infinite; p<0·0001) and those with persistent MRD positivity (HR 5·88, 95% CI 1·18-33·33; p=0·015) at the 2-year landmark. Haematological and non-haematological serious adverse events occurred in 19 patients (18%). The most common adverse events of grade 3 or worse were decreased lymphocyte count in 48 (44%) patients and decreased neutrophil count in 47 (44%) patients. One death occurred on study due to sepsis and heart failure and was considered unrelated to the study drug., Interpretation: Serial measurements of MRD allow for dynamic assessment of risk for disease progression. Early intervention should be investigated for patients with loss of MRD negativity. Sustained MRD positivity is not categorically an unfavourable outcome and might portend prolonged stability of low-level disease., Funding: Memorial Sloan Kettering and Celgene., Competing Interests: Declaration of interests MA reports personal fees from Invivoscribe, Biocartis, and AstraZeneca, outside the submitted work. BD reports personal fees from Medscape, outside the submitted work. ADo reports grants from Roche; grants and personal fees from Takeda; and personal fees from PeerView, Physician's Education Resource (PER), Seattle Genetics, and EUSA Pharma, outside the submitted work. SG reports personal fees and advisory role (scientific advisory board) from Actinnum, Celgene, Bristol Myers Squibb, Sanofi, Amgen, Pfizer, GlaxoSmithKline, JAZZ, Janssen, Omeros, Takeda, and Kite, outside the submitted work. HH reports grants from Celgene, during the conduct of the study; and grants from Celgene, Takeda, and Janssen, outside the submitted work. CH reports Honorarium from Invivoscribe, outside the submitted work. MH reports research funding from the Swedish Blood Cancer Foundation, the Karolinska Institute Foundations, and clinical trial collaborations with GlaxoSmithKline, Amgen, and Daiichi Sankyo. NK reports research funding through Amgen and participates in advisory board with Medimmune. OLah reports serving on Advisory Board for MorphoSys. OLan reports grants from Amgen, Janssen, and Takeda; Data Monitoring Committee from Janssen, Merck, and Takeda; and personal fees from Amgen, Janssen, GlaxoSmithKline, AstraZeneca, and The Binding Site, outside the submitted work. AML reports grants from Novartis, during the conduct of the study; grants from Bristol Myers Squibb; personal fees from Trillium Therapuetics; grants, personal fees and non-financial support from Pfizer; and grants and personal fees from Janssen, outside the submitted work. AML also has a patent US20150037346A1 with royalties paid. SM reports research funding from Allogene Therapeutics, Juno/Bristol Myers Squibb, Takeda Oncology, and Janssen Oncology; personal fees from Plexus communication, and Physician Education Resource, outside the submitted work. MS reports personal fees and other from Angiocrine Bioscience and Omeros Corporation; personal fees from McKinsey & Company, Kite, and i3Health, outside the submitted work. GLS reports research funding from Janssen and Amgen outside the submitted work. US reports personal fees from Physicians Educations Resources; grants and other from Celgene/Bristol Myers Squibb; other from Janssen; and grants from Parker Institute for Cancer Immunotherapy and Myeloma Crowd, outside the submitted work. ELS reports personal fees from Bristol Myers Squibb, Fate Therapuetics, Precision Biosciences, and Chimera Therapuetics, outside the submitted work. ELS has several patents for varying CAR T cells and antibody products for multiple myeloma with royalties paid to Bristol Myers Squibb. CT reports other from Janssen Research and Development outside the submitted work. KT reports non-financial support from The Binding Site; and grants and personal fees from Sebia, outside the submitted work. DJC, ADe, SD, HJL, SXL, KM, FM, KM, TP, LR, MR, and EHR declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Current accessibility to child and adolescent mental health services is negatively affected by the shortage of mental health providers. The primary care provider or pediatrician is in a key position to identify behavioral health concerns, coordinate services, and provide treatment to the patient., Aim: This project aimed to improve access to children's mental health care by creating and implementing an educational course on the collaborative care model (CoCM), a model of integrated care that embeds mental health professionals into the primary care setting., Methods: Pre- and post-surveys were embedded in the online CoCM course to track course completion, identify clinical staff knowledge, and identify clinical staff interest in implementing the CoCM in practice., Results: Following project implementation, clinical staffs' responses from the pre- and post-surveys represented an increase in knowledge and interest in implementing the CoCM in practice after taking the online course., Conclusion: This project suggests further exploration of funding and planning to implement a pilot of the CoCM in a primary care practice setting., (© 2021 Wiley Periodicals LLC.)

Background: Daratumumab-based combination therapies have shown high rates of complete response (CR) and minimal residual disease negativity in patients with multiple myeloma. However, daratumumab, an IgGκ monoclonal antibody, interferes with electrophoretic techniques making it difficult to reliably define residual disease versus CR, especially in patients with IgGκ multiple myeloma., Methods: Enrichment with polyclonal sheep antibody-coated magnetic microparticles combined with MALDI-TOF mass spectrometry (MALDI-TOF MS) analysis was used to detect M-proteins in serial samples from newly diagnosed multiple myeloma patients treated with daratumumab-based therapy. The performance of the MALDI-TOF MS assay was compared to that of a routine test panel (serum protein electrophoresis (SPEP), immunofixation (IFE) and serum free light chain (FLC))., Results: Comparison of MALDI-TOF MS to SPEP/IFE/FLC showed a concordance of 84.9% (p < 0.001). When MALDI-TOF MS and FLC results were combined, the M-protein detection rate was the same or better than the routine test panel. For the 9 patients who obtained CR during follow-up, MALDI-TOF MS detected an M-protein in 46% of subsequent samples. Daratumumab could be distinguished from the M-protein in 215/222 samples., Conclusion: MALDI-TOF MS is useful in assessing CR in patients treated with monoclonal antibody-based therapies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

For patients diagnosed with multiple myeloma (MM) there have been significant treatment advances over the past decade, reflected in an increasing proportion of patients achieving durable remissions. Clinical trials repeatedly demonstrate that achieving a deep response to therapy, with a bone marrow assessment proving negative for minimal residual disease (MRD), confers a significant survival advantage. To accurately assess for minute quantities of residual cancer requires highly sensitive methods; either multiparameter flow cytometry or next generation sequencing are currently recommended for MM response assessment. Under optimal conditions, these methods can detect one aberrant cell amongst 1,000,000 normal cells (a sensitivity of 10 -6 ). Here, we will review the practical use of MRD assays in MM, including challenges in implementation for the routine diagnostic laboratory, standardisation across laboratories and clinical trials, the clinical integration of MRD status assessment into MM management and future directions for ongoing research., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Multiple Myeloma, the second most prevalent hematologic malignancy, yet lacks an established curative therapy. However, overall response rate to modern four-drug regimens approaches 100%. Major efforts have thus focused on the measurement of minute quantities of residual disease (minimal residual disease or MRD) for prognostic metrics and therapeutic response evaluation. Currently, MRD is assessed by flow cytometry or by next generation sequencing to track tumor-specific immunoglobulin V(D)J rearrangements. These bone marrow-based methods can reach sensitivity thresholds of the identification of one neoplastic cell in 1,000,000 (10 -6 ). New technologies are being developed to be used alone or in conjunction with established methods, including peripheral blood-based assays, mass spectrometry, and targeted imaging. Data is also building for MRD as a surrogate endpoint for overall survival. Here, we will address the currently utilized MRD assays, challenges in validation across labs and clinical trials, techniques in development, and future directions for successful clinical application of MRD in multiple myeloma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear., Objectives: Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers., Methods: We obtained sera and assessed MGUS among 1,638 male farmers ≥ 50  years of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides., Results: The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; p < 0.001 ). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, OR = 1.82 (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, OR = 2.49 (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [ OR = 2.42 (95% CI: 1.29, 4.54); p trend = 0.006 ]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use., Discussion: This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960.

Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) may soon replace routine electrophoretic methods for monitoring monoclonal proteins in patients with multiple myeloma. To further evaluate the clinical utility of this assay, we compared the performance of MALDI-TOF-MS head-to-head with an established bone marrow-based measurable residual disease assay by flow cytometry (Flow-BM-MRD), using Memorial Sloan Kettering Cancer Center's 10-color, single-tube method. Our results suggest that MALDI-TOF-MS adds value to bone marrow-based MRD testing and may be most useful for early detection of relapse in peripheral blood compared to current electrophoretic methods., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Importance: Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). Risk models that estimate the risk of progression from MGUS to multiple myeloma use data from a single time point, usually the initial workup., Objective: To longitudinally investigate the alterations of serum immune markers with stable vs progressive MGUS., Design, Setting, and Participants: This prospective cross-sectional cohort study included 77 469 adult participants aged 55 to 74 years in the screening arm of the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnosis of progressing MGUS (n = 187) or stable MGUS (n = 498), including light-chain subtype, from November 1993, through December 2011. For each participant, all available serially stored prediagnostic serum samples (N = 3266) were obtained. Data analysis was performed from April 2018, to December 2018., Main Outcomes and Measures: Serum protein and monoclonal immunoglobulin levels, serum free light chains, and serum light chains within each immunoglobulin class were measured., Results: Of 685 individuals included in the study, 461 (67.3%) were men; the mean (SD) age was 69.1 (5.6) years. In cross-sectional modeling, risk factors associated with progressive MGUS were IgA isotype (adjusted odds ratio [OR], 1.80; 95% CI, 1.03-3.13; P = .04), 15 g/L or more monoclonal spike (adjusted OR, 23.5; 95% CI, 8.9-61.9; P < .001), skewed (<0.1 or >10) serum free light chains ratio (adjusted OR, 46.4; 95% CI, 18.4-117.0; P < .001), and severe immunoparesis (≥2 suppressed uninvolved immunoglobulins) (adjusted OR, 19.1; 95% Cl, 7.5-48.3; P < .001). Risk factors associated with progressive light-chain MGUS were skewed serum free light chains ratio (adjusted OR, 44.0; 95% CI, 14.2-136.3; P < .001) and severe immunoparesis (adjusted OR, 48.6; 95% CI, 9.5-248.2; P < .001). In longitudinal analysis of participants with serial samples prior to progression, 23 of 43 participants (53%) had high-risk MGUS before progression; 16 of these 23 (70%) experienced conversion from low-risk or intermediate-risk MGUS within 5 years. Similar results were found for light-chain MGUS., Conclusions and Relevance: The findings of evolving risk patterns support annual blood testing and risk assessment for patients with MGUS or light-chain MGUS.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Context: Challenging clinical scenario in which elevated β-human chorionic gonadotropin (HCG, subsequently termed HCG) levels suggested occult tumor metastases after removal of bilateral testicular cancers and metastases from them and as well as after chemotherapy., Case Report: A 22-year-old male, post excision of bilateral testicular tumors, who had no imaging or clinical evidence of residual tumor but an elevated HCG raising the question of the presence and location of occult tumor metastases. Clinical Questions. Does luteinizing hormone (LH) cross-react with HCG in current assays? What levels of testosterone and estradiol are necessary to suppress LH and follicle-stimulating hormone (FSH) in a male patient with bilateral orchiectomy, and therefore lacking inhibin? Does the pituitary secrete HCG and under what circumstances?, Assessment: Current HCG assays no longer cross-react with LH as did prior assays, but the presence of heterophile antibodies and other factors such as biotin can still cause false positive HCG levels. In the chronic post-orchiectomy state, the pituitary is relatively resistant to LH and FSH suppression by testosterone. The pituitary secretes HCG in very small amounts unless interruption of negative feedback results in high LH and FSH whereupon HCG levels become elevated. Clinical Conclusion. A GnRH antagonist suppressed both LH and HCG in this patient indicating that the elevated HCG was secreted by the pituitary and not by occult tumor metastases. Further credence for this conclusion resulted from the lack of a progressive increase in HCG levels over a 4-year period of follow-up and from no evidence of metastatic tumors on serial imaging.

Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood., Objective: To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS., Design, Setting, and Participants: Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781)., Exposures: WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002., Main Outcomes and Measures: Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS., Results: Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34-2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3-fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93)., Conclusions and Relevance: Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype.

A child's age in comparison to the age of her or his classmates (relative age) has been found to be an influential factor on academic achievement, particularly but not exclusively at the beginning of formal schooling. However, few studies have focused on the generalizability of relative age effects. To close this gap, the present study analyzes the generalizability across students with and without immigrant backgrounds, across three student cohorts that entered school under a changing law of school enrollment, and across classes. To this end, we capitalized on representative large-scale data sets from three student cohorts attending public schools in Berlin, the capital of Germany. We analyzed the data using a multilevel framework. Our results for the overall student sample indicate relative age effects for reading and mathematics in favor of the relatively older students in Grade 2 that become somewhat smaller in size in Grade 3. By Grade 8, relative age effects had vanished in reading and had even reversed in favor of the relatively young in mathematics. Furthermore, relative age effects were not found to be systematically different among students with and without immigrant backgrounds, student cohorts, or across classes. Taken together, these results empirically underscore the broad generalizability of the findings as found for the overall student population and replicate the pattern of findings on relative effects as identified by the majority of previous studies.

Context: Bupropion overdose commonly causes generalized seizures and central nervous system depression. Less commonly, cardiotoxicity has been reported. The toxicity of the parent drug compared to its active metabolite hydroxybupropion is uncertain., Case Details: A 31-year-old man presented to the emergency department with altered mental status after an intentional overdose of bupropion. Three hours after admission he developed status epilepticus requiring intubation, and 13 h after admission he developed marked widening of the QRS complex and prolongation of the QTc interval. Serial serum bupropion levels peaked with the onset of cardiotoxicity (334 ng/mL) and fell into the therapeutic range within 24 h, which coincided with normalization of his ECG intervals. Levels of the metabolite hydroxybupropion peaked later (4302 ng/mL) and remained elevated even after neurological and cardiotoxic symptoms resolved., Discussion: Cardiotoxicity appears to be caused primarily by bupropion rather than its active metabolite hydroxybupropion.

Context: Lactic acidosis is a well-recognized consequence of metformin. Hypoglycemia has been reported previously in metformin overdose, but the presence of other co-ingestions (e.g., a sulfonylurea) was not definitively excluded., Case Details: A 15-year-old girl ingested 75 g of metformin and 3 g of quetiapine. On examination in the emergency department 2 h later, she was drowsy but had normal vital signs. She developed lactic acidosis, hypotension, and recurrent and severe hypoglycemia (15 mg/dL and 20 mg/dL), requiring boluses of 50%dextrose. The first episode of hypoglycemia occurred approximately 4 h after ingestion. Serum metformin level 2 h after ingestion was 267 mg/L (therapeutic range, 0.465-2.5), and serum insulin was 2 mU/L (normal range, 6-35). Extensive laboratory investigation using high-resolution mass-spectrometry ruled out other possible hypoglycemic agents. She recovered after hemodialysis., Discussion: Metformin overdose can cause severe hypoglycemia in the absence of other antidiabetic drugs. Potential mechanisms of metformin-induced hypoglycemia include decreased hepatic glucose production, decreased glucose absorption, and poor oral intake.