DigitalCommons@The Texas Medical Center
Not a member yet
41791 research outputs found
Sort by
Correspondence to Letter to the Editor on “Genomic Biomarkers To Predict Response to Atezolizumab Plus Bevacizumab Immunotherapy in Hepatocellular Carcinoma: Insights From the IMbrave150 Trial”
No full text
BARD: A Seamless Two-Stage Dose Optimization Design Integrating Backfill and Adaptive Randomization
No full textOne common approach for dose optimization is a two-stage design, which initially conducts dose escalation to identify the maximum tolerated dose, followed by a randomization stage where patients are assigned to two or more doses to further assess and compare their risk-benefit profiles to identify the optimal dose. A limitation of this approach is its requirement for a relatively large sample size. To address this challenge, we propose a seamless two-stage design, BARD (Backfill and Adaptive Randomization for Dose Optimization), which incorporates two key features to reduce sample size and shorten trial duration. The first feature is the integration of backfilling into the stage 1 dose escalation, enhancing patient enrollment and data generation without prolonging the trial. The second feature involves seamlessly combining patients treated in stage 1 with those in stage 2, enabled by covariate-adaptive randomization, to inform the optimal dose and thereby reduce the sample size. Our simulation study demonstrates that BARD reduces the sample size, improves the accuracy of identifying the optimal dose, and maintains covariate balance in randomization, allowing for unbiased comparisons between doses. BARD designs offer an efficient solution to meet the dose optimization requirements set by Project Optimus, with software freely available at www.trialdesign.org
Fruquintinib in Less Pretreated Patients: Multivariate Profile-Matching Analysis of FRESCO-2 to FRESCO
No full textBackground: In the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) studies, fruquintinib vs placebo, plus best supportive care, significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). These studies were conducted in temporally and geographically diverse populations that received distinct prior therapies; FRESCO patients were less pretreated than FRESCO-2 patients. This analysis assessed the efficacy and safety of fruquintinib in a less pretreated global population than the FRESCO-2 intention-to-treat (ITT) population.
Methods: In FRESCO and FRESCO-2, patients were randomized 2:1 to receive oral fruquintinib 5 mg or matched placebo. Profile matching was undertaken using the following variables: age, Eastern Cooperative Oncology Group performance status, RAS status, number of metastatic sites, liver metastases, and number of prior treatment lines. OS, progression-free survival (PFS), and safety were assessed.
Results: Of 691 patients in FRESCO-2, 152 (fruquintinib n = 103; placebo n = 49) were matched to the FRESCO ITT population. After matching, the FRESCO-2 subset and FRESCO ITT population had similar baseline characteristics and pretreatment profiles. In the FRESCO-2 subset, FRESCO ITT population, and combined dataset, respectively, unstratified hazard ratios for OS were 0.63, 0.62, and 0.63, and for PFS were 0.34, 0.27, and 0.30; 63.7 %, 61.2 %, and 61.8 % of patients had grade ≥ 3 treatment-emergent adverse events with fruquintinib.
Conclusion: Clinically meaningful efficacy of fruquintinib was maintained in a global patient population with less pretreated mCRC than the FRESCO-2 ITT population, with no new safety signals, demonstrating efficacy regardless of prior treatment lines
Cancer-Associated Fibroblasts As Mediators of Tissue Microenvironment Remodeling in Cancer
No full textCancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest in the field of anticancer therapy: immunotherapy, metabolism, and extracellular vesicles. We also highlight the substantial role of CAFs in modulating the immune microenvironment and the recent advances in targeting CAFs for cancer treatment
Prognostic Significance of Micropapillary Pattern and Risk Factors in Patients With Resected Stage I Lung Adenocarcinoma and Possible Benefit of Adjuvant Therapy: A Real-World Multicenter Study
No full textBackground: Micropapillary (MP) pattern has been identified as a negative prognostic factor in patients with lung adenocarcinoma, but it has not been recognized as a high-risk factor for patients with stage IB lung adenocarcinoma treated with adjuvant chemotherapy. This multicenter cohort study aimed to evaluate the prognostic value of histological subtypes for stage I lung adenocarcinoma and to determine the relative survival benefit of adjuvant chemotherapy for subgroups based on MP pattern.
Methods: This retrospective study included 412 patients with stage I lung adenocarcinoma [according the eighth edition of the tumor-node-metastasis (TNM) classification] with MP pattern who underwent complete surgical resection between January 2010 and December 2019. Patients were classified into 3 groups based on the proportion of MP component (10% and 50% as the threshold): MP component \u3e50% (n=8), 10-50% (n=273) and \u3c 10% (n=131).
Results: Among the 412 patients, the median age was 63 years, and 73.4% (113/154) patients with MP component ≥10% and 63.8% (51/80) of those with MP component \u3c 10% had epidermal growth factor receptor (EGFR) mutations. Patients with MP component \u3e50% had a shorter overall survival (OS) compared with those with MP components of 10-50% [10-50% vs. \u3e50%: hazard ratio (HR) =0.293, 95% confidence interval (CI): 0.083-1.027; P=0.052] or \u3c 10% (\u3c 10% vs. \u3e50%: HR =0.214, 95% CI: 0.056-0.816; P=0.02). Notably, in the univariate analysis, the factors associated with a worse recurrence-free survival (RFS) were spread-through-air-space (STAS) status (HR =2.131, 95% CI: 1.104-4.112; P=0.02), male sex (HR =1.693, 95% CI: 1.048-2.735; P=0.03), smoking history (HR =1.817, 95% CI: 1.126-2.931; P=0.01), and tumor size \u3e2 cm (HR =1.832, 95% CI: 1.138-2.949; P=0.01).
Conclusions: MP component and risk factors might be considered critical features for patients with stage I lung adenocarcinomas and may inform the selection of patients who may benefit from adjuvant chemotherapy although no randomized evidence is available
Additional Evidence From a Case Report Supports a Novel Hypothesis on the Association Between Complex Regional Pain Syndrome and Lymphedema
No full textA previous report of 4 heterogeneous cases demonstrated that automated manual lymphatic drainage therapy (AMLDT), administered by a novel, pneumatic mat of 16 pressurized air channels that inflate and deflate sequentially to mimic the stretch and release action of manual lymphatic drainage therapy (MLD), altered lymphatic contractility and relieved pain. Near-infrared fluorescence imaging (NIRF-LI) was used 1 h before AMLDT, during 1 h of AMDLT, and 30-60 min after treatment to obtain images that could be used to determine lymphatic contractility, as measured by pulsing frequency over a given timeframe. Herein, a case of type 2 complex regional pain syndrome (CRPS, with nerve dysfunction confirmed) and lymphedema following a complex fracture on the lower leg is reported in further detail, with a discussion explaining the association between autonomic and lymphatic dysfunction and their combined contribution to the development of chronic pain. More specifically, this case provides clinical evidence of the association between autonomic nervous system dysfunction, lymphatic dysfunction, and CRPS. We believe that the regulation of lymphatic flow is a potential therapeutic pathway to alleviate the symptoms of CRPS. Further research on the association between autonomic and lymphatic dysfunction and pain is warranted, particularly in patients with CRPS and symptoms of edema following leg fractures
The Extracellular Domains of the AMPA, Kainate, and Orphan Delta Receptor Regulate Channel Gating in Distinct Ways
No full textThe ionotropic glutamate receptors are ligand-gated cationic channels essential for neuroplasticity and neurological functions such as learning, memory, behavior, cognition, and motor coordination. Mutations in these channels are linked to various disorders including autism, ataxia, and epilepsy, making them compelling pharmacological targets. Within this family, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptor mediate their function through fast glutamate-gated ionotropic activity, which needs precise structural changes to perform properly. While Cryo-EM structures have provided snap shots of these proteins, questions remain regarding the dynamics across conformations and individual roles of the extracellular amino-terminal and agonist binding domain in dictating function. Specifically, how these domains contribute to modulation in function by modulators such as pH and binding proteins, including those involved in trans-synaptic connections, remain largely unknown. Here, I investigate the structure-function relationships of the extracellular domains in the AMPA, kainate, and orphan delta receptor, all which create trans-synaptic complexes in the brain. My studies reveal that coupling of the extracellular domains increases the intrinsic activity of the AMPA and kainate receptor and induces the delta receptor to have intrinsic ligand-gated activity. In addition, these studies reveal a novel mechanism of inhibition produced by protonation and perampanel-like drugs. Taken together, this work provides new insights into the distinct roles of the extracellular amino-terminal domain and the agonist-binding domain
Islet Single-Cell Transcriptomic Profiling During Obesity-Induced Beta Cell Expansion in Female Mice
No full textTargeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-bod
Folliculin Deletion in the Mouse Kidney Results in Cystogenesis of the Loops of Henle via Aberrant TFEB Activation
No full textThe mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. Herein, nephron-specific Flcn knockout mice exhibited cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen lined by enlarged epithelia. Single-cell RNA sequencing revealed many up-regulated genes, especially in the knockout LoH. These genes included those related to lysosomal activity and mammalian target of rapamycin complex 1 activation and are likely targets of transcription factor E3 (TFE3)/transcription factor EB (TFEB). Although the double Flcn/Tfe3 knockout only ameliorated the glomerular cysts, the double Flcn/Tfeb knockout largely reversed most of the phenotypes along the entire nephron. Thus, Flcn deletion led to cystogenesis via aberrant TFEB activation. These findings show the essential role of the FLCN-TFEB signaling pathway in nephron development, particularly in LoH, and shed light on the pathogenesis of Birt-Hogg-Dubé syndrome