Clinical and Fundamental Research Progressions on Tumor-Infiltrating Lymphocytes Therapy in Cancer

Malignant tumors represent a significant threat to human health. Among the various therapeutic strategies available, cancer immunotherapy-encompassing adoptive cell transfer (ACT) and immune checkpoint blockade therapy-has emerged as a particularly promising approach following surgical resection, radiotherapy, chemotherapy, and molecular targeted therapies. This form of treatment elicits substantial antigen-specific immune responses, enhances or restores anti-tumor immunity, thereby facilitating the control and destruction of tumor cells, and yielding durable responses across a range of cancers, which can lead to the eradication of tumor lesions and the prevention of recurrence. Tumor-infiltrating lymphocytes (TILs), a subset of ACT, are characterized by their heterogeneity and are found within tumor tissues, where they play a crucial role in mediating host antigen-specific immune responses against tumors. This review aims to explore recent advancements in the understanding of TILs biology, their prognostic implications, and their predictive value in therapeutic contexts

Circulating Tumor DNA Monitoring and Blood Tumor Mutational Burden in Patients With Metastatic Solid Tumors Treated With Atezolizumab

Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade. We sequenced cell-free DNA collected at the start of therapy, on treatment, and at the end of therapy for 153 patients treated with atezolizumab as part of the pan-tumor MyPathway study (NCT02091141). ctDNA tumor fraction (TF) and bTMB were assessed for correlation with progression-free survival (PFS) and overall survival (OS). We found that molecular response (MR, ≥50% decrease in TF at cycle 3 day 1) was associated with improved PFS (9.7 vs 1.5 months from C3D1; HR = 0.27) and OS (21.1 vs 14.3 months from C3D1; HR = 0.44). These findings were consistent when limited to patients with stable disease (SD; PFS HR = 0.55; OS HR = 0.39). bTMB was correlated with tissue-based TMB (tTMB) when TF was high (≥1%), but not with OS in this cohort. In total, 61% of baseline samples had predicted clonal hematopoiesis (CH) variants. No correlation between maximum variant allele frequency (maxVAF) of predicted CH and TF was seen. In summary, MR is associated with outcomes for patients treated with atezolizumab and could stratify patients with SD. While CH was common, maxVAF for CH variants was not associated with ctDNA TF. Quantification of ctDNA enables therapy response monitoring and is critical for interpretation of bTMB as a proxy for tTMB

Technical and Clinical Validity of Assessing Measurable Residual Disease by Multicolor Flow Cytometry in an Unselected Acute Myeloid Leukemia Patient Cohort

Context.—: Following the validation of a multicolor flow cytometry (MFC) assay for measurable residual disease (MRD) in acute myeloid leukemia (AML), this study examines its clinical applicability. Objective.—: To evaluate the practicality and performance of MFC-based MRD detection in AML. Design.—: Prospectively assessed AML MRD MFC in unselected AML patients achieving morphologic remission with follow-up studies, molecular genetics, and survival data. Results.—: Among 379 patient bone marrow samples in this cohort, an interpretable result was obtained in 359 (95%). A total of 57 of the 359 cases (16%) were positive for MRD, and the most frequently observed immunophenotype was CD34+CD117+ myeloid (n = 46; 81%), followed by CD34-/CD117+ myeloid (n = 8; 14%) and monocytic (n = 3; 5%). Of 57 MRD+ cases, 6 (11%) had no leukemia-associated immunophenotypes available, and 16 of 51 (31%) with leukemia-associated immunophenotype for comparison exhibited significant immunophenotypic drift/switch, highlighting the importance of the deviation from normal approach. The remaining 302 cases were MRD negative; among these, 21 (6%) displayed a preleukemic immunophenotype that was associated with persistent clonal hematopoiesis in 18 patients (86%). A positive MFC result was strongly associated with subsequent follow-up positive MRD (41 of 45 [91%] versus 14 of 240 [6%], P \u3c .01), morphologic relapse (42 of 55 [76%] versus 48 of 301 [16%], P \u3c .01), an inferior overall survival (12.5 months versus not reached, P \u3c .01), and leukemia-free survival (6.5 months versus not reached, P \u3c .01). Among MRD-negative patients, a preleukemic phenotype was associated with a shorter overall survival (P = .03), but not leukemia-free survival (P = .16). Conclusions.—: Our study provides data-driven technical insights for laboratories considering MFC AML MRD implementation and offers strong evidence supporting the utility of MRD assessment by MFC in patients with AML undergoing various stages of treatment and surveillance

Don\u27t Miss The TMC Library Webinar Series

Whether you\u27re a student, a physician, or a faculty member, every great research project starts with a clear plan. This session will walk you through the essential steps of turning a research idea into a structured plan using the PICO framework. We\u27ll cover how to develop focused research questions and discuss the value of using established protocols to ensure your work is sound and reproducible.Come learn the foundational skills needed for successful research in a welcoming and practical Lunch & Learn environmen

An Introduction to History of Medicine

Monthly Monday Seminars at Noon for the Academic Year: Attendance at seven sessions required for credit Includes Special Speakers as part of the TMC History of Medicine Society sponsored by Houston Methodist Hospital Spring merge with Baylor Medical College medical student elective Additional activities available: Scavenger Hunt at the TMC Library Archives Houston Methodist Hospital Lectures (Sponsored by the TMC History of Medicine Society) Rice University Lectures Baylor Medical College seminar

Automated Radiotherapy Treatment Planning for Breast Cancer: A Robust to ol for Global Deployment

Breast cancer incidence continues to rise worldwide, particularly in low- and middle-income countries, where limitations in resources already constrain access to timely care. Radiotherapy is a cornerstone of breast cancer management, proven to significantly lower both recurrence and mortality. However, a growing shortage of radiation staff worldwide threatens the prompt delivery of these treatments.This thesis proposes an automated solution to address the limited accessibility of radiotherapy planning in breast cancer management by developing an end-to-end automated treatment planning model and evaluating its performance and limitations across diverse patient populations. An automated contouring model was trained using data from 104 whole-breast patients. The model’s outputs were quantitatively assessed using the Dice similarity coefficient (DSC) and mean surface distance (MSD), and qualitatively reviewed by physicians to determine clinical acceptability. Five automated conventional planning approaches were developed, complemented by an established RapidPlan model for volumetric arc therapy. These included conventional tangents for whole-breast treatment, variations for supraclavicular node (SCLV) irradiation with or without axillary nodes, and two approaches for comprehensive regional lymph node irradiation—either photon wide tangents with an SCLV field or photon tangents with a matched electron field targeting the internal mammary nodes (IMN). All algorithms begin by generating contours automatically for the breast clinical target volume, regional lymph nodes, and relevant organs at risk. Subsequently, gantry angles and field shapes are created and optimized to ensure adequate target coverage while constraining doses to nearby critical structures. Optimization relies on field weighting for the lymph node fields and a field-in-field technique for the tangents. These algorithms were tested for clinical validity on 15 internal whole-breast patients (150 plans) and 40 external patients from four institutions across Switzerland, Argentina, Iran, and the United States (360 plans). Plan evaluations focused on target coverage and adherence to normal tissue dose limits, and were reviewed by a radiation oncologist (5-point scale for the internal dataset) and a medical physicist (accept or edit for the external dataset). Further large-scale testing was performed on 272 internal and 285 external patients from six different countries (Argentina, Iran, Jordan, United States, South Africa and Switzerland).), enabling a comprehensive assessment of plan quality via dosimetric analysis and physicist review. The rate of automated plans requiring edits was compared across treatment sites, and fault tree analysis was employed to elucidate underlying reasons for any modifications. Automated contouring achieved DSC values above 0.70 for target volumes and an MSD under 3 mm. Two physicians deemed 63% of automatically generated contours acceptable without further edits. For the 15 internal patients, physician review indicated that 74% automated plans were clinically acceptable as is. Notably, when using automated contours in conjunction with the RapidPlan model, 100% of plans required no further modifications. Similarly, physicist review of 40 multi-institutional cases confirmed that 79% of automated plans were ready to use, with the rest needing minor edits. A broader evaluation encompassing 540 patients (4,860 plans) revealed that 78% of automated plans required no revisions, whereas 22% needed adjustments. The rate of edits was statistically comparable across institutions, except for data from Jordan and Switzerland, which exhibited better performance, and Yale, which included intentionally challenging cases. Automated planning treating IMNs with tangent fields was more robust than using electron fields. Fault tree analysis identified decisions about clinical compromises (target coverage vs. normal tissue doses) as the primary cause of plan modifications, followed by patient anatomical and positioning variations. In conclusion, this thesis demonstrates the feasibility of a fully automated radiotherapy planning model for whole-breast cases. The approach successfully accommodates a wide range of clinical protocols and achieves robust performance across diverse patient populations

Anti-Tumor Activity of Camptothecin Analog Conjugate of an RSPO4-Based Peptibody Targeting LGR4/5/6 in Preclinical Models of Colorectal Cancer

Background: Antibody-drug conjugates (ADCs) are a significant advancement in targeted cancer therapy, but none are approved for colorectal cancer (CRC). LGR4/5/6, highly expressed in most CRCs, are promising targets. While LGR5-targeting ADCs show strong anti-tumor effects, their efficacy is limited by LGR5 loss in some CRC cells. RSPO4, a natural ligand for LGR4/5/6, binds all three receptors with high affinity. This research develops RSPO4-based peptibody drug-conjugates (PDCs) to simultaneously target LGR4/5/6, offering a novel therapeutic approach for CRC. Methods: LGR4/5/6 expression in CRCs was analysed using RNA-seq datasets and Western blot. Peptibody binding affinities were measured, conjugated to camptothecin analog, CPT2, and tested for cytotoxicity in CRC cell lines. Antitumor efficacy was evaluated in vivo using CRC cell line and patient-derived xenograft (PDX) models. Results: Peptibody was engineered by fusing a mutant RSPO4 furin-domain to human IgG1 Fc, retaining high-affinity LGR4/5/6 binding without enhancing Wnt/β-catenin signalling. Conjugated with CPT2 molecules, the PDC showed strong antitumor activity in CRC cell lines and dose-dependent tumor growth inhibition in xenograft and patient-derived models. Conclusion: Preclinical data showed that LGR4/5/6-targeting PDC exhibited potent cytotoxicity in vitro and robust antitumor efficacy in CRC xenograft and PDX models, making its potential as a promising therapeutic approach for CRC

Time to Treatment in Pediatric Patients With Repeated Episodes of Status Epilepticus

Objective: To compare pediatric patients who presented with repeated status epilepticus episodes to patients with a single episode of status epilepticus and identify distinguishing clinical factors. Methods: Retrospective analysis of a multicenter, prospective observational cohort of pediatric patients with status epilepticus between 2011 and 2019. Results: Out of 504 status epilepticus episodes in 420 patients, 50 patients (10.3%) had repeated episodes of status epilepticus. The only predictor of repeated status epilepticus was a prior diagnosis of epilepsy. There was no difference in time to treatment with the first benzodiazepine in patients presenting with their first status epilepticus episode compared to their second status epilepticus episode [median 10 (interquartile range 5-30) vs. 14 (4.5-52.5) minutes; (p = 0.24)] or in time to treatment with the first non- benzodiazepine anti-seizure medication (ASM) [61 (37-125) vs. 71 (34.5-117.5) minutes; p = 0.61]. In patients with repeated status epilepticus episodes with onset outside the hospital, the percentage of patients treated by caregivers did not improve between the first and second status epilepticus episode (61% vs. 60%, p = 0.56). However, the time to first benzodiazepine was shorter in patients treated by caregivers compared to those who were not [5 (0-25) vs. 55 (41-120) minutes; p \u3c 0.001]. Conclusions: Time to treatment with benzodiazepine and non-benzodiazepine ASM in patients with repeated episodes of status epilepticus does not improve for a second episode of status epilepticus, suggesting additional opportunities for intervention and teaching

Association of Genetic Scores Related to Insulin Resistance With Neurological Outcomes in Ancestrally Diverse Cohorts From the Trans-Omics for Precision Medicine (TOPMed) Program

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in \u3e17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P \u3c  0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P \u3c  0.007) of metabolic syndrome and obesity pPSs with general cognitive function, and of lipodystrophy pPSs with total cranial volume. A higher genetic predisposition to IR is associated with lower brain size, and a genetic predisposition to specific IR-related type 2 diabetes subtypes, such as metabolic syndrome and mechanisms of IR mediated through obesity and lipodystrophy, is potentially involved in cognitive decline

ReSort Enhances Reference-Based Cell Type Deconvolution for Spatial Transcriptomics Through Regional Information Integration

Motivation: Spatial transcriptomics (ST) captures positional gene expression within tissues but lacks single-cell resolution. Reference-based cell type deconvolution methods were developed to understand cell type distributions for ST. However, batch/platform discrepancies between references and ST impact their accuracy. Results: We present Region-based Cell Sorting (ReSort), which utilizes ST\u27s region-level data to lessen reliance on reference data and alleviate these technical issues. In simulation studies, ReSort enhances reference-based deconvolution methods. Applying ReSort to a mouse breast cancer model highlights macrophages M0 and M2 enrichment in the epithelial clone, revealing insights into epithelial-mesenchymal transition and immune infiltration. Availability and implementation: Source codes for ReSort are publicly available at (https://github.com/LiuzLab/RESORT), implemented in Python