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Building a Pre-Surgical Multiparametric-MRI-Based Morphologic, Qualitative, Semiquantitative, First and High-Order Radiomic Predictive Treatment Response Model for Undifferentiated Pleomorphic Sarcoma To Replace RECIST
No full textBackground: Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft-tissue sarcomas. It demonstrates post-therapeutic hemosiderin deposition, granulation tissue formation, fibrosis, and calcification. Our research aims to establish the multiparametric MRI (mp-MRI) value for predicting UPS treatment response.
Methods: An IRB-approved retrospective study included 33 extremity UPS patients with pre-operative mp-MRI, including diffusion-weighted imaging (DWI), contrast-enhanced susceptibility-weighted imaging (CE-SWI), and perfusion-weighted imaging with dynamic contrast-enhancement (PWI/DCE), and surgical resection between February 2021 and May 2023. Lesions were visually classified on CE-SWI into one of 6 morphology patterns. On PWI/DCE, lesions were classified into one of 6 patterns, and time-intensity curves (TICs) were classified as types I-V. Patients were categorized into three groups based on the percentage of pathology-assessed treatment effect (PATE) in the surgical specimen: Responders (\u3e = 90% PATE, n = 16), partial-responders (31-89% PATE, n = 10), and non-responders (\u3c = 30% PATE, n = 7).
Results: At post-radiation therapy (PRT), a CE-SWI Complete-Ring pattern was observed in 71% of responders (p = 7.71 × 10-6). On PWI/DCE images, 79% of responders displayed a Capsular pattern (p = 1.49 × 10-7), and 100% demonstrated a TIC-type II (p = 8.32 × 10-7). ROC analysis comparing responders (n = 14) vs. partial/non-responders (n = 16) at PRT showed that the model combining PWI/DCE TIC-type II, PWI/DCE Capsular pattern, and CE-SWI Complete-Ring pattern yielded the highest classification performance (AUC = 0.99), outperforming PWI/DCE Capsular + TIC-type II (AUC = 0.97), PWI/DCE Capsular (AUC = 0.89), PWI/DCE TIC-type II (AUC = 0.88), and CE-SWI Complete Ring (AUC = 0.79). Contrary to prior reports, DWI/ADC played a secondary role in predicting response: ADC mean & skewness (AUC = 0.63). RECIST demonstrated 100% stability at PRT and 100% pseudo-progression at PC in responders and partial/non-responders (AUC = 0.47).
Conclusion: Mp-MRI-derived features are valuable in assessing UPS treatment response. A pre-operative model that combines PWI/DCE TIC-type II, PWI/DCE Capsular pattern, and CE-SWI Complete Ring pattern can reliably predict successfully treated UPS with \u3e = 90% PATE, outperforming RECIST, which was proven unreliable in separating responders from partial/non-responders. Institutions that have not yet implemented CE-SWI can rely on a single-sequence approach based on PWI/DCE, combining the presence of TIC II and Capsular enhancement as criteria for response prediction
Alleviation of Liver Fibrosis by Inhibiting a Non-canonical ATF4-Regulated Enhancer Program in Hepatic Stellate Cells
No full textLiver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. Analysis of human data confirms a strong correlation between HSC ATF4 expression and liver fibrosis progression. Importantly, a small molecule inhibitor targeting ATF4 translation effectively mitigates liver fibrosis. Together, our findings identify a mechanism promoting liver fibrosis and reveal new opportunities for treating this otherwise non-targetable disease
Dedifferentiated Liposarcomas Treated With Immune Checkpoint Blockade: The MD Anderson Experience
No full textBackground: Dedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.
Methods: We conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between 2018 and 2023. Patient demographics, disease characteristics, treatment history, and response to ICB were analyzed. Immunohistochemical analysis was performed on tumor samples to assess immune-related markers.
Results: ORR by RECIST 1.1 was 3.2% (n=1/31). Among all patients (n=31), 6% achieved partial radiographic response, while 39% had stable disease, and 55% showed progressive disease. Median progression-free survival (PFS) was 3.5 (95%CI:1.9, 4.7) months, and overall survival (OS) after ICB initiation was 19.7 (95%CI: 8.8, not reached) months. Patients without prior systemic therapy demonstrated better OS (p=0.004). Immunohistochemistry revealed no relationship between pre- or post-ICB expression of CD8, CD20, CD21 and PDL-1 and response.
Conclusion: While the response to ICB in DDLPS remains limited, specific immune markers may influence treatment outcomes. CD20/21 post-ICB appear more important for prognosis. Further research is warranted to identify predictive factors for ICB efficacy in DDLPS
Phase I Study of Bms-986299, an NLRP3 Agonist, As Monotherapy and in Combination With Nivolumab and Ipilimumab in Patients With Advanced Solid Tumors
No full textPurpose: BMS-986299 is a first-in-class, NOD-, LRR-, and pyrin-domain containing-3 (NLRP3) inflammasome agonist enhancing adaptive immune and T-cell memory responses.
Materials and methods: This was a phase-I (NCT03444753) study that assessed the safety and tolerability of intra-tumoral BMS-986299 monotherapy (part 1A) and in combination (part 1B) with nivolumab, and ipilimumab in advanced solid tumors. Reported here are single-center results.
Results: 36 patients were enrolled, with breast (31%), colorectal (17%), and head and neck (14%) being the more commonly enrolled cancers. Most patients (58%) had received prior immunotherapy. Therapy was well-tolerated, with G1-G2 fever (70%), neutrophilia (36%), and leukocytosis (33%) being the most common treatment-related adverse events with one case of G4 interstitial nephritis and one case of G3 hepatotoxicity and G3 colitis. Intratumoral BMS-986299 monotherapy resulted in dose-dependent increases in systemic exposure with increase in tumor CTLs (67%), CD4+ TILs (63%), along with notable above twofold increases in serum IL-1B, G-CSF and IL-6 at doses above 2000 µg. Systemic BMS-986299 exposure was positively associated with systemic cytokine elevation for G-CSF and IL-6. No antitumor activity was noted in BMS-986299 monotherapy cohort. However, in the combination therapy cohort (BMS-986299+nivolumab+ipilimumab), overall objective response rate was 10%, with confirmed PRs observed in TNBC, hormone receptor-positive, human epidermal growth factor receptor 2 negative breast cancer, and cutaneous squamous cell carcinoma.
Conclusion: BMS-986299 in combination with immune checkpoint inhibitors demonstrated manageable toxicities, good tolerability, and promising antitumor activity in certain cancer types.
Trial registration number: NCT03444753
Statistical Identification of Cell Type-Specific Spatially Variable Genes in Spatial Transcriptomics
No full textAn essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene\u27s spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real datasets, Celina uncovers ct-SVGs associated with tumor progression and patient survival in lung cancer, identifies metagenes with unique spatial patterns linked to cell proliferation and immune response in kidney cancer, and detects genes preferentially expressed near amyloid-β plaques in an Alzheimer\u27s model
Hif Regulates Multiple Translated Endogenous Retroviruses: Implications for Cancer Immunotherapy
No full textClear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy
ImmuneLENS Characterizes Systemic Immune Dysregulation in Aging and Cancer
No full textRecognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells
Improved Overall Survival in an Anti-Pd-L1 Treated Cohort of Newly Diagnosed Glioblastoma Patients Is Associated With Distinct Immune, Mutation, and Gut Microbiome Features: A Single Arm Prospective Phase I/II Trial
No full textThis phase I/II trial aims to evaluate the efficacy of concurrent atezolizumab with radiation therapy and temozolomide (TMZ) followed by adjuvant atezolizumab and TMZ in newly diagnosed glioblastoma (GBM) patients and to identify pre-treatment correlates with outcome (N = 60). Trial number: NCT03174197. The primary outcome was overall survival (OS) whereas secondary outcomes were retrospective global-omics analyses to identify pre-treatment immune and genetic tumor features that correlated with survival. Concurrent use of atezolizumab with radiation and TMZ demonstrated OS in line with published trials for newly diagnosed GBM. Tumor genomic (WES and/or targeted NGS panel), transcriptomic (RNAseq) and tissue microenvironment imaging, as well as fecal metagenomic sequencing were conducted. Gene set enrichment analysis of tumors identified multiple immune-based transcriptomic programs to distinguish patients with longer versus shorter survival (p ≤ 0.01). GBM immune enrichment was highly associated with the pre-treatment tumor mesenchymal subtype and patient gastrointestinal bacterial taxa profile
Enhanced Efficacy of Ipilimumab Plus Nivolumab in Angiogenic Subtypes of Metastatic Clear-Cell Renal Cell Carcinoma
No full textIn metastatic clear-cell renal cell carcinoma (mccRCC), choosing between immuno-oncology (IO) combinations and IO plus anti-VEGF therapies is uncertain. The BIONIKK trial revealed that ipilimumab plus nivolumab (Ipi/Nivo) achieved a 70% objective response rate in angiogenic cluster1/2 versus 41% in cluster4/5, which featured T-effector/cell-cycle signatures (p = 0.048). Complete responses were exclusively observed in cluster1/2 (p = 0.012), with longer progression-free survival (p = 0.014). Ipi/Nivo may particularly benefit angiogenic mccRCC, supporting molecular subtype-based treatment strategies
Photoacoustic Imaging for Image-Guided Gastric Tube Placement: Ex Vivo Characterization
No full textOver 250,000 gastrostomy tubes (G-tubes) are placed annually in the United States. Percutaneous endoscopic gastrostomy (PEG) is the most widely used clinical method for placing G-tubes within the stomach. However, endoscope detectability is limited due to the scattering of light by tissues. Poor organ visibility and low sensitivity of the palpation techniques cause blind needle insertions, which cause colon/liver perforations, abdominal bleeding, and gastric resections. Additionally, imaging artifacts and the poor distinguishability between water-filled tissues make ultrasound (US) imaging-based techniques incompatible with G-tube placement. The risk of ionizing radiation exposure and the confinement of fluoroscopy to radiology suites limits its bedside utility in patients. Considering these limitations, we propose to design a safe, point-of-care integrated US and photoacoustic (PA) imaging system for accurate G-tube placement procedures, for a broad spectrum of patients, and to characterize the system\u27s effectiveness. Our proposed technology utilizes a clinically safe contrast agent and a dual-wavelength approach for precise procedures. Our ex vivo tissue studies indicated that PA imaging accurately differentiates the different organs at specific wavelengths. Our characterization studies revealed that PA imaging could detect lower concentrations of Indocyanine Green (ICG) dye coating the colon wall, minimizing the risk of ICG dye-related toxicity and providing safer G-tube placements