EClinicalMedicine最新文献

Background: In the EC-CRT-001 phase II study, the combination of toripalimab (an anti-programmed death-1 antibody) and definitive chemoradiotherapy (CRT) has shown promising efficacy in patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Here, we reported the long-term outcomes and post-hoc exploratory analyses.

Methods: This single-arm, phase II trial enrolled 42 patients diagnosed with unresectable stage I-IVA ESCC was conducted at Sun Yat-sen University Cancer Center between November 2019 and January 2021. Treatment consisted of chemotherapy (weekly 50 mg/m² of paclitaxel and 25 mg/m² of cisplatin for five cycles), concurrent radiotherapy (50.4 Gy in 28 fractions), and toripalimab (240 mg every 3 weeks for up to 1 year). The primary endpoint was clinical complete response (CR) rate at 3 months after CRT completion. The 3-year overall survival (OS) and progression-free survival (PFS) rates were evaluated. Additionally, the exploratory objectives included analysing recurrence patterns, assessing the associations between immune-related adverse events (irAEs) and efficacy, and identifying potential predictors for irAEs. The trial was registered with ClinicalTrials.gov (NCT04005170).

Findings: With a median follow-up of 44.3 months (IQR 40.8-46.1), the 3-year OS and PFS rates were 44.8% (95% CI 31.9-62.8) and 35.7% (95% CI 23.8-53.6), respectively. Patients who failed to achieve a clinical complete response (CR) demonstrated significantly worse OS (hazard ratio [HR] = 13.73, 95% CI 4.43-42.54, P < 0.0001) and PFS (HR = 32.08, 95% CI 8.57-120.10, P < 0.0001). Disease recurrence occurred in 23 of 42 patients (55%), with recurrences being earlier and more frequent in the non-CR group compared to the CR group. Patients experiencing irAEs showed a significantly higher CR rate (72% vs. 39%, P = 0.082) and better PFS (HR = 0.43, 95% CI 0.19-0.93, P = 0.027) than those without irAEs. GON4L mutation was associated with a lower incidence of irAEs (P = 0.036).

Interpretation: The updated survival outcomes confirmed the efficacy of toripalimab plus definitive CRT in locally advanced ESCC. Moreover, the development of irAEs may predict a more favourable prognosis.

Funding: National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Sci-Tech Project Foundation of Guangzhou.

Background: During surgery, intraoperative hypotension is associated with postoperative morbidity and should therefore be avoided. Predicting the occurrence of hypotension in advance may allow timely interventions to prevent hypotension. Previous prediction models mostly use high-resolution waveform data, which is often not available.

Methods: We utilised a novel temporal fusion transformer (TFT) algorithm to predict intraoperative blood pressure trajectories 7 min in advance. We trained the model with low-resolution data (sampled every 15 s) from 73,009 patients who were undergoing general anaesthesia for non-cardiothoracic surgery between January 1, 2017, and December 30, 2020, at the General Hospital of Vienna, Austria. The data set contained information on patient demographics, vital signs, medication, and ventilation. The model was evaluated using an internal (n = 8113) and external test set (n = 5065) obtained from the openly accessible Vital Signs Database.

Findings: In the internal test set, the mean absolute error for predicting mean arterial blood pressure was 0.376 standard deviations-or 4 mmHg-and 0.622 standard deviations-or 7 mmHg-in the external test set. We also adapted the TFT model to binarily predict the occurrence of hypotension as defined by mean arterial blood pressure < 65 mmHg in the next one, three, five, and 7 min. Here, model discrimination was excellent, with a mean area under the receiver operating characteristic curve (AUROC) of 0.933 in the internal test set and 0.919 in the external test set.

Interpretation: Our TFT model is capable of accurately forecasting intraoperative arterial blood pressure using only low-resolution data showing a low prediction error. When used for binary prediction of hypotension, we obtained excellent performance.

Funding: No external funding.

Obesity and type 2 diabetes mellitus (T2DM) present major global health challenges, with an increasing prevalence worldwide. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a pivotal treatment option for both conditions, demonstrating efficacy in blood glucose management, weight reduction, cardiovascular disease prevention, and kidney health improvement. GLP-1, an incretin hormone, plays a crucial role in glucose metabolism and appetite regulation, influencing insulin secretion, insulin sensitivity, and gastric emptying. The therapeutic use of GLP-1RAs has evolved significantly, offering various formulations that provide different efficacy, routes of administration, and flexibility in dosing. These agents reduce HbA1c levels, facilitate weight loss, and exhibit cardiovascular protective effects, making them an integral component of T2DM and obesity management. This review will discuss the currently approved medication for T2DM and obesity, and will also highlight the advent of novel agents which are dual and triple hormonal agonists which represent the future direction of incretin-based therapy.

Funding: National Institutes of HealthNIDDKU24 DK132733 (FCS), UE5 DK137285 (FCS), and P30 DK040561 (FCS).

Background: Early prediction of lymph node status after neoadjuvant chemotherapy (NAC) facilitates promptly optimization of treatment strategies. This study aimed to develop and validate a deep learning network (DLN) using baseline computed tomography images to predict lymph node metastasis (LNM) after NAC in patients with locally advanced gastric cancer (LAGC).

Methods: A total of 1205 LAGC patients were retrospectively recruited from three hospitals between January 2013 and March 2023, constituting a training cohort, an internal validation cohort, and two external validation cohorts. A transformer-based DLN was developed using 3D tumor images to predict LNM after NAC. A clinical model was constructed through multivariate logistic regression analysis as a baseline for subsequent comparisons. The performance of the models was evaluated through discrimination, calibration, and clinical applicability. Furthermore, Kaplan-Meier survival analysis was conducted to assess overall survival (OS) of LAGC patients at two follow-up centers.

Findings: The DLN outperformed the clinical model and demonstrated a robust performance for predicting LNM in the training and validation cohorts, with areas under the curve (AUCs) of 0.804 (95% confidence interval [CI], 0.752-0.849), 0.748 (95% CI, 0.660-0.830), 0.788 (95% CI, 0.735-0.835), and 0.766 (95% CI, 0.717-0.814), respectively. Decision curve analysis exhibited a high net clinical benefit of the DLN. Moreover, the DLN was significantly associated with the OS of LAGC patients [Center 1: hazard ratio (HR), 1.789, P < 0.001; Center 2:HR, 1.776, P = 0.013].

Interpretation: The transformer-based DLN provides early and effective prediction of LNM and survival outcomes in LAGC patients receiving NAC, with promise to guide individualized therapy. Future prospective multicenter studies are warranted to further validate our model.

Funding: National Natural Science Foundation of China (NO. 82373432, 82171923, 82202142), Project Funded by China Postdoctoral Science Foundation (NO. 2022M720857), Regional Innovation and Development Joint Fund of National Natural Science Foundation of China (NO. U22A20345), National Science Fund for Distinguished Young Scholars of China (NO. 81925023), Guangdong Provincial Key Laboratory of Artificial Intelligence in Medical Image Analysis and Application (NO. 2022B1212010011), High-level Hospital Construction Project (NO. DFJHBF202105), Natural Science Foundation of Guangdong Province for Distinguished Young Scholars (NO. 2024B1515020091).

Background: International hypertension treatment guidelines recommend initiating pharmacological treatment with combination therapy and using fixed dose single pill combinations (SPCs) to improve adherence. However, few countries have adopted combination therapy as a form of first-line treatment and SPC uptake in low- and middle-income countries is low due in part to cost and availability. Evidence on costs and cost-effectiveness is needed as health authorities consider incorporating new recommendations into national clinical practice guidelines.

Methods: Over a 30-year time horizon, we used an Excel-based Markov cohort state-transition model to assess the financial costs (screening, treatment, program, and supply chain costs) and socio-economic outcomes (health outcomes, value of lives saved, productivity losses averted) of three antihypertensive treatment scenarios. A baseline scenario scaled treatment among adults age 30 plus while assuming continuation of the widespread practice of initiating treatment with monotherapy. Scenarios one and two scaled treatment while initiating patients on two antihypertensive medications, either as separate pills or as a SPC. Analysis inputs are informed by country-specific data, meta-analyses of the blood-pressure lowering of antihypertensive medications, and own-studies of medication costs. We compared costs, cost-effectiveness, and net-benefits across scenarios, and assessed uncertainty in a one-way sensitivity analysis.

Findings: Using dual combination therapy (with or without SPCs) as first-line treatment would increase costs relative to current practices that largely use monotherapy. Required additional annual resources averaged as much as 3.6, 0.9, and 0.2 percent of government health expenditures in the analysis' low-, lower-middle, and upper-middle income countries. However, across 24 countries, over the next 30 years, combination therapy with separate pills could save 430,000 more lives and combination therapy with SPCs could save 564,000 more lives compared to baseline treatment practices. Administration of two or more medications using SPCs generated higher net benefits in most countries (16/24) compared to the baseline scenario.

Interpretation: First line treatment employing SPCs is likely to generate higher net benefits compared to status quo treatment practices in countries with relatively higher incomes. To improve population health, national health systems would benefit from reducing structural and other barriers to the use of combination therapy and SPCs.

Funding: This journal article was supported by TEPHINET cooperative agreement number 1NU2HGH000044-01-0 funded by the US Centers for Disease Control and Prevention.

Background: Thyroid ultrasound examinations using a cohort study design (from the Fukushima Health Management Survey [FHMS]) were conducted after the nuclear power plant accident caused by the Great East Japan Earthquake in 2011. This study investigated the association between radiation exposure and the detection of thyroid cancer in children and adolescents.

Methods: The cohort study has been conducted in Fukushima prefecture in Japan since 2011. The primary outcome was the external dose. We enrolled 253346 examinees who lived in Fukushima at the time of the accident (Dataset A), including 113120 examinees who had data on external radiation exposure (ERE) (Dataset B). The median dose in the examinee's district was used for missing dose. The association between ERE and detection of thyroid cancer or suspected thyroid cancer was analyzed using Poisson regressions with two types of explanatory variables: sex, age, overweight status, and district (Model 1), and past medical history, family history of thyroid cancer, frequency of seafood consumption, and frequency of seaweed consumption in addition to Model 1 (Model 2).

Findings: During the second and third rounds of examinations, a total of 97 thyroid patients were detected, for a detection rate of 10.328 [ ${10}^5{\text{year}}^{-1}$ ] (95% confidence interval: 8.464-12.602 [ ${10}^5{\text{year}}^{-1}$ ]). Multivariate Poisson regression showed that the detection rate ratio of the ERE (1+ mSv) to <1 (mSv) was 1.577 (0.715-3.394) in Model 1 and 1.596 (0.726-3.512) in Model 2, for Dataset A; and 1.677 (0.746-3.773) in Model 1 and 1.669 (0.743-3.748) in Model 2, for Dataset B.

Interpretation: Our study showed no association between radiation exposure with extremely low dose which were more than 99.9% of all the exposure was less than 5 mSv, and thyroid cancer detection, when the follow-up period was an average of 3.7 years at the present, using the cohort study design.

Funding: The National Health Fund for Children and Adults Affected by Nuclear Incidents in Japan.

Background: The precise associations between common clinical biomarkers and hepatocellular carcinoma (HCC) risk remain unclear but hold valuable insights for HCC risk stratification and prediction.

Methods: We examined the linear and nonlinear associations between the baseline levels of 32 circulating biomarkers and HCC risk in the England cohort of UK Biobank (UKBB) (n = 397,702). The participants were enrolled between 2006 and 2010 and followed up to 31st October 2022. The primary outcome is incident HCC cases. We then employed random survival forests (RSF) to select the top ten most informative biomarkers, considering their association with HCC, and developed a point-based risk score to predict HCC. The performance of the risk score was evaluated in three validation sets including UKBB Scotland and Wales cohort (n = 52,721), UKBB non-White-British cohort (n = 29,315), and the Taizhou Longitudinal Study in China (n = 17,269).

Findings: Twenty-five biomarkers were significantly associated with HCC risk, either linearly or nonlinearly. Based on the RSF model selected biomarkers, our point-based risk score showed a concordance index of 0.866 in the England cohort and varied between 0.814 and 0.849 in the three validation sets. HCC incidence rates ranged from 0.95 to 30.82 per 100,000 from the lowest to the highest quintiles of the risk score in the England cohort. Individuals in the highest risk quintile had a 32-73 times greater risk of HCC compared to those in the lowest quintile. Moreover, over 70% of HCC cases were detected in individuals within the top risk score quintile across all cohorts.

Interpretation: Our simple risk score enables the identification of high-risk individuals of HCC in the general population. However, including some biomarkers, such as insulin-like growth factor 1, not routinely measured in clinical practice may increase the model's complexity, highlighting the need for more accessible biomarkers that can maintain or improve the predictive accuracy of the risk score.

Funding: This work was supported by the National Natural Science Foundation of China (grant numbers: 82204125) and the Science and Technology Support Program of Taizhou (TS202224).

Background: New options for RSV prevention are available for the 2023/2024 RSV season, nirsevimab, a monocolonal antibody, and RSVpreF maternal vaccine, that target infants entering their first RSV season. Countries vary in implementation of one or both strategies to reduce the RSV burden among infants.

Methods: This study utilized retrospective cohort data from 47 children's hospitals in the United States Pediatric Health Information Systems (PHIS) database between 2015 and 2019. Patients hospitalized with RSV or bronchiolitis aged 0-15 months were included based on birth timing relative to the RSV season. Annualized hospitalization rates per 100,000 were calculated from extrapolated population estimates. Recommended prevention strategies were applied to age cohorts to compare protection afforded by nirsevimab and maternal immunization strategies.

Findings: 72,209 RSV hospitalizations were included in the study. Compared to those born nine months prior to the season (n = 2116; 375/100,000 per year), those born at the start of the season were 9.44 (9.02-9.89) times as likely to be hospitalized for RSV (n = 19,979; 3542/100,000 per year). Both strategies would prevent most of these hospitalizations. Maternal immunization would not prevent hospitalizations of infants aged two or 3 months at season start, who were respectively 2.95 (2.80-3.10) and 2.22 (2.11-2.34) times as likely to be hospitalized. Proportionally more preterm infants were hospitalized in their second RSV season, resulting in less protection (up to 40% to >80% unprotected).

Interpretation: These findings suggest without a more narrowly targeted strategy, current nirsevimab recommendations may not be as cost efficient for infants born further outside of the RSV season, and those born later in the season who are more likely to be hospitalized in subsequent seasons. Conversely, it may be more beneficial to begin maternal immunization further in advance of the season. Immunization strategies should be based on the RSV seasons within specific regions.

Funding: None.