Citations

Abstract Background Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusions Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Background: Very few long-term data are available on patients undergoing mitral valve surgery for chronic ischemic mitral regurgitation (CIMR). Objective:to identify determinants of survival and adverse cardiovascular events, at very long-term outcome. Methods and Results: We reviewed complete left and right ventricular echocardiographic data, six-minute walking test (6-MWT) and BNP levels at pre, peri and follow-up, on 137 consecutive patients who underwent restrictive mitral annuloplasty (RMA) or mitral valve replacement (MVR) and CABG, for CIMR. Combined adverse cardiovascular events were defined as composite of death, heart failure, angina, myocardial infarction and re-hospitalization. Mean age was 67±0.7. Preoperative EF was 35±06%. Among 137 patients, 46% underwent RMA and 54% had MVR. Median follow- up was 7 years (range: 0.3-15.4). Early mortality was 7% (p=NS). In the RMA 42% of patients experienced MR recurrence. Overall survival at 5, 10 and 15 years were 84, 76 and 62% in RMA, and 87, 62 and 54% in MVR (p=0.65). At univariate analysis, preop B-blocker, 6-MWT, mean transmitral gradients and RV size were predictors of adverse events.The Cox Hazard multivariate analysis identified preoperative atrial fibrillation (p=0.005), preop BNP (p=0.025) as independent predictors of long-term mortality.Freedom from cardiovascular events at 5, 10 and 15 years were 90, 75 and 48% in RMA, and 90, 62 and 45% in MVR (p=0.57). . The Cox Hazard multivariate analysis identified preop B-blocker therapy (p=0.001), atrial fibrillation (p=0.01), postoperative mean transmitral gradients (p=0.047 ) and indexed effective orifice area (p=0.02) as independent predictors of adverse cardiovascular events. Conclusions: Our study confirms an high rate of true MR recurrence, at very long-term follow-up. Among collected variables, preoperative BNP and atrial fibrillation were independent predictors of survival, whereas B-blocker therapy, atrial fibrillation, postoperative mean transmitral gradients and indexed effective orifice area were independent predictors of adverse cardiovascular events. Type of surgery did not affect the very long-term outcome.

Abstract Background Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing. Methods Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided. Results Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P < .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers. Conclusion Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.

Background Elective percutaneous coronary intervention (PCI) is performed to relieve symptoms of angina. Identifying patients who will benefit symptomatically after PCI would be clinically advantageous but robust predictors of symptom resolution are ill-defined. Methods Prospective indexing of baseline angina status, clinical, and procedural characteristics were collected over a 5-year period in a regional revascularization registry. At 1-year follow-up, angina resolution was assessed. We performed a stepwise selection algorithm to identify predictors of persistent angina at 1 year. Results A total of 777 patients were included in the analysis and the median follow-up was 387 days. Mean age of the cohort was 66.6 years, 23.8% were female and 23.3% had baseline Canadian Cardiovascular Society class 3 or 4 angina. Overall, 13.1% had persistent angina. The only predictor of persistent angina was the presence of a residual chronic total occlusion after PCI with odds ratio of 3.06 (95% confidence interval, 1.81–5.17). Residual stenoses 50–69%, 70–89%, and 90–99% were not associated with residual angina after PCI. Conclusion Most patients achieved symptom resolution with PCI and optimal medical therapy. A residual chronic total occlusion after PCI was associated with persistent angina. Other degrees of stenoses were not associated with persistent angina.

The muscle wasting and impaired muscle function associated with critical llness in ICU patients have negative consequences for recovery from primary disease, but are also the most persistent and debilitating of problems for ICU survivors years after hospital discharge. This study aims at improving our understanding of the mechanisms underlying the muscle wasting in ICU patients by conducting time‐resolved analyses of skeletal muscle structure and function together with measurements of protein synthesis rate, myofibrillar protein and gene expression and intracellular signaling in response to post‐synaptic block of neuromuscular transmission (NMB), sedation, mechanical ventilation and muscle unloading at durations varying from hours to two wks by using a unique experimental rat ICU model. Skeletal muscle structure and function were well maintained during the first four days, followed by a dramatic and progressive decline in muscle size and function. The preferential loss of the molecular motor protein myosin and impaired forcegenerating capacity (specif force) are the major causes underlying the impaired skeletal muscle function in the ICU model. Muscle unloading due to lack of weightbearing (external unloading) and muscle membrane depolarization (internal unloading) are forwarded as very important underlying factors. Supported by the Sweish Research Council and AFM

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

3597 Background: Colon cancer (CC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years) is increasing. There are limited data suggesting that, as a group, patients with early onset CRC (eoCC) may have different phenotypic characteristics compared to those with late onset CRC (loCC, age ≥ 50 years). Methods: Individual patient data on 35,713 subjects with stage III CC from 25 randomized studies (recruiting between 1987 and 2009) in the ACCENT database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age group. Overall survival (OS), disease-free survival (DFS), recurrence free rate (RFR), and survival after recurrence (SAR) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for gender, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness and molecular markers. Results: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III eoCC (n = 6246) had similar distributions according to gender, race, PS, risk group, tumor sidedness and T/N stage compared to those with loCC (n = 29467). Patients with eoCC were significantly less likely to be overweight (30.2% vs 36.2%) but more commonly had ≥ 12 lymph nodes resected (69.5% vs 58.7%). The eoCC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%), and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher frequency of Lynch syndrome in eoCC. In univariate analysis, patients with stage III eoCC had significantly better OS, DFS, and SAR; the difference between 3-year DFS and RFR strongly suggests the OS/DFS difference between these the eoCC and loCC may be due to increased competing risks and comorbidities in patients with loCC. In multivariate analysis, age at onset lost its prognostic value when outcome was adjusted for molecular markers. The clear relation between age of onset and KRAS/BRAF status was confirmed in the interaction analysis. Conclusions: Tumor biology was an important determinant of prognosis regardless of patient age. In multivariate analysis age of onset was not a statistically significant determinant of outcome.[Table: see text]

3517 Background: Incidence of early-onset colorectal cancer (eoCRC, age < 50) is steadily increasing. Decisions on adjuvant treatment (adjTx) regimen and duration should consider tx adherence, toxicity (tox) and expected outcomes in a population with life-expectancy longer than late onset CRC (loCRC, age ≥ 50). Methods: Individual patient data from stage II/III patients (pts) from 6 randomised trials in the IDEA database were used to compare characteristics, tx adherence, and adverse events of eoCRC to loCRC. To reduce the confounder of non-cancer-related deaths due to age/co-morbidities, time-to-recurrence (TTR) and cancer-specific survival (CSS) were compared by stratified Gay k-sample test. 5-year cancer-specific mortality (CSM) rate were estimated by adjusted cumulative incidence function. 3-year relapse-free survival (RFS) rate were compared by stratified and adjusted COX models. Results: Out of 16,349 pts included, 1564 (9.6%) were eoCRC. Compared to loCRC, eoCRC had lower percent of male pts (51% vs 57%, p < 0.01) better performance status (PS0 86% vs 80%, p < 0.01), similar T stage distribution (% T1-3/T4: 76/24 vs 77/23, p = 0.97), higher rate of N2 disease (24% vs 22%, p < 0.01), more likely to complete pre-planned duration of adjTx (83.2% vs 78.2%, p < 0.01) and received a higher tx intensity especially with 6 month tx (mean oxaliplatin dose intensity 75% vs 72%, p < 0.01; capecitabine 85% vs 78%, p < 0.01; 5FU 85% vs 82% p < 0.01). Gastrointestinal tox was more common in eoCRC (any grade nausea 58% vs 45%, p < 0.01; any grade vomiting 22% vs 16%, p < 0.01); haematological tox was more frequent in loCRC (62% vs, 69%, p = < 0.01); any grade neuropathy rate was similar (75%). Significant interaction was found between age and T stage for TTR (p = 0.04). Clinical outcome estimates and comparisons are shown in Table. Notably, high risk stage III (T4/N2) eoCRC had significantly lower 3-y RFS rate (54% vs 64%, HRadj 0.74, p < 0.01). Conclusions: eoCRC have better tx adherence than loCRC, as expected. While in high risk stage II and low risk stage III, cancer-specific outcomes are not different, in high risk stage III young age is negatively prognostic and associated with significantly higher relapse rate and risk of CRC death; this is despite a higher administered adjTx-intensity, suggesting a more aggressive disease biology. Clinical trial information: NCT00749450 (SCOT); NCT00646607 (TOSCA); NCT01150045 (CALGB/SWOG 80702); NCT00958737 (IDEA France) [Table: see text]