TPS4246 Background: Gastroesophageal adenocarcinoma (GEA) is a major cause of global cancer-related mortality. A common standard of care for frontline advanced GEA is 5-fluorouracil and oxaliplatin (FOLFOX), with the addition of immune checkpoint inhibitors (ICI) in patients with a PD-L1 combined positive score (CPS) of > 1. Adding ICIs improves median overall survival (OS) by 2-4 months, with increased benefit seen with higher CPS scores (Leone et al, ESMO Open , 2024). There remains a significant need to improve ICI outcomes and expand the portion of patients who benefit. In GEA, vascular endothelial growth factors (VEGF) are associated with poor prognosis, influencing immune suppression and T cell exhaustion. There is strong mechanistic rationale for cooperativity between anti-VEGF antibodies and ICI in GEA, as well as evidence of clinical benefit in treatment-refractory gastric cancer (Kim et al, Cancer Immunol Res , 2025). Ivonescimab is a novel bispecific antibody that simultaneously targets PD-1 and VEGF, in a spatially constrained manner, impairing neoangiogenesis and remodeling the suppressive tumor microenvironment. Ivonescimab has evidence of safety and efficacy in colorectal and hepatocellular cancers and is approved for the treatment of PD-L1+ lung cancer in China (Deng et al, ESMO 2024; Li et al, ESMO 2025; Xiong et al, Lancet , 2025). Methods: This single-arm, multi-institutional phase II study seeks to evaluate ivonescimab in combination with FOLFOX as frontline therapy in GEA. Adults with locally advanced unresectable or metastatic HER-2 negative GEA are eligible. Patients must have disease that can be evaluated radiographically and may not have received prior systemic therapy for advanced disease. Positive PD-L1 expression is not required for eligibility. We plan to enroll 40 patients. To allow for collection of early immune modulation data, patients will commence therapy with a single dose of ivonescimab 20 mg/kg at discretion of the treating investigator. Subsequent cycles will continue with the addition of FOLFOX (dosed per institutional standards) to ivonescimab, given on day 1 and day 15 of a 28-day cycle. Imaging will be performed every 6 weeks until week 24, at which point imaging will change to every 9 weeks. Treatment will continue until disease progression, withdrawal of consent, or death. The primary objective is to define efficacy of ivonescimab in combination with FOLFOX as measured by the 6-month progression-free survival (PFS) rate. Secondary objectives include safety and tolerability, objective response and clinical benefit rates, median PFS and OS. Translational correlative studies are planned to explore tumor and immunologic determinants of response. This study is currently open and enrolling (NCT07070466). Clinical trial information: NCT07070466 .

ObjectiveObjectiveThis study aimed to explore the role of the miR-21/Mef2c/Sost pathway in the pathogenesis of diabetic osteoporosis (DOP) and to investigate whether metformin ameliorates DOP by regulating this signaling pathway.MethodsWe compared bone mineral density (BMD), bone turnover biomarkers, and bone miR-21 expression levels between elderly female patients with and without diabetes. Diabetic mice and high-glucose-treated MLO-Y4 osteocytes were used to explore the involvement of the miR-21/Mef2c/Sost pathway in DOP. miR-21 mice and MLO-Y4 osteocytes transfected with miR-21 mimics or inhibitors were utilized to verify the regulatory effect of the Mef2c/Sost pathway on bone metabolism. Furthermore, we explored the therapeutic effect and underlying mechanism of metformin in improving DOP by targeting the miR-21/Mef2c/Sost pathway.ResultsDiabetic patients exhibited decreased bone miR-21 expression and reduced BMD, both of which were positively correlated with glycemic control status. Consistently, miR-21 was significantly downregulated in diabetic mice and high-glucose-cultured MLO-Y4 osteocytes. Both miR-21 and diabetic mice presented elevated protein levels of MEF2C and sclerostin, reduced expression of Cyclin D1 and RUNX2, as well as impaired bone strength and bone quality. As a direct target gene of miR-21, Mef2c was upregulated under high-glucose conditions, whereas its expression was reversed by miR-21 overexpression in MLO-Y4 osteocytes. The downstream gene Sost of Mef2c showed a consistent expression trend. Mechanically, metformin restored bone miR-21 expression in diabetic mice, increased the protein levels of Cyclin D1 and RUNX2 via inhibiting the Mef2c/Sost pathway, and ultimately improved bone strength and bone quality in diabetic mice.ConclusionThe miR-21/Mef2c/Sost pathway critically contributes to DOP pathogenesis. Metformin improves bone health in diabetic mice by restoring miR-21 expression. This study is the first to demonstrate the association between metformin and the miR-21/Mef2c/Sost pathway in DOP, highlighting the skeletal protective effect of metformin beyond its glycemic regulation function and providing a novel therapeutic target for DOP treatment.

[This corrects the article DOI: 10.3389/fonc.2022.913736.].

To investigate the association between D-dimer level changes and venous thromboembolism (VTE) risk in endometrial cancer patients undergoing surgery. This retrospective cohort study included 307 endometrial cancer patients who underwent surgical treatment at Fujian Maternity and Child Health Hospital between January 2022 and December 2024, with follow-up to December 2025. D-dimer change was the exposure variable and VTE occurrence the outcome. Multivariable logistic regression assessed independent effects after adjusting for 17 covariates, including age, body mass index, FIGO stage, and comorbidities. Threshold effect and stratified analyses were conducted. Each one-unit increase in D-dimer change was significantly associated with higher VTE risk (adjusted OR = 1.202; 95

Introduction and Objective: A Phase I clinical trial of 2 doses of bacillus Calmette-Guérin (BCG) in adults with type 1 diabetes (T1D) demonstrated induction of regulatory T cells and durable improvements in HbA1c from restored lymphoid glucose metabolism. Pancreatic insulin did not contribute to glucose control. Two additional open-label clinical trials of BCG in adults with T1D showed similar reductions in HbA1c. A Phase II, double-blind, placebo-controlled trial of BCG in 150 subjects with juvenile-onset T1D or latent autoimmune diabetes in adults (LADA) was undertaken with the primary endpoint of improved HbA1c (NCT02081326). Here we present 5-year data on subjects in the Phase II trial with juvenile-onset T1D. Methods: Adults with T1D (age of onset < 21 y) were followed for 5 years and received 6 doses of intradermal (ID) BCG (Tokyo 174 strain, Japan BCG Laboratory, Japan) or placebo (n=34 BCG; n=24 placebo). The primary outcome was reduction in HbA1c. Secondary outcomes were insulin use, time with normoglycemia, autoantibody levels, and stimulated C-peptide secretion. Results: BCG was safe and statistically significantly reduced mean HbA1c levels from 7.84 ± 0.16% (Year 0) to 7.30 ± 0.22% (Year 5; P=0.0006). There was a statistically significant reduction in insulin use in the BCG-treated group, from 0.68 ± 0.04 U/kg/day (Year 0) to 0.63 ± 0.03 U/kg/day (Year 5; P=0.024). CGM data showed up to 183.7% improvement over baseline in time spent in normoglycemia (blood sugar 70-99mg/dL) with no increased episodes of hypoglycemia. C-peptide levels were low or non-detectable at enrollment and were not improved at Year 5. Conclusion: This study shows that multi-dose BCG is safe and lowers HbA1c, reduces insulin need, and improves time with normoglycemia without increases in hypoglycemic events in adults with juvenile-onset T1D. BCG’s therapeutic effect on blood sugar control is independent of pancreas function and is likely a durable correction of an underlying aerobic lymphoid metabolic defect. Disclosure D.L. Faustman: None. J. Braley: None. N. Hullavarad: None. E. Bulczynski: None. J. Dorsey: None. N. Kartsounis: None. L. Tran: None. B.J. Thach: None. H. Hayashi: None. D.A. Mounier: None. L. Adams: None. S. Bradley: None. S. Hashiguchi: None. H. Zheng: None. W.M. Kuhtreiber: None.

e16135 Background: Perioperative chemoimmunotherapy is emerging as a global standard for non-metastatic gastroesophageal cancers, but data in phase III trials are mixed. Event-free survival (EFS) is a common endpoint in perioperative trials but whether EFS is a surrogate for overall survival in the era of chemoimmunotherapy is not well studied. Understanding EFS performance as a surrogate for overall survival is important to inform regulatory approval and early access to promising agents in this tumor type. Methods: We performed a systematic literature review to identify all randomized controlled trials (RCTs) evaluating neoadjuvant or perioperative systemic therapy for gastroesophageal adenocarcinomas. Using weighted linear regression of the hazard ratios extracted from the published literature, a meta-analysis was performed to evaluate the strength of correlation between EFS and overall survival (OS) across trials. Consistent with criteria from the Institute for Quality and Efficiency in Health Care, strong correlation was defined as a correlation coefficient (R) ≥0.85. Sensitivity analyses examining trials with heterogeneous tumor locations, perioperative systemic therapy only, and those with a clear definition of EFS, were performed to evaluate the consistency of the findings. Results: A total of 30 RCTs were included in the main analysis. Trial-level comparison identified a positive relationship between EFS and OS (estimated coefficient 0.68, 95% CI, 0.50–0.85; p < 0.001) corresponding to a correlation coefficient (R) of 0.83. Surrogate threshold effect (STE) analysis identified an HR for EFS of 1.18 or lower as a threshold at which the lower bound of the 95% confidence interval for HR_OS excluded 1.0.This correlation was preserved in sensitivity analyses, including 20 studies that defined EFS as beginning from cycle 1, day 1 of neoadjuvant therapy (slope relating log(HR_EFS) to log(HR_OS) was 0.6536 (95% CI, 0.4551–0.8521; p < 0.0001). Conclusions: EFS remains a good surrogate for OS in modern phase III perioperative chemoimmunotherapy trials including MATTERHORN, supporting the validity of intermediate endpoints for use in treatment regulatory decisions and drug development in operable gastroesophageal adenocarcinomas.

Time delays exist between inpatient blood glucose measurements, insulin administration and meal timing. The clinical impacts of time delay on insulin dosing and hypoglycaemia risk have not been fully evaluated. In this single-centre observational study, hospitalised individuals treated with insulin wore blinded Dexcom G6 Pro continuous glucose monitors (CGM) and received usual diabetes care. CGM values were matched by time to point-of-care (POC) blood glucose values and correctional insulin administration episodes. For each matched episode, time delay between POC measurement and correctional insulin administration and the difference between corresponding CGM values were calculated. Clinical impact of time delay was identified if insulin dosing would have changed with an updated glucose measurement. Across 243 participants, 2204 matched glucose–correctional insulin administration episodes were identified. Mean time delay (± SD) was 52.5 ± 37.4 min with mean absolute difference between CGM values of 1.0 ± 1.2 mmol/l. Had an updated CGM value at time of insulin administration been used, a different dose of correctional insulin may have been given in 28.4

Background Dose Adjustment For Normal Eating is a 5-day, group-based clinical education programme for adults with type 1 diabetes, training them in the complex self-management skills, enabling them to optimise both their glycaemic management and quality of life. Although Dose Adjustment For Normal Eating is associated with improvements in many aspects of diabetes management, including psychological outcomes, it has been challenging to maintain the biomedical improvements for longer term, which have remained well above the glucose levels recommended by National Institute for Health and Care Excellence. Objectives We aimed to develop and evaluate Dose Adjustment For Normal Eating plus, an enhanced version of Dose Adjustment For Normal Eating, to enable improvements in glycaemic management (glycated haemoglobin) without compromising the quality of life. The objectives of the programme were to modify the existing Dose Adjustment For Normal Eating curriculum and evaluate it in a cluster randomised controlled trial. Design This programme comprised four workstreams. The first three workstreams focused on redevelopment of the Dose Adjustment For Normal Eating intervention to become ‘Dose Adjustment For Normal Eating plus’: involving revision of the curriculum for a 5-day, group-based programme, including relevant behaviour change techniques (workstream 1); development of a new structured, pro-active, follow-up programme to be delivered by Dose Adjustment For Normal Eating plus facilitators post course to support ongoing diabetes self-management (workstream 2); and development of a new technology interface to help glucose pattern recognition to inform improved self-management (workstream 3). We used mixed methods to review, develop and refine the Dose Adjustment For Normal Eating plus intervention (course, individual support and technological aspects). The intervention was piloted in three National Health Service specialist diabetes centres and was reviewed via two iterative waves before finalisation. Workstream 4 was a cluster randomised controlled trial using a pragmatic, parallel group (1 : 1) allocation design (Dose Adjustment For Normal Eating vs. Dose Adjustment For Normal Eating plus), with concurrent process and health economic evaluations. The primary biomedical outcome was the between-group difference in glycated haemoglobin at 12 months. The primary psychological outcome was the between-group difference in the impact of type 1 diabetes on quality of life (using Audit of Diabetes-Dependent Quality of Life-15) at 12 months. Setting The workstreams and the randomised controlled trial were undertaken in university and National Health Service specialist centres in England and Scotland. Participants Four hundred and seventy-one adults aged ≥ 18 years with confirmed diagnosis of type 1 diabetes participated in the cluster randomised controlled trial, which was 144 fewer than planned and approximately 77% of the planned sample size. Intervention Dose Adjustment For Normal Eating plus is a standardised 5-day educational course (described above), delivered 1 day per week over 5 weeks in groups, meeting face to face, followed by five individual support sessions over 12 months. An online platform supports the upload, visualisation, pattern recognition and review of glycaemic data for participants and clinicians. Trial outcome measures In the cluster randomised controlled trial, the primary biomedical outcome was glycaemia, defined as glycated haemoglobin, at 12 months. The primary psychological outcome was the impact of diabetes on quality of life (assessed using the widely recognised scale, Audit of Diabetes-Dependent Quality of Life-15). Key secondary biomedical outcomes included rates and proportions of severe hypoglycaemia and diabetic ketoacidosis. Key secondary psychological outcomes included diabetes-specific distress, diabetes-specific positive well-being and fear of hypoglycaemia. Results In the primary intention-to-treat population (309), mean glycated haemoglobin reduced from 9.1% to 8.2% (75.9–66.5 mmol/mol) in the Dose Adjustment For Normal Eating group and from 9.1% to 8.1% (75.6–65.1 mmol/mol) in the Dose Adjustment For Normal Eating plus group. The cluster randomised controlled trial showed no evidence of a between-group difference at 12 months in glycated haemoglobin {point estimate [95% confidence interval −0.014 (−0.284 to 0.255); p = 0.915]}, or diabetes-specific quality of life {point estimate [95% confidence interval 0.2 (−0.1 to 0.5); p = 0.21]}. At 12 months, significant between-group differences were observed, favouring Dose Adjustment For Normal Eating plus, in secondary psychological outcomes (diabetes-specific distress, diabetes-specific positive well-being and actions taken to avoid hypoglycaemia). Limitations Due to trial-suspension during coronavirus disease, we recruited 471 adults to the cluster randomised controlled trial, 144 fewer than planned. Although this reduced overall statistical power, we showed that the difference in glycated haemoglobin between the groups was far below that we considered a meaningful clinical difference (0.5%). Recruitment also meant that more participants were using continuous glucose monitoring, both before and during the trial than we anticipated. This may have reduced additional benefit of the Dose Adjustment For Normal Eating plus intervention on glycated haemoglobin. The pandemic probably influenced diabetes self-management during the trial in both groups. Conclusions Dose Adjustment For Normal Eating plus did not lead to greater falls in glycated haemoglobin at 12 months compared to Dose Adjustment For Normal Eating, but these falls were double those reported in previous Dose Adjustment For Normal Eating randomised controlled trials. Sixty-eight per cent of participants showed clinically relevant improved glucose levels. Those in Dose Adjustment For Normal Eating plus reported significant falls in diabetes distress, positive well-being and qualitative research reported positive experiences of Dose Adjustment For Normal Eating plus among participants and health professionals. Future work In view of major improvements in diabetes distress and positive experiences in both participants and health professionals, the Dose Adjustment For Normal Eating executives, who co-ordinate the delivery of Dose Adjustment For Normal Eating courses, are planning to include key elements of Dose Adjustment For Normal Eating plus in future courses, particularly structured support to participants following the course and key elements of the curriculum. Study registration This study is registered as IRAS: 235621 and ISRCTN: 42908016. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0514-20013) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 21. See the NIHR Funding and Awards website for further award information. Plain language summary Researchers from hospitals and universities in the United Kingdom and psychologists from Australia received money from the National Institute for Health Research to undertake research to improve an education programme. It helps adults with type 1 diabetes to self-treat their condition and improve their health and quality of life. We built on the existing (DAFNE) course by including key steps in self-treating diabetes, new technology and support after the course, calling it DAFNEplus. Adults with diabetes helped in all areas of the research. Between 2018 and 2022, 471 adults with type 1 diabetes from 13 diabetes centres across the United Kingdom took part in a trial. Centres were chosen by chance to teach either DAFNE or the new DAFNEplus course. All those involved, attended a 5-day course, but DAFNEplus added five follow-up sessions and used technology to feedback results and glucose patterns. Those taking part provided blood to measure glucose and other lab tests and questionnaires. We talked to both participants receiving and staff providing DAFNEplus and recorded their experiences. Results were collected before the course and 12 months later. The trial was badly affected by COVID-19, but enough people took part for us to collect reliable results. At 12 months, glucose levels and quality of life had improved, but there were no differences between those on the standard DAFNE and those on DAFNEplus. Glucose levels actually improved by twice the amount we had previously found in DAFNE trials in both groups. The people doing DAFNEplus also had improved levels of diabetes distress and other quality-of-life measures. The people and staff who took part in the research programme were particularly positive about the DAFNEplus approach, and we are working out how to include some parts of DAFNEplus in future DAFNE courses. Scientific summary Background Successful long-term management of type 1 diabetes (T1D) requires sustained individual engagement in complex self-management behaviours to maintain blood glucose [glycated haemoglobin (HbA1c)] levels within an optimal range. In 2002, we published a randomised controlled trial (RCT) reporting results of a 5-day training course, showing significantly improved levels of glucose and quality of life (QoL) at 12 months with no change in the control group. Although structured education programmes lead to clinically significant decreases in HbA1c, increased hypoglycaemia awareness and improved QoL, these benefits are not always sustained and glucose levels rarely reach recommended targets. The work of the Dose Adjustment For Normal Eating (DAFNE) collaborative and its associated research programmes have provided important understanding, including qualitative work, which has suggested roles in therapeutic interventions for: ongoing structured long-term support, including behaviour change science to support initial and ongoing learning and technology, facilitating links between professionals and a person with diabetes. Objectives The overall aim of Dose Adjustment For Normal Eating plus (DAFNEplus) was to refine the existing DAFNE curriculum, embedding behavioural science frameworks in all aspects of the intervention, addressing ‘ongoing support’, and including technological support, to aid long-term maintenance of HbA1c within an acceptable clinical range with no negative effects on participant’s QoL. Methods and results Workstream 1 The specific aims of this workstream (WS) were to: specify behaviours involved in T1D self-management and barriers and enablers to sustaining these behaviours specify behaviour change techniques (BCTs) included in the existing DAFNE intervention and examine whether they target the identified barriers/enablers identify additional BCTs with the potential to address barriers/enablers not currently targeted generate recommendations for revising the existing DAFNE curricula via stakeholder consultation and consensus integrate recommendations into a coproduced DAFNEplus intervention, pilot and refine the intervention ahead of the trial. This WS applied behavioural science to refine the existing DAFNE structured education programme into DAFNEplus. We identified underlying behaviours and influencing factors contributing to T1D self-management, and we identified 51 unique BCTs to address these. This enabled co-design of the DAFNEplus intervention which was piloted and refined in three centres and then taken forward for the evaluation of effectiveness and cost-effectiveness in a cluster RCT (cRCT) (WS4), and a parallel process evaluation was performed to explore the mechanisms of action, acceptability and fidelity (WS4). Workstream 2 The aims were to explore participants’ self-management after attending structured T1D education and their unmet need(s) for support to sustain improvements in glycaemic management and then to develop an evidence-informed model to guide effective follow-up support following DAFNEplus. To inform the design of effective follow-up support, we undertook a meta-ethnography of qualitative studies focusing on self-management of T1D, following structured education. We expressed the synthesis as a logic model: Follow-Up Support for Effective T1D Self-management (FUSED). The FUSED model provided an explanation of why people find it difficult to maintain T1D self-management following structured education, and it outlined the elements required for effective follow-up support. Following on from this activity, we undertook a further systematic review to identify the most effective type of education programme to support sustained improvements in glycaemia. Workstream 3 Workstream 3 aimed to develop technological resources to support learning and understanding of individual glycaemic control. The Glucollector web-based platform is supported by the WithCare+ device for data acquisition and by developed bespoke tools for modelling, decision support and visual representation and interpretation. It incorporates functionalities to support shared visualisation for patients and clinicians based on collected data from various monitoring devices, automated feedback, goal setting and self-care facilitation. The WithCare+ device transmits data securely on self-care behaviours like blood glucose measurements [including both capillary glucose readings and continuous glucose monitoring (CGM) from Libre flash monitoring], carbohydrate intake and insulin doses. It supports linking to activity tracking devices and prompts users to contextualise abnormal readings. Clinician versions are available for in-clinic use. Pilot and feasibility trial We undertook a pilot study to assess the feasibility and best approach to developing the logistics of the cRCT. We considered recruitment, intervention delivery, participant engagement and data collection methods, with the intention of refining the prototype DAFNEplus programme to optimise the intervention prior to the trial. The prototype DAFNEplus programme was piloted in two waves, at three DAFNE centres, at: Sheffield Teaching Hospitals NHS Foundation Trust King’s College Hospital NHS Foundation Trust Norfolk and Norwich University Hospitals NHS Foundation Trust This was a non-randomised feasibility pilot where all participants received the intervention. The pilot intervention was delivered by practising DAFNE educators (diabetes specialist nurses, dietitians and physicians) at each participating site, who had undertaken training in DAFNEplus. We anticipated that the DAFNEplus programme could be optimised with participants from eight courses across the three centres. The number of courses was selected to enable all centres to complete at least two DAFNEplus courses during the pilot. Eight DAFNEplus courses involving 54 patient participants were completed. The collaborative working group We developed a novel structured collaborative working group (CWG) process to use findings from the embedded qualitative work and feedback from other stakeholders (e.g. individuals involved in designing and delivering the intervention) to make iterative refinements to the intervention prior to the RCT. Pilot study components Pilot study process evaluation Glucollector/Withcare+ user testing Collection of outcome measures Pilot study key outcomes We piloted and iteratively amended the DAFNEplus curriculum via two waves of pilot courses. All eight DAFNEplus cohorts in the pilot study were given access to the technology and structured follow-up support as part of the intervention. In line with the work developing and refining the curriculum, the CWG used the same approach to optimising the structured support and technology. The qualitative research with DAFNEplus participants and facilitators enabled the identification of key barriers and facilitators to delivery and receipt of the intervention in real time. In addition, we were able, through the CWG, to mobilise the knowledge generated through both the pilot study and patient and public involvement feedback, to iteratively develop the intervention and address any identified shortcomings. The Your Self-management And You study advised on the primary and other psychological-related, patient-reported outcome measures. The health economists completed an evaluation of the potential cost-effectiveness of DAFNEplus compared to standard DAFNE in an NHS setting. This is detailed within the health economic evaluation. Workstream 4 cluster randomised trial Introduction A cRCT was conducted to examine the effectiveness of the intervention (DAFNEplus) compared with standard DAFNE. Concurrent health economic and process evaluations were undertaken. The aim of this superiority cRCT was to investigate whether DAFNEplus enabled improved and sustained diabetes self-management behaviours, leading to better glucose management (i.e. reduced mean HbA1c by minimum clinically significant difference of 0.5%) at 12 months than achieved with standard DAFNE, without compromising QoL [Coates E, Amiel S, Baird W, Benaissa M, Brennan A, Campbell MJ, et al.; DAFNEplus group. Protocol for a cluster randomised controlled trial of the DAFNEplus (Dose Adjustment For Normal Eating) intervention compared with 5x1 DAFNE: a lifelong approach to promote effective self-management in adults with type 1 diabetes. BMJ Open 2021;11:e040438]. Objectives The primary objective was to compare the effect of DAFNEplus to standard DAFNE on glycaemia (HbA1c) at 12 months (primary biomedical outcome). The secondary objectives were: to compare the effects of DAFNEplus to standard DAFNE on: diabetes-specific QoL at 12 months (primary psychological outcome) glycaemia (HbA1c) at 6 months (medium-term outcome) other biomedical outcomes, including severe hypoglycaemic episodes, diabetic ketoacidosis (DKA), weight, body mass index, blood pressure and lipids secondary psychological outcomes, including diabetes distress, diabetes-specific positive well-being and fear of hypoglycaemia to undertake a mixed-methods process evaluation to aid understanding of the cRCT findings and inform decision-making about the implementation of DAFNEplus in clinical care post trial to assess the fidelity of delivery of DAFNEplus to undertake a health economic analysis to determine the cost-effectiveness of DAFNEplus versus standard DAFNE. Design The trial used a pragmatic, parallel group, superiority cluster randomised (1 : 1 allocation) controlled design involving 14 NHS specialist diabetes centres. Centre randomisation was implemented rather than individual participants, as contamination of the control arm may have occurred if educators were trained in DAFNEplus (intervention) and still were required to deliver standard DAFNE (control). Cluster randomised controlled trial methods Participants Participants were considered eligible if they were ≥ 18 years of age, had a diagnosis of T1D for at least 6 months (or post honeymoon), were prepared to undertake multiple daily injection therapy and frequent self-monitoring of blood glucose, could attend all sessions as part of the intervention and the principal investigator was confident that they could adhere to the protocol requirements. Those currently using continuous subcutaneous insulin infusion pump therapy or who had attended a DAFNE course within the last 5 years were ineligible. Intervention DAFNEplus was facilitated by practising DAFNE educators (diabetes nurses, dietitians and physicians) in the NHS, all of whom had previous experience in DAFNE training. An extensive training package was undertaken by all intervention staff. Randomisation All participating centres were randomised on a 1 : 1 basis to control (standard DAFNE course) or the intervention arm (DAFNEplus programme). End points The primary biomedical outcome was HbA1c at 12 months. The study was powered for this single, primary end point. All additional analyses were performed to further inform this primary end point and should be interpreted accordingly. The number of participants achieving glycaemic control [defined as either a HbA1c < 7.5% (58 mmol/mol) or a decrease in HbA1c of ≥ 0.5% (≥ 5.5 mmol/mol)] were calculated at both 6 and 12 months post course. Other secondary biomedical outcomes included: severe hypoglycaemia, as defined by the American Diabetes Association, both rates and proportion of those affected; DKA, both rates and proportion of those affected. Participant safety was assessed by way of adverse and serious adverse reporting. All participants were included in safety summaries. We also collected and will analyse 24-month outcome data (HbA1c and severe hypoglycaemic episodes) after the main study has been reported. The primary psychological outcome was diabetes-specific QoL at 12 months, measured using the Audit of Diabetes-Dependent Quality of Life-15 (ADDQoL-15). Secondary psychological outcomes included: diabetes-specific QoL (Diabetes Attitudes Wishes and Needs Impact of Diabetes Profile); diabetes distress [Problem Areas in Diabetes scale-11 (PAID)-11)]; diabetes-specific positive well-being [4-item subscale of the Well-Being Questionnaire (28 items)]; and fear of hypoglycaemia (HFS-II short-form). Statistical analysis Three analyses populations were defined: Primary intention-to-treat (ITT) population composed of consented participants with baseline HbA1c > 7.5%, analysed as per their randomisation allocation, regardless of treatment adherence and protocol non-compliances. Full ITT population composed of consented participants, analysed as per their randomisation allocation, regardless of treatment adherence and protocol non-compliances. Per-protocol population composed of the subset of the primary ITT population who adhered to their assigned intervention. For all analysis populations, participants recruited in 2020, who did not attend at least one session of the initial DAFNE course, were excluded. This was due to courses not running during the COVID-19 pandemic. Cluster randomised controlled trial results Key findings: biomedical outcomes Four hundred and seventy-one people were recruited from 13 sites over 4 years, which was 144 fewer than planned (approximately, 77% of the planned sample size, which was planned to recruit over 3 years). In the primary ITT population, mean HbA1c reduced from 9.1% to 8.2% (75.9–66.5 mmol/mol) in the DAFNE group and from 9.1% to 8.1% (75.6–65.1 mmol/mol) in the DAFNEplus group. There was no evidence of a between-arm difference in HbA1c at 12 months {point estimate [95% confidence interval (CI) −0.014 (−0.284 to 0.255); p = 0.915]} in the primary ITT population. This was consistent with sensitivity analyses, including those adjusting for adherence, and varying assumptions about missing data. In the full ITT population (245 DAFNE, 178 DAFNEplus) of those we have baseline and 12-month HbA1c paired measurements, around 70% improved their glucose levels during the trial; either HbA1c < 7.5%, fall in HbA1c, or both measures at 12 months. No evidence of between-group difference was found for any of the secondary end points. In the full ITT population (423, DAFNE 245, DAFNEplus 178), number of adverse events reported was low. During follow-up, at least one episode of severe hypoglycaemia was experienced by 3% in the DAFNEplus arm (vs. 7% in the DAFNE arm) in the full as-randomised population. Key findings: psychological outcomes In the ITT analyses, the adjusted mean difference in the impact of diabetes on QoL [i.e. the ADDQoL-15 average weighted impact score at 12 months (primary psychological outcome)] was 0.2 (95% CI −0.1 to 0.5; p = 0.21), equivalent to a standardised effect size of d= 0.1 (95% CI −0.1 to 0.4). For the secondary psychological outcomes, at 12 months, there was a statistically significant difference in diabetes distress (PAID: adjusted mean difference −3.3, p = 0.001 and d = −0.4) and hypoglycaemia avoidance (HFS-II behaviour subscale: adjusted mean difference −1.1, p = 0.002 and d = −0.3), and diabetes-specific positive well-being (4-item subscale of the WBQ-28: adjusted mean difference 0.9, p = 0.004 and d= 0.4), favouring the DAFNEplus intervention. The economic evaluation alongside the trial showed that DAFNEplus had an incremental cost of £611 versus DAFNE, an incremental quality-adjusted life-year (QALY) of + 0.008 and an incremental cost-effectiveness ratio (ICER) of £78,147 per QALY gained, considerably above National Institute for Health and Care Excellence’s (NICE’s) typical maximum acceptable ICER of £20,000–£30,000 per QALY gained. All our scenario analyses, including complete-case analysis and conducting a long-term extrapolation model of biomedical outcomes had ICERs above £20,000 per QALY gained. NICE’s typical range for a maximum acceptable ICER is £20,000–30,000 per QALY gained, and the ICER for DAFNEplus versus DAFNE is highly likely to exceed this range. Limitations Due to trial-suspension during the pandemic, we recruited 471 adults to the cRCT, 144 fewer than planned. Although this reduced overall statistical power, our results showed that differences in HbA1c between the two groups was close to zero and far below that we considered a meaningful clinical difference (0.5%). Delays in recruitment also meant that more participants were using CGM, both before and during the trial than we anticipated. This may have reduced additional benefit of the DAFNEplus intervention on HbA1c. The pandemic probably influenced diabetes self-management during the trial in both groups. Conclusions The DAFNEplus did not lead to greater falls in HbA1c at 12 months compared to DAFNE, but these falls were double those reported in previous DAFNE RCTs. Sixty-eight per cent of participants showed clinically relevant improved glucose levels. Those in DAFNEplus (compared with DAFNE) reported significant falls in diabetes distress, positive well-being, and qualitative research reported positive experiences of DAFNEplus among participants and health professionals. Study registration This study is registered as IRAS: 235621 and ISRCTN: 42908016. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0514-20013) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 21. See the NIHR Funding and Awards website for further award information.

Introduction and Objective: A Phase I clinical trial of 2 doses of bacillus Calmette-Guérin (BCG) in adults with juvenile-onset type 1 diabetes (T1D) demonstrated durable improvements in HbA1c, but a pilot trial in patients with LADA, who have older age of onset (AOO), slower decline in insulin production, and lack of lymphoid glycolysis defects vs juvenile-onset T1D, showed no HbA1c improvement with BCG. A Phase II, double-blind, placebo-controlled trial of BCG in 150 subjects with juvenile-onset T1D or LADA was undertaken with the primary endpoint of improved HbA1c (NCT02081326). Here we present 5-year data on subjects in the Phase II trial with LADA. Methods: Adults with LADA (AOO ≥ 21 y) were followed for 5 years and received 6 doses of intradermal (ID) Tokyo BCG (Japan BCG Laboratory, Japan) or placebo (n=68 BCG; n=27 placebo). The primary outcome was reduction in HbA1c. Secondary outcomes included insulin use, time spent in normoglycemia, autoantibody levels, and stimulated C-peptide secretion. Results: BCG was shown to be safe in LADA but did not statistically significantly improve HbA1c. However, insulin-dose adjusted A1c (IDAA1c) statistically significantly decreased with BCG (BCG P=0.044; placebo P=0.230), independent of weight but dependent on insulin use. Insulin use decreased by 2.89% in BCG-treated subjects, but increased by 22.08% in the placebo group (P=0.021). At enrollment, most subjects had remaining C-peptide and autoantibodies. BCG treatment led to preservation of C-peptide (P=0.01790), restoration of stimulated C-peptide (P=0.04) and a decrease in IA2 and GAD autoantibodies (P=0.0003). Conclusion: At Year 5, patients with LADA did not demonstrate significant HbA1c reduction with BCG, but did show improved insulin resistance, slowed C-peptide decay, restored stimulated peak C-peptide, and decreased diabetes-associated autoantibodies, suggesting diminished autoimmunity. Disclosure D.L. Faustman: None. J. Braley: None. N. Hullavarad: None. E. Bulczynski: None. J. Dorsey: None. N. Kartsounis: None. L. Tran: None. B.J. Thach: None. H. Hayashi: None. D.A. Mounier: None. L. Adams: None. S. Bradley: None. S. Hashiguchi: None. H. Zheng: None. W.M. Kuhtreiber: None.

Vitamin D receptor (VDR) agonists promote quiescence of cancer-associated fibroblasts and improve efficacy of chemotherapy in preclinical models of pancreatic cancer. We conducted a run-in phase trial with primary endpoint of safety when the VDR agonist paricalcitol is given with first-line gemcitabine and albumin-bound paclitaxel (GA) in patients with metastatic pancreatic cancer. Secondary endpoints included pharmacodynamic analyses. Thirty-six patients were randomized to GA plus placebo, GA plus intravenous paricalcitol or GA plus oral paricalcitol with pretreatment and on-treatment tumor biopsies. Paricalcitol was safely administered with GA, although five patients (42%) receiving oral paricalcitol had grade 2-4 hypercalcemia and required dose reduction. Nuclear VDR protein expression was heterogeneous across patients, and VDR was expressed in tumor, immune and stromal cells. Compared to pretreatment specimens, on-treatment biopsies had decreased proportion of αSMA+ fibroblasts, altered fibroblast VDR activation signature and greater density and spatial colocalization of CD8+ T cells with tumor cells in the GA-plus-paricalcitol arms. VDR expression was predictive of tumor response in the GA-plus-paricalcitol arms. Paricalcitol can be safely administered with chemotherapy to patients with metastatic pancreatic cancer, and on-treatment biopsies indicated favorable modulation of the tumor microenvironment by paricalcitol as predicted by preclinical models. ClinicalTrials.gov identifier: NCT03520790 .

Aims: We investigated the association between continuous glucose monitoring (CGM) metrics and clinical outcomes in the nonintensive care unit (non-ICU) setting. Methods: In this observational cohort study, patients on non-ICU floors wore blinded Dexcom G6 Pro CGM. CGM metrics and occurrence of CGM-detected severe hypoglycemia were measured. Clinical data, including infection, diabetic ketoacidosis, renal replacement therapy, thrombosis, and 30-day post-discharge readmissions and emergency department (ED) visits were identified from the medical record and participant phone interview. Multivariate regression assessed predictors of CGM-detected severe hypoglycemia and the associations between CGM metrics and clinical outcomes. Regression models using CGM data or reference glucose data were compared with receiver operating characteristic (ROC) curves. Results: A total of 326 hospitalized adults were enrolled with median % time in range 70-180 mg/dL 44.5% (17.1, 70.2%), % time above range >180 mg/dL 54.8% (28.8, 82.3%), and % time below range 0.6% (0, 0.2%). Predictors of severe hypoglycemia included type 1 diabetes, female gender, lower admission hemoglobin, lower A1c, and longer hospital stay. Regression analyses demonstrated an association of 30-day ED visits with increased %TAR (P = 0.01). ROC curves showed models using CGM data or reference data predicted clinical outcomes similarly. Conclusions: CGM can be useful in identifying patients at risk of inpatient hypoglycemia and 30-day ED visits.

OBJECTIVES:Inpatient diet orders are commonly prescribed in clinical practice and may influence the glycemic management in hospitalized patients, yet empirical data remain limited. This study aimed to evaluate the relationship between diet orders and continuous glucose monitoring (CGM) derived glycemic measures in noncritically ill hospitalized adults. METHODS:This secondary analysis used data from a prospective, observational study. Inpatient diet orders were extracted from clinical documentation and standardized into 11 general diet order categories. The primary outcome was percent time in range (70-180 mg/dL). Secondary outcomes included time above range, time below range, and glycemic variability. Associations were examined using multivariate linear mixed-effects models, accounting for demographics, insulin therapy, and other relevant medications. RESULTS:The analytical sample included 283 hospitalized adults (mean age 60.7 years, body mass index 38.5 kg/m2, 36.4% female), primarily admitted to medical units, with most having type 2 diabetes (77.4%). CGM-derived glycemic measures and insulin therapy use varied significantly across inpatient diet orders. Compared to a regular diet, a regular diet with restrictions was associated with lower time in range and higher time above range, whereas diabetic and liquid diets were associated with higher time below range. Measures of glucose variability did not differ across diet orders. CONCLUSIONS:Inpatient diet orders are modestly associated with 24-hour CGM-derived glycemic measures adjusted by insulin therapy and other related medications. Future research is needed to standardize diet order classifications and assess their impact on inpatient glycemic management.

Introduction and Objective: Little is known about glycemic control in the immediate post-hospital discharge period. Methods: In this observational study, patients wore blinded Dexcom G6 Pro CGM during their hospital stays and for up to 10 days post-discharge. Clinical data were extracted from the electronic medical record. Percent time in range (70-180 mg/dl, %TIR), above range (>180 mg/dl, %TAR), below range (<70 mg/dl, %TBR), and episodes of hypoglycemia from the inpatient and post-discharge periods were calculated. The difference between inpatient and post-discharge glycemic control was analyzed with paired t-tests. Predictors of post-discharge glycemic control were evaluated with logistic regression. Results: This cohort of 24 adults (mean age 65.7 ± 13.6 years, 37.5% female) had post-discharge mean %TIR 43.9 ± 33.2%, mean %TAR 55.9 ± 33.3%, and median %TBR 0% (0, 0.04). Glycemic control was similar pre- and post-discharge (post-discharge vs inpatient %TIR -3.7 ± 22.5%, p=0.4). CGM detected 16 episodes of hypoglycemia <70 mg/dl post-discharge. Of the clinical factors assessed, only measures of inpatient glycemic control were associated with achieving post-discharge glycemic control (Table). Conclusion: Inpatient glycemic control may impact post-discharge glycemic control, though the mediators are unclear. CGM may be useful in identifying hypoglycemia after discharge. R. Patel: None. M. O'Connor: None. A. Sabean: None. A. Ashley: None. H. Zheng: None. J. Yan: None. B. Steiner: None. N. Anandakugan: None. M.M. Calverley: None. R. Bartholomew: None. E. Greaux: None. L.E. Castellanos: None. M.E. Larkin: None. S.J. Russell: Employee; Beta Bionics, Inc. Stock/Shareholder; Beta Bionics, Inc. M.S. Putman: Consultant; Anagram Therapeutics. Research Support; Dexcom, Inc. Other Relationship; Vertex Pharmaceuticals Incorporated. K.L. Flint: None. National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119699-S1 and T32DK007028); Dexcom Investigator Initiated Studies grant

PURPOSE:Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC. METHODS:Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS). RESULTS:Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine. CONCLUSION:LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.

OBJECTIVE:Transitions of care at hospital discharge are critical time periods for people with diabetes, but little is known about glycemia in the immediate postdischarge period. METHODS:In this observational study, participants wore blinded Dexcom G6 Pro CGM during hospital admission on nonintensive care floors and then continued wearing blinded continuous glucose monitoring (CGM) for up to 10 days posthospital discharge. Clinical data were extracted from the electronic medical record. Percent time in range 70-180 mg/dl (TIR), above range, and below range from the inpatient and postdischarge periods were calculated. The percentage of participants achieving TIR ≥50% and ≥70%, incidence of hypoglycemia after discharge, change in inpatient and postdischarge CGM metrics, and predictors of postdischarge glycemia were determined. RESULTS:A total of 24 adults (mean age 65.7 ± 13.6 years, 37.5% female) wore CGM after discharge with mean TIR 43.9 ± 33.2%, mean time above range 55.9 ± 33.3%, and median time below range 0% (0, 0.04). Of these participants, 41.7% had TIR ≥50%, and 29.2% had TIR ≥70%. Glycemia predischarge and postdischarge was similar (postdischarge vs inpatient TIR -3.7 ± 22.5%, P = .4). Of the clinical factors assessed, only inpatient glycemia was associated with achieving postdischarge glycemic targets. CGM detected 13 episodes of hypoglycemia occurring in 6 participants (25%) postdischarge. CONCLUSIONS:Glycemia during the postdischarge period is suboptimal and glucose levels in the hospital may be an important predictor of glycemia after hospitalization. CGM may be useful in identifying hypoglycemia after discharge. Further studies are needed to understand the utility of CGM after hospital discharge.

Background: Blood pressure (BP) exhibits a circadian rhythm characterized by higher levels during wakefulness and lower levels during sleep; however, the functional and structural impact of the rhythms of BP remains uncertain. Methods: Two hundred hypertensive males aged 55 and older without overt cardiovascular or cerebrovascular diseases were enrolled in this longitudinal study. Of these, 188 were included in the analyses (12 lacked valid BP records for part of the 24 h period). Rhythmic profiling of BP was performed using ARSER, and rhythmicity was considered significant at P < 0.05. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology (CKD–EPI) formula. The primary outcome was the change in eGFR. Results: The average age was 64.9±7.2 years. For systolic BH (SBP), 38 of the subjects exhibited a 12 h rhythm and 43 subjects a 24 h rhythm; for DBP, 38 exhibited a 12 h rhythm and 36 exhibited a 24 h rhythm. During the three-year follow-up period, 16 of the subjects died and 36 were lost to follow-up. The mean eGFR at baseline and follow-up were, respectively, 86.6 ± 14.0 and 81.0 ± 17.1 mL min−1 1.73 m−2 (P = 0.001). The urinary albumin:creatinine ratio did not vary significantly among the groups (P = 0.059). Subjects with 12 h rhythmic SBP exhibited a smaller reduction in eGFR than those with arrhythmic SBP (P = 0.014). However, the changes in eGFR were similar among the groups displaying 12 h or 24 h rhythmic DBP or arrhythmic DBP. We defined a decline in eGFR as a reduction >1/2 SD between baseline and follow-up. Adjusting for confounding factors (including age, smoking, alcohol consumption, diabetes mellitus, BMI, albumin levels, administration time of antihypertensive drugs, and duration of hypertension), the risk of a decline in eGFR was 70% lower in subjects with 12 h rhythmic SBP than in those with arrhythmic SBP (heart rate [HR] = 0.307 [0.108–0.874], P = 0.027). Conclusion: SBP with a 12 h period is a protective predictor of the decline in eGFR in hypertensive males. It is therefore necessary to focus on the rhythmic profiling of BP.

OBJECTIVE:To identify the risk factors associated with pulmonary embolism (PE) in malignant tumor patients with lower limb deep vein thrombosis (LLDVT). METHODS:We retrospectively analyzed the clinical data of 45 patients with PE (observation group) and 255 patients without PE (control group) admitted to The Second Affiliated Hospital of Shandong First Medical University between June 2020 and January 2025. Various clinical parameters, including LLDVT density ratio, D-dimer, homocysteine (Hcy) and cardiac troponin I (cTNI), were compared between the two groups. Logistic regression analysis was performed to identify independent risk factors for PE. RESULTS:The observation group had significantly higher values for LLDVT density ratio (P<0.001), D-dimer (P=0.004), Hcy (P<0.001), cTNI (P<0.001), and Wells scores (P<0.001) compared to the control group. Logistic regression revealed that LLDVT density ratio, Hcy, cTNI, and Wells scores were independent risk factors for PE in these patients. Pearson correlation analysis showed significant positive associations between the LLDVT density ratio (r=0.822, P<0.001), Hcy (r=0.899, P<0.001), cTNI (r=0.890, P<0.001), and Wells scores. ROC curve analysis indicated that the combined model (LLDVT density ratio, Hcy, and cTNI) had a higher AUC (0.852) than individual markers. CONCLUSION:LLDVT density ratio, Hcy, and cTNI are independent predictors of PE in malignant tumor patients with LLDVT. These markers are closely associated with PE severity, which could assist in optimizing clinical management for these patients.

BACKGROUND:Prolonged cardiopulmonary bypass (CPB) causes hemolysis, reducing nitric oxide availability and increasing the risk of acute kidney injury (AKI) after cardiac surgery. While previous studies suggest inhaled nitric oxide may reduce AKI in certain populations, its effect in patients with preexisting endothelial dysfunction, a condition marked by impaired nitric oxide production, is unknown. This trial investigates whether perioperative nitric oxide administration reduces AKI in patients with preexisting endothelial dysfunction undergoing prolonged CPB. METHODS:The authors conducted a double-blind, single-center, placebo-controlled, randomized clinical trial involved 250 adult cardiac surgery patients with preexisting endothelial dysfunction undergoing CPB lasting more than 90 min. Participants were randomized to either receive nitric oxide at 80 ppm via the oxygenator during CPB, continuing postoperatively via ventilator and facemask, or a placebo of nitrogen-oxygen gas mixture for 24 h. The primary outcome was the incidence of postoperative AKI, defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Secondary outcomes included AKI severity and the need for renal replacement therapy during hospitalization and at 6 weeks, 90 days, and 1 yr. RESULTS:Of the 250 patients (median age, 66 yr; interquartile range, 59, 73 yr; 56 [22.4%] women), 125 were assigned to each group. AKI occurred in 55 (44.0%) patients in the nitric oxide group and 54 (43.2%) patients in the control group (adjusted odds ratio, 1.00; 95% CI, 0.59 to 1.69). Secondary outcomes, including stage 1, 2, or 3 AKI and renal replacement therapy at all timepoints, were also similar between groups. CONCLUSIONS:In cardiac surgery patients with preexisting endothelial dysfunction undergoing prolonged CPB, perioperative administration of 80 ppm nitric oxide for 24 h did not significantly reduce postoperative AKI. These findings do not support the routine use of nitric oxide in this patient population.