Clinical efficacy and safety of chimeric antigen receptor T-cell therapy for mantle cell lymphoma with secondary central nervous system involvement.

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.

Moderate renal impairment does not preclude the accuracy of 24-hour urine normetanephrine measurements for suspected pheochromoctyoma.

OBJECTIVE: A 24-hour urine nor/metanephrine (urine NM-MN) measurements are a recommended first step in pheochromocytoma diagnosis. We hypothesized the presence of renal impairment (CKD) significantly confounds the results obtained in a urine NM-MN collection, giving artificially lower measurements. DESIGN: Retrospective review of a comprehensive laboratory database with all urine NM-MN results from Southern Alberta from 2010 to 2018 (n = 15 505). After excluding high probability pheochromocytoma cases, results from patients with three levels of CKD (n = 796) were compared to those without CKD to determine the potential CKD effect. PATIENTS: All patients having urine NM-MN collection during the time period, irrespective of ordering physician or test indication. MEASUREMENTS: Urine NM-MN was measured by liquid chromatography-tandem mass spectrometry and glomerular filtration rate determined within a median of 1.9 days, as estimated by CKD-EPI equation. RESULTS: In subjects with mild-to-moderate renal impairment, there was no continuous gradient between subnormal renal function and urine NM-MN measures. When the estimated GFR was < 15 mL/min/m2 , the hypothesized effect on lowered urine NM-MN became apparent. CONCLUSIONS: A 24-hour urine NM-MN measurement is unlikely to be affected by mild-to-moderate renal impairment and may be used as a reliable diagnostic test. With more advanced renal impairment, CKD-specific reference ranges or an alternative test may be needed.

Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. METHODS: Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. RESULTS: Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. CONCLUSIONS: Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.

Concordance between laboratories in metal ion testing in patients with metal-on-metal hip implants.

BACKGROUND: Testing of whole blood or serum metal ion levels has become an important part of assessing and monitoring the performance of metal-on-metal bearings, both in hip resurfacing arthroplasty and in total hip replacement. The aim of this study was to determine the concordance between 2 laboratories testing cobalt and chromium ion levels in patients with metal-on-metal bearings. METHODS: Serum and whole blood samples from patients who had undergone metal-on-metal resurfacing or large-diameter total hip arthroplasty were tested for cobalt and chromium ions in laboratory A (a recognized laboratory) and laboratory B (tasked with testing clinical specimens). Laboratory A performed cobalt and chromium testing on whole blood, and laboratory B performed cobalt testing on whole blood and chromium testing on serum. RESULTS: Samples from 104 patients were tested. Laboratory B reported lower whole blood cobalt levels than laboratory A. Furthermore, laboratory A reported that all patients had elevated whole blood cobalt ion levels compared to the normal reference values for the laboratory, whereas laboratory B reported that 46 patients (44.2%) had whole blood cobalt ion levels within the normal reference range for the laboratory. CONCLUSION: This comparative study highlights the importance of using a single laboratory for metal ion testing, as values generated from different laboratories may not be directly comparable. With recent literature suggesting that whole blood cobalt levels as low as 1 ppb may be a predictor of adverse reactions to metal debris, accurate clinical measurement needs to be increasingly exact.

CONTEXTE: Le dosage sanguin ou sérique d'ions métalliques est devenu une étape importante de l'évaluation et du suivi des prothèses à couple de frottement métal-métal utilisées en arthroplastie de resurfaçage ou totale de la hanche. La présente étude visait à évaluer la concordance entre les résultats de 2 laboratoires pour le dosage du cobalt et du chrome chez des patients porteurs de ces prothèses. MÉTHODES: Des prélèvements de sérum et de sang entier de patients porteurs d'une prothèse de resurfaçage ou d'une prothèse totale à grand diamètre de hanche à couple métal-métal ont été expédiés au laboratoire A (un laboratoire reconnu) et au laboratoire B (spécialisé en analyse d'échantillons cliniques) pour le dosage des ions cobalt et chrome. Le laboratoire A a effectué toutes ses analyses sur des prélèvements de sang entier, et le laboratoire B a utilisé le sang entier pour le dosage du cobalt et le sérum pour le dosage du chrome. RÉSULTATS: Les prélèvements de 104 patients ont été analysés. Le laboratoire B a détecté des taux sanguins de cobalt inférieurs à ceux du laboratoire A. De plus, le laboratoire A a indiqué que tous les patients présentaient des taux de cobalt sanguins élevés par rapport à ses valeurs de référence, alors que le laboratoire B a déterminé que le taux de cobalt sanguin de 46 patients (44,2 %) se trouvait dans sa fourchette de valeurs de référence normales. CONCLUSION: Cette étude comparative vient souligner l'importance de choisir un seul laboratoire pour le dosage des ions métalliques, car les valeurs générées par des établissements différents pourraient ne pas être directement comparables. Comme des études récentes semblent indiquer que des taux de cobalt sanguins aussi faibles que 1 p. p. milliard pourraient être des prédicteurs de réaction indésirable aux débris métalliques, la précision et l'exactitude des mesures cliniques revêtent une importance croissante.

Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia.

Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring "5+2" reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68-96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33-81%) and 42% (90% CI 17-65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).

FLT3 inhibitor-induced neutrophilic dermatosis.

The FLT3-ITD mutation is associated with poor outcomes in acute myeloid leukemia. Multiple FMS-like tyrosine kinase 3 (FLT3)-inhibitors have been studied in clinical trials. Recently, potent FLT3 inhibition was shown to induce terminal differentiation of FLT3-mutant myeloblasts. In 3 patients who developed characteristic skin nodules on initiation of FLT3-inhibition, we conducted dermatopathologic evaluation of skin samples, as well as FLT3 and NPM1 mutational analysis and fluorescence in situ hybridization. All 3 patients demonstrated characteristically deep dermal and subcutaneous neutrophilic infiltrates without evidence of myeloblasts. Discovery of FLT3-ITD and NPM1 mutations in 2 of the samples, as well as the presence of FLT3-ITD and deletion of 7q in the other, confirmed the ancestry of the differentiated neutrophils as that of the original FLT3-mutant myeloblasts. FLT3 inhibition can lead to clinically distinct dermatoses, which suggests the effect of FLT3 inhibition on myeloid differentiation and a manifestation of a broader "syndrome" associated with this therapy.

AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/ß-catenin signaling pathway.

Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and ß-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates ß-catenin in mouse bone marrow cells. Inhibition of COX suppresses ß-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of ß-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/ß-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.

Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate.

Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.

Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response.

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.

Clinical Outcomes and Toxicity in Older Adults Receiving Chimeric Antigen Receptor T Cell Therapy.

Chimeric antigen receptor T cell therapy (CAR-T) has transformed the treatment landscape for adults with relapsed/refractory hematologic malignancies, but few studies have examined outcomes in older adults. We aimed to evaluate clinical outcomes and treatment toxicity in older adults receiving CAR-T for hematologic malignancies and to describe outcomes and toxicities in older adults age 75+ years compared to those age 65 to 74 years. We conducted a retrospective analysis of 141 adult patients age 65+ years (46.1% age 75+ years) who received commercial CAR-T at Massachusetts General Hospital between December 2017 and June 2023. We abstracted clinical outcomes from a review of the electronic health record, including (1) toxicity (ie, cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]); (2) health care utilization; (3) overall survival (OS); and (4) event-free survival (EFS). We analyzed the association of age (65 to 74 years versus 75+ years) with toxicity and health care utilization using the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. We examined the association of age with OS and EFS using multivariable Cox regression, controlling for covariates. The median patient age was 77 years (range, 75 to 91 years) in the 75+ year group and 69 years (ranges, 65 to 74 years) in the 65 to 74 year group. There were no statistically significant differences between the 75+ year group and the 65 to 74 year group in the rates of CRS (75.4% versus 84.2%; P = .21), grade 3+ CRS (1.5% versus 6.6%; P = .24), ICANS (38.5% versus 48.7%; P = .24), grade 3+ ICANS (16.9% versus 21.1%; P = .49), or infections (23.1% versus 29.0%; P = .45). There were no significant between-group differences in hospital readmissions within 30 days of CAR-T (10.8% versus 21.1%; P = .11), intensive care unit admissions within 30 days of CAR-T (7.7% versus 9.2%; P = 1.000), or median hospital length of stay (13 days versus 14 days; P = .29) among age groups. In a multivariable Cox regression analysis controlling for CAR-T product, Eastern Cooperative Oncology Group Performance Status, lactate dehydrogenase level, bridging therapy use, and history of deep venous thromboembolism, age 75+ years was not associated with OS (hazard ratio [HR], .95; P = .86) or EFS (HR, 1.28; P = .30). We identified favorable OS and toxicity outcomes across age categories in older adults receiving CAR-T for B cell non-Hodgkin lymphoma or multiple myeloma, underscoring that age alone is not a contraindication for CAR-T.

Trends in all-cause mortality among patients with chronic myeloid leukemia: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Outcomes for patients with chronic myeloid leukemia (CML) have improved after the advent of tyrosine kinase inhibitors (TKIs), which target the BCR/ABL fusion gene product. Nonetheless, differences in survival persist between age groups. The authors performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess 5-year overall survival (OS) in various patient age groups. METHODS: Patients who had a diagnosis of CML were identified using the SEER 19 registries database. Patients who were included had SEER diagnosis codes for CML not otherwise specified (code 9863) and BCR/ABL-positive CML (code 9875) diagnosed between January 2000 and December 2005. Patients were divided into cohorts based on age at diagnosis: ages 15 to 44 years, 45 to 64 years, 65 to 74 years, and 75 to 84 years. OS was estimated using the Kaplan-Meier method, and Cox regression was used to estimate predictors of patient survival. RESULTS: In total, 5138 patients with a new CML diagnosis were identified. Five-year OS improved for all patients between the years 2000 and 2005. Compared with patients who were diagnosed in 2000, 5-year survival improved among patients ages 15 to 44 years (hazard ratio [HR] for mortality, 0.424; P < .0001), ages 45 to 64 years (HR, 0.716; P = .0315), and ages 65 to 74 years (HR, 0.692; P = .0126); and patients ages 75 to 84 years had an increased 5-year OS rate from 19.2% in 2000 to 36.4% in 2005 (HR, 0.568; P < .0001). CONCLUSIONS: OS at 5 years improved among all patients, including those ages 75 to 84 years, a group with historically poor outcomes. However, older age retained an association with worse survival, suggesting opportunities for further progress.

Association between baseline body mass index and overall survival among patients over age 60 with acute myeloid leukemia.

Acute myeloid leukemia (AML) is more common and more lethal among patients over the age of 60. Increased body mass index (BMI) has been associated with a higher incidence of various malignancies, including AML. We sought to determine whether patient BMI at the time of AML diagnosis is related to overall survival (OS) among elderly patients. We identified 97 patients with AML diagnosed after the age of 60 and treated with cytarabine-based induction chemotherapy. The median age was 68 years (range 60-87); 52% of patients were male, and our study population was predominantly white (89% of patients). The median OS for all patients was 316 days (95% CI 246-459). The hazard ratio for mortality was increased among patients with a BMI < 25 compared to BMI ≥ 30 (HR 2.14, P = 0.009, 95% CI 1.21-3.77), as well as with older age (HR 1.76, P = 0.015, 95% CI 1.12-2.79) and with secondary versus de novo disease (HR 1.95, P = 0.006, 95% CI 1.21-3.14). After multivariable analysis, we did not find a significant association between OS and other potential confounders such as coronary artery disease or diabetes among these patients. We conclude that increased BMI was independently associated with improved OS among older AML patients at our institution.

Antimicrobial stewardship, procalcitonin testing, and rapid blood-culture identification to optimize sepsis care in critically ill adult patients: A quality improvement initiative.

We examined the effect of an antimicrobial stewardship program (ASP), procalcitonin testing and rapid blood-culture identification on hospital mortality in a prospective quality improvement project in critically ill septic adults. Secondarily, we have reported antimicrobial guideline concordance, acceptance of ASP interventions, and antimicrobial and health-resource utilization.

Updated reference intervals for urine normetanephrine have no effect on test sensitivity but fewer false positives.

OBJECTIVE: We previously highlighted the problem of frequent false positives in 24 h urine normetanephrine(UNM) measurements owing to reference intervals that are inappropriately low for the population being screened for pheochromocytoma. Using a large population database, we devised new age-stratified reference intervals for the 24 h UNM test that were higher compared to previous. However, it was uncertain as to whether this would compromise test sensitivity for true pheochromocytoma cases. DESIGN AND METHODS: Retrospective analysis of all pheochromocytoma cases from a recently constructed provincial registry. All confirmed cases had their diagnostic UNM results retrospectively re-analysed according to the newly proposed UNM reference intervals to determine the percentage and phenotype of cases that might have been theoretically missed with the new reference range. RESULTS: After excluding pediatric and non-secretory head and neck paragangliomas, there were 60 confirmed pheochromocytoma cases. Using prior reference intervals, 51/60 (85%) had an abnormally high UNM. Of the 9 with normal UNM, 4 had a high urine metanephrine(UMN), 5 had normal levels of both UNM and UMN such that 55/60 had abnormal test results, representing the historical combined test sensitivity of 92%. Using the proposed reference interval, 43/60 (72%) had high UNM results. Of the 17 with normal UNM, 12 had high UMN, 5 had normal levels of both UNM and UMN. Therefore, 55/60 patients had had elevations in either UNM or UMN, corresponding to an identical combined test sensitivity of 92%. CONCLUSIONS: Reference intervals for UNM derived from actual clinical population screening data are higher than in traditional healthy volunteers. Use of these more appropriate reference intervals can significantly reduce the false positive rate without compromising test sensitivity for true pheochromocytoma.

5-Fluorouracil associated neurovascular toxicities.

Fluorouracil (5-FU) is a commonly used chemotherapeutic agent in many cancers. The widely reported adverse effects are infusion reactions, rash, fever, nausea, vomiting, peripheral neuropathy, and hepatic injury. However, there are limited data about its neurological side effects. Herein, we are reporting 3 cases of 5-FU induced neurovascular toxicities. Cerebral vasospasm with associated transient ischemia is a rare but significant adverse effect of the 5-FU. Stroke-like presentation makes timely recognition extraordinarily important. Differentiating stroke mimics is crucial as recombinant tissue plasminogen activator therapy should be given within a 4.5 hours window after an ischemic stroke. We suggest that 5-FU induced cerebral vasospasm can present with acute stroke-like symptoms. Physicians should be aware of stroke mimics as a differential diagnosis to spare their patients from unnecessary invasive and high-risk treatments.

Inpatient Measurements of Urine Metanephrines are Indistinguishable from Pheochromocytoma: Retrospective Cohort Study.

BACKGROUND: Pheochromocytoma is a rare cause of acute cardiovascular disease; however, any severe illness may have high catecholamines, simulating pheochromocytoma. We determined the spectrum of urine metanephrines from inpatient and outpatient collections without pheochromocytoma, compared with confirmed pheochromocytoma patients. METHODS: Retrospective analysis using centralized laboratory data serving all outpatients and hospitals in southern Alberta. The analysis comprised 24-hour urine normetanephrine and metanephrine (UNM-UMN) results collected from hospital inpatients, community outpatients, and patients from a comprehensive provincial pheochromocytoma registry. RESULTS: There were 974 unique inpatients (including 132 from intensive care), 6802 outpatients, and 58 pheochromocytoma patients. Among outpatient, general ward, and intensive care unit (ICU) patients, 18.7%, 34.4%, and 67.4% of results, respectively, were supranormal. Although pheochromocytoma patients had higher median UNM-UMN vs inpatients, there was substantial overlap. Receiver operating characteristic (ROC) analysis showed area under the curve (AUC) of 0.64-0.91 to detect true pheochromocytoma (P < .0001), with progressively poorer discrimination among hospitalized and ICU-dependent patients. A 24-hour urine normetanephrine >6.95 nmol/d had 98% specificity for pheochromocytoma when inpatient general ward samples were included, but only 46% sensitivity and 13% positive predictive value for pheochromocytoma. Considering ICU collections, 98% specificity required results more than fivefold above the upper reference limit and still had poor positive predictive value. A model combining both UNM and UMN results as a cross-product marginally improved the ROC AUC, but improved sensitivity in outpatients and ward patients but not ICU patients. CONCLUSION: There is a high degree of overlap in UNM-UMN between hospitalized patients and pheochromocytoma; high test specificity is not achieved in this population unless >3-5 times the upper reference limit.

Properly Collected Plasma Metanephrines Excludes PPGL After False-Positive Screening Tests.

CONTEXT: False-positive results are common for pheochromocytoma/paraganglioma (PPGL) real-world screening. OBJECTIVE: Determine the correlation between screening urine and seated plasma metanephrines in outpatients where PPGL was absent, compared to meticulously prepared and supine-collected plasma metanephrines with age-adjusted references. DESIGN: Retrospective cohort study. SETTING: Databases from a single-provider provincial laboratory (2012-2018), a validated PPGL registry, and a manual chart review from a specialized endocrine testing unit. PATIENTS: PPGL registry data excluded known PPGL cases from the laboratory database. Outpatients having both urine and plasma metanephrines <90 days apart. METHODS: The correlation between urine and seated plasma measures along with the total positivity rate. All cases of plasma metanephrines drawn in the endocrine unit were reviewed for test indication and test positivity rate. RESULTS: There were 810 non-PPGL pairs of urine and plasma metanephrines in the laboratory database; 46.1% of urine metanephrines were reported high. Of seated outpatient plasma metanephrines drawn a median of 5.9 days later, 19.2% were also high (r = 0.33 and 0.50 for normetanephrine and metanephrine, respectively). In contrast, the meticulously prepared and supine collected patients (n = 139, 51% prior high urine metanephrines) had <3% rate of abnormal high results in patients without known PPGL/adrenal mass. CONCLUSIONS: There was a poor-to-moderate correlation between urine and seated plasma metanephrines. Up to 20% of those with high urine measures also had high seated plasma metanephrines in the absence of PPGL. Properly prepared and collected supine plasma metanephrines had a false-positive rate of <3% in the absence of known PPGL/adrenal mass.