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A Sample Size Analysis of a Mathematical Model of Longitudinal Tumor Volume and Progression-Free Survival for Bayesian Individual Dynamic Predictions in Recurrent High-Grade Glioma
No full textPatients with recurrent high-grade glioma (rHGG) have a poor prognosis with median progression-free survival (PFS) ofheterogenous, suggesting a clinical need for prognostic models. Bayesian data analysis can exploit individual patient follow-up imaging studies to adaptively predict the risk of progression. We propose a novel sample size analysis for Bayesian individual dynamic predictions and demonstrate proof of principle. We coupled a nonlinear mixed effects tumor growth inhibition model with a survival model. Longitudinal tumor volumes and time-to-progression were simulated for 2000 in silico rHGG patients. Bayesian individual dynamic predictions of PFS curves were evaluated using area under the receiver operating characteristic curve (AUC) and Brier skill score (BSS). We investigated the effects of sample size on AUC and BSS margins of error. A power law relationship was observed between sample size and margins of error of AUC and BSS. Sample size was also found to be negatively correlated with margins of error and landmark time. We explored the use of this sample size analysis as a clinical look-up table for prospective clinical trial design and retrospective clinical data analysis. Here, we motivate the application of Bayesian individual dynamic predictions as a clinical end point for clinical trial design. Doing so could aid in the development of study protocols with patient-specific adaptations (escalate or de-escalate dose or frequency of drug administration, increase or decrease the frequency of follow-up, or change therapeutic modality) according to patient-specific prognosis. Future developments of this approach will focus on further model development and validation
Reducing HAPIs in the ICU with a Turn Team
No full textAbstract
Purpose: The purpose of this quality improvement (QI) project was to decrease hospital-acquired pressure injury (HAPI) rates within an Intensive Care Unit (ICU) by implementing a two-nurse turning and repositioning schedule.
Background: The QI project was implemented in a 24-bed Medical-Surgical ICU at a for-profit community hospital in Northwest Houston, Texas, in the United States of America. The project was developed and initiated at the project site because there was an increase in the HAPI rate above the organization’s target rate of zero.
Methodology: Baseline HAPI rates and turning charting compliance were obtained. A baseline Likert scale survey was distributed to staff to assess perceived abilities and compliance with turning patients every two hours. The project lead, unit manager, director, skin champions, and charge nurses introduced the two-nurse turning and repositioning schedule and implementation plan to the staff during unit huddles and staff meetings. The project lead tracked the data and modified the project as needed using the Plan-Do-Study-Act method. During the three-month implementation phase, monthly project data results and updates were provided to unit staff and key stakeholders.
Results: The HAPI rate for pre-intervention was 2.38%, and the post-intervention rate was 1.68%. There was an overall improvement in Likert scale confidence scores of perceived abilities and compliance with turning patients every two hours.
Implications: Reducing HAPI can lead to decreased length of stay, improved patient outcomes, reduced risk of infection and sepsis, and reduced hospital costs. The QI process increases the ability of nurses to adhere to the quality standard of turning ICU patients every two hours. Implementing the two-nurse turning and repositioning schedule should be considered, as it promotes improved patient care and teamwork
Improving No-Show Rates at a Federally Qualified Health Center (FQHC)
No full textThe purpose of this quality improvement project was to improve no-show and missed appointments among adult patients at a federally qualified health center (FQHC) located in greater Houston, TX in the adult medicine department. This intervention aimed to decrease no-show and missed appointment rates to 20% or below to improve productivity, yield less staff burnout, and improve patient healthcare outcomes. A 4-week initiative was completed to identity top reasons and to reduce no-shows. A no-show outreach initiative was developed and used in the electronic health record (EHR) and targeted to patients identified as most likely to not show cancel an appointment within 24 hours of the scheduled time. The Plan-Do-Study-Act (PDSA) method was used for two cycles to improve implementation. In addition, a validated tool to assess provider burnout, called the Provider Fulfillment Index (PFI). There was a total of 338 combined no-show and missed appointments over an 8-week period. The high-risk no-show intervention reduced the combined no-show and missed appointment rate from 33% to 15.6%. There was no significant change to provider burnout throughout the project. It is important to address no-show behavior unique to organizational culture such as an FQHC to improvement health care outcomes and productivity. A personalized and tailored reminder system for future appointments requires team effort, patient involvement, and long-term consistency to be effective
Spanish-Speaking Patient Perspectives: Benefits and Barriers of Telemedicine in Genetic Counseling
No full textTelemedicine has rapidly expanded, yet research on its impact within genetic counseling remains limited, particularly for Spanish-speaking patients. Existing studies on patient perspectives are limited and the influence of telemedicine on effective service delivery in a Spanish-speaking population lacks robust data. This study aims to fill that gap, investigating the perceived benefits, barriers, and desires of telemedicine genetic counseling for this growing population. A total of 66 Spanish-speaking patients fully completed a survey about their genetic counseling appointments, both in person and via telemedicine, at UTHealth Houston and Harris Health clinics. The anonymous survey collected demographic data and Likert scale responses on benefits, barriers, and preferences for telemedicine genetic counseling. Parking cost savings (65.2%), equal care quality (60.6%), and reduced wait times (56.1%) were the top reported benefits of telemedicine genetic counseling. The most common reported barrier was navigating technology (51.5%), which was more frequently identified by patients seen via telemedicine. While an overall preference for in person genetic counseling was reported, those with telemedicine experience showed a greater desire for telemedicine-based genetic counseling. Statistical analyses using Wilcoxon rank-sum test and Kruskal-Wallis with post-hoc Dunn’s test revealed factors associated with significant differences in perceived benefits, barriers, and desires for telemedicine genetic counseling: language(s) known and recent telemedicine experience. Compared to bilingual patients, those who knew only Spanish reported significantly more barriers of telemedicine, yet a greater desire for it. Individuals with telemedicine experience were more likely to identify the benefits and barriers and reported a higher desire for this delivery model. This study highlights the impact of prior telemedicine experience in shaping Spanish-speaking patients’ perceptions and preferences for genetic counseling mode. Future research should focus on optimizing and tailoring telemedicine services for Spanish-speaking populations and assessing the challenges and benefits of their lived experience
An Investigation into the Potential of Cell Therapies for Acute Myeloid Leukemia (AML) Treatment
No full textDespite recent advances in acute myeloid leukemia (AML) treatment, curative rates remain poor with high rates of relapse and many patients are unable to tolerate the intensive chemotherapy standard of care regimen. Cell therapies have shown great success against hematologic malignancies but face several challenges including treatment-related toxicities and human-leukocyte antigen (HLA) matching. Natural killer (NK) cells and gamma delta (γδ) T cells offer alternative effector cell options for cell therapies that do not require HLA-matching and have shown low toxicity in previous studies. In this project, we sought to evaluate FT538 induced pluripotent stem cell-derived NK (iPSC-NK) and donor-derived Vγ9Vδ2 T cells as “off-the-shelf” treatment options for AML patients unable to tolerate intensive chemotherapies or with high-risk disease.
We used live cell imaging to analyze the effect of FT538 iPSC-NKs on AML cell lines and primary AML cells derived from high-risk AML patients, demonstrating potent effector-to-target cell ratio (E:T)-dependent apoptosis in all samples. Flow cytometric analysis revealed that when used in combination with approved AML therapies cytarabine, gilteritinib, and venetoclax, the apoptotic effect induced by iPSC-NKs increased in an E:T and dose-dependent manner, with iPSC-NK viability unaffected by cytarabine. Similarly, we observed donor-derived Vγ9Vδ2 T cells induced E:T-dependent apoptosis on AML cell lines and primary AML cells and extended survival in a Molm-13 GFP Luc xenograft model. Vγ9Vδ2 T cells also exerted an effective apoptotic effect in combination with venetoclax in the venetoclax resistant cell line, OCI-AML3, and improved survival in an OCI-AML3 GFP Luc xenograft model
Denial of Inpatient Genetic Testing: A Study on Outpatient Yield and Outcomes
No full textThis study investigates the difference in diagnostic yield between patients approved for inpatient genetic testing compared to those denied inpatient testing and the effect of an earlier diagnosis on outcomes and medical/clinical care. In the literature, research has explored the impact of a diagnostic delay for patients with genetics conditions, assessed the utility of genetic testing in the inpatient setting, and described the impact to care of an earlier diagnosis. However, gaps remain on research exploring the diagnostic yields of inpatient versus outpatient settings and the potential impact to care an inpatient genetic testing request denial may pose. This is the first study to determine if denial of inpatient genetic testing leads to a diagnostic delay and delay in subsequent medical services that impact care. This study reviewed 1,052 charts of patients admitted inpatient who received a genetic consult between July 2018 and June 2023 and further reviewed charts of children that followed up at the outpatient genetics clinic after inpatient discharge. Data was collected on recommendations for genetic testing, completion of genetic testing, results of genetic testing, and management recommendations based on a diagnosis. Statistical data analysis was completed to identify differences between inpatient and outpatient groups. The results indicated the outpatient group had nearly twice as high diagnostic yield and a 6-month diagnostic delay compared to the inpatient group. Management recommendations did not differ between the groups suggesting a subsequent delay to changes in care for the outpatient group. In addition, public insurance holders took 3 weeks longer to attend the outpatient clinic and private insurance holders were 28% less likely to be approved for inpatient genetic testing. Inclusion of genetic providers in the review of inpatient genetic testing requests should be considered to improve inpatient and outpatient outcomes
T2-Weighted Imaging of Rectal Cancer Using a 3D Fast Spin Echo Sequence With and Without Deep Learning Reconstruction: A Reader Study
No full textPurpose: To compare image quality and clinical utility of a T2-weighted (T2W) 3-dimensional (3D) fast spin echo (FSE) sequence using deep learning reconstruction (DLR) versus conventional reconstruction for rectal magnetic resonance imaging (MRI).
Methods: The study included 50 patients with rectal cancer who underwent rectal MRI consecutively between July 7, 2020 and January 20, 2021 using a T2W 3D FSE sequence with DLR and conventional reconstruction. Three radiologists reviewed the two sets of images, scoring overall SNR, motion artifacts, and overall image quality on a 3-point scale and indicating clinical preference for DLR or conventional reconstruction based on those three criteria as well as image characterization of bowel wall layer definition, tumor invasion of muscularis propria, residual disease, fibrosis, nodal margin, and extramural venous invasion.
Results: Image quality was rated as moderate or good for both DLR and conventional reconstruction for most cases. DLR was preferred over conventional reconstruction in all of the categories except for bowel wall layer definition.
Conclusion: Both conventional reconstruction and DLR provide acceptable image quality for T2W 3D FSE imaging of rectal cancer. DLR was clinically preferred over conventional reconstruction in almost all categories
Acute BRCAness Induction and AR Pathway Blockage Through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer
No full textCurrent treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained BRCAness state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent antitumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population
Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients With HR+/HER2- Metastatic Breast Cancer
No full textBackground: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.
Methods: Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5 months), while progressors were categorized as early-progressors (EP, mPFS = 3 months) and late-progressors (LP, mPFS = 11 months). Metastatic sites included liver, pleural effusions, ascites, and bone. InferCNV distinguished tumor cells, and functional analysis utilized the Molecular Signatures Database.
Results: LP tumors displayed enhanced Myc, EMT, TNF-α, and inflammatory pathways compared to those EP tumors. Samples from BL and LP responders showed increased tumor-infiltrating CD8+ T cells and natural killer (NK) cells compared to EP non-responders. Notably, despite a high frequency of CD8+ T cells in responding tumors, a functional analysis revealed significant upregulation of genes associated with stress and apoptosis in proliferative CD4+ and CD8+ T cells in BL tumors compared to in EP and LP tumors. These genes, including HSP90 and HSPA8, are linked to resistance to PD1/PD-L1 immune checkpoint inhibitors. A ligand-receptor analysis showed enhanced interactions associated with inhibitory T-cell proliferation (SPP1-CD44) and suppression of immune activity (MDK-NCL) in LP tumors. Longitudinal biopsies consistently revealed dynamic NK cell expansion and enhanced cytotoxic T cell activity, alongside upregulation of immune activity inhibition, in LP tumors compared to in BL tumors. Notably, the predictive biomarker panel from BL tumor cells was validated in 2 independent cohorts, where it consistently predicted a significant improvement in mPFS duration in signature-high versus -low groups.
Conclusion: This study underscores the significance of molecular biomarkers in predicting clinical outcomes to CDK4/6i. Tumor-infiltration CD8+ T and NK cells may also serve as baseline predictors. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, providing a personalized and effective approach for managing HR+/HER2- mBC and improving patient outcomes
Defining the Role of Adjuvant Radiotherapy for Biliary Tract Cancers: A Site-Specific Propensity-Matched Analysis
No full textBackground: Biliary tract cancers (BTCs) have distinct tumor biology but share a poor prognosis, with a 5-year-survival-rate of 5-19%. Surgical resection is the only potential cure, but recurrences are common. The role of adjuvant radiotherapy (XRT) remains unclear.
Methods: Using the National Cancer Database (2006-2018), we analyzed resected non-metastatic BTCs. Patients who survived beyond 90 days post-surgery were included, while those with R2 resections or neoadjuvant therapy were excluded. Propensity matching was performed based on predictors of adjuvant radiation, age, and sex. Survival outcomes were compared between no adjuvant therapy, chemotherapy alone, and XRT ± chemotherapy.
Results: Among 21,275 patients, including 5308 intrahepatic cholangiocarcinoma (IHC), 2689 perihilar cholangiocarcinoma (PHC), 3092 distal cholangiocarcinoma (DCC), and 10,186 gallbladder cancer (GBC) cases, adjuvant XRT did not improve survival for IHC. For PHC and DCC, XRT improved survival over no adjuvant therapy (PHC: 31.2 vs. 26.3 months, p = 0.004; DCC: 33.7 vs. 27.0 months, p = 0.015) but not over chemotherapy alone. For GBC, XRT significantly improved survival compared to both no adjuvant therapy and chemotherapy (30.2 vs. 26.6 and 24.6 months; p = 0.05 and p = 0.001).
Conclusions: XRT provides a survival benefit for GBC, especially in node-positive and R1-resected patients. For PHC and DCC, XRT improves outcomes compared to no therapy, but its benefit over chemotherapy is uncertain. No benefit was observed for IHC