[Posted 31/Oct/2023]

AUDIENCE: Hematology, Family Medicine

KEY FINDINGS: Myeloablative fractionated busulfan regimen results in low nonrelapse mortality without a higher relapse rate. This regimen is a viable myeloablative alternative for patients who receive a reduced intensity regimen because of age or comorbidity.

BACKGROUND: Traditional conditioning regimens for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce nonrelapse mortality (NRM) while retaining antileukemic effects.

DETAILS: Authors performed a phase 2 trial for adults with hematological malignancies receiving matched related or unrelated allo-HCT. Participants received busulfan 80 mg/m² as outpatients on days -20 and -13 before transplant. Fludarabine 40 mg/m² was administered on days -6 to -3, followed by busulfan dosed to achieve a target area under the curve of 20,000 mol/min for the whole course. The primary end point was day-100 NRM. Seventy-eight patients were included, with a median age of 61 years (range, 39-70 years), who received transplantation for acute leukemia (24%), myelodysplastic syndrome (27%), or myeloproliferative disease/chronic myeloid leukemia (44%). HCT-specific comorbidity index (HCT-CI) was >=3 in 34 (44%). With a median follow-up of 36.4 months (range, 2.9-51.5), the 100-day, 1-year, and 3-year NRM rates were 3.8%, 8%, and 9.3%, respectively, without a significant difference in age or HCT-CI score. The 1-year and 3-year relapse incidence was 10% and 18%, respectively. The 3-year overall survival was 80%, without a significant difference in age or HCT-CI score and was similar for patients aged >60 years and those aged <60 years as well as for those with HCT-CI >=3 and HCT-CI <3. Overall, a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities.

Copyright © The American Society of Hematology. All rights reserved.

Source: Popat, U. R., Pasvolsky, O., Nassett, R. Jr., et al. (2023). Myeloablative Fractionated Busulfan For Allogeneic Stem Cell Transplant In Older Patients Or Patients With Comorbidities. Blood Adv.. 2023; 7(20): 6196-6205. Published: October, 2023. DOI: 10.1182/bloodadvances.2023010850.

Fluoropyrimidine Chemotherapy: Mortality and Cardiovascular Risk in Gastrointestinal Cancer

[Posted 4/Jul/2025]

AUDIENCE: Oncologists, Cardiologists, Cardio-Oncologists, and Researchers involved in the treatment of gastrointestinal cancers.

KEY FINDINGS:

• Fluoropyrimidine-based chemotherapy significantly reduced the absolute risk of all-cause mortality at 1 year (RD: -7.7%; 95% CI: -8.7% to -6.7%).
• There was a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%), primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%).
• No increased risk of acute coronary syndromes was observed, even in patients with pre-existing coronary artery disease.
• The substantial survival benefit of fluoropyrimidines in GI cancer patients outweighs the small risk of cardiac arrhythmia and arrest.

BACKGROUND: Fluoropyrimidine chemotherapy is a primary first-line treatment for many gastrointestinal cancers. However, concerns regarding its cardiotoxicity often lead to the use of alternative treatments in patients with pre-existing cardiovascular disease. This study aimed to quantitatively assess the risks of all-cause mortality and acute cardiovascular events associated with fluoropyrimidine treatment to inform clinical decision-making.

DETAILS: This observational cohort study utilized a target trial emulation framework with linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. The study included 103,110 adult patients (mean age 69.7 years, 59% male) diagnosed with tumors eligible for first-line fluoropyrimidine-based chemotherapy. Researchers compared all-cause mortality and a composite of hospitalization for acute cardiovascular events (including acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) between patients receiving fluoropyrimidine-based chemotherapy and those undergoing alternative management. The findings indicate that the improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer is a significant benefit that should encourage oncologists to avoid undue clinical conservatism, particularly when treating patients with co-existing cardiovascular disease.

Copyright © Authors. All rights reserved.

Source: Abiodun, A. T., Ju, C., Welch, C. A., et al. Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer. J Am Coll Cardiol CardioOnc.. 2025; 7(4): 345-356. Published: June, 2025. DOI: 10.1016/j.jaccao.2025.01.019.

[Posted 27/May/2025]

AUDIENCE: Gastroenterology, Ob/Gyn, Internal Medicine

KEY FINDINGS: Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations.

BACKGROUND: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs.

DETAILS: Authors studied ~200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ~9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation >=600 µg/day (p-interactions <0.05).

Copyright © Elsevier Inc. All rights reserved.

Source: India-Aldana, S., Midya, V., Betanzos-Robledo, L., et al. Impact of Metabolism-Disrupting Chemicals and Folic Acid Supplementation on Liver Injury and Steatosis in Mother-Child Pairs. Journal of Hepatology. 2025; 82(6): 956-966. Published: June, 2025. DOI: 10.1016/j.jhep.2024.11.050 .

A Cohort Study From the EINSTEIN-Jr Phase 3 Trial

[Posted 18/May/2025]

AUDIENCE: Hematology, Pediatric

KEY FINDINGS: Incidences of recurrent venous thromboembolism and bleeding during extended-phase anticoagulant treatment were low and similar to those observed during acute-phase treatment and adult studies on extended-phase anticoagulant treatment, providing valuable information for clinical practice on extended anticoagulation in children.

BACKGROUND: Extended-phase anticoagulation of venous thromboembolism in children is not well documented nor systematically reported. Previously, we reported on recurrent venous thromboembolism and bleeding during acute-phase anticoagulation in EINSTEIN-Jr, a randomised controlled study in 500 children with venous thromboembolism comparing rivaroxaban to standard anticoagulants. The aim of the present study was to evaluate the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation.

DETAILS: Children aged 17 years or younger, who were enrolled in the EINSTEIN-Jr trial (NCT02234843) from 107 paediatric hospitals in 28 countries, and who had previously completed a 3-month acute anticoagulation treatment phase (1-month in children <2 years with catheter-related venous thromboembolism) for acute venous thromboembolism within the trial were included in this cohort study. After completion of the preceding acute anticoagulation treatment phase, children could extend study treatment for up to 9 months (or up to 2 months for children <2 years with catheter-related venous thromboembolism). Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist). The main outcomes were suspected recurrent venous thromboembolism (primary efficacy outcome) and clinically relevant bleeding (principal safety outcome), both confirmed or refuted by appropriate objective testing. Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study. We also compared demographic and clinical characteristics of those administered any extended-phase anticoagulation (whether within or outside the framework of the study) with those not administered extended-phase anticoagulation, applying multivariable logistic regression. 248 (51%) children received extended-phase anticoagulation between Nov 14, 2014, and Jan 15, 2019, 214 within the study and 34 outside the framework of the study. During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence 3.0%; 95% CI 0.9-9.8). Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3.3%; 1.2-9.2). Fatal venous thromboembolism or major bleeding did not occur. Outcome rates were similar with rivaroxaban or standard anticoagulants. Symptomatic index venous thromboembolism (odds ratio 1.88; 95% CI 1.14-3.11), unprovoked venous thromboembolism or persistent risk factor (2.16; 1.46-3.19), and residual thrombosis on repeat imaging (3.79; 2.52-5.71) were associated with the decision to extend anticoagulation.

Copyright © Elsevier Ltd. All rights reserved.

Source: Male, C., Lensing, A. W. A., Chan, A. K. C., et al. Extended-Phase Anticoagulant Treatment of Acute Venous Thromboembolism in Children: A Cohort Study From the EINSTEIN-Jr Phase 3 Trial. The Lancet Haematology. 2025; 12(5):5, e357-e364. Published: April, 2025. DOI: PIIS2352-3026(25)00067-5.

A Meta-analysis of Diagnostic Test Accuracy

[Posted 12/May/2025]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Study establishes evidence of the superior diagnostic accuracy of conventional SATs over rapid SATs for detecting H. pylori infection in adults. Also, authors provide valuable insights into the impact of using monoclonal or polyclonal antibodies and different assessment techniques on diagnostic accuracy measures.

BACKGROUND: The stool antigen test (SAT) is a convenient noninvasive option for the diagnosis of Helicobacter pylori (H. pylori) infection. However, despite having been previously evaluated, there is currently a lack of evidence regarding the comparative accuracy of conventional and rapid SATs utilizing monoclonal or polyclonal antibodies in adults. Here, authors perform a thorough statistical synthesis to determine and compare the diagnostic accuracy of conventional and rapid SATs for the diagnosis of H. pylori infection in adults.

DETAILS: Authors conducted independent searches through July 25, 2023, for studies evaluating the accuracy of SAT against a reference standard. Authors assessed methodological quality using Quality Assessment of Diagnostic Accuracy Studies-2 and calculated overall accuracy measures using the bivariate random-effect model. Authors also conducted subgroup analyses based on model and assessment technique, and Spearman correlation analysis to investigate a possible threshold effect. Authors generated summary receiver operating characteristic curves to assess heterogeneity and evaluated publication bias. Conventional SAT demonstrated superior sensitivity (92.19% vs 85.79%), specificity (92.93% vs 91.18%), likelihood ratios (LR+ 9.68 vs 8.16; LR- 0.10 vs 0.15), and area under the curve (0.958 vs 0.940) compared with rapid SAT. Notably, the diagnostic odds ratio for conventional SAT (114.70) significantly outperformed rapid SAT (diagnostic odds ratio: 57.72). Correlation analysis revealed no threshold effect and summary receiver operating characteristic curves showed consistent accuracy for both tests.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Silva Luz, M., Tianeze de Castro, C., Bueno Lemos, F. F., et al. (20245). Stool Antigen Test for Helicobacter Pylori Infection in Adults: A Meta-analysis of Diagnostic Test Accuracy. Journal of Clinical Gastroenterology. 2025; 59(5): 393-404. Published: May/June 2025, 2025. DOI: 10.1097/MCG.0000000000002102.

[Posted 25/Mar/2025]

AUDIENCE: Pediatric, Family Medicine

KEY FINDINGS: Authors report a prospective study involving children that showed overestimation of saturation by pulse oximetry that was attributable to skin tone. This overestimation could lead to undertreatment of hypoxemia and contribute to racial inequities in outcomes. Additional studies are needed in populations with a greater proportion of persons with darker skin tone. The findings emphasize that current FDA guidance for pulse-oximeter validation (https://www.fda.gov/media/72470/download?attachment), which recommends only limited involvement of persons with darkly pigmented skin without a formal definition, is inadequate in ensuring equity in pulse-oximetry accuracy. New guidance is currently under consideration. On the basis of these results, there is potential for improvement in both bias and precision.

BACKGROUND: Findings from the Pulse Oximetry and Skin Tone in Children (POSTer-Child) study were published February 12, 2025 in a letter to the editor of The New England Journal of Medicine. First author Joseph Starnes, MD, MPH, is a fellow in Pediatric Cardiology.

DETAILS: Retrospective studies have shown overestimation of oxygen saturation by pulse oximetry in adult and pediatric patients from races that may be associated with darker skin. These retrospective studies share key limitations, including race as a poor surrogate for skin tone and paired measurements of oxygen saturation as assessed by pulse oximetry (SpO2) and of arterial oxygen saturation (SaO2) in the medical record. Limited prospective laboratory-based and clinical studies that used measured skin tone in adults have shown worse pulse-oximeter performance among patients with darker skin than among those with lighter skin. Very few prospective studies have involved children.

In the Pulse Oximetry and Skin Tone in Children (POSTer-Child) study, authors enrolled 320 patients younger than 21 years of age undergoing cardiac catheterization in 2024. Skin tone was measured with the use of a spectrophotometer. SpO₂ was recorded with the use of two pulse oximeters (Nellcor and Masimo) at the exact time of blood sampling for measurement of fractional saturation by co-oximetry. Pulse-oximetry bias (SpO₂-SaO₂), precision (standard deviation of bias), and accuracy root mean square error (ARMS) were calculated (for all three measures, higher values indicate worse pulse-oximeter performance), as was the percentage of patients with occult hypoxemia (SaO₂ of <88% when SpO₂ is >=92%). Additional methodologic details are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. The population was similar to the U.S. population but showed relative underrepresentation of Hispanic children. A total of 48 of 319 patients (15.0%) identified as Black, and 44 (13.8%) identified as Hispanic.

Average bias was 1.32 percentage points for the Nellcor device and 1.88 percentage points for the Masimo device. Bias was higher among children with darker skin (individual typology angle [ITA] category 5 or 6) than among those with lighter skin (ITA category 1 or 2) for both pulse oximeters (P<0.001). Precision and ARMS were also higher for children with darker skin. ARMS was substantially higher than the Food and Drug Administration (FDA) cutoff of three for children in ITA category 5 or 6. Occult hypoxemia was present in 4 of 56 children (7%) in ITA category 5 or 6 for the Nellcor device and in 5 of 60 children (8%) for the Masimo device, as compared with 0 of 81 children and 3 of 88 children (3%), respectively, in ITA category 1 or 2.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Starnes, J., Welch, W., Henderson, C. C., et al. (2024). Pulse Oximetry and Skin Tone in Children. NEJM. 2025; 392: 1033-1034; Published: February 17, 2025. DOI: 10.1056/NEJMc2414937.