RCT Results: Could Risk-Based Breast Cancer Screening Safely Replace Annual Mammography?

BACKGROUND AND PURPOSE:

• Esserman et al. (JAMA, 2025) investigated whether risk-based breast cancer screening is a feasible alternative to annual mammography

METHODS:

• Parallel-group, pragmatic, multicenter randomized clinical trial
  • Women Informed to Screen Depending on Measures of Risk (WISDOM) trial 
  • Women from all 50 US states
• Participants
  • 40 to 74 years
  • Without
    • Prior diagnoses of breast cancer
    • Ductal carcinoma in situ
    • Prophylactic bilateral mastectomy
  • Women who declined randomization were enrolled in an observational cohort
• Interventions
  • Risk-based screening based on the following
    • Sequencing of 9 breast cancer susceptibility genes | Polygenic risk score | The Breast Cancer Surveillance Consortium (v2) risk prediction tool
    • Highest risk
      • ≥6% 5-year risk | High-penetrance pathogenic variant
      • Strategy: alternating mammography and MRI every 6 months and counseling
    • Elevated risk
      • Top 2.5 risk percentile by age
      • Strategy: Annual mammography and risk-reduction counseling
    • Average risk
      • Strategy: Biennial mammography
    • Low risk
      • Aged 40 to 49 years and <1.3% 5-year risk
      • Strategy: No screening until risk is ≥1.3%, or age 50
  • Annual screening with mammography
• Primary outcomes
  • Noninferiority for stage ≥IIB cancers
  • Superiority for reducing biopsy rates
• Secondary outcomes
  • Identification of stage ≥IIA cancers
  • Mammogram rates
  • Uptake of prevention strategies in higher risk cohorts
  • Preference for screening group in the observational cohort
  • Ductal carcinoma in situ
  • MRI
  • Stage-specific cancer rates

RESULTS:

• 28,372 women
  • Mean age: 54 (SD, 9.6) | Non-Hispanic White: 77%
  • Median follow-up: 5.1 years
• The rate of stage ≥IIB cancers was noninferior in the risk-based compared with the annual group
  • Risk-based: 30.0 (95% CI, 16.3 to 43.8) per 100,000 person-years
  • Annual: 48.0 (95% CI, 30.1 to 65.5) per 100,000 person-years
  • Rate difference (RD) −18.0 per 100,000 person-years (95% CI, −40.2 to 4.1)
• The rate of breast biopsies was not lower in the risk-based group
  • RD 98.7 per 100,000 person-years (95% CI, −17.9 to 215.3)
• This was despite fewer mammograms in the risk-based group
  • RD 3835.9 (95% CI, −4516.8 to −3154.9)
• As risk category increased, so did the cumulative incidence of
  • Cancer
  • Biopsy
  • Mammogram
  • MRI
• In the observational cohort, the majority of participants chose risk-based screening: 89%

CONCLUSION:

• A risk-based breast cancer screening approach did not lead to safety concerns (higher rates of later stage disease) nor reduce the number of biopsies performed
• The authors state

The WISDOM study demonstrated that a risk-based approach successfully stratifies the population for breast cancer risk and is safe and acceptable to women

Work is ongoing in the next platform iteration, WISDOM 2.0, to utilize PRS for subtype-specific and ancestry-based risk assessment, along with radiographic (AI) measures of risk

Learn More – Primary Sources:

Risk-Based vs Annual Breast Cancer Screening: The WISDOM Randomized Clinical Trial

Meta-Analysis: Do GLP-1RAs Impact Risk of Obesity-Related Cancer?

BACKGROUND AND PURPOSE:

• Whether GLP-1RAs, such as semaglutide or tirzepatide, are associated with cancer risk is unclear
• Ko et al. (Annals of Internal Medicine, 2025) investigated the risk for obesity-related cancer associated with GLP-1RAs

METHODS:

• Systematic review and meta-analysis
• Inclusion criteria
  • Randomized placebo-controlled trials
  • Studies that reported on cancer outcomes
    • Thyroid | Pancreatic | Colorectal | Gastric | Esophageal | Liver | Gallbladder | Breast | Ovarian | Endometrial | Kidney | Multiple myeloma | Meningioma
• Study design
  • Risk of bias was assessed
  • Certainty of evidence was assessed with GRADE criteria
  • Random-effects meta-analysis was used to generate pooled odds ratios
• Primary outcome
  • Cancer risk

RESULTS:

• 48 trials | 94,245 participants
• GLP-1RAs probably have little or no effect on risk of
  • Thyroid cancer
    • Odds ratio (OR) 1.37 (95% CI, 0.82 to 2.31)
    • –1 to 9 cases per 10,000 patients treated | Moderate certainty
  • Pancreatic cancer
    • OR 0.84 (95% CI, 0.53 to 1.35)
    • –9 to 6 per 10,000 patients treated | Moderate certainty
  • Breast cancer
    • OR 0.95 (95% CI, 0.60 to 1.49)
    • –10 to 12 per 10,000 patients treated | Moderate certainty
  • Kidney cancer
    • OR 1.12 (95% CI, 0.78 to 1.60)
    • –5 to 13 per 10,000 patients treated | Moderate certainty
• GLP-1RAs may have little or no effect on
  • Colorectal | Esophageal | Liver | Gallbladder | Ovarian | Endometrial cancer
  • Multiple myeloma | Meningioma
  • All low certainty
• The effect of GLP1-RAs on gastric cancer is very uncertain
• These results remained the same after additional analyses
  • Trials with low risk of bias
  • Studies on semaglutide or tirzepatide
• Results were also consistent across subgroups stratified by
  • Follow-up duration | Population | GLP-1RA class | Weight loss profile | Dose | Duration of action

CONCLUSION:

• GLP1-RAs may have little to no impact on the risk of cancers associated with obesity
• While the strength of this study is the use of RCTs, follow-up time was limited
• The authors state

Taken together, these findings offer important insights into the safety of GLP-1RAs but highlight the need for longer-term studies with cancer-specific end points to clarify potential risks or protective effects

Learn More – Primary Sources:

Risk for Cancer With Glucagon-Like Peptide-1 Receptor Agonists and Dual Agonists: A Systematic Review and Meta-analysis

Meta-Analysis: Is Transabdominal Cervical Cerclage Better at Reducing Preterm Birth vs Transvaginal Cerclage?

BACKGROUND AND PURPOSE:

• Bobotis et al. (AJOG, 2025) compared the impact of transvaginal and transabdominal cervical cerclage on obstetrical and perinatal outcomes in women at risk for preterm birth

METHODS:

• Systematic review and meta-analysis
• Inclusion criteria
  • Randomized and observational studies
  • Studies that assessed the impacts of different cervical cerclage surgical approaches on obstetrical and neonatal outcomes for women at risk of preterm birth
• Study design
  • The Risk of Bias was assessed
  • Quality of evidence was assessed with GRADE criteria
  • Pooled risk ratios were calculated using a random-effects model
• Primary outcomes
  • Perinatal mortality
  • Preterm birth

RESULTS:

• 12 studies | 1110 patients
  • History of TVC failure: 5 studies
  • History of cervical surgery (e.g., conization): 3 studies
• Transabdominal cerclage (both open and laparoscopic approaches) was associated with a lower rate of perinatal mortality than transvaginal cerclage
  • Risk ratio (RR) 0.36 (95% CI, 0.14 to 0.95)
  • I2=50% | 8 studies | 975 participants
  • Low-quality evidence
• The rate of preterm birth was also lower in the transabdominal cerclage group
  • RR 0.49 (95% CI, 0.25 to 0.94)
  • I2=73% | 8 studies | 932 participants
  • Low-quality evidence
• The rates of perinatal mortality and preterm birth were similar among patients who underwent open vs laparosopic transabdominal cerclage
  • Perinatal mortality
    • RR 1.24 (95% CI, 0.35 to 4.35)
    • I2=0% | 3 studies | 122 participants
  • Preterm birth
    • RR 1.23 (95% CI, 0.60 to 2.54)
    • I2=40% | 2 studies | 99 participants

CONCLUSION:

• Transabdominal cerclage is associated with reduced rates of perinatal mortality and preterm birth particularly among patients with previous transvaginal cerclage failure or surgically altered cervix  
• The authors state

Given the frequency of prematurity and the increased associated morbidity and mortality, TACs deserve further study as a potential therapeutic option for these patients

Learn More – Primary Sources:

Transabdominal vs transvaginal cervical cerclage in the prevention of preterm birth: a systematic review and meta-analysis

Cochrane Review: What are the Long-Term Benefits of HPV Vaccination and How Common Are Rare Vaccine-Related Adverse Events?

BACKGROUND AND PURPOSE:

• Henschke et al. (Cochrane Database of Systematic Reviews, 2025) assessed population-level effects of HPV vaccination programs on HPV-related disease and harms from vaccination

METHODS:

• Systematic review and meta-analysis
• Inclusion criteria
  • Population-level studies that compared outcomes before and after the introduction of the HPV vaccine
  • Individual-level nonrandomized comparative studies
• Study design
  • Risk of bias was assessed with tools appropriate for included study types
  • Certainty of evidence was assessed with GRADE criteria
  • Meta-analysis was adjusted for confounding, with a focus on those receiving HPV vaccination at or before the age of 16 years
• Primary outcomes
  • Cervical cancers and other cancers
  • High-grade pre-cancer lesions
  • Adverse events

RESULTS:

• 225 studies | 132 million individuals
  • Cohort studies: 86 | Case-control studies: 4 | Cross-sectional studies: 46 | Pre-post vaccination studies: 69 | RCT extensions: 5 | Case series: 2 | ≥1 type of analysis: 13
  • Reported on females only: 177 | Reported on males only: 11 | Reported on both: 37
  • Risk of bias was moderate to critical

Cervical Cancer

• HPV vaccination likely reduces the incidence of cervical cancer
  • 20 studies | Moderate certainty
• From cohort studies. There was a reduced risk of cervical cancer following HPV vaccination in the long term
  • Risk ratio (RR) 0.37 (95% CI, 0.25 to 0.56) | I2=88%
  • 5 studies | 4,390,23 females
• There was a significant interaction with age at vaccination, with a greater risk reduction in younger people
  • Vaccinated ≤16 years of age
    • RR 0.20 (95% CI, 0.09 to 0.44) | I²=69%
    • 4.54 million person-years
• Other studies that reported no cases of cervical cancer in HPV vaccination groups: 6
• Other studies that reported a reduction in cervical cancer incidence with HPV vaccination: 8

CIN3+

• HPV vaccination likely reduces the incidence of CIN3+
  • 23 studies | Moderate certainty
• In cohort studies, vaccination at or before 16 years of age reduced CIN3+ incidence in the long term
  • RR 0.26 (95% CI, 0.12 to 0.56) | I²=80%
  • 2 cohort studies | 1.5 million females
• Other studies that reported a decreased risk of CIN3+ with vaccination: 7
• Other studies that reported no difference in the risk of CIN3+: 1

CIN2+

• HPV vaccination likely reduces the incidence of CIN2+
  • 37 studies | Moderate certainty
• In cohort studies with females vaccinated ≤16 years, a reduction in risk was seen in the
  • Medium term
    • RR 0.59 (95% CI, 0.54 to 0.65) | I2=0%
    • 2 cohort studies | 233,468 females
  • Long term
    • RR 0.38 (95% CI, 0.31 to 0.45) | I2=64%
    • 5 cohort studies | 6,455,176 females

Anogenital Warts

• HPV vaccination likely reduces the incidence of anogenital warts
  • 47 studies | Moderate certainty
• In cohort studies, the pooled impact of HPV vaccination on rates of anogenital warts indicated a reduction in the
  • Medium term
    • RR 0.53 (95% CI, 0.37 to 0.77) | I2=98%
    • 4 cohort studies | 6,430,295 females | 313 males
  • Long term
    • RR 0.47 (95% CI, 0.36 to 0.61) | I2=99%
    • 13 cohort studies | 5,802,969 females and males
• Other studies that reported a decrease in anogenital warts with HPV vaccination: 23
• Other studies that reported no difference in anogenital warts with HPV vaccination: 6

Other Cancers

• There was little evidence on the effect of HPV vaccination on adenocarcinoma in situ
  • 3 studies | Very low certainty
• There was also little evidence on the effect of HPV vaccination on vulval cancer
  • 5 studies | Very low certainty

Adverse Events From Vaccination

• HPV vaccination was likely not associated with an increased risk of
  • Postural orthostatic tachycardia syndrome
  • Chronic fatigue syndrome/myalgic encephalomyelitis
  • Paralysis
  • Complex regional pain syndrome
  • Premature ovarian failure
  • Infertility or sexual activity
• HPV vaccination may not be associated with an increased risk of Guillain-Barré syndrome
  • Low certainty

CONCLUSION:

• HPV vaccination reduces the risk of cervical cancer and high-grade CIN
  • Benefits appear to be greater when vaccination occurs earlier in adolescence
• The authors state

There are now long‐term outcome data from different countries and from different study designs that consistently report a reduction in the development of high‐grade CIN and cervical cancer in females vaccinated against HPV in early adolescence

There is evidence that HPV vaccination does not increase the risk of the most common adverse events reported on social media

Learn More – Primary Sources:

Effects of human papillomavirus (HPV) vaccination programmes on community rates of HPV-related disease and harms from vaccination

How Much Does Physical Activity in Later Life Help Protect Against Dementia?

BACKGROUND AND PURPOSE:

• Marino et al. (JAMA Network Open, 2025) examined whether higher physical activity levels in early adult life, midlife, or late life are associated with lower risk of all-cause or Alzheimer disease (AD) dementia

METHODS:

• Prospective cohort study
  • Data derived from the Framingham Heart Study
• Population
  • Dementia Free
  • Had physical activity measured at baseline
• Exposures
  • Self-reported physical activity using the physical activity index
    • Composite score weighted by hours spent sleeping and in sedentary, slight, moderate, or heavy activity
  • Time in adult life course participants entered the study
    • Early adult life (1979 to 1983)
    • Midlife (1987 to 1991)
    • Late life (1998 to 2001)
• Study design
  • Follow-up was for 37.2 (SD, 7.1) years for those who entered in early adult life to 14.5 (SD, 6.6) years for those who entered in late life
• Primary outcome
  • All-cause and AD dementia

RESULTS:

• Early life: 1526 participants
  • Mean age: 36.7 (SD, 4.7) years | 53.8% female
• Midlife: 1943 participants
  • Mean age: 54.0 (SD, 5.8) years | 52.0% female
• Late life: 885 participants
  • Mean age: 71.0 (SD, 4.5) years | 53.4% female
• Cases of incident all-cause dementia during follow-up: 567
• Higher levels of midlife and late-life physical activity (quintile 4 or 5) were associated with lower risk of all-cause dementia, compared to lower levels (quintile 1)
  • Midlife
    • Q4 vs Q1: HR 0.60 (95% CI, 0.41 to 0.89)
    • Q5 vs Q1: HR 0.59 (95% CI, 0.40 to0.88)
  • Late life
    • Q4 vs Q1: HR 0.64 (95% CI, 0.42 to 1.00)
    • Q5 to Q1: HR 0.55 (95% CI, 0.35 to 0.87)
• There were no associations between early adult–life physical activity and dementia risk
• Findings were similar for Alzheimer’s-specific dementia

CONCLUSION:

• Higher levels of physical activity in midlife and late life were associated with reduced risk of incident dementia
  • Physical activity in early adult life was not associated with dementia risk reductions
• The authors state

This study is among the first to evaluate the potential critical periods for physical activity in association with dementia risk

These findings may inform future efforts to delay or prevent dementia through timing interventions and public health promotion efforts during the most relevant stages of the adult life course

Learn More – Primary Sources:

Physical Activity Over the Adult Life Course and Risk of Dementia in the Framingham Heart Study

Does the Current USPSTF Lung Cancer Screening Recommendation Exclude Patients at High-Risk?

BACKGROUND AND PURPOSE:

• The US Preventive Services Task Force (USPSTF) currently recommends lung cancer screening with low-dose computed tomography for adults >50 years with a history of smoking
  • Lung cancer rates among never smokers are increasing, suggesting that the current recommendations may exclude some at-risk populations
• Yang et al. (JAMA Network Open, 2025) evaluated the proportion of patients with lung cancer who meet or are excluded from USPSTF criteria 

METHODS:

• Retrospective cohort study
  • Data derived from electronic medical records at Northwestern University, Chicago
• Population
  • Individuals with lung cancer diagnosed between 2018 and 2023
  • Individuals were stratified by 2021 USPSTF eligibility
    • Age 50 to 80 | ≥20 pack-years | Current or quit <15 years
• Exposure
  • Diagnosis of lung cancer
• Study design
  • Group comparisons were performed using Pearson χ2 or Fisher exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables
  • Cox proportional hazards models were used to calculate hazard ratios
• Primary outcome
  • Proportion of patients meeting USPSTF criteria
• Secondary outcomes
  • Survival
  • Clinical characteristics
  • Impact of expanded screening scenarios on detection, cost-effectiveness, risk

RESULTS:

• 997 patients
  • Median age: 67 (IQR, 18 to 99) | Women: 58.0%
  • Met USPSTF criteria: 35.1%
• The individuals that did not meet USPSTF criteria included
  • More women
    • Met criteria: 52.0% women | Did not meet criteria: 61.0% women
  • More Asian patients
    • Met criteria: 3.7% Asian | Did not meet criteria: 9.6% Asian
  • More never smokers
    • Met criteria: 0% | Did not meet criteria: 38.0%
  • More individuals with adenocarcinoma diagnoses
    • Met criteria: 55.0% | Did not meet criteria: 72.0%
• Individuals who did not meet screening criteria were more likely to have better survival outcomes
  • Met criteria: median 4.4 (IQR, 3.7 to 6.0) years
  • Did not meet criteria: median 9.5 (IQR, 6. 6 to 12.3) years
  • Hazard ratio (HR) 0.67 (95% CI, 0.55 to 0.82) | P<0.001
• Reasons for screening eligibility among ineligible patients with lung cancer
  • Never smoker: 24.8%
  • Quit longer than 15 years: 13.0%
  • <20 pack-years: 6.5%
  • Aged outside 50 to 80 rang: 4.1%
• Detection would improve to 62.1% if criteria were expanded to include
  • Age 40 to 85 years
  • ≥10 pack-years
  • No cessation limit
• The modeled age-based screening (40 to 85 years) detected 93.9% of cases
  • Deaths prevented annually: 26,124 (95% CI, 20,000 to 32,248)
  • Cost per life saved: $101,000 (95% CI, 82,000 to 120,000)
• The cost of screening per life saved was lower for the modeled lung cancer screening, compared to breast cancer screening or colorectal cancer screening
  • Breast cancer: $890,000 (95% CI, $700,000 to $1,100,000)
  • Colorectal cancer: $920,000 (95% CI, $700,000 to $1,200,000)
• Additional analysis confirmed robust findings across all parameter ranges
  • Probability of superior cost-effectiveness: 98.7%

CONCLUSION:

• Current USPSTF lung cancer screening guidelines exclude many patients who go on to be diagnosed with lung cancer
  • This excluded group is disproportionately female and never-smokers
• The authors state

Current USPSTF guidelines missed nearly two-thirds of cases, disproportionately excluding women, individuals from minoritized racial and ethnic groups, and never-smokers with favorable prognoses

Age-based screening (40-85 years) could enhance detection to 93.9%, prevent 26 124 deaths annually, and prove 6-fold more cost-effective than existing cancer screening programs

Learn More – Primary Sources:

Age-Based Screening for Lung Cancer Surveillance in the US

RCT Results: Is Chest Wall Radiotherapy Necessary for Patients with Intermediate Risk-Breast Cancer?

BACKGROUND AND PURPOSE:

• Intermediate-risk breast cancer refers to patients with stage II breast cancer and involvement of 1-3 axillary nodes or node negative with additional risk factors (e.g., larger tumor size, histologic grade 3 or lymphovascular invasion)
• Kunkler et al. (NEJM, 2025) investigated overall survival of postmastectomy radiotherapy selectively delivered to the chest wall in patients with intermediate-risk breast cancer

METHODS:

• International, phase 3, randomized trial
  • SUPREMO (Selective Use of Postoperative Radiotherapy after Mastectomy) trial
  • UK (125 sites) | Europe (25 sites in 7 countries) | Israel (1 site) | Turkey (1 site)
• Participants
  • Women with intermediate-risk breast cancer treated with mastectomy, an axillary procedure and systemic therapy
    • Stage pT1N1, pT2N1, or pT3N0 or
    • Stage pT2N0 with a histologic grade of 3, lymphovascular invasion, or both
• Interventions
  • Chest-wall irradiation (40 to 50 Gy)
  • No irradiation
• Study design
  • Analysis was by intention to treat
• Primary outcome
  • Overall survival at 10 years
• Secondary outcomes
  • Chest-wall recurrence
  • Regional recurrence
  • Disease-free survival
  • Distant metastasis-free survival
  • Cause of death
  • Radiation-related adverse events

RESULTS:

• Irradiation group: 808 participants | No irradiation group: 799 participants
  • Median follow-up: 9.6 years
• There was no significant difference in overall survival between the groups
  • Irradiation: 81.4% | No irradiation: 81.9%
  • Hazard ratio (HR) for death: 1.04 (95% CI, 0.82 to 1.30) | P=0.80
• There were fewer chest-well recurrences in the irradiation group
  • Irradiation: 1.1% | No irradiation: 2.5%
  • Between group difference <2 percentage points
  • HR 0.45 (95% Ci, 0.20 to 0.99)
• There was no difference in
  • Disease-free survival
    • Irradiation: 76.2% | No irradiation: 75.5%
    • HR for recurrence or death: 0.97 (95% CI, 0.79 to 1.18)
  • Distant metastasis-free survival
    • Irradiation: 78.2% | No irradiation: 79.2%
    • HR for distant metastasis or death: 1.06 (95% CI, 0.86 to 1.31)

CONCLUSION:

• For breast cancer patients with intermediate-risk of recurrence treated with mastectomy and contemporary adjuvant systemic therapy, radiotherapy of the chest wall did not improve overall survival rates
• The authors suggest that while local therapy supports better systemic treatment, current systemic therapies have passed the point where chest-wall irradiation adds benefit
• The authors state

We hope that our results stimulate a reevaluation of the evidence base for indications for chest-wall irradiation

Continuing to recommend chest-wall irradiation, in contexts in which evidence of benefit is marginal and the procedure is potentially detrimental, may divert limited resources from more effective treatments

Learn More – Primary Sources:

What is the Potential Effectiveness of Universal Screening for Germline Pathogenic Variants Among Women with Invasive Breast Cancer?

How Prevalent are Non-Colorectal or Endometrial Cancers Among Individuals with Lynch Syndrome?

BACKGROUND AND PURPOSE:

• There is emerging evidence that Lynch Syndrome (LS) is associated with additional cancer types beyond colorectal and endometrial cancer
• Negro et al. (eClinicalMedicine, 2025) evaluated the incidence of non-colorectal/endometrial cancers in individuals with LS

METHODS:

• Retrospective cohort study
  • Data derived from 2 centers in Italy
  • Between 1995 and 2023
• Population
  • Patients with LS
• Exposures
  • Mismatch repair proteins (MMRs) immunohistochemistry detected gene mutations
• Study design
  • Standardized incidence ratios (SIRs) were calculated, with adjustment for
    • Age | Sex | Country
• Primary outcome
  • Cancer type
  • Age at diagnosis
  • Time to LS confirmation

RESULTS:

• 570 patients with LS
  • Median age at diagnosis of LS: 50 (IQR, 38 to 61) years
• Malignancies detected
  • Colorectal cancer: 44% of patients
  • Endometrial cancer: 17% of patients
  • Non-colorectal or endometrial cancer: 40%
• Most common types of non-colorectal/endometrial cancer
  • Urothelial: 8%
  • Breast: 8%
  • Ovarian: 6%
  • Gastric: 4%
• Cancers with the highest standardized incidence ratios
  • Small intestine: SIR 10.54 (95% CI, 5.90 to 17.39)
  • Urothelium/kidney: SIR 7.55 (95% CI, 5.42 to 10.24)
  • Gastric: SIR 4.68 (95% CI, 2.90 to 7.16)
  • Ovary: SIR 3.80 (95% CI, 2.32 to 5.87)
  • Pancreas: SIR 3.09 (95% CI, 1.69 to 5.18)
• Patients diagnosed with non-colorectal/endometrial cancers before genetic testing: 11%
  • Later developed colorectal or endometrial cancer: 46%
  • Median time to onset
    • Colorectal cancer: 10 (IQR, 5 to 15) years
    • Endometrial cancer: 6 (IQR, 2 to 9) years

CONCLUSION:

• 40% of LS patients were diagnosed with a non-colorectal or endometrial cancer
• 11% of these diagnoses occurred before genetic testing
• The authors state

The spectrum of extracolonic malignancies linked to the syndrome is broader than previously recognized and differs significantly from the original descriptions

In addition to the well-established malignancies, a growing number of additional cancers are emerging as candidates for inclusion in LS spectrum

Learn More – Primary Sources:

Incidence of non-colorectal/endometrial malignancies in individuals with Lynch syndrome: a retrospective cohort study

Meta-Analysis: Are Viral Infections Associated with Increased Risk of Cardiovascular Disease?

BACKGROUND AND PURPOSE:

• SARS-CoV-2 infection is known to increase the risk of acute myocardial infarction and stroke but other viral infections may also carry risk for future cardiovascular disease (CVD)
• Kawai et al. (Journal of the American Heart Association, 2025) examined the association between viral infections and risk of CVD

METHODS:

• Systematic review and meta-analysis
• Inclusion criteria
  • Cohort and case-control studies
  • Studies that examined the association of any viral infection with the risk of CVD
  • Excluded: Cross sectional studies
• Study design
  • Random effects models were used to estimate pooled adjusted risk ratio (aRR)
• Primary outcome
  • Cardiovascular disease, including coronary heart disease (CHD) and stroke

RESULTS:

• 155 studies
• HIV infection was consistently associated with an elevated risk of
  • CHD: pooled aRR 1.60 (95% CI, 1.38 to 1.85)
  • Stroke: aRR 1.45 (95% CI, 1.26 to 1.67)
• SARS-CoV-2 was associated with an increased risk of
  • CHD: aRR 1.74 (95% CI, 1.44 to 2.11)
  • Stroke aRR 1.69 (95% CI, 1.23 to 2.31)
• In self-controlled case series studies, laboratory‐confirmed influenza infection was associated with an elevated risk of
  • Acute myocardial infarction: pooled incidence rate ratio (IRR) 4.01 (95% CI, 2.66 to 6.05)
  • Stroke during the first month: IRR 5.01 (95% CI, 3.41 to 7.37)
• In cohort studies, hepatitis C virus infection was associated with a higher risk of
  • CHD: RR 1.27 (95% CI, 1.13 to 1.42)
  • Stroke: RR 1.23 (95% CI, 1.04 to 1.46)
• Herpes zoster was also associated with an elevated risk of
  • CHD: RR 1.12 (95% CI, 1.08 to 1.15)
  • Stroke: RR 1.18 (95% CI, 1.09 to 1.27)
• There is insufficient evidence to determine whether there is a link between cytomegalovirus and CVD
• There is limited evidence that there is an increased risk of CVD with
  • Hepatitis A virus
  • Herpes simplex virus type 1
  • Respiratory syncytial virus
  • Human papillomavirus
  • Dengue
  • Chikungunya

CONCLUSION:

• Several viral infections are associated with an increased risk of CVD, including coronary heart disease and stroke
  • Influenza
  • SARS-CoV-2
  • HIV
  • Hep C
  • Herpes zoster
• The authors suggest that vaccination may be an important method for preventing cardiovascular disease
• The authors state

Our study highlights the importance of integrated preventive measures, especially for adults with traditional risk factors for CVD

Learn More – Primary Sources:

Viral Infections and Risk of Cardiovascular Disease: Systematic Review and Meta‐Analysis

RCT Results: Does Azelastine Nasal Spray Reduce the Risk of COVID?

BACKGROUND AND PURPOSE:

• Azelastine is an antihistamine nasal spray that has shown antiviral activity against respiratory viruses, including SARS-CoV-2
• Lehr et al. (JAMA Internal Medicine, 2025) assessed the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults

METHODS:

• Double-blind, placebo-controlled, single-center trial
  • CONTAIN study
  • Conducted in the state of Saarland, Germany
  • From March 2023
• Participants
  • 18 to 65 years
  • Healthy adults from the general population
• Interventions
  • Azelastine: 0.1%, nasal spray, 3 times daily for 56 days | If developed acute symptoms, confirmed SARS-CoV-2 infection of knowledge of contact with infected person then5 times daily over 3 days
  • Placebo
• Study design
  • SARS-CoV-2 rapid antigen testing (RAT) was conducted twice weekly
    • Positive results were confirmed with PCR testing
  • Patients who were symptomatic but had a negative RAT test underwent multiplex PCR for respiratory viruses
  • Analysis was by intention to treat
• Primary outcome
  • PCR-confirmed SARS-CoV-2 infections

RESULTS:

• Azelastine: 227 participants | Placebo: 223
  • Female: 66.4% | Mean age: 33.0 (SD, 13.3) years
  • White: 92.7% | African: 0.9% | Asian: 4.9% | Other: 1.6%
• The incidence of PCR-confirmed SARS-CoV-2 infection was significantly lower in the azelastine group
  • Azelastine: 2.2% | Placebo: 6.7%
  • Odds ratio (OR) 0.31 (95% CI, 0.11 to 0.87)
• Azelastine demonstrated an increase in mean time to SARS-CoV-2 infection among infected participants
  • Azelastine: 31.2 (SD, 9.3) days | Placebo: 19.5 (SD, 14.8) days
• Azelastine also reduced the overall number of PCR-confirmed symptomatic infections
  • Azelastine: 9.3% | Placebo: 22.0%
• Participants in the azelastine group also had lower incidence of PCR-confirmed rhinovirus infections
  • Azelastine: 1.8% | Placebo: 6.3%
• Adverse events were similar between the groups

CONCLUSION:

• Azelastine nasal spray was associated with a reduced incidence of SARS-CoV-2 infection
• The authors state

The established safety profile, over-the-counter availability, and ease of use of azelastine nasal spray support its potential as a practical, scalable on demand approach to preexposure prophylaxis, particularly in high-risk settings such as large gatherings or travel

… larger trials are warranted to confirm efficacy against SARS-CoV-2 and to explore potential benefits against other respiratory pathogens across more diverse populations and settings

Learn More – Primary Sources:

Azelastine Nasal Spray for Prevention of SARS-CoV-2 Infections: A Phase 2 Randomized Clinical Trial

RCT Results: Does Candesartan Reduce Migraine Days for Those with Episodic Migraine?

BACKGROUND AND PURPOSE:

• Candesartan is an angiotensin receptor blocker currently used for hypertension and heart failure and is available as a generic
• Øie et al. (The Lancet, 2025) evaluated the safety, tolerability, and efficacy of candesartan for the preventive treatment of episodic migraine

METHODS:

• Randomized, triple-blind, placebo-controlled, parallel-group trial
  • Norway and Estonia
• Participants
  • Adults 18 to 64 years
  • Experiencing 2 to 8 migraine attacks (with or without aura) per month
• Interventions
  • Oral candesartan 16 mg daily for 12 weeks
  • Placebo
• Study design
  • Acute migraine medication was permitted during the trial
    • Use of additional preventative treatments was prohibited
  • Analysis was by intention to treat
  • Safety analysis included all participants who received ≥1 dose of the trial drug
• Primary outcome
  • Change in mean number of migraine days per 4 weeks from baseline, to weeks 9 to 12

RESULTS:

• Candesartan 16 mg: 156 participants | Candesartan 8 mg: 150 participants | Placebo: 151 participants
  • Mean age: 38.7 (SD, 10.0) | Female: 86%
  • Mean number of migraine days at baseline: 5.7 (SD, 2.5)
• At weeks 9 to 12, there was a significant reduction in number of migraine days in both the candesartan 16 mg group and the placebo group, though the reduction was significantly greater in the candesartan 16 mg group
  • Candesartan 16 mg: 2.04 days (95% CI, 1.65 to 2.41) | P<0.0001
  • Placebo: 0.82 days (95% CI, 0.38 to 1.23) | P=0.0003
  • Difference: –1.22 (59% CI, –1.75 to –0.70) | P<0.001
• The most common adverse event with candesartan 16 mg was dizziness
  • Candesartan 16 mg: 30% | Placebo: 13%
• Serious adverse events
  • Candesartan 16 mg group: 3% | Placebo group: 1%
• Adverse events leading to discontinuation
  • Candesartan 16 mg: 3% | Placebo: 3%

CONCLUSION:

• In this multicenter study, daily candesartan 16 mg was an effective preventative treatment for those with episodic migraine
• The authors state

These findings support its role as a clinically meaningful and evidence-based option for migraine prevention

However, further clinical trials and real-world data from registry studies are necessary to assess its long-term efficacy

Learn More – Primary Sources:

Candesartan versus placebo for migraine prevention in patients with episodic migraine: a randomised, triple-blind, placebo-controlled, phase 2 trial

What Risk Factors are Associated with Progressive Hearing Loss?

BACKGROUND AND PURPOSE:

• Dillard et al. (JAMA Network Open, 2025) examined the 25-year cumulative incidence and progression of hearing loss and related risk factors

METHODS:

• Population-based cohort study
  • Framingham Offspring Study
• Population
  • Individuals in Framingham, MA with data from hearing examinations
• Exposures
  • Age | Sex | Education | Noise exposure history | Smoking and heavy drinking
  • Measured hypertension | Stroke risk (Framingham Stroke Risk Profile [FSRP]) | Low-density lipoprotein | High-density lipoprotein | Total cholesterol | Fasting blood glucose | Systolic and diastolic blood pressure | Waist circumference
• Study design
  • Hearing defined by worse-ear pure-tone average (PTA) of thresholds at frequencies
    • 0.5 | 1.0 | 2.0 | 4.0 kHz
  • Logistic and linear regression models were used to determine exposures associated with outcomes
    • Adjustment for sex and age
• Primary outcome
  • Hearing loss
    • Defined as PTA more than 25 dB HL
  • Hearing loss progression
    • Annualized increase in PTA

RESULTS:

• 511 participants
  • Mean age: 52.2 (SD, 7.2 | Range, 34.7 to 74.4)
  • Male: 41.5%
• 25-year cumulative incidence of hearing loss: 56.2%
• Mean hearing loss progression: 51.1 (SD, 11.6) dB
• Factors associated with incident hearing loss
  • Older age
  • Lower education
  • High noise exposure
  • Among participants aged >50 years
    • Hypertension | Higher FSRP
• Factors associated with hearing loss progression
  • Older age
  • Female sex
  • Lower education
  • Among participants aged >50 years
    • Hypertension | Higher diastolic BP

CONCLUSION:

• The 25-year cumulative incidence of hearing loss among aging adults was 56%
• Cardiovascular factors, such as elevated stroke risk (FSRP), hypertension, and higher diastolic blood pressure, were linked to the onset or progression of hearing loss in participants >50 years at baseline
• The authors state

Results from this study corroborate hearing loss as a common public health concern that may be at least partially preventable and provide important information regarding the incidence and natural history of hearing loss

Learn More – Primary Sources:

The 25-Year Incidence and Progression of Hearing Loss in the Framingham Offspring Study

Semaglutide and Cardiovascular Outcomes: Is Weight Loss the Only Factor?

BACKGROUND AND PURPOSE:

• In the SELECT trial, semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) reduced major cardiovascular events (MACE) in patients with obesity and preexisting cardiovascular conditions in participants without diabetes
• Deanfield et al. (The Lancet, 2025) examined whether factors beyond weight loss and waist circumference contribute to reductions in MACE risk

METHODS:

• Prespecified secondary analysis of a randomized, double-blind, placebo-controlled trial
  • SELECT trial
  • 41 countries
• Participants
  • Individuals ≥45 years
  • BMI ≥27 kg/m2
• Interventions
  • Once-weekly semaglutide with target dose of 2.4 mg 
  • Placebo
• Exposures
  • Adiposity change in the first 20 weeks | 104 weeks
• Study design
  • Adiposity measures included weight and waist circumference
• Primary outcome
  • Risk of MACE after 20 weeks
    • Composite: Cardiovascular death | Non-fatal myocardial infarction | Non-fatal stroke

RESULTS:

• 17,604 patients in SELECT
• Semaglutide reduced the incidence of MACE compared to placebo, regardless of baseline weight and waist circumference
• Within the semaglutide group, lower baseline bodyweight and waist circumference were associated with a lower incidence of MACE
  • Reduction in risk per 5 kg lower bodyweight
    • Hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.99) | P=0.001
  • Reduction in risk per 5 cm smaller waist circumference
    • HR 0.96 (95% CI, 0.93 to 0.99) | P=0.004
• In the placebo group, lower baseline waist circumference but not bodyweight was associated with a lower MACE risk
  • Lower baseline waist circumference
    • HR 0.96 (95% CI, 0.94 to 0.99) | P=0.007
  • Lower baseline bodyweight
    • HR 0.99 (95% CI, 0.97 to 1.01) | P=0.28
• In the placebo group, weight loss was paradoxically associated with increased MACE risk
• In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk
  • Greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk
• The observed benefit on MACE was mediated through waist circumference reduction, though this was minimized after adjustment for time-varying changes in waist circumference
  • HR 0.86 (95% CI, 0.77 to 0.97)

CONCLUSION:

• Semaglutide lowered cardiovascular risk independent of early weight loss, although there was a linear relationship associated with decreasing waist circumference  
• The authors state

This supports the reconceptualisation of GLP-1RAs as potential cardiovascular disease-modifying agents, with implications for clinical practice and health-care policy

Learn More – Primary Sources:

Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial

17 Years Later: Evaluating the Impact of the HPV Vaccine on Cancer Rates

BACKGROUND AND PURPOSE:

• While clinical trials showed the HPV vaccine is highly effective, its real-world impact especially among high-risk adolescents and young women is less well understood
• DeSieghardt et al. (JAMA Pediatrics, 2025) examined effectiveness and herd protection in this high-risk population over the first 17 years following HPV vaccine introduction

METHODS:

• Cross-sectional study
  • Data from 6 surveillance studies from 2006 to 2023
• Population
  • A consecutive sample of sexually experienced adolescent girls and young women aged 13 to 26 years
• Exposure
  • HPV vaccination status
    • Defined as receipt of ≥1 vaccine dose
  • HPV vaccine type
    • 2-valent vaccine (2vHPV) | 4-valent vaccine (4vHPV) | 9-valent vaccine (9vHPV)
• Study design
  • The prevalence of vaccine-type HPV was compared in vaccinated participants from studies 2 through 6, vs unvaccinated participants in study 1
  • Inverse probability of treatment weighting with propensity score was used to balance comparison groups
• Primary outcomes
  • Vaccine effectiveness
  • Herd protection

RESULTS:

• 2335 participants
  • Mean age: 18.9 (SD, 2.7) years
  • African American: 65.4% | Asian: 0.6% | Native American: 0.3% | White: 24.9% | Multiracial: 6.5% | Hispanic: 7.4%
  • Reported a STI history: 51.2% | Reported ≥2 male sex partners: 78.9%
• Vaccination rates increased from 2006 to 2023
  • 2006: 0% | 2023: 82.1%
• Among vaccinated participants, positivity for HPV types decreased between 2006 and 2023
  • 2vHPV studies
    • 2006: 27.7% | 2023: 0.4%
    • Relative difference 98.4%
  • 4vHPV studies
    • 2006: 35.4% | 2023: 2.1%
    • Relative difference 94.2%
  • 9vHPV studies
    • 2006: 48.6% | 2023: 11.8%
    • Relative difference: 75.7%
• Positivity for different HPV types also decreased among unvaccinated participants, though gains were smaller than vaccinated participants
  • 2vHPV studies
    • 2006: 25.8% | 2023: 7.3%
    • Relative difference: 71.6%
  • 4vHPV studies
    • 2006: 25.3% | 2023: 6.1%
    • Relative difference: 75.8%
  • 9vHPV studies
    • 2006: 42.7% | 2023: 31.3%
    • Relative difference: 27.2%
• There were significant reductions in the odds of at least 1 HPV type for 2vHPV, 4vHPV and 9vHPV studies
  • 2vHPV studies
    • All participants: Adjusted odds ratio (aOR) 0.03 (95% CI, 0.01 to 0.07)
    • Vaccinated participants: aOR 0.01 (95% CI, <0.01 to 0.05)
    • Unvaccinated participants: aOR 0.23 (95% CI, 0.08 to 0.63)
  • 4vHPV studies
    • All participants: aOR 0.06 (95% CI, 0.03 to 0.10)
    • Vaccinated participants: aOR 0.04 (95% CI, 0.02 to 0.08)
    • Unvaccinated participants: aOR 0.19 (95% CI, 0.07 to 0.52)
  • 9vHPV studies
    • All participants: aOR 0.22 (95% CI, 0.16 to 0.31)
    • Vaccinated participants: aOR 0.14 (95% CI, 0.09 to 0.21)

CONCLUSION:

• 17 years after the introduction of HPV vaccination, population-level vaccine effectiveness and herd immunity remain high
• The authors state

Our findings provide new evidence of robust effectiveness and herd protection in sexually experienced adolescent girls and young women at relatively high risk of HPV and associated cancers, even if they did not receive the recommended 2- or 3-dose vaccine series

Learn More – Primary Sources:

Population-Level Effectiveness and Herd Protection 17 Years After HPV Vaccine Introduction

Do LLMs Reason as Well as Attending Physicians?

BACKGROUND AND PURPOSE:

• It is challenging to measure large language model (LLM) performance on tasks requiring reasoning
• Script Concordance Testing (SCT) is a way to measure how well decisions can be adjusted when new information becomes available
• McCoy et al. (NEJM AI, 2025) created a SCT benchmark for LLM assessment to assess reasoning capabilities of these algorithms vs medical professionals  

METHODS:

• Public benchmark of 750 SCT questions
  • Drawn from 10 international, diverse datasets (9 newly releases) across multiple specialties
• SCT benchmark
  • Each item presents a clinical vignette
  • Data is added and the model is asked how the added data changed the likelihood of a diagnosis or management option
  • Model performance is scored against expert-panel responses
• Assessed
  • 10 state-of-the-art LLMs
  • 1070 medical students
  • 193 residents
  • 300 attending physicians

RESULTS:

• Overall, LLMs showed markedly lower performance on the SCT than they usually show on medical multiple-choice benchmarks
• Across prompting conditions, OpenAI’s o3 achieved the highest performance
  • OpenAI’s o3: 67.8% (SD, 1.2)
  • GPT-4o: 63.9% (SD, 1.3)
  • OpenAI’s o1-preview: 58.2% (SD, 1.3)
  • DeepSeek R1: 55.5% (SD, 1.4)
  • Google’s Gemini 2.5 Pro Preview: 52.1% (SD, 1.4)
• Reasoning-optimized models matched or exceeded student performance on multiple examinations but did not reach the level of senior residents or attending physicians
• Response-pattern analysis showed systematic overconfidence
  • Reasoning-tuned models overused strong, definitive answers
  • This suggests that training AI to explain its thinking step-by-step might actually make it less flexible when dealing with uncertain medical situations

CONCLUSION:

• Even among LLMs explicitly tuned for reasoning, SCT found that the clinical reasoning these models could display was limited
• The authors state

Our analysis of model response patterns reveals that even state-of-the-art LLMs exhibit striking overconfidence, disproportionately favoring extreme belief shifts and failing to recognize when new information should not alter clinical hypotheses

Learn More – Primary Sources:

Assessment of Large Language Models in Clinical Reasoning: A Novel Benchmarking Study

RCT Results: Lower Dose Oral Semaglutide Weight Loss Treatment for Obesity and Overweight

BACKGROUND AND PURPOSE:

• The OASIS 1 Trial found that 50 mg oral semaglutide reduced body weight and cardiovascular risk in individuals with overweight and obesity
  • A dose of 25 mg may also be appropriate for this population
• Wharton et al. (NEJM, 2025) evaluated the efficacy and safety of a lower 25 mg oral semaglutide dose for participants with overweight or obesity

METHODS:

• 71-week, double-blind, randomized, placebo-controlled trial
  • OASIS 4 Trial
  • 22 sites in four countries (Canada, Germany, Poland, and the US)
• Participants
  • Without diabetes
  • BMI ≥30 or BMI ≥27 with at least one obesity-related complication
• Interventions
  • Oral semaglutide, 25 mg, once daily
  • Placebo
• Study design
  • All participants were counseled in lifestyle interventions
• Primary outcomes
  • Percent change in body weight at week 64
  • Reduction of 5% or more in body weight
• Secondary outcomes
  • Reductions in body weight of ≥10% | ≥15% | ≥20%
  • Change in the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score

RESULTS:

• Oral semaglutide: 205 | Placebo: 102
• There was a significantly greater mean change in body weight at week 64 in the oral semaglutide group
  • Oral semaglutide: –13.6% | Placebo: –2.2%
  • Estimated difference, −11.4 percentage points (95% CI, −13.9 to −9.0) | P<0.001
• Participants in the oral semaglutide group were significantly more likely than those in the placebo group to have body-weight reductions of ≥5%, ≥10%, ≥15% and ≥20% (P<0.001 for all comparisons)
• Those who received oral semaglutide also had improved IWQOL-Lite-CT Physical Function score (P<0.001)
• Gastrointestinal adverse events were more common with oral semaglutide
  • Oral semaglutide: 74.0% | Placebo: 42.2%

CONCLUSION:

• For individuals with overweight or obesity and without diabetes, once daily oral semaglutide (25 mg) led to significantly greater body weight reduction vs placebo
• The authors state

In our trial, oral semaglutide at a dose of 25 mg once daily led to a clinically relevant mean reduction in body weight of 13.6%

Almost a third of the participants in the oral semaglutide group had a reduction in body weight of 20% or more

Learn More – Primary Sources:

Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity

Does Regular Brisk Walking Reduce Mortality Risk in Low-Income, Predominantly Black Populations?

BACKGROUND AND PURPOSE:

• Liu et al. (American Journal of Preventative Medicine, 2025) investigated the effects of factors like walking pace on mortality, including in low-income and Black populations

METHODS:

• Secondary analysis of a prospective cohort study
  • Data from Southern Community Cohort Study (please see ‘Learn More – Primary Sources’ on details regarding this study)
  • 12 southeaster US states | Recruitment mostly from community health centers
  • Between 2002 and 2009
  • Predominantly low-income and Black (approximately 70%)
• Participants
  • Adults
  • 40 to 79 years
• Exposures
  • Walking pace and duration
  • Demographic info
  • Lifestyle factors
• Primary outcome
  • Mortality

RESULTS:

• 85,000 adults
  • Median follow-up: 16.7 years
  • Deaths: 26,862
• There was a significant link between daily fast walking for as little as 15 minutes a day and lower all-cause mortality
  • Hazard Ratio (HR) 0.81 (95% CI, 0.75 to 0.87)
• Daily slow walking of even >3 hours was only associated with a modest reduction in risk
  • HR 0.96 (95% CI, 0.91 to 1.00)
• Fast walking was associated with reduced mortality, independent of leisure-time physical activity levels
• The inverse association was more pronounced for mortality due to cardiovascular diseases than cancers
• While all groups benefitted from fast walking, participants with baseline comorbidities showed larger risk reductions compared to generally healthy participants

CONCLUSION:

• Even 15 minutes of fast walking daily was associated with reduced risk of all-cause mortality in a diverse population and can be effective in reducing health disparities

Learn More – Primary Sources:

Daily Walking and Mortality in Racially and Socioeconomically Diverse U.S. Adults

Southern Community Cohort Study (SCCS)