[Posted 6/May/2022]

AUDIENCE: Oncology, Pediatric, Internal Medicine

KEY FINDINGS: In addition to leukemia, RAI treatment for childhood and young-adulthood DTC was associated with increased risks of several solid cancers, particularly more than 20 years after exposure, supporting the need for long-term surveillance of these patients.

BACKGROUND: Since the 1980s, both the incidence of differentiated thyroid cancer (DTC) and use of radioactive iodine (RAI) treatment increased markedly. RAI has been associated with an increased risk of leukemia, but risks of second solid malignancies remain unclear. We aimed to quantify risks of second malignancies associated with RAI treatment for DTC in children and young adults, who are more susceptible than older adults to the late effects of radiation.

DETAILS: Using nine US SEER cancer registries (1975-2017), estimated relative risks (RRs) for solid and hematologic malignancies associated with RAI (yes v no or unknown) using Poisson regression among >= 5- and >= 2-year survivors of nonmetastatic DTC diagnosed before age 45 years, respectively. Among 27,050 >= 5-year survivors (median follow-up = 15 years), RAI treatment (45%) was associated with increased risk of solid malignancies (RR = 1.23; 95% CI, 1.11 to 1.37). Risks were increased for uterine cancer (RR = 1.55; 95% CI, 1.03 to 2.32) and nonsignificantly for cancers of the salivary gland (RR = 2.15; 95% CI, 0.91 to 5.08), stomach (RR = 1.61; 95% CI, 0.70 to 3.69), lung (RR = 1.42; 95% CI, 0.97 to 2.08), and female breast (RR = 1.18; 95% CI, 0.99 to 1.40). Risks of total solid and female breast cancer, the most common cancer type, were highest among >= 20-year DTC survivors (RRsolid = 1.47; 95% CI, 1.24 to 1.74; RRbreast = 1.46; 95% CI, 1.10 to 1.95). Among 32,171 >= 2-year survivors, RAI was associated with increased risk of hematologic malignancies (RR = 1.51; 95% CI, 1.08 to 2.01), including leukemia (RR = 1.92; 95% CI, 1.04 to 3.56). We estimated that 6% of solid and 14% of hematologic malignancies in pediatric and young adult DTC survivors may be attributable to RAI.

Copyright © American Society of Clinical Oncology

Source: Pasqual, E., Schonfeld, S., Morton, L. M., et al. (2022). Association Between Radioactive Iodine Treatment for Pediatric and Young Adulthood Differentiated Thyroid Cancer and Risk of Second Primary Malignancies. ournal of Clinical Oncology . 2022; 40(13): 1439-1449. Published: May 1, 2022. DOI: 10.1200/JCO.21.01841.

[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.

[Posted 14/Mar/2025]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.

BACKGROUND: The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear.

DETAILS: Goal of the study is to define the function of IQGAP3 in gastric cancer (GC) development and progression. Authors studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours. Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Shimura, M., Matsuo, J., Pang, S.,et al. (2024). IQGAP3 Signalling Mediates Intratumoral Functional Heterogeneity to Enhance Malignant Growth. Gut. 2025; 74(3): 364-386. Published: March, 2025. DOI: 10.1136/gutjnl-2023-330390.