A phase I, multicenter, open-label, first-in-human study of DS-6157a in patients with advanced gastrointestinal stromal tumor

PURPOSE: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. RESULTS: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. CONCLUSIONS: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated

Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-B10): A single-arm phase IV trial

PURPOSE: Standard-of-care first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is pembrolizumab plus platinum and fluorouracil (FU). However, FU is associated with potential challenges (continuous 4-day infusion, high administration costs, and cardiovascular and gastrointestinal toxicities), creating a clinical need for alternative chemotherapy combinations. We evaluated the efficacy and safety of first-line pembrolizumab plus carboplatin and paclitaxel for R/M HNSCC in the open-label, single-arm, phase IV KEYNOTE-B10 study (ClinicalTrials.gov identifier: NCT04489888). METHODS: Eligible adults had previously untreated, histologically or cytologically confirmed R/M HNSCC regardless of PD-L1 status, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received pembrolizumab 200 mg intravenously once every 3 weeks for ≤35 cycles and carboplatin AUC 5 mg/mL/min intravenously once every 3 weeks for ≤6 cycles and investigator\u27s choice of paclitaxel 100 mg/m RESULTS: Between October 27, 2020, and April 29, 2022, 149 patients were screened and 101 received treatment. As of February 20, 2023, the median follow-up was 18.9 months (range, 9.1-27.0). At this final analysis, 49 (49%) of 101 patients had an objective response (95% CI, 38.4 to 58.7), including seven patients (7%) with a confirmed complete response. Of the 101 treated patients, grade 3-5 and serious treatment-related adverse events occurred in 76 (75%) and 27 (27%), respectively. There were no new safety signals. CONCLUSION: Pembrolizumab plus carboplatin and paclitaxel showed promising antitumor activity and a manageable safety profile in first-line R/M HNSCC, suggesting this combination may be an alternative option for this patient population

A retrospective analysis of the efficacy of immunotherapy in metastatic soft-tissue sarcomas

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients-72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS

3D transient heat transfer numerical analysis of multiple energy piles

This paper presents a three-dimensional (3D) transient heat transfer numerical model for multiple energy piles based on the finite volume method (FVM). The initial and boundary conditions are established and the effects of “thermal short-circulating” between two pipes of a U-tube in energy pile are investigated. Thermal partial differential equations are discretized at the spatial nodal points and solved by linear approximation method. Temperature variations of working fluid, energy pile and its surrounding soil from simulation program are compared with experimental data to validate the developed model. In addition, the influences of fluid flow rate and U-tube shank spacing are analysed. It is established that the shank spacing should be set in a range of 0.06m to 0.10m to reduce heat transfer between the two pipes and meet the structural requirement. Meanwhile, the flow rate should be controlled in a range of 0.5m3/h to 0.7m3/h to avoid the low outlet fluid temperature and decrease the influence of “thermal short-circuiting”

A three-dimensional numerical model of borehole heat exchanger heat transfer and fluid flow

Common approaches to the simulation of borehole heat exchangers assume heat transfer within the circulating fluid and grout to be in a quasi-steady state and ignore axial conduction heat transfer. This paper presents a numerical model that is three-dimensional, includes explicit representations of the circulating fluid and other borehole components, and so allows calculation of dynamic behaviours over short and long timescales. The model is formulated using a finite volume approach using multi-block meshes to represent the ground, pipes, fluid and grout in a geometrically correct manner. Validation and verification exercises are presented that use both short timescale data to identify transport delay effects, and long timescale data to examine the modelling of seasonal heat transfer and show the model is capable of predicting outlet temperatures and heat transfer rates accurately. At long timescales borehole heat transfer seems well characterized by the mean fluid and borehole wall temperature if the fluid circulating velocity is reasonably high but at lower flow rates this is not the case. Study of the short timescale dynamics has shown that nonlinearities in the temperature and heat flux profiles are noticeable over the whole velocity range of practical interest. The importance of representing the thermal mass of the grout and the dynamic variations in temperature gradient as well as the fluid transport within the borehole has been highlighted. Implications for simplified modelling approaches are also discussed

Cardiovascular magnetic resonance in patients with pectus excavatum compared with normal controls

<p>Abstract</p> <p>Purpose</p> <p>To assess cardiothoracic structure and function in patients with pectus excavatum compared with control subjects using cardiovascular magnetic resonance imaging (CMR).</p> <p>Method</p> <p>Thirty patients with pectus excavatum deformity (23 men, 7 women, age range: 14-67 years) underwent CMR using 1.5-Tesla scanner (Siemens) and were compared to 25 healthy controls (18 men, 7 women, age range 18-50 years). The CMR protocol included cardiac cine images, pulmonary artery flow quantification, time resolved 3D contrast enhanced MR angiography (CEMRA) and high spatial resolution CEMRA. Chest wall indices including maximum transverse diameter, pectus index (PI), and chest-flatness were measured in all subjects. Left and right ventricular ejection fractions (LVEF, RVEF), ventricular long and short dimensions (LD, SD), mid-ventricle myocardial shortening, pulmonary-systemic circulation time, and pulmonary artery flow were quantified.</p> <p>Results</p> <p>In patients with pectus excavatum, the pectus index was 9.3 ± 5.0 versus 2.8 ± 0.4 in controls (P < 0.001). No significant differences between pectus excavatum patients and controls were found in LV ejection fraction, LV myocardial shortening, pulmonary-systemic circulation time or pulmonary flow indices. In pectus excavatum, resting RV ejection fraction was reduced (53.9 ± 9.6 versus 60.5 ± 9.5; P = 0.013), RVSD was reduced (P < 0.05) both at end diastole and systole, RVLD was increased at end diastole (P < 0.05) reflecting geometric distortion of the RV due to sternal compression.</p> <p>Conclusion</p> <p>Depression of the sternum in pectus excavatum patients distorts RV geometry. Resting RVEF was reduced by 6% of the control value, suggesting that these geometrical changes may influence myocardial performance. Resting LV function, pulmonary circulation times and pulmonary vascular anatomy and perfusion indices were no different to controls.</p

Metrics for optimising the multi-dimensional value of resources recovered from waste in a circular economy: A critical review

© 2017 The Authors - Established assessment methods focusing on resource recovery from waste within a circular economy context consider few or even a single domain/s of value, i.e. environmental, economic, social and technical domains. This partial approach often delivers misleading messages for policy- and decision-makers. It fails to accurately represent systems complexity, and obscures impacts, trade-offs and problem shifting that resource recovery processes or systems intended to promote circular economy may cause. Here, we challenge such partial approaches by critically reviewing the existing suite of environmental, economic, social and technical metrics that have been regularly observed and used in waste management and resource recovery systems' assessment studies, upstream and downstream of the point where waste is generated. We assess the potential of those metrics to evaluate ‘complex value’ of materials, components and products, i.e., the holistic sum of their environmental, economic, social and technical benefits and impacts across the system. Findings suggest that the way resource recovery systems are assessed and evaluated require simplicity, yet must retain a suitable minimum level of detail across all domains of value, which is pivotal for enabling sound decision-making processes. Criteria for defining a suitable set of metrics for assessing resource recovery from waste require them to be simple, transparent and easy to measure, and be both system- and stakeholder-specific. Future developments must focus on providing a framework for the selection of metrics that accurately describe (or at least reliably proxy for) benefits and impacts across all domains of value, enabling effective and transparent analysis of resource recovery form waste in circular economy systems.We gratefully acknowledge support of the UK Natural Environ-ment Research Council (NERC) and the UK Economic and SocialResearch Council (ESRC) who funded this work in the context of‘Complex Value Optimisation for Resource Recovery’(CVORR)project (Grant No. NE/L014149/1)