EClinicalMedicine最新文献

Despite the availability of a wide range of antihypertensive agents, a significant proportion of individuals with resistant hypertension (RHTN) struggle to achieve blood pressure (BP) control. Obesity ranks among the most significant modifiable risk factors for RHTN, with 56-91% of patients with RHTN classified as overweight or obese. Glucagon-like peptide-1 receptor agonist (GLP-1 RAs) are a class of anti-obesity medications that have recently demonstrated efficacy in reducing BP and improving cardiovascular (CV) outcomes in individuals with overweight or obesity. Among the available GLP-1-based therapies, liraglutide, semaglutide, and tirzepatide have been approved for chronic weight management in this population. Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, has the greatest effect on weight loss and BP reduction compared to GLP-1 RAs alone. To our knowledge, no trials have directly evaluated the effect of GLP-1 RAs or dual GLP-1/GIP receptor agonists on RHTN management. In this review article, we propose that targeting weight loss through GLP-1-based therapies should be explored as a treatment option for individuals with RHTN who are overweight or obese.

Background: Hepatocellular carcinoma (HCC) surveillance is currently performed using a one-size-fits-all strategy with ultrasound plus AFP (US + AFP). There is increasing interest in risk-stratified and precision surveillance strategies incorporating individual risk and variance in surveillance test performance; however, the cost-effectiveness of these approaches has not been evaluated.

Methods: We conducted a cost-effectiveness analysis to evaluate four surveillance strategies (no surveillance, universal US + AFP surveillance, risk-stratified surveillance, and precision surveillance) in a simulated cohort of 50-year-old patients with compensated cirrhosis. The most cost-effective strategy was that with the highest incremental cost-effectiveness ratio (ICER) and below the willingness-to-pay (WTP) threshold of $150,000/QALY gained. Model inputs were based on literature review, and costs were derived from the Medicare fee schedule.

Findings: The precision surveillance strategy demonstrated variation in recommended surveillance test based on HCC risk category and patient factors. US + AFP, risk-stratified, and precision surveillance detected more HCC cases per 100,000 population than no surveillance, with a higher proportion of early-stage cases for precision surveillance (67.6%) than risk-stratified (63.8%), universal ultrasound (63.2%), and no surveillance (38.0%). Compared to no surveillance, precision surveillance was most cost-effective, with an ICER of $104,614/QALY gained, whereas US + AFP and risk-stratified surveillance were both dominated. Compared to US + AFP, risk-stratified surveillance was cost saving and dominated US + AFP, whereas precision surveillance was cost-effective, with an ICER of $98,103/QALY gained. Results were sensitive to survival with early-stage HCC, cost of early-stage HCC treatment, and surveillance utilization. Precision surveillance remained the most cost-effective when WTP thresholds exceeded $110,000/QALY gained.

Interpretation: A precision surveillance strategy is the most cost-effective method for HCC surveillance. This approach could maximize surveillance benefits in high-risk patients, while minimizing surveillance harms in low-risk individuals.

Funding: National Cancer Institute (U01 CA230694, R01 CA222900, R01 CA212008, and U24ca086368) and Cancer Prevention Research Institute of Texas (CPRIT) (RP200554).

Background: Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood.

Methods: A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10^-8) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV₁, FVC, and FEV₁/FVC) in subjects aged 4-50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old.

Findings: We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV₁/FVC from school age (7-10 years; β: -0.13 z-scores per one PRS z-score increase [-0.15, -0.11], q-value = 7.04 × 10^-53) to adulthood (41-50 years; β: -0.16 [-0.19, -0.13], q-value = 1.31 × 10^-24); and (2) lower FEV₁ (from school age: 7-10 years; β: -0.07 [-0.09, -0.05], q-value = 1.65 × 10^-9, to adulthood: 41-50 years; β: -0.17 [-0.20, -0.13], q-value = 4.48 x 10^-20). No effect modification by smoking, sex, or a diagnosis of asthma was observed.

Interpretation: We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards.

Funding: This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.

Background: Colorectal cancer is common and prognosis is improving. The conditions of survivors of treatment, including financial consequences, are thus important. The aim of this study was to quantify loss of earnings and work loss in working-age patients with colon and rectal cancer relative to matched comparators.

Methods: The study utilised data from the CRCBaSe database that is generated from the nationwide Swedish ColoRectal Cancer Register and includes data from several Swedish nationwide registers. The study period was 1995-2020 for rectal cancer patients and 2007-2020 for colon cancer patients. A retrospective population-based nationwide cohort study on earnings, disposable income, and work loss, in survivors of stage I-III colorectal cancer treatment was undertaken. Median regression was used to analyse earnings and disposable income, and logistic regression to analyse the probability of work loss.

Findings: A cohort of 8863 colorectal cancer survivors diagnosed before 2017 and 52,514 comparators matched on birth year, legal sex, and county of residence, was analysed. There was a clear reduction in earnings between the calendar year prior to and the calendar year after diagnosis, from € 31,319 to € 23,924 for colon cancer patients and from € 32,636 to € 22,647 for rectal cancer patients, and earnings never fully recovered during the 5-year follow-up. Disposable income was practically unaltered. The probability of work loss increased in the calendar year of diagnosis, from 29.8% to 25.3% the previous year to 83.3% and 84.4% for colon and rectal cancer patients respectively, and never fully recovered. The probability of work loss was similar between colon and rectal cancer survivors, but was higher among patients with rectal cancer who had received neoadjuvant therapy.

Interpretation: This study shows that despite an extensive welfare system providing maintained disposable income, there is a financial burden in the form of increased risk of work loss and a reduction in earnings among survivors of colorectal cancer.

Funding: The study was supported by the Swedish Cancer Society, the Swedish Cancer and Allergy Foundation, and the Stockholm Cancer Society, and supported by grants provided by the Regional Agreement on Medical Training and Clinical Research (ALF) between the Stockholm County Council and Karolinska Institutet.

Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer (LARC) increases pathologic complete response (pCR) rate and reduces the risk of systemic recurrences over chemoradiotherapy (CRT) in randomised trials, e.g., the RAPIDO trial. A modified RAPIDO schedule was prospectively explored in Sweden to evaluate TNT in routine health care before the RAPIDO results were published.

Methods: Between July 2016 and June 2020, 273 patients with high-risk LARC (clinical tumour stage cT4, clinical nodal stage cN2, extramural vascular invasion, involved mesorectal fascia or enlarged lateral lymph nodes) were treated in a prospective observational cohort study at 16 hospitals (LARCT-US). Another 189 patients at 18 (including the 16) hospitals were similarly treated (ad modum LARCT-US, AdmL) during the same period. Inclusion and exclusion criteria were identical to the RAPIDO trial. Patients received short-course radiotherapy (5 × 5 Gy for 5 days) followed by four cycles of CAPOX or six FOLFOX-6, followed by total mesorectal excision or, if clinical complete response (cCR), inclusion into a watch-and-wait (W&W) study. The primary endpoint was complete response (CR), i.e., the sum of pCR in specimens and cCR exceeding one year in W&W patients. Safety was assessed in all patients.

Findings: Compared to the RAPIDO trial, patients were older, and tumours more advanced. Median follow-up was 4.8 years (IQR 4.2-5.2). In LARCT-US all patients received radiotherapy and 268 (98%) started chemotherapy whereas in AdmL all patients received radiotherapy and chemotherapy. In LARCT-US 34 patients had pCR and 31 sustained cCR resulting in a CR-rate of 24% (95% CI 20-28). In AdmL, results were similar (23%, 95% CI 17-30). Locoregional recurrences were 6% (95% CI 4-10) and 5% (95% CI 2-9), respectively, both at 3 years and at last follow-up. Neurotoxicity, recorded in LARCT-US, was lower than in RAPIDO (EORTC-QLQ-CIPN20 tingling toes or feet mean score 24 (SD 31) vs 43 (SD 37)). One treatment-associated death occurred.

Interpretation: Despite older patients and more advanced tumours, results similar to the RAPIDO trial were obtained. Hence, two chemotherapy cycles less do not compromise the results maintaining a high CR-rate. This TNT schedule resulted in favourable outcomes in a nation-wide real-life situation.

Funding: Swedish Cancer Society.

Background: Exocrine Pancreatic insufficiency (EPI) occurs following acute pancreatitis (AP) at variably reported rates and with unclear recovery timeline. The aim of this study was to establish the prevalence and predictors of EPI at 12 months after AP in a prospective cohort.

Methods: In this prospective, multicentre, longitudinal cohort study, adult participants (≥18 years) admitted to the hospital with an AP attack (defined by Revised Atlanta Classification) were enrolled in a United States multi-centre longitudinal cohort (Sites: The Ohio State University, University of Pittsburgh, and Johns Hopkins University). Patients were excluded if they had pancreatic cancer, chronic pancreatitis, or malabsorptive disease (including previously diagnosed EPI). Participant data was obtained by interview and by review of the electronic medical record. EPI was assessed by stool fecal elastase (FE-1) levels collected at baseline, 3 months, and 12 months (primary endpoint). EPI was defined by FE-1 <200 μg/g; severe FE-1 level ≤100 μg/g; mild FE-1 101-200 μg/g. Multivariable logistic regression was used to identify predictors of EPI at 12 months. This study is registered with ClinicalTrials.gov, NCT03063398.

Findings: EPI was observed in 29 (34.1%) of the 85 participants [44 (51.8%) male, mean age 54.7 ± 14.1 years] who provided stool samples at 12 months. For the study overall, participants were recruited between June 22, 2017 and October 18, 2021. A total of 5794 individuals were screened, 311 of whom were eligible for the study. 112 participants provided stool samples at baseline, 79 completed stool samples at 3 months, and 85 completed samples at 12 months. 64 participants included samples at all 3 timepoints. In univariable analysis, factors significantly associated with EPI at 12 months included recurrent (versus index) AP, pre-existing diabetes, alcohol, and idiopathic etiologies, and increasing severity of AP. In multivariable analysis, the odds of having EPI at 12 months increased 4-fold with idiopathic AP etiology (Odds Ratio 4.095, 95% Confidence Interval [CI] 1.418, 11.826), and 3-fold with moderately severe or severe AP (Odds Ratio 3.166, 95% CI 1.156, 8.670), and baseline diabetes mellitus (Odds Ratio 3.217, 95% CI 1.113, 9.298). Even individuals with an index mild attack of AP (n = 39) developed severe EPI at 12 months (prevalence 12.8%).

Interpretation: EPI as diagnosed by FE-1 is present in over one third of prospectively assessed patients at 12 months post-AP. Since EPI develops in patients with mild AP, investigations are needed to understand the mechanisms of injury and identify methods for tailored screening.

Funding: This study was supported by an Investigator Initiated Research Grant from AbbVie, Inc.

Background: Premature ovarian failure (POF) is a prevalent and severe condition that impairs female health but there is currently no effective treatment available to restore ovarian function. Human amniotic epithelial cells (hAECs) exhibit ovarian protection in pre-clinical models. Thus, we conducted a single-arm, phase 1 clinical trial to assess the safety and efficacy of allogenic hAECs in treating POF.

Methods: A total of 35 patients received 6 × 10⁷ hAECs via ovarian artery and completed a five-month follow-up from December 30, 2020 to January 31, 2022. The follow-up assessments were conducted at various intervals after hAECs treatment, including one month (Visit-1, V-1), three months (Visit-2, V-2), and five months (Visit-3, V-3) post-treatment. The primary endpoints were incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of transvaginal ultrasound results, sex hormone levels, Menopausal Quality of Life (MENQOL) questionnaire, as well as reproductive indicators. This trial was registered at www.clinicaltrials.gov as NCT02912104.

Findings: No serious AEs were observed throughout the five-month follow-up period. The most common AE was hematoma (7/35, 20.00%), and other AEs include pelvic pain (4/35, 11.43%), fever (2/35, 5.71%), anaphylaxis (2/35, 5.71%), and hepatotoxicity (1/35, 2.86%). After hAECs transplantation (hAECT), significant improvements were observed in the levels of endometrial thickness, left ovarian volume, sex hormones (follicle-stimulating hormone (FSH) and estradiol (E2)), and MENQOL scores in all patients during the five-month follow-up period. Among them, 13 participants (37.14%) experienced spontaneous menstrual bleeding, and 20.00% (7/35) reported more than one regular menstrual bleeding post-hAECT. In this response group, significant improvements were observed in endometrial thickness, left ovarian volume, levels of FSH, E2, anti-Müllerian hormone (AMH), and MENQOL scores one month after hAECT in comparison to pre-hAECT.

Interpretation: hAECT via ovarian artery is safe, well-tolerated and temporarily ameliorates endometrial thickness, ovarian size, hormone levels, and menopausal symptoms in POF patients. Further randomized controlled trial of hAECs with longer follow-up period and a larger sample size is warranted.

Funding: National Natural Science Foundation of China (No. 82271664), the Interdisciplinary Program of Shanghai Jiao Tong University (YG2022ZD028), the Shanghai Municipal Health Committee (202240345), Shanghai Key Laboratory of Embryo Original Diseases (No. Shelab2022ZD01), Shanghai Municipal Education Commission (No. 20152236), and National Key Research and Development Program of China (No. 2018YFC1004802), Shanghai Clinical Research Center for Cell Therapy, China (No. 23J41900100).