Clopidogrel resistance is common in patients undergoing vascular and coronary interventions

Objectives “Clopidogrel resistance,” also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. Methods In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer’s exact test was used to determine significance. Results From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence ( p = 0.78). Conclusion “Clopidogrel resistance” or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Development and Validation of a Machine Learning Model Predicting Arteriovenous Fistula Failure in a Large Network of Dialysis Clinics

Background: Vascular access surveillance of dialysis patients is a challenging task for clinicians. We derived and validated an arteriovenous fistula failure model (AVF-FM) based on machine learning. Methods: The AVF-FM is an XG-Boost algorithm aimed at predicting AVF failure within three months among in-centre dialysis patients. The model was trained in the derivation set (70% of initial cohort) by exploiting the information routinely collected in the Nephrocare European Clinical Database (EuCliD®). Model performance was tested by concordance statistic and calibration charts in the remaining 30% of records. Features importance was computed using the SHAP method. Results: We included 13,369 patients, overall. The Area Under the ROC Curve (AUC-ROC) of AVF-FM was 0.80 (95% CI 0.79–0.81). Model calibration showed excellent representation of observed failure risk. Variables associated with the greatest impact on risk estimates were previous history of AVF complications, followed by access recirculation and other functional parameters including metrics describing temporal pattern of dialysis dose, blood flow, dynamic venous and arterial pressures. Conclusions: The AVF-FM achieved good discrimination and calibration properties by combining routinely collected clinical and sensor data that require no additional effort by healthcare staff. Therefore, it can potentially enable risk-based personalization of AVF surveillance strategies.

CTNI-04. RECURRENT GLIOBLASTOMA LONG-TERM SURVIVORS TREATED WITH CUSP9v3

CUSP9v3 is a new treatment regimen for glioblastoma. It consists of continuous daily use of 9 drugs repurposed from general medicine. Their primary non-oncology uses are given in parentheses: aprepitant (nausea), auranofin (rheumatoid arthritis), celecoxib (pain), captopril (hypertension), disulfiram (alcohol abuse), itraconazole (fungal infection), minocycline (bacterial infection), ritonavir (viral infection) and sertraline (depression). All drugs have preclinical or clinical data indicating that they can retard glioblastoma growth, as reviewed in the published background papers. In CUSP9v3 all 9 medicines are given daily with added metronomic, low-dose (20 mg/m2 BSA twice daily) temozolomide. After 3 years of daily, uninterrupted use of CUSP9v3, of an initial cohort of 10 recurrent glioblastoma patients, as of May 2021, 3 are alive, functioning well, progression-free at 44, 44, and 57 months after recurrence and CUSP9v3 started. We report now that there were no unexpected toxicities from this combination of 10 daily drugs, although all patients required dose reduction of one or more of the drugs. CUSP9v3 was reasonably well-tolerated. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose reduction or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. There were no treatment-related deaths. In the 3 long-term survivors, the median neutrophil-to-lymphocyte ratio decreased from 2.5 to 1.5 during CUSP9v3 treatment. In the group of the 3 shortest-term survivors that ratio increased from 4.7 to 14.3. CUSP9v3 follows the injunction of Palmer et al. that cancer therapy can be constructed using drug combinations that are independently effective, with non-overlapping mechanisms of action, and non-overlapping resistance pathways. We interpret the data accrued over the last few decades on the ever-shifting spatial and temporal growth drives active at any given moment in glioblastoma as requiring a complex pharmacological approach like CUSP9v3.

P.056 Optimizing IVIg Use for Neuromuscular Conditions in British Columbia, Canada – Targeting High and Chronic User Groups

Background: Neuromuscular conditions account for 1/3 of IVIg use in BC and costs over $10 million annually. Since 2013, the BC Neuromuscular Review Panel has developed diagnostic and treatment algorithms for the use of IVIg. A framework was created to review high dose and chronic users. Methods: Utilizing Central Transfusion Registry data, all patients treated with IVIg for approved neuromuscular conditions (CIDP, MG, MMN) since April 1, 2013 were identified. Annual cohorts for patients using higher than usual dose and chronic use (>3 years) were established, and evaluated annually. Patient specific recommendations were made. Results: The initial cohort identified 38 high users of 377 patients receiving IVIg. 27 appropriate, 9 “not appropriate”. Subsequent cohorts showed a decrease in number of patients receiving inappropriate IVIg doses. In BC there has been a 36% increase in neuromuscular patients treated with IVIg (377 in 2013/14 to 512 in 2016/17). Despite this, IVIg the program has effectively reduced the annual grams/patient from 516 gm/patient in 2013/14 to 489 gm/patient in 2016/17. Conclusions: The BC Neuromuscular IVIg Review confirms that the majority of IVIg use is appropriate. Following yearly cohorts of chronic and high dose users helps optimize IVIg use, which may lead to improved patient care.

Grading mitral regurgitation using 4D flow CMR: comparison to transthoracic echocardiography

Background Mitral Regurgitation (MR) is currently primarily assessed using multiple transthoracic echocardiography (TTE) parameters. Two-dimensional Cardiac Magnetic Resonance (CMR) can be used in difficult cases but has limited agreement with TTE for quantifying MR. We hypothesized that 4D Flow CMR may help to quantify MR. Purpose To determine the 4D Flow CMR thresholds that achieve the best agreement with TTE for grading MR. Methods We conducted a single-center prospective study of patients evaluated for chronic primary MR in 2016–2020. MR was evaluated blindly by TTE and 4D Flow CMR respectively by two cardiologists and two radiologists with decades of experience. MR was graded with both methods as mild, moderate or severe. 4D Flow CMR measurements included MR regurgitant volume per beat (RV) and mitral anterograde flow per beat (MF). RF was obtained as the ratio RV/MF. Additionally, MF was compared to left ventricular stroke volume (LVSV) by cine-CMR. Results We included 33 patients in the initial cohort and 33 in the validation cohort. Inter-observer agreement was good for TTE and excellent for 4D Flow CMR. Agreement between MF and LVSV was excellent. Using recommended TTE thresholds (30 mL, 60 mL, 30%, 50%), agreement was moderate for RV and RF. The best agreement between 4D Flow CMR and TTE was obtained with CMR thresholds of 20 mL and 40 mL for RV (κ=0.93; 95% CI, 0.8–1) and 20% and 37% for RF (κ=0.90; 95% CI, 0.7–0.9). In the validation cohort, agreement between TTE and 4D Flow CMR was good with the optimal thresholds (κ= 0.78; 95% CI, 0.61–0.94). Conclusion We propose CMR thresholds that provide a good agreement between TTE and CMR for grading MR. Further studies are needed to fully validate 4D-Flow CMR accuracy for primary MR quantification. FUNDunding Acknowledgement Type of funding sources: None. Quantification of MR using 4D Flow CMR

Scoliosis in Children: Impact of Goal Directed Therapies on Intra-operative and Postoperative Outcomes

Background: Scoliosis is among interventions with high postoperative complication rates due to the characteristics of the surgery where blood loss, transfusion and fluid requirements can be increased. A monocentric retrospective observational study was undertaken earlier to determine predictors of intraoperative and postoperative outcomes in surgical patients. In this initial cohort there were patients who underwent scoliosis surgery and a secondary analysis to describe outcomes in these patients was realized and presented here.Objective: To describe intraoperative and postoperative outcomes in patients under 18 years old in scoliosis surgery included in the initial study and to propose improvement implementation measures.Methods: Secondary analysis of patients in scoliosis surgery. The study was approved by the Ethics Committee.Results: There were 116 patients with a mean age of 147.5 ± 40.2 months. Twenty-eight patients (24.1%) presented intraoperative and or postoperative complications. The most common intraoperative complication was hemorrhagic shock in 3 patients (2.6%). The most common postoperative organ failure was neurologic in seven patients (6%), respiratory in 3 patients (2.6%), cardio-circulatory in 2 patients (1.7%) and renal failure in one patient (0.9%).The most common postoperative infection was surgical wound sepsis in 8 patients (6.9%), urinary sepsis in three patients (2.6%), abdominal sepsis and septicemia in two patients (1.7%) respectively.Twelve patients (10.3%) had reoperations. Fifty-six patients (48.3%) had intraoperative transfusion.There was no in-hospital mortality.Conclusion: Integrating goal directed therapies in this surgical setting could improve postoperative outcomes

Scoliosis in Children: Impact of Goal Directed Therapies on Intra-operative and Postoperative Outcomes

Background: Scoliosis is among interventions with high postoperative complication rates due to the characteristics of the surgery, where blood loss, transfusion and fluid requirements can be increased.A monocentric retrospective observational study was undertaken earlier to determine predictors of intraoperative and postoperative outcomes in surgical patients. In this initial cohort, there were patients who underwent scoliosis surgery, and a secondary analysis to describe outcomes in these patients was realized and is presented here.Objective: To describe intraoperative and postoperative outcomes in patients under 18 years old in scoliosis surgery included in the initial study and to propose improvement implementation measures.Methods: Secondary analysis of patients undergoing scoliosis surgery. The study was approved by the Ethics Committee.Results: There were 116 patients with a mean age of 147.5 ± 40.2 months. Twenty-eight patients (24.1%) presented intraoperative and/or postoperative complications. The most common intraoperative complication was hemorrhagic shock in 3 patients (2.6%). The most common postoperative organ failure was neurologic in seven patients (6%), respiratory in 3 patients (2.6%), cardio-circulatory in 2 patients (1.7%) and renal failure in one patient (0.9%).The most common postoperative infection was surgical wound sepsis in 8 patients (6.9%), urinary sepsis in three patients (2.6%), and abdominal sepsis and septicemia in two patients (1.7%).twelve patients (10.3%) had reoperations.Fifty-six patients (48.3%) had intraoperative transfusion.There was no in-hospital mortality.Conclusion: Integrating goal-directed therapies in this surgical setting could improve postoperative outcomes.

The added value of PSMA PET/MR radiomics for prostate cancer staging

Purpose To evaluate the performance of combined PET and multiparametric MRI (mpMRI) radiomics for the group-wise prediction of postsurgical Gleason scores (psGSs) in primary prostate cancer (PCa) patients. Methods Patients with PCa, who underwent [68 Ga]Ga-PSMA-11 PET/MRI followed by radical prostatectomy, were included in this retrospective analysis (n = 101). Patients were grouped by psGS in three categories: ISUP grades 1–3, ISUP grade 4, and ISUP grade 5. mpMRI images included T1-weighted, T2-weighted, and apparent diffusion coefficient (ADC) map. Whole-prostate segmentations were performed on each modality, and image biomarker standardization initiative (IBSI)-compliant radiomic features were extracted. Nine support vector machine (SVM) models were trained: four single-modality radiomic models (PET, T1w, T2w, ADC); three PET + MRI double-modality models (PET + T1w, PET + T2w, PET + ADC), and two baseline models (one with patient data, one image-based) for comparison. A sixfold stratified cross-validation was performed, and balanced accuracies (bAcc) of the predictions of the best-performing models were reported and compared through Student’s t-tests. The predictions of the best-performing model were compared against biopsy GS (bGS). Results All radiomic models outperformed the baseline models. The best-performing (mean ± stdv [%]) single-modality model was the ADC model (76 ± 6%), although not significantly better (p > 0.05) than other single-modality models (T1w: 72 ± 3%, T2w: 73 ± 2%; PET: 75 ± 5%). The overall best-performing model combined PET + ADC radiomics (82 ± 5%). It significantly outperformed most other double-modality (PET + T1w: 74 ± 5%, p = 0.026; PET + T2w: 71 ± 4%, p = 0.003) and single-modality models (PET: p = 0.042; T1w: p = 0.002; T2w: p = 0.003), except the ADC-only model (p = 0.138). In this initial cohort, the PET + ADC model outperformed bGS overall (82.5% vs 72.4%) in the prediction of psGS. Conclusion All single- and double-modality models outperformed the baseline models, showing their potential in the prediction of GS, even with an unbalanced cohort. The best-performing model included PET + ADC radiomics, suggesting a complementary value of PSMA-PET and ADC radiomics.

18F-FMISO-PET Hypoxia Monitoring for Head-and-Neck Cancer Patients: Radiomics Analyses Predict the Outcome of Chemo-Radiotherapy

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by 18F-fluoromisonidazole (18F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of 18F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal 18F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆RF). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two 18F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUCW2 = 0.82 and AUCW5 = 0.81 in initial cohort (N = 25) and AUCW2 = 0.79 and AUCW5 = 0.80 in validation cohort. Radiomics analysis of 18F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT.

Pre-term Infants in Major Abdominal Surgery and Postoperative Outcome

Background: A monocentric observational study was undertaken in pediatric surgical patients in neurosurgery, abdominal and orthopedic surgery to determine predictors of postoperative outcome. In this cohort of 594 patients with a mean age of 90.86±71.80 months there were 25 pre-terms aged less than 37 weeks. A description of postoperative outcome was undertaken in these pre-term infants. Objective: The objective of this study was to describe the characteristics in pre-term patients in this initial cohort. Methods: Secondary analysis of pre-term patients included in the initial retrospective observational study. The Ethics Committee approved the study. Results: 25 pre-terms aged <37 weeks were included with a mean weight of 2.43±0.75 kg in major neonatal abdominal surgery. 9 patient presented postoperative complications among which 1 had an intra-operative cardiac arrest, 4 had postoperative respiratory failure, 2 had pulmonary sepsis, 1 had surgical wound sepsis, 1 had septicemia and 1 had multi-organ sepsis. Conclusion: In this cohort of 25 critically ill pre-terms in major neonatal abdominal surgery, the most common postoperative complications concerned the respiratory system which included respiratory failure and pulmonary sepsis. There was no in-hospital mortality.