P495: UNLOCKING THE POTENTIAL OF SYNTHETIC PATIENTS FOR ACCELERATING CLINICAL TRIALS: RESULTS OF THE FIRST GIMEMA EXPERIENCE

Background: Artificial intelligence is contributing to improve different medicine areas including clinical trial design. One field that holds a great potential is represented by the use of digital data as an alternative to real ones. The generation of a virtual cohort of patients might be advantageous since an artificial group of patients resembles the real dataset in all the key features but it does not include any identifiable real-patient data, tackling - by a privacy standpoint – the “burden” of collecting data subjects’ consent as well as the shortcomings of common anonymization techniques. Aims: To test the feasibility of this approach and evaluate its potential in clinical trial design, we built an in-silico cohort based on the large dataset of patients enrolled in the GIMEMA AML1310 study (Venditti et al. 2019), which entailed a “3 + 7”-like induction and a risk-adapted, MRD-directed post-remission transplant allocation. Methods: To create the synthetic cohort of patients, a machine learning generative model was constructed from the real individual-level data of the AML1310 study, capturing its patterns and statistical properties. AML1310 enrolled 500 patients (median age 49 years old) in 55 GIMEMA Institutions. All patients were NCCN2009 risk classified and analyzed by morphology, cytogenetics, molecular biology and multiparametric flow cytometry. The subset of 445 patients with ELN2017 risk classification available was used. To this purpose, the R package “synthpop” was used considering a parametric method: for binary data the logistic regression, for a factor with > 2 levels the polytomous logistic regression, for an ordered factor with > 2 levels the ordered polytomous logistic regression. For time to event variables the classification and regression trees method was used. Next, we verified the adherence of the virtual cohort to the original one in terms of age, gender, PS, WBC count, FLT3 and NPM1 mutations, risk category, CR achievement, MRD, transplant rate. Virtual and real cohorts were also compared in terms of survival outcomes. Results: By using the real-patient dataset from the AML1310 trial, a virtual cohort of 850 patients, named synthAML1310, was generated. By comparing the two cohorts, we observed that the clinico-biological characteristics and response evaluations (CR and MRD rates) did not differ significantly. Moreover, as depicted in Figure 1, the curves of OS and DFS were superimposable. Indeed, at 2 years, OS was 57% (52.5%-61.9%) in the original and 59.1% (55.9%-62.6%) in the synthAML1310 cohort. DFS was 55.1% (49.8%-60.9%) in the original and 55.1% (51.3%-59.2%) in the synthetic cohort. Summary/Conclusion: These results demonstrate the success of this approach in producing a virtual dataset that perfectly mimics the original and that, from a “privacy by design” perspective, minimizes the risk of re-identification of patients. Mirroring an AML population treated with a conventional chemotherapeutic approach, synthAML1310 is suitable to represent the control group when testing novel innovative treatments, most likely in an in-silico randomized trial, but also in other settings like propensity score matching analyses in observational studies. Shifting to an in-silico trial would overcome the challenges of randomized trials and it would be beneficial also for patients. since, they would receive only the experimental treatment without being exposed to the “less active“ therapy, thus limiting treatment failures and toxicity. Also, enrolment and the attainment of final results would be faster

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients

Abstract Background Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. Methods Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient’s peripheral blood mononuclear cells (PBMCs). 5′-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. Results We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. Conclusions We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients

Clinician-reported symptomatic adverse events in cancer trials: are they concordant with patient-reported outcomes?

We investigate the concordance, in terms of favoring the same treatment arm, between clinician-reported symptomatic adverse events (AEs) and information obtained via patient-reported outcomes (PRO) measures in cancer randomized controlled trials (RCTs)

The level of patient-reported outcome reporting in randomised controlled trials of brain tumour patients: A systematic review

Background: To determine the net clinical benefit of a new treatment strategy, information on both survival and patient-reported outcomes (PROs) is required. However, to make an adequately informed decision, PRO evidence should be of sufficiently high quality. Objective: To investigate the methodological quality of PRO reporting in randomised controlled trials (RCTs) in patients with brain tumours, and to assess the proportion of studies that should impact clinical decision-making. Methods: We conducted a systematic literature search in several databases covering January 2004 to March 2012. We selected relevant RCTs and retrieved the following data: (1) basic trial demographics and PRO characteristics, (2) quality of PRO reporting and (3) risk of bias. Studies that should impact clinical decision-making based on their methodological robustness were analysed systematically. Results: We identified 14 RCTs, representing over 3000 glioma patients. Only two RCTs (14%) satisfied sufficiently many key methodological criteria to provide high-quality PRO evidence, and should therefore impact clinical decision-making. Important methodological limitations in other studies were lack of reporting of the extent (43%) and reasons (86%) of missing data and statistical approaches to handle this (71%). PRO results were not interpreted in 79% of the studies and clinical significance was not discussed in 86%. Studies with high-quality PRO evidence generally showed lower risk of bias. Conclusions: Investigators involved in brain tumour research should pay special attention to methodological challenges identified in current work. The level of PRO reporting should continue to improve in order to facilitate a critical appraisal of study results

Additional file 2: Figure S2. of A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients

Chromatograms of the 400 nt-5′-RACE products not subjected to subcloning. (TIFF 155 kb