Background Curative-intent management of locally recurrent rectal cancer (LRRC) generally comprises neoadjuvant therapy and surgery. In patients with unresectable LRRC, where surgical intervention is not feasible, management is limited to non-operative bimodality therapy with systemic therapy and radiotherapy. Evidence guiding the optimisation of non-operative management remains limited. In this context, the therapeutic goal is to achieve prolonged local control while minimising treatment-related adverse events and preserving quality of life. Radiotherapy dose escalation has been proposed as a potential strategy to achieve this balance. However, its feasibility and safety in the non-operative management of unresectable LRRC have not yet been established. As such, this study aims to evaluate the feasibility and safety of this radiotherapeutic approach, and to determine its impact on both symptom control and oncological outcomes. Methods This prospective, multicentre, single-arm feasibility study will enrol 30 patients with unresectable or inoperable LRRC without distant metastases, or with (oligo)metastatic disease not requiring immediate systemic therapy. Previously irradiated patients will undergo reirradiation with stereotactic body radiotherapy (re-SBRT; 5 × 9 Gy) when feasible, or, alternatively hyperfractionated chemo-reirradiation (50.4 Gy in 1.2 Gy twice-daily fractions with concurrent capecitabine). Radiotherapy-naïve patients will receive chemoradiotherapy with a simultaneous integrated boost (25 × 2.6 Gy, EQD2Gyα/β=5Gy of 71 Gy with concurrent capecitabine). [1] The primary endpoint is treatment regimen feasibility, defined as grade ≥ 3 acute radiotherapy-related adverse events (CTCAE version 5.0) occurring in no more than seven patients (23%). Secondary endpoints include late adverse events, quality of life and symptom control, and 1- and 3-year progression-free survival, disease-free survival, and overall survival. Discussion This protocol describes the STEP-UP study, which will determine the feasibility of radiotherapy dose escalation in unresectable LRRC. If feasible and safe, this approach could provide an effective treatment intensification strategy to improve local control and symptom burden in patients with unresectable LRRC, addressing a major unmet clinical need. Trial registration ClinicalTrials.gov: NCT07721181Overview of Medical-Scientific Research in the Netherlands (OMON) Registry: NL-011150.International Clinical Trial Registry Platform (ICTRP): NL-OMON61161.
Video-based monitoring technologies enable continuous and contactless monitoring of vital signs. This study evaluates the clinical concordance and determinants of performance of contactless video-based heart and respiratory rate monitoring compared with reference standards in a heterogeneous population of critically ill patients. In this prospective observational study, 35 intensive care unit patients were continuously monitored for 24 h. Video-based heart rate and respiratory rate were compared with the clinical reference standard. Agreement was assessed using Bland–Altman plots, intraclass correlation coefficients (ICC), and error grid analyses. Generalized estimating equations (GEE) identified factors affecting agreement. For heart rate, bias was 2.1 bpm (limits − 33.6 to 37.7), with 81.9
BACKGROUND AND AIMS:Left bundle branch area pacing (LBBAP) promotes physiological synchronous activation of the left ventricle and may be particularly beneficial in patients with atrioventricular block (AVB), but its mortality benefit remains unclear. This study aims to compare long-term survival in AVB patients receiving either LBBAP or right ventricular pacing (RVP) and to analyse predictors of mortality during LBBAP. METHODS:MELOS RELOADED, a multicentre European collaboration, was a registry-based study of pacemaker patients with AVB, left ventricular ejection fraction (LVEF) >40% and ventricular pacing >20%. The primary outcome was all-cause mortality based on national registries. A 1:1 propensity score matching was performed between the RVP and LBBAP groups. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to estimate survival. RESULTS:In total, 3382 patients receiving LBBAP or RVP were matched. At 4-year follow-up, the Kaplan-Meier curve showed an absolute difference in survival of 11.8% in favour of LBBAP (P < .001). LBBAP was a robust predictor of reduced mortality with a hazard ratio (HR) of 0.53 (95% confidence interval 0.42-0.65, P < .001). Within the LBBAP group, the following independent predictors of increased mortality were identified: lack of confirmed left bundle branch capture (HR 1.85, P < .001), lower percentage of ventricular pacing (HR 1.12), and age. CONCLUSIONS:This is the first large study demonstrating the long-term survival benefit of LBBAP. This strengthens the use of LBBAP in AVB patients with preserved/mildly reduced LVEF while awaiting the results of randomized trials. Confirmation of left bundle branch capture seems advisable to achieve optimal results with LBBAP.
BACKGROUND:Intravascular ultrasound (IVUS) guidance during percutaneous coronary intervention (PCI) has been associated with increased stent optimization and reduced adverse events among patients with complex coronary-artery lesions, but adoption of this strategy in Western countries remains low. Although practice guidelines recommend intracoronary imaging for anatomically complex lesions, evidence from current European practice is limited. METHODS:In this investigator-initiated, international, open-label, randomized, controlled trial, we assigned patients undergoing complex PCI to either IVUS-guided PCI, performed with the use of prespecified stent-optimization criteria, or angiography-guided PCI. The primary end point was target-vessel failure, defined as a composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-vessel revascularization. RESULTS:Of the 2020 patients who underwent randomization, 1010 in the IVUS-guided PCI group and 1009 in the angiography-guided PCI group were included in the primary analysis. The mean age of the patients was 69 years, 79.4% were men, and 27.4% presented with an acute coronary syndrome. The mean procedure duration was 88.8 minutes with IVUS-guided PCI and 66.2 minutes with angiography-guided PCI. Dilation with balloon angioplasty after stent implantation was performed in 91.3% of the IVUS-guided PCI procedures and in 84.5% of the angiography-guided PCI procedures. At a median follow-up of 19.0 months (interquartile range, 15.2 to 23.4), target-vessel failure had occurred in 140 patients (13.9%) in the IVUS-guided PCI group and in 112 patients (11.1%) in the angiography-guided PCI group (hazard ratio, 1.25; 95% confidence interval, 0.97 to 1.60; P = 0.08). Procedural complications occurred in 11.3% of the IVUS-guided PCI procedures and in 10.2% of the angiography-guided PCI procedures. The frequency of adverse events appeared to be similar in the two groups. CONCLUSIONS:Among patients undergoing complex high-risk PCI, a strategy of routine IVUS-guided PCI performed with the use of prespecified stent-optimization criteria was not associated with a lower risk of target-vessel failure than angiography-guided PCI alone. (Funded by Boston Scientific; IVUS-CHIP ClinicalTrials.gov number, NCT04854070.).
BACKGROUND:Risk of irinotecan-related severe toxicity is significantly higher in patients carrying 2 dysfunctional UGT1A1 gene variants, characterized as poor metabolizers (PMs), following standard irinotecan dosing. Since 2020, we implemented UGT1A1 genotype-guided dosing of irinotecan in routine clinical practice to reduce toxicity in PMs. This study evaluates its impact on severe toxicity in a real-world cohort. PATIENTS AND METHODS:Our study cohort included adult patients who received UGT1A1 genotype-guided irinotecan dosing at 6 Dutch hospitals between December 2020 and April 2024. Patients were included in the primary analysis if irinotecan was dosed according to UGT1A1 genotype (ie, 100% ±10% dose intensity for intermediate and normal metabolizers [IM/NMs] and 70% ±10% for PMs) in at least cycle 1. Toxicities, hospitalizations, and treatment alterations were collected for cycles 1-3 and graded according to CTCAE version 5.0. Endpoints were compared between PMs with a 70% starting dose and fully dosed IM/NMs. RESULTS:A total of 501 patients were included in the primary analysis; 54 of whom were PMs (10.8%). Baseline characteristics were evenly distributed between groups. The incidences of overall severe toxicity (29.6% vs 34.0%; P=.52), febrile neutropenia (3.7% vs 5.8%; P=.76), severe neutropenia (17.0% vs 17.8%; P=.88), severe diarrhea (13.0% vs 15.0%; P=.69), and toxicity-related hospitalization (14.8% vs 21.7%; P=.24) were comparable between dose-reduced PMs and fully dosed IM/NMs. In a secondary analysis, 9 UGT1A1 PMs who received an unintended full irinotecan dose experienced more severe toxicity than PMs with a 70% starting dose (overall severe toxicity: 77.8% vs 29.6%; P=.009). CONCLUSIONS:UGT1A1 genotype-guided dosing of irinotecan improves patient safety and treatment tolerability of irinotecan. A 70% starting dose of irinotecan for UGT1A1 PMs is necessary to normalize the risk of severe toxicity to that of IM/NMs.
