Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE.

BACKGROUND: Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. PATIENTS AND METHODS: Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. RESULTS: Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. CONCLUSIONS: Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2. TRIAL REGISTRATION: NCT03812796 (registered 23rd January 2019).

Cardiovascular responses during free-diving in the sea.

Cardiac output has never been assessed during free-diving diving in the sea. Knowledge of human diving response in this setting is therefore scarce. 3 immersions were performed by 7 divers: at depths of 10 m, 20 m and 30 m. Each test consisted of 3 apnea phases: descent, static and ascent. An impedance cardiograph provided data on stroke volume, heart rate and cardiac output. Mean blood pressure, arterial O2 saturation and blood lactate values were also collected. Starting from a resting value of 4.5±1.6 L∙min(-1), cardiac output at 10 m showed an increase up to 7.1±2.2 L∙min(-1) (p<0.01) during the descent, while conditions during the static and ascent phases remained unchanged. At 20 m cardiac output values were 7.3±2.4 L∙min(-1) and 6.7(±1).2 L∙min(-1) during ascent and descent, respectively (p<0.01), and 4.3±0.9 L∙min(-1) during static phase. At 30 m cardiac output values were 6.5±1.8 L∙min(-1) and 7.5±2 L∙min(-1) during descent and ascent, respectively (p<0.01), and 4.7±2.1 L∙min(-1) during static phase. Arterial O2 saturation decreased with increasing dive depth, reaching 91.1±3.4% (p<0.001 vs. rest) upon emergence from a depth of 30 m. Blood lactate values increased to 4.1±1.2 mmol∙L(-1) at the end of the 30 m dive (p<0.001 vs. rest). Results seem to suggest that simultaneous activation of exercise and diving response could lead to an absence of cardiac output reduction aimed at an oxygen-conserving effect.

Muscle ischemic preconditioning does not improve performance during self-paced exercise.

Muscle ischemic preconditioning (IP) has been found to improve exercise performance in laboratory tests. This investigation aims at verifying whether performance is improved by IP during self-paced exercise (SPE) in the field. 11 well-trained male runners performed 3 randomly assigned 5 000 m self-paced running tests on an outdoor track. One was the reference (RT) test, while the others were performed following muscle IP (IPT) and a control sham test (ST). Average speeds were measured during each test. Mean values in oxygen uptake (VO2), aerobic energy cost (AEC) during race and post-race blood lactate (BLa) were gathered. Data showed that none of the studied variables were affected by IPT or ST with respect to the RT test. Average speeds were 4.63±0.31, 4.62±0.31 and 4.60±0.25 m·s(-1) for the RT, the ST and the IPT tests, respectively. Moreover, there was no difference among tests in speed reached during each lap. VO2 was 3.5±0.69, 3.74±0.85 and 3.62±1.19 l·min(-1). AEC was 1.04±0.15, 1.08±0.1 and 1.09±0.15 kcal·kg(-1)·km(-1). Finally, post-race BLa levels reached 12.85±3.54, 11.88±4.74 and 12.82±3.6 mmol·l(-1). These findings indicate that performance during SPE is not ameliorated by ischemic preconditioning, thereby indicating that IP is not suitable as an ergogenic aid.

Content validation of a tool for assessing risks for drug-related problems to be used by practical nurses caring for home-dwelling clients aged ≥65 years: a Delphi survey.

PURPOSE: Home care services are becoming a critically important part of health care delivery as populations are aging. Those using home care services are increasingly older, more frail than previously, and use multiple medications, making them vulnerable to drug-related problems (DRPs). Practical nurses (PN) visit home-dwelling aged clients frequently and, thus, are ideally situated to identify potential DRPs and, if needed, to communicate them to physicians for resolution. This study developed and validated the content of a tool to be used by PNs for assessing DRP risks for their home-dwelling clients aged ≥65 years. METHODS: The first draft of the tool was based on two systematic literature reviews and clinical experience of our research group. Content validity of the tool was determined by a three-round Delphi survey with a panel of 18 experts in geriatric care and pharmacotherapy. An agreement by ≥80% of the panel on an item was required. RESULTS: The final tool consists of 18 items that assess risks for DRPs in home-dwelling aged clients. It is divided into four sections: (1) Basic Client Data, (2) Potential Risks for DRPs in Medication Use, (3) Characteristics of the Client's Care and Adherence, and (4) Recommendations for Actions to Resolve DRPs. CONCLUSIONS: The Delphi process resulted in a structured DRP Risk Assessment Tool that is focused on the highest priority DRPs that should be identified and resolved. The tool also assists the PNs to identify solutions to these problems, which is a unique feature compared to similarly purposed prior tools.

Quantitative response of IMS detector for mixtures containing two active components.

This study describes the relationship between the output signal of the ion mobility spectrometry (IMS) detector and the concentrations of two compounds being simultaneously introduced into the reaction section. Investigations were performed for three pairs of compounds, that is, dimethyl methylphosphonate (DMMP) and acetone, methyl tert-butyl ether (MTBE), and acetone, as well as trimethylamine (TMA) and n-nonylamine (NA). Vapors of the investigated compounds were produced in a two-channel generator with permeation sources and a dilution system based on mass-flow controllers. The generator design and the method of concentration determination are discussed in this paper. It was found that admixture can differently influence detection of an analyte. The presence of acetone does not effect the signal corresponding to dimer ions of DMMP. For pairs MTBE + acetone and TMA + NA characteristic peaks of analyte ions diminish with growing concentration of admixture, however, the detection based on the peak of the asymmetric dimer containing proton-bound molecules of both compounds is effective. For the detection of TMA in the presence of NA, the signal generated by the asymmetric dimer ions is meaningfully higher than the signals of monomer or dimer TMA ions measured without the NA admixture. The course of calibration dependencies was analyzed on the basis of a simple mathematical model of the reaction region. This model provided an estimation of the intensity of the signal for a given ionic species for definite concentration of analyte.