Early Trials Research Articles

Prior probability cues bias sensory encoding with increasing task exposure

When observers have prior knowledge about the likely outcome of their perceptual decisions, they exhibit robust behavioural biases in reaction time and choice accuracy. Computational modelling typically attributes these effects to strategic adjustments in the criterion amount of evidence required to commit to a choice alternative - usually implemented by a starting point shift - but recent work suggests that expectations may also fundamentally bias the encoding of the sensory evidence itself. Here, we recorded neural activity with EEG while participants performed a contrast discrimination task with valid, invalid, or neutral probabilistic cues across multiple testing sessions. We measured sensory evidence encoding via contrast-dependent steady-state visual-evoked potentials (SSVEP), while a read-out of criterion adjustments was provided by effector-selective mu-beta band activity over motor cortex. In keeping with prior modelling and neural recording studies, cues evoked substantial biases in motor preparation consistent with criterion adjustments, but we additionally found that the cues produced a significant modulation of the SSVEP during evidence presentation. While motor preparation adjustments were observed in the earliest trials, the sensory-level effects only emerged with extended task exposure. Our results suggest that, in addition to strategic adjustments to the decision process, probabilistic information can also induce subtle biases in the encoding of the evidence itself.

Prior probability cues bias sensory encoding with increasing task exposure.

When observers have prior knowledge about the likely outcome of their perceptual decisions, they exhibit robust behavioural biases in reaction time and choice accuracy. Computational modelling typically attributes these effects to strategic adjustments in the criterion amount of evidence required to commit to a choice alternative - usually implemented by a starting point shift - but recent work suggests that expectations may also fundamentally bias the encoding of the sensory evidence itself. Here, we recorded neural activity with EEG while participants performed a contrast discrimination task with valid, invalid, or neutral probabilistic cues across multiple testing sessions. We measured sensory evidence encoding via contrast-dependent steady-state visual-evoked potentials (SSVEP), while a read-out of criterion adjustments was provided by effector-selective mu-beta band activity over motor cortex. In keeping with prior modelling and neural recording studies, cues evoked substantial biases in motor preparation consistent with criterion adjustments, but we additionally found that the cues produced a significant modulation of the SSVEP during evidence presentation. While motor preparation adjustments were observed in the earliest trials, the sensory-level effects only emerged with extended task exposure. Our results suggest that, in addition to strategic adjustments to the decision process, probabilistic information can also induce subtle biases in the encoding of the evidence itself.

Early comparison robotic bronchoscopy versus electromagnetic navigational bronchoscopy for biopsy of pulmonary nodules in a thoracic surgery practice.

Pulmonary nodules are frequently encountered in high-risk patients. Often these require biopsy which can be challenging. We relate our experience comparing use of electromagnetic navigational bronchoscopy (ENB) to a robotic bronchoscopy system (RB). A retrospective review of patients undergoing bronchoscopic biopsy from 2015 to 2021. The timeframe overlapped with transition from ENB using Veran SPiN system to RB using Ion system by Intuitive. Patient and nodule characteristics were collected. Primary end point was overall diagnostic yield which was defined by pathologic confirmation of malignancy or benign finding. Secondary outcomes included diagnostic yield based on overall size of nodules and need for further work up and testing. 116 patients underwent ENB or RB of 134 nodules. No perioperative complications occurred. Diagnostic yield of ENB was 49.5% (41/91 nodules) versus 86.1% (37/43 nodules) for RB. Average nodule size for ENB was 2.55cm versus 1.96cm for RB. When divided based on size, ENB had a 30% diagnostic yield for nodules 1-2cm (11/37 nodules, mean size 1.46cm) and 64% yield for nodules 2-3cm (14/22 nodules, mean size 2.38cm). RB had an 81% yield for nodules 1-2cm (mean size 1.41cm) and 100% yield for nodules 2-3cm (mean 2.3cm). RB showed superiority over ENB in early implementation trials for biopsy of suspicious pulmonary nodules. It is a safe technology allowing for increased access to all lung fields and utilization in the thoracic surgical practice will be paramount to advancing the field.

Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial

BackgroundEfficacy and/or safety profiles limit topical psoriasis treatments. ObjectiveEvaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. MethodsIn this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. ResultsOverall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LimitationsIntertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. ConclusionsIn this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

Regression From Early GDM to Normal Glucose Tolerance and Adverse Pregnancy Outcomes in the Treatment of Booking Gestational Diabetes Mellitus Study.

To compare pregnancy outcomes among women with a normal oral glucose tolerance test (OGTT) before 20 weeks' gestation (early) and at 24-28 weeks' gestation (late) (no gestational diabetes mellitus, or No-GDM), those with early GDM randomized to observation with a subsequent normal OGTT (GDM-Regression), and those with GDM on both occasions (GDM-Maintained). Women at <20 weeks' gestation with GDM risk factors who were recruited for a randomized controlled early GDM treatment trial were included. Women with treated early GDM and late GDM (according to the World Health Organization's 2013 criteria) were excluded from this analysis. Logistic regression compared pregnancy outcomes. GDM-Regression (n = 121) group risk factor profiles and OGTT results generally fell between the No-GDM (n = 2,218) and GDM-Maintained (n = 254) groups, with adjusted incidences of pregnancy complications similar between the GDM-Regression and No-GDM groups. Women with early GDM but normal OGTT at 24-28 weeks' gestation had pregnancy outcomes that were similar to those of individuals without GDM. Identifying early GDM likely to regress would allow treatment to be avoided.

Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. Randomized controlled trial stratified by time-since-menopause. Academic institution. Healthy postmenopausal women. Oral E2 with/without sequential vaginal progesterone. Standard lipids and 21 LPs quantitated by ion mobility every 6 months. Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Ovarian cancer immunotherapy: non-standard solution — non-standard respons

Ovarian cancer is a serious problem in clinical oncology due to the frequent detection of the disease in late stages, as well as the extremely low effectiveness of treatment at the stage of development of resistance to platinum drugs. The use of immunotherapy in this setting is not a standard option, but several early phase trials of its potential effectiveness are described in the literature. This clinical case presents a successful experience with the use of immune checkpoint inhibitors in a pretreated patient with platinum-resistant metastatic ovarian cancer, which was accompanied by various immune-related adverse events.

Automated rating of background parenchymal enhancement in MRI of extremely dense breasts without compromising the association with breast cancer in the DENSE trial

ObjectivesBackground parenchymal enhancement (BPE) on dynamic contrast-enhanced MRI (DCE-MRI) as rated by radiologists is subject to inter- and intrareader variability. We aim to automate BPE category from DCE-MRI. MethodsThis study represents a secondary analysis of the Dense Tissue and Early Breast Neoplasm Screening trial. 4553 women with extremely dense breasts who received supplemental breast MRI screening in eight hospitals were included. Minimal, mild, moderate and marked BPE rated by radiologists were used as reference. Fifteen quantitative MRI features of the fibroglandular tissue were extracted to predict BPE using Random Forest, Naïve Bayes, and KNN classifiers. Majority voting was used to combine the predictions. Internal-external validation was used for training and validation. The inverse-variance weighted mean accuracy was used to express mean performance across the eight hospitals. Cox regression was used to verify non inferiority of the association between automated rating and breast cancer occurrence compared to the association for manual rating. ResultsThe accuracy of majority voting ranged between 0.56 and 0.84 across the eight hospitals. The weighted mean prediction accuracy for the four BPE categories was 0.76. The hazard ratio (HR) of BPE for breast cancer occurrence was comparable between automated rating and manual rating (HR = 2.12 versus HR = 1.97, P = 0.65 for mild/moderate/marked BPE relative to minimal BPE). ConclusionIt is feasible to rate BPE automatically in DCE-MRI of women with extremely dense breasts without compromising the underlying association between BPE and breast cancer occurrence. The accuracy for minimal BPE is superior to that for other BPE categories.

Abstract 4696: ERBB2 signaling and inhibition in bladder cancer

Abstract The role of human epidermal growth factor receptor-2 (HER2) protein and the inhibition of its oncogenic signaling pathway, ERBB2, is well defined and found to be beneficial in combination with standard chemotherapies in breast and certain gastro-intestinal cancers. Targeting the ERBB2 pathway has had unclear or inconsistent results in early trials in bladder cancer (BLCA) and the efficacy of its combination with cisplatin, a standard BLCA chemotherapy, is not known. In this study, we identify the transcriptomic oncogenic signatures that correlate with ERBB2 signaling in BLCA, explore how HER2 expression in BLCA cell lines correlates with treatment response in vitro, and evaluate the potential of ERBB2 inhibition in combination with cisplatin for BLCA. We analyzed the tumor transcriptome from the Cancer Genome Atlas (TCGA) study of BLCA with single sample Gene Set Enrichment Analyses (ssGSEA) for Hallmark and Oncogenic gene sets. We performed multiple Pearson correlation analyses of HER2 protein levels and ERBB2 signaling with other signaling pathways in the TCGA BLCA tumors and adjusted the significance for multiple comparisons using the Benjamini-Hochberg method. Immunoblotting was used to assess HER2 protein levels across a panel of bladder cancer cell lines. We then assessed cell viability and colony formation upon exposure to the specific ERBB2 inhibitor, tucatinib. Synergy between cisplatin and tucatinib in BLCA cell lines was evaluated using the Chou-Talalay method. In the TCGA BLCA dataset, HER2 protein positively correlates with ERBB2 signaling with a Pearson correlation coefficient of 0.45 and an adjusted p-value of 1.73E-17. ERBB2 signaling has multiple significant positive and negative correlations. ERBB2 signaling negatively correlates with the DNA repair gene set with a Pearson coefficient of -0.5 and an adjusted p-value of 1.40E-22. HER2 protein expression varies greatly between bladder cancer cell lines: HT-1197 and UMUC3 have lower HER2 expression, with HT-1376, T24, RT4, 5637, and SW780 showing higher HER2 expression. HT-1197 and RT4 had the lowest IC50s for tucatinib and showed a strong response to low doses of tucatinib in the colony formation assay. Cisplatin and tucatinib have synergetic growth inhibition (combination index &amp;lt;1) at low concentration levels in the HT-1197 and SW780 cell lines. Multiple oncogenic pathways coexist with ERBB2 signaling in BLCA. The varied response to specific ERBB2 inhibition and the lack of correlation of the response with HER2 protein level in cell lines alludes to alternative oncogenic pathways. A strong negative correlation of ERBB2 signaling with the DNA response pathway in the TCGA BLCA dataset, combined with preclinical evidence of synergy between tucatinib and cisplatin, indicates a potential for development of the combination as a clinical treatment strategy and warrants further study. Citation Format: Constance Caparas-Spaugy, Chris Stubben, Ken Boucher, Bingjian Feng, Aaron Atkinson, David Nix, Bradley Cairns, Sumati Gupta. ERBB2 signaling and inhibition in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4696.

Generative Artificial Intelligence as a Tool for Teaching Communication in Nutrition and Dietetics Education-A Novel Education Innovation.

Although effective communication is fundamental to nutrition and dietetics practice, providing novice practitioners with efficacious training remains a challenge. Traditionally, human simulated patients have been utilised in health professions training, however their use and development can be cost and time prohibitive. Presented here is a platform the authors have created that allows students to interact with virtual simulated patients to practise and develop their communication skills. Leveraging the structured incorporation of large language models, it is designed by pedagogical content experts and comprises individual cases based on curricula and student needs. It is targeted towards the practice of rapport building, asking of difficult questions, paraphrasing and mistake making, all of which are essential to learning. Students appreciate the individualised and immediate feedback based on validated communication tools that encourage self-reflection and improvement. Early trials have shown students are enthusiastic about this platform, however further investigations are required to determine its impact as an experiential communication skills tool. This platform harnesses the power of artificial intelligence to bridge the gap between theory and practice in communication skills training, requiring significantly reduced costs and resources than traditional simulated patient encounters.

Abstract 4546: Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma

Abstract Uveal melanoma (UM) is a hard-to-treat arginine auxotrophic cancer with approximately 50% of patients succumbing to metastases predominantly to the liver with a median overall survival of 19-22 months and a 5 year survival of around 10%. Novel drug strategies are urgently needed beyond the currently available immunotherapies that provide durable disease control in a small subset of patients. Arginine deprivation with pegylated arginine deiminase (ADI-PEG20; pegargiminase) is a novel anti-metabolite therapy which demonstrated activity in early phase trials in patients with UM, and more recently, increased survival in patients with the aggressive arginine-dependent cancer, non-epithelioid mesothelioma in the global phase 3 trial, ATOMIC-Meso. Here, we investigated the preclinical rationale for combining pegargiminase with melphalan, a drug which is delivered directly to the liver using an FDA-approved device from Delcath for patients with hepatic-centric UM disease. Two of four uveal melanoma cell lines were negative for expression of the rate-limiting enzyme for arginine production, argininosuccinate synthetase 1 (ASS1) and were submitted for drug evaluation accordingly. ADI-PEG20 treatment of ASS1-deficient cell lines 91.2 and MP41 demonstrated sensitivity to ADI-PEG20 (500ng/ml) compared to MP38 and MP46 ASS1-proficient cell lines. Moreover, the combination of ADI-PEG20 and melphalan (0.77µM) had at least an additive effect on ASS1 negative cell lines in 2D assay (92.1 p-value 0.0061; MP41 p-value is 0.0053). UM cell line proliferation was decreased by 50% in the combination group compared to ADI-PEG20 alone by 6 days of culture. Experiments to assess cytotoxicity and cell death analysis are ongoing. This drug combination therapy has the potential to improve outcomes in patients with uveal melanoma. Based on the good tolerability and safety of both drugs in patients, a clinical trial of pegargiminase with melphalan is planned for 2024 (ATOMIC-UM). Citation Format: Iuliia Pavlyk, Josephine Carpentier, Emilia Appolonia Szlosarek, Pui Ying Chan, John S. Bomalaski, Peter Wojciech Szlosarek. Pegargiminase and melphalan as a novel drug combination strategy for uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4546.

Abstract 1224: 3D models of chemotherapy- and PARPi-resistant ovarian cancer indicate essential roles for JAK/STAT signaling in mediating drug resistance

Abstract Ovarian cancer is the deadliest gynecological cancer with a low 5-year overall survival rate that affects over 300,000 women globally each year. Given lack of routine screening procedures, ovarian cancer patients are frequently diagnosed with late-stage disease that rapidly progress despite initial responses to front line therapy. PARPi and VEGFi targeted therapies have improved progression free survival in small subsets of patients but have largely failed to improve overall survival. Since the robust uptake of PARPis in the front line setting, resistance to this class of drugs is a growing problem. The literature is filled with many novel treatment approaches, but the vast majority fail to gain traction in pre-clinical models and early phase trials. A contributing factor to these disappointments relates to the prevalent use of 2D monoculture model systems that do not recapitulate the tumor microenvironment. To address this issue, we utilized the Rastrum 3D cell printer to grow ovarian cancer cells and PDX models in bio-functional matrices which provide optimal stiffness and extracellular matrix components specific to the ovarian tumor microenvironment. We found that ovarian cancer cells grown under these conditions exhibit dramatic up-regulation of the JAK/STAT signaling pathway, including autocrine/paracrine signaling factors, which correlated with increased sensitivity to JAK/STAT inhibitors. This affect was lost when STAT1 and STAT3 knockout cell lines were grown in this 3D environment. Ovarian tumors are known to be rich in cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). We incorporated primary CAFs into this 3D culture system and found they could promote ovarian cancer cell growth only in cancer cells with intact JAK/STAT signaling further indicating the essential role of this pathway in mediating tumor progression. Co-culture with M2 macrophages was also found to induce ovarian cancer cell growth, particularly in resistant models. Conversely, co-culture with M1 macrophages inhibited treatment naïve ovarian cancer cell growth but not resistant cell line growth. Single-cell RNAseq of the complex 3D cultures elucidated profound differences in the cross-talk between these cell types that is dependent on cancer cell sensitivity to standard-of-care agents. Finally, the addition of JAK/STAT inhibitors was found to substantially alter this cross-talk between cell types and inhibit cancer cell viability. These data further implicate the importance of JAK/STAT signaling, specifically in clinically relevant 3D models, in supporting ovarian cancer progression and response to chemotherapy and PARPi treatment. Ongoing studies are aimed at confirming these findings in pre-clinical mouse models and to elucidate the most effective JAK/STAT inhibitors in vivo with the goal of informing the design of future clinical trials. Citation Format: Esther Rodman, Xiyin Wang, Hannah Smith, Xiaonan Hou, Scott Kaufmann, John Weroha, John Hawse. 3D models of chemotherapy- and PARPi-resistant ovarian cancer indicate essential roles for JAK/STAT signaling in mediating drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1224.

Early Mobilization Dose Reporting in Randomized Clinical Trials With Patients Who Were Mechanically Ventilated: A Scoping Review.

The aim of this scoping review was to investigate the mobilization dose reporting in the randomized clinical trials (RCTs) of patients receiving mechanical ventilation in the intensive care unit. In this scoping review, RCTs published from inception to December 2022 were searched in relevant electronic databases. Trials that involved adults receiving mechanical ventilation (>48hours) and any early mobilization modality were analyzed. Two independent authors screened, selected, and extracted data. The mobilization doses of the intervention groups (IGs) and the comparator groups (CGs) were assessed as the proportion of reported items/total applicable from the main items of the Consensus on Exercise Reporting Template (CERT). Twenty-three RCTs comprising 2707 patients (1358 from IG and 1349 from CG) were included, involving studies on neuromuscular electrical stimulation (n = 7), progressive mobility (n = 6), leg cycling (n = 3), tilt table (n = 1), and multicomponent (n = 6) mobilization. The pooled reporting of CERT items was 68% (86% for IG and 50% for CG). The most reported CERT items were type of exercise (100%) and weekly frequency (100%) for IG, whereas the least reported were intensity (4%) and individualization (22%) for CG. Regardless of the group, individualization, progression, and intensity of mobilization were the least reported items. Eight IGs (35%) reported all CERT items, whereas no CGs reported all of them. Deficits in mobilization dose reporting of intensive care unit RCTs were identified, especially for exercise intensity in adults receiving mechanical ventilation. One-third of IG reported all exercise dosing items, whereas no CG reported all of them. Future studies should investigate the details of optimal dosage reporting, particularly for CG. The lack of dose reporting may partially explain the inconsistency in the meta-analysis results of early mobilization trials, thus limiting the interpretation for clinical practice in the intensive care unit.

Abstract 27: A single amino acid mutated AFP specific T cell receptor uniting synergistic functionalities of CD4 and CD8 T Cells with no cross-activity

Abstract Background: Genetically engineered T cells with T cell receptor (TCR-T) cell therapy have shown great potential for cancer treatment by targeting tumor-associated antigens. Despite its success in treating various tumor types, such as synovial sarcoma, head and neck tumors, and cervical cancer, its application in liver cancer is limited. Alpha-fetoprotein (AFP), a highly expressed tumor-associated antigen in liver cancer, is an ideal target for TCR-T cell therapy. Although early human trials have confirmed the safety of AFP-targeting TCR-T products, their efficacy is still modest, highlighting the need for further research and development. Methods: We developed a robust strategy combining ex vivo stimulation and single-cell paired TCR sequencing to identify AFP-recognizing TCRs in liver cancer patients. To optimize TCR expression and minimize mispairing, we employed codon optimization and replaced the constant regions with murine counterparts. Furthermore, structural analysis guided the affinity optimization of the CDR3 region to enhance the antitumor function of the selected TCR. The anti-tumor efficacy of TCR-T cells was rigorously evaluated through in vitro cytotoxicity assays using the Real-Time Cell Analyzer (RTCA) system and in vivo antitumor assessment in immunodeficient mouse xenograft models. Antigen specificity, HLA restriction, and other potential toxicity were carefully evaluated in both in vitro and in vivo models. Results: We successfully cloned a highly effective TCR that recognizes the AFP158-166 epitope presented by HLA-A*0203. After sequence optimization, we further changed a single amino acid on the TCR vβ chain based on AI prediction. The expression and functionality of this TCR was significantly improved. When introduced into human T cells, the single amino acid mutated TCR demonstrated robust and specific anti-tumor activity in various models, including cultured tumor cells, patient-derived organoids, and mouse xenografts models. Notably, this TCR also redirected CD4 T cells to recognize tumor cells, induced the secretion of multiple cytokines, and maintained long-lasting anti-tumor effects. Our rigorous screening assays confirmed that the TCR showed no cross-reactivity with the human proteome or major HLA subtypes. Additionally, extensive preclinical safety assessments in tumor-bearing animals treated with ST08A01-AM14 TCR-T cells showed no significant safety concerns. Conclusion: In this study, we have developed an HLA-A*0203 restrict AFP158-166 specific TCR-T therapy, which exhibits exceptional anti-tumor effects while ensuring a favorable safety profile. The promising results support the further investigation against AFP-positive solid tumors in clinic. Citation Format: Chen-Song Huang, shudan Ou, Jun Li, Junjun Chu, Yanyan Han. A single amino acid mutated AFP specific T cell receptor uniting synergistic functionalities of CD4 and CD8 T Cells with no cross-activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 27.

Abstract 2386: Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer

Abstract Introduction: Despite a decade of metastatic colorectal cancer (mCRC) therapeutic innovations, a comprehensive synthesis of patient outcome and risk-benefit assessment of phase 1/2 trials, extending beyond single-center studies, is missing. The aim of this meta-analysis is to assess efficacy, safety, and trends over time for phase 1 and 2 mCRC trials by examining clinical benefit rate (CBR), overall response rate (ORR), grade 3 or higher adverse events (AE), and discontinuation due to AE. Methods: The protocol and search were preregistered on PROSPERO. We searched PubMed and Embase for publications of phase 1/2 trials between 2010-2022. Reports were screened for inclusion criteria, followed by data-extraction by two researchers. Trials reporting on non-standard therapies for treatment-refractory mCRC or trials reporting specific mCRC efficacy data were included. CBR was defined as the proportion of patients with complete/partial response or stable disease ≥14 weeks. We used logit transformations for pooled effect analysis via a random-effects model, assigning study weights by the inverse variance method. Subgroup analyses were performed for publication year, preselection on molecular traits, and drug class: antiangiogenics, chemotherapy, immunomodulator, targeted therapy, or vaccine. Data are presented with 95% confidence intervals (CI); reported differences had non-overlapping CIs. Results: The search strategy yielded 4175 unique reports, from which we extracted data for 279 trials. Most trials were phase 1 (63%). ORR was limited to 6% [6-7] in both phase 1 and 2, CBR was higher in phase 2 than in phase 1 trials (36% vs 27%). Trials testing antiangiogenic drugs had the highest CBR (47%) and immunomodulators the highest ORR (8%). Trials with patients preselected on molecular traits had higher CBR compared to other trials (38% vs 28%). We observed an increase in efficacy, especially in phase 2 trials, with a CBR rising from 22% to 42% between trials published in 2010-2012 and 2019-2021. Compared with 2010-2012, trials in 2019-2021 were more often testing immunomodulators (23% vs 4%), performed on molecular preselected populations (38% vs 4%), and including younger patients (median age &amp;lt;60 in 66% vs 44%). The occurrence of grade 3+ AE was 33% [28-38] in both phase 1 and 2. AE led to discontinuation in 12% of phase 1 trial patients, and 7% of phase 2 patients. Grade 3+ AE occurred in 4% of vaccine trial patients, in contrast to 41% in trials on targeted therapies. Occurrence of grade 3+ AE did not change over time. Conclusion: We found limited ORR and CBR in early phase trials conducted in 2010-2021 for mCRC patients, while noting severe AEs in many patients. However, during this period, clinical benefit rate increased for phase 2 trials, possibly due to evolving study strategies that entail testing new treatment types in a younger, fitter, and stricter preselected study population based on molecular traits. Citation Format: Maarten A. Huismans, Lidwien P. Smabers, Niels N. van Nieuwenhuijzen, Monique C. Minnema, Miriam Koopman, Hugo J. Snippert, Anne M. May, Jeanine M. Roodhart. Meta-analysis of efficacy and safety in early-phase clinical trials for refractory colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2386.

RBMA: A robust Bayesian Model Averaging Method for phase II basket trials based on informative mixture priors

Oncology drug research in the last few decades has been driven by the development of targeted agents. In the era of targeted therapies, basket trials are often used to test the antitumor activity of a novel treatment in multiple indications sharing the same genomic alteration. As patient population are further fragmented into biomarker-defined subgroups in basket trials, novel statistical methods are needed to facilitate cross-indication learning to improve the statistical power in basket trial design. Here we propose a robust Bayesian model averaging (rBMA) technique for the design and analysis of phase II basket trials. We consider the posterior distribution of each indication (basket) as the weighted average of three different models which only differ in their priors (enthusiastic, pessimistic and non-informative). The posterior weights of these models are determined based on the effect of the experimental treatment in all the indications tested. In early phase oncology trials, different binary endpoints might be chosen for different indications (objective response, disease control or PFS at landmark times), which makes it even more challenging to borrow information across indications. Compared to previous approaches, the proposed method has the flexibility to support cross-indication learning in the presence of mixed endpoints. We evaluate and compare the performance of the proposed rBMA approach to competing approaches in simulation studies. R scripts to implement the proposed method are available at https://github.com/xwang317/rBMA.

The Innovative and Evolving Landscape of Topical Exosome and Peptide Therapies: A Systematic Review of the Available Literature.

Abstract Background Topical anti-aging therapies provide non-invasive delivery of active therapeutics. Exosomes, or extracellular nanovesicles, and peptides, small strings of amino acids, have shown promise as topical therapies in early trials, but neither is FDA approved. Objectives This review aims to elucidate the current and future landscape of topical exosomes and peptides as a therapeutic for skin rejuvenation. Methods A literature search was conducted using the keywords “peptides” OR “exosomes” AND “skin” OR “rejuvenation”. Primary endpoints included mechanisms of action in humans or live animals as well as clinical data supporting the use of exosomes or peptides topically for skin rejuvenation or wound healing. Secondary endpoints were safety, side effects, and efficacy. The articles were collected, organized, and sorted using the Covidence software for systematic review. Results Nine articles evaluating topical application of exosomes and nine of peptides met inclusion criteria. Topical exosomes were found to increase collagen deposition, accelerated wound healing, and overall cosmesis improvement. Several clinical trials are currently underway. Topical peptides were found to improve appearance of fine lines and wrinkles, elasticity and viscoelasticity, skin texture, skin thickness, and potential for accelerated wound healing. Peptides are quite common in “cosmeceutical” products, and several patents have been filed for topical peptide products aimed at increasing skin rejuvenation. This could indicate movement towards pursuing FDA approval. Conclusion The future of topical exosome and peptide products for the purpose of skin rejuvenation appears promising. Preliminary data from the studies reviewed here indicates that these products have the potential to be safe and effective.

Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles.

Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol. Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol. In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A). Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] -2.4 [95% CI -4.1 to -0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM -1.8 [95% CI -3.1 to -0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM -1.5 [95% CI -2.6.1 to -0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM -0.07 [95% CI -0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM -0.07 [95% CI -0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8-38.1%] and a 35% [95% CI 26.6-43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist. The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between. In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates. This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest. The study was registered at Clinical Trials Gov. (NCT04108039).

Early testing for improving growth under water shortage in Eucalyptus globulus Labill.

Aim of study: We aimed at identifying differences in the response to water shortage between Eucalyptus globulus clones. Area of study: Field trials were established in SW Spain. Material and methods: Potted plants from six clones were grown in a greenhouse for 35 days under two watering regimes. Two clones were F0 genotypes and the other four were F1 (hybrid) genotypes, including one inbred clone. Differences in stomatal conductance, hydraulic traits, growth and specific leaf area (SLA) were analyzed. Main results: Water shortage decreased SLA, growth in height and leaf area and leaf-specific hydraulic conductivity (KLmax). We measured the highest growth in F1 genotypes and the lowest in the clone in which SLA was lowest. The inbred clone showed the highest growth reduction under water shortage. There was substantial hysteresis between leaf water potential (Y) and native embolism, most probably a result of combined cavitation and refilling. High losses of hydraulic conductance were compatible with high stomatal conductances. Maximum values of stomatal conductance decreased with the soil water content estimated from predawn Y and were lowest in the inbred clone, showing less plasticity and a diminished ability to cope with high temperatures, which could explain its poor development under field conditions. Research highlights: Soil water content and predawn Y appeared as critical factors controlling stomata closure, while stomatal conductance and SLA could be useful to predict differences in growth and survival from early trials.

Disease Course of Korean African Swine Fever Virus in Domestic Pigs Exposed Intraorally, Intranasally, Intramuscularly, and by Direct Contact with Infected Pigs.

African swine fever (ASF) is a fatal contagious disease affecting swine. The first Korean ASF virus (ASFV) isolate (Korea/Pig/Paju1/2019) was used to compare the disease course of ASFV in pigs inoculated via the four routes. In the challenge experiment, domestic pigs were infected via the intraoral (IO) and intranasal (IN) routes with a 106 50% hemadsorbing dose (HAD50) and an intramuscular (IM) injection of 103 HAD50. In the direct contact (DC) group, five naïve pigs were brought into direct contact with two IM-ASFV-infected pigs. IO-, IN-, and IM-inoculated pigs showed similar disease courses, whereas DC pigs had comparable ASF syndrome after a 7-day latent period. The disease course in the DC route, one of the most common routes of infection, was not significantly different from that in the IO and IN routes. IM and DC groups differed in terms of the severity of fever and hemorrhagic lesions in the lymph nodes and spleen, indicating that the IM route, suitable for early vaccine development trials, is not appropriate for studying the ASFV infection mechanism, including early stage of infection, and IO and IN challenges with a designated dose can be alternatives in trials for assessing ASFV pathogenicity and vaccine efficacy investigations.