PROACT 2.0: A new open-source tool to improve patient-doctor communication in clinical trials.

The use of Digital Healthcare Products is leading to significant improvements in clinical practice. Herein, we discuss the development of PROACT 2.0 (Patient Reported Opinions About Clinical Tolerability v2.0), a novel open-source mobile and web application developed at Fondazione IRCCS Istituto Nazionale Tumori in Milan. It was developed in collaboration with The Christie, Manchester, in the context of work package 2 of the UpSMART Accelerator project, involving a consortium of referral cancer centers from the UK, Spain and Italy. PROACT 2.0 enhances communication between patients and healthcare providers in cancer clinical trials, allowing patients to report adverse events and side effects, and healthcare teams to collect valuable patient-reported outcome measures for treatment management. PROACT 2.0 supports text, audio, and video messaging, offering a secure, non-urgent communication channel that integrates with, or replaces, traditional methods. Its user-friendly and multilingual interface provides a new route for patient engagement and streamlines the handling of logistical information. Positive feedback from initial testing warrants future enhancements for broader applicability in cancer research and treatment.

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.

A pilot study assessing the prognostic value of CK18 and nDNA biomarkers in severe sepsis patients.

BACKGROUND AND OBJECTIVES: Severe sepsis and septic shock have posed significant treatment challenges for many years. Recently, a number of circulating apoptosis biomarkers have emerged, such as full-length and caspase-cleaved cytokeratin 18 (CK18) and nucleosomal DNA (nDNA), that may be predictive of likely outcome. This non-interventional study aimed to assess the ability of enzyme-linked immunosorbent assays (ELISAs) for these biomarkers to provide clinically useful information to guide the management of sepsis. METHODS: This study was conducted in patients admitted to the intensive care unit with severe sepsis at five US centres. Blood samples for assessment of plasma levels of full-length CK18 (measured by the M65® ELISA) and caspase-cleaved CK18 (measured by the M30-Apoptosense® ELISA) and nDNA (measured by ELISA) were collected from patients within 2 hours of consent (baseline) and on days 2, 4 and 8. Blood samples from 17 healthy volunteers acted as controls. Levels of each biomarker were presented descriptively. RESULTS: A total of 22 patients (mean age 60 [range, 24-83] years; 50% male) were included in the study. The mean APACHE II score was 24.4 (range 7-50). One-third of patients had three organ system failures and over one-half had septic shock. Three patients died during the study. Full-length and caspase-cleaved CK18 levels decreased within 48 hours following initiation of treatment of sepsis in patients who survived, whereas increases were observed in the same timeframe in patients who died within 28 days of admission. Baseline nDNA and total soluble CK18 levels (caspase-cleaved and total intact) were significantly (p ≤ 0.05) higher in patients who required renal support than those who did not. CONCLUSIONS: Despite the small numbers of subjects assessed in the current study, these results confirm that measurement of apoptosis biomarkers may help to provide clinically useful information to manage sepsis and expedite development of novel therapeutics. However, further investigations to fully assess their prognostic value are required.