Overdiagnosis of Papillary Thyroid Cancer in the United States
A US simulation study estimated that 72% to 94% of papillary thyroid cancer cases diagnosed between 1991 and 2019 were overdiagnosed. Reducing ultrasonography for nonpalpable thyroid nodules was modeled to substantially lower PTC incidence, with less than a 0.1% change in overall mortality. The findings highlight the potential role of reducing unnecessary imaging and diagnosis while recognizing that the estimates are model-based.
KEY FINDINGS: The findings indicate that PTC overdiagnosis remained substantial even after accounting for a possible underlying increase in true disease incidence. The modeling suggests that limiting unnecessary ultrasonography referrals for nonpalpable thyroid nodules could reduce detection of cancers unlikely to affect population mortality, potentially reducing unnecessary diagnoses and treatment-related burdens without a meaningful modeled increase in overall mortality. Because these findings are based on a simulation model rather than observed outcomes from an intervention, they should be interpreted as population-level estimates rather than evidence that reducing imaging is appropriate for individual patients.
BACKGROUND: Papillary thyroid cancer (PTC) incidence in the United States has increased substantially over recent decades, largely driven by detection of small, early-stage tumors, while population-level mortality has remained relatively stable. This pattern has raised concern that some thyroid cancers detected through imaging may never have become clinically significant. This study used a validated simulation model to estimate the extent of PTC overdiagnosis in the United States and examine the potential effects of reducing thyroid ultrasonography for nonpalpable thyroid nodules.
DETAILS: Researchers used the Papillary Thyroid Carcinoma Microsimulation Model (PATCAM) to evaluate PTC incidence among US adults aged 18 years or older from 1991 through 2019. The model accounted for changes in underlying thyroid cancer risk and estimated the proportion and absolute number of PTC cases considered overdiagnosed, defined in the model as cancers whose detection and treatment did not affect population mortality. The investigators also modeled the potential effects of reducing thyroid ultrasonography referrals for nonpalpable thyroid nodules.
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Between 1991 and 2019, the model estimated that 72% to 94% of diagnosed PTC cases were overdiagnosed. The estimated proportion was 75% to 95% among women and 63% to 90% among men. The corresponding absolute rate of overdiagnosis was 13 to 17 per 100,000 women and 3 to 5 per 100,000 men, translating to an estimated 443,212 to 573,705 women and 107,804 to 154,504 men overdiagnosed with PTC during the 28-year period. The model further estimated that reducing thyroid ultrasonography for nonpalpable nodules by 33% would reduce PTC incidence in 2019 by 17%, from 18 to 15 per 100,000 individuals. A 67% reduction in ultrasonography was associated with a modeled 41% reduction in incidence, from 18 to 11 per 100,000. In both scenarios, the modeled change in overall mortality was less than 0.1%.
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Source: Francis, D. O., Davies, L., Zhang, Y., et al. Overdiagnosis of Papillary Thyroid Cancer. JAMA Network Open. 2026; 9(2): e2559852. Published: February 24, 2026. DOI: 10.1001/jamanetworkopen.2025.59852
Timing of Vascular Access Creation in Older Adults With ESKD
A prospective European cohort of older adults with ESKD found that only 32% of AVFs were created within the defined 6-month window before hemodialysis initiation, while 42% were created early and 26% late. The findings highlight the difficulty of predicting dialysis timing and the need for better tools to individualize vascular access planning.
KEY FINDINGS: In this European cohort of older adults with ESKD, vascular access creation frequently did not coincide with the timing of hemodialysis initiation. More than 4 in 10 AVFs were created early, while approximately 1 in 4 were created late, resulting in substantial use of CVCs at dialysis initiation. The findings highlight the difficulty of predicting dialysis initiation in older adults and support the development of clinical prediction tools to better individualize vascular access planning.
BACKGROUND: Planning vascular access for older adults with end-stage kidney disease (ESKD) is challenging because the timing of hemodialysis initiation is difficult to predict. Arteriovenous fistulas (AVFs) created too early may remain unused, whereas delayed creation can result in hemodialysis being initiated through a central venous catheter (CVC). This study evaluated the timing of vascular access creation relative to hemodialysis initiation in older patients across Europe.
DETAILS: This secondary analysis used data from the EQUAL cohort, a prospective observational study involving patients aged 65 years or older with stage 4 or 5 chronic kidney disease in six European countries. Patients were included when their estimated glomerular filtration rate fell below 15 mL/min/1.73 m², provided they received a vascular access and had at least 6 months of follow-up. AVF timing was categorized as early when hemodialysis did not begin within 6 months after AVF creation, on time when hemodialysis was initiated with an AVF within 6 months, and late when hemodialysis was initiated with a CVC before or within 6 months after AVF creation.
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A total of 332 patients were analyzed. An AVF was the first vascular access in 221 patients (67%), while 111 patients (33%) initially received a CVC. Among those initially receiving a CVC, 53 patients (48%) subsequently underwent AVF creation. At dialysis initiation, 158 patients (54%) were using an AVF and 136 (46%) were using a CVC. Among the 274 patients who underwent AVF creation, access was created on time in 88 patients (32%), early in 114 (42%), and late in 72 (26%). Despite the high proportion of early AVF creation, most fistulas were eventually used, with 90% of patients initiating hemodialysis within 3 years after AVF creation.
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Source: Heggen, B. D. C., Chesnaye, N. C., Dekker, F. W., et al. Vascular Access Surgery Timing: A Prospective European Cohort Study in Elderly Patients with ESKD. Kidney360. 2026; 7(9): 2066-2074. Published: September 22, 2026. DOI: 10.34067/KID.0000001180.
AI-Assisted Colonoscopy for Colorectal Lesion Detection in Lynch Syndrome
A multicentre randomized trial of 733 patients with Lynch syndrome found that AI-assisted colonoscopy did not significantly increase adenoma detection compared with high-definition white-light colonoscopy alone (33.8% vs 30.9%; P=0.41). AI-based lesion characterization showed good sensitivity and specificity but did not clearly improve on expert optical diagnosis in specialized surveillance settings.
KEY FINDINGS: In this international randomized trial conducted at specialized Lynch syndrome surveillance centres, adding AI-assisted detection to high-definition white-light colonoscopy did not significantly increase adenoma detection. Although the CADx system demonstrated good sensitivity and specificity for lesion differentiation, it did not clearly provide an advantage over expert optical diagnosis in this specialist setting. The findings indicate that the benefit of AI-assisted colonoscopy may depend on the expertise and clinical setting in which it is deployed.
BACKGROUND: Individuals with Lynch syndrome undergo regular colonoscopic surveillance because of their increased risk of colorectal cancer. Artificial intelligence (AI)-based computer-aided detection (CADe) has improved adenoma detection in average-risk colorectal cancer screening, but evidence in Lynch syndrome surveillance has been limited. The CADLY2 trial evaluated whether AI-assisted colonoscopy could improve adenoma detection and whether computer-aided optical diagnosis (CADx) could accurately differentiate neoplastic from non-neoplastic colorectal lesions.
DETAILS: This international, multicentre, open-label, randomized controlled trial was conducted at nine specialized hereditary cancer surveillance centres in Belgium, Germany, the Netherlands, and Spain. Adults aged 18 years or older with genetically confirmed Lynch syndrome undergoing surveillance colonoscopy were randomly assigned to high-definition white-light (HD-WL) colonoscopy alone or HD-WL colonoscopy assisted by the CAD EYE AI system. CADe was used during withdrawal to identify lesions, while CADx was used after lesion detection to assist with optical differentiation. The primary outcome was adenoma detection rate, defined as the proportion of patients with at least one histopathologically confirmed adenoma.
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Between May 9, 2023, and October 30, 2025, 757 patients were randomly assigned to HD-WL colonoscopy (377) or AI-assisted colonoscopy (380). The primary analysis included 733 patients: 369 in the HD-WL group and 364 in the AI-assisted group. Adenoma detection occurred in 30.9% of patients undergoing HD-WL colonoscopy compared with 33.8% receiving AI-assisted colonoscopy. The odds ratio was 1.14 (95% CI, 0.83-1.57; P=0.41), indicating no statistically significant improvement in adenoma detection with CADe. In the lesion-level analysis, CADx differentiated neoplastic from non-neoplastic lesions with a sensitivity of 85.9% (95% CI, 82.0-89.1) and specificity of 91.4% (95% CI, 89.4-93.0). Three adverse events occurred in the AI-assisted group, including two mild post-polypectomy bleeding events and one serious pulmonary embolism or deep venous thrombosis considered unrelated to the procedure. No adverse events were reported in the HD-WL group.
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Source: Hüneburg, R., van Bokhorst, Q. N. E., Pellisé, M., et al. Artificial intelligence-assisted detection and optical differentiation of colorectal lesions in Lynch syndrome surveillance (CADLY2): a multicentre, open-label, randomised controlled superiority trial. The Lancet Gastroenterology & Hepatology. 2026; 11(10): 875-886. Published: October, 2026. DOI: 10.1016/S2468-1253(26)00163-9.
Real-World Study Finds No Significant Difference in Heart Failure Risk Between Biosimilar and Reference Trastuzumab
In real-world practice, trastuzumab biosimilars were not associated with a statistically significant increase in heart failure compared with reference trastuzumab, supporting their cardiac safety. However, older age, anthracycline use, and greater comorbidity burden remain important risk factors, and larger studies are needed to assess cardiac safety differences among individual biosimilars.
KEY FINDINGS: In this large real-world cohort of patients with early-stage HER2-positive breast cancer, biosimilar trastuzumab use increased markedly between 2018 and 2024 without a statistically significant difference in heart failure risk compared with reference trastuzumab. Overall heart failure occurred in 5.9% of the study population. Comorbidity burden and older age were associated with higher heart failure risk, emphasizing the importance of cardiovascular risk assessment during HER2-directed therapy. Because this was a retrospective claims-based study, longer follow-up and additional real-world studies are needed to further evaluate long-term cardiac outcomes.
BACKGROUND: Trastuzumab is an important treatment for HER2-positive breast cancer, but cardiac dysfunction, including heart failure, remains a recognized safety concern. Biosimilar trastuzumab products have expanded treatment access and may reduce costs, although real-world data comparing their cardiac safety with the reference product remain limited. This study evaluated the uptake of biosimilar trastuzumab and compared heart failure risk between patients receiving biosimilar and reference trastuzumab in routine clinical practice.
DETAILS: The investigators analyzed patients aged ≥18 years with breast cancer who received trastuzumab between 2018 and 2024 using the IQVIA PharMetrics Plus Closed Health Plan Claims database. Patients who underwent breast cancer surgery within the first year after diagnosis were considered to have early-stage disease. Individuals with a heart failure diagnosis before breast cancer surgery were excluded. Trastuzumab products were identified using Healthcare Common Procedure Coding System Level II codes, while heart failure was identified using International Classification of Diseases codes. The analysis used multivariable cause-specific Cox proportional hazards regression to evaluate the association between trastuzumab type and subsequent heart failure risk. The study included 5,135 patients, of whom 43.9% received reference trastuzumab.
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Use of biosimilar trastuzumab increased substantially during the study period, from 0% in 2018 to 71.3% in 2024 (P<0.001). Overall, heart failure occurred in 5.9% of patients, including 5.5% of those receiving reference trastuzumab and 6.3% of those receiving biosimilar trastuzumab (P=0.26). After adjustment for relevant factors, there was no statistically significant difference in heart failure risk between biosimilar and reference trastuzumab (adjusted HR, 1.16; 95% CI, 0.92-1.46). In contrast, patients with a Charlson Comorbidity Index score ≥2 had a higher heart failure risk than those with a score of 0 (adjusted HR, 1.52; 95% CI, 1.11-2.08). Older age was also associated with greater risk: compared with patients aged 18-54 years, the adjusted HR was 1.61 (95% CI, 1.19-2.19) for those aged 65-74 years and 1.95 (95% CI, 1.29-2.96) for those aged ≥75 years.
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Source: Jackson, I., Zhang, N., Sullivan, M., et al. Real-World Cardiotoxicity of Biosimilar versus Reference Trastuzumab in Early HER2-Positive Breast Cancer. JACC: CardioOncology. Published: September 10, 2026. DOI: 10.1016/j.jaccao.2026.07.009.
Formononetin May Protect Against Anthracycline Cardiotoxicity Through Cardiac Metabolic Improvement
A preclinical study identified ERRa as an early metabolic regulator of anthracycline-induced cardiotoxicity, with its reduction occurring before overt cardiac dysfunction. Formononetin, an ERRa activator, improved cardiac metabolism and function in mouse and pig models while also enhancing doxorubicin's anticancer activity in breast cancer organoids. The findings suggest a potential dual-action strategy for protecting the heart during anthracycline therapy, but clinical studies are still needed.
KEY FINDINGS: The findings identify ERRα downregulation as an early and potentially causal component of anthracycline-induced cardiac injury. Formononetin improved cardiac energy metabolism and function in experimental models while retaining, and potentially enhancing, doxorubicin's anticancer activity in breast cancer organoids. The study therefore suggests that pharmacologic activation of ERRα could represent a future strategy for simultaneously addressing anthracycline cardiotoxicity and cancer treatment. However, the evidence remains preclinical, and clinical studies are required to determine whether these findings translate into cardioprotection in patients receiving anthracycline chemotherapy.
BACKGROUND: Anthracyclines such as doxorubicin are effective anticancer agents, but their use can be limited by anthracycline-induced cardiotoxicity (AIC). Early metabolic disturbances in cardiac muscle may contribute to the development of cardiac dysfunction. This study investigated the role of estrogen-related receptor α (ERRα), a regulator of cardiac energy metabolism, in AIC and evaluated whether pharmacologic activation of ERRα with formononetin could provide cardiac protection while maintaining anticancer activity.
DETAILS: The investigators used a porcine model of anthracycline cardiotoxicity to examine changes in ERRα over time and cardiomyocyte-specific gain- and loss-of-function mouse models to assess its functional role. Mechanistic experiments, including ChIP-qPCR, reporter assays, and microscale thermophoresis, were used to investigate how formononetin interacts with the ERRα pathway. Cardiac tissue from patients who had received chemotherapy was also examined, while human breast cancer patient-derived organoids were used to evaluate potential effects on tumor activity. ERRα expression was reduced in hearts from the porcine AIC model and in cardiac tissue from patients treated with chemotherapy. In pigs, the reduction occurred at the 6-week subclinical stage, before overt cardiac dysfunction developed. Increasing ERRα expression specifically in cardiomyocytes enhanced mitochondrial metabolic programs and fatty-acid oxidation and preserved systolic function after doxorubicin exposure, whereas ERRα reduction worsened metabolic dysfunction and cardiac impairment.
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Drug screening identified formononetin as a selective ERRα activator. In mouse and pig models, formononetin increased ERRα activity, improved cardiac mitochondrial metabolism, and reduced anthracycline-associated cardiac injury. Mechanistic experiments indicated that formononetin interacts with the ERRα/PGC-1α complex and promotes its stability, supporting activation of downstream metabolic pathways.
Importantly, formononetin also demonstrated anticancer activity in human breast cancer patient-derived organoids. Treatment with formononetin alone reduced organoid viability and proliferation, while combining formononetin with doxorubicin produced greater antitumor effects.
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Source: Wang, X., Ling, G., Wei, Y., et al. Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement. Circulation Research. 2026; 139(7): e329042. Published: September 11, 2026. DOI: 10.1161/CIRCRESAHA.126.329042.
Self-Sampling HPV Testing Increases Cervical Cancer Screening Uptake in Primary Care
A Singapore randomized trial found that offering HPV self-sampling increased cervical cancer screening uptake from 42.8% to 56.6%. More than half of screened women chose self-sampling, suggesting that flexible screening options may help reach women who otherwise remain unscreened.
KEY FINDINGS: Offering HPV self-sampling as an additional screening option substantially increased cervical cancer screening participation and high-risk HPV detection compared with clinician sampling alone in this Singapore primary care population. The benefit was particularly relevant to women who had never previously undergone screening, suggesting that providing greater choice and convenience may help reach populations that are otherwise difficult to engage. More than half of screened women in the intervention group selected self-sampling, indicating substantial acceptance of this approach. However, lower uptake among women with less educational attainment highlights the need for targeted education and engagement strategies when implementing self-sampling programs.
BACKGROUND: Cervical cancer screening remains suboptimal in Singapore, where clinician-collected HPV testing has been the standard approach. Concerns related to discomfort, privacy, embarrassment, or the clinical setting may discourage some women from participating in screening. This pragmatic randomized controlled trial evaluated whether offering self-sampling for HPV DNA testing alongside clinician sampling could increase cervical cancer screening uptake and detection of high-risk human papillomavirus (HPV) compared with clinician sampling alone.
DETAILS: The open-label, 2-arm randomized controlled trial used a Zelen design and was conducted across National Healthcare Group Polyclinics in Singapore. Women aged 30-69 years who were due for cervical cancer screening were randomly assigned 1:1 to an intervention group or usual care. Women in the intervention group were offered clinician sampling followed by self-sampling if they did not choose clinician sampling, whereas women receiving usual care were offered clinician sampling alone. The primary outcome was detection of high-risk HPV DNA, with screening uptake as the secondary outcome.
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Between August 2024 and February 2025, 650 women were randomized, with 640 participants included in the final analysis, 320 in each group. Subgroup analyses evaluated outcomes according to previous screening history, while multivariable analyses examined factors associated with screening choices.
High-risk HPV detection was significantly greater when self-sampling was offered alongside clinician sampling than with clinician sampling alone: 3.1% versus 0.3%, respectively, representing an absolute difference of 2.8% (95% CI, 0.8-4.8; P<.001). The higher detection rate was driven by greater screening participation, with screening uptake reaching 56.6% in the intervention group compared with 42.8% with usual care, an absolute difference of 13.8% (95% CI, 6.0-21.4; P<.001).
The increase in screening uptake was particularly evident among women who had no previous screening and those with a regular screening history. Among women who underwent screening in the intervention group, 56.4% selected self-sampling. Lower educational attainment was associated with lower odds of choosing self-sampling rather than declining screening altogether.
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Source: Ng, X. R., Quek, I. P., Pereira, M. J., et al. Effect of Self-Sampling HPV DNA Testing on Cervical Cancer Screening in Singapore's Primary Care: Pragmatic Randomized Controlled Trial Annals of Family Medicine.. 2026; 24(4): 291-300. Published: July, 2026. DOI: 10.1370/afm.250683.
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