tbuckley/cabot-search huggingface dataset:
Financial toxicity from PARP inhibitors in castrate-resistant prostate cancer.
Authors: David Joseph Benjamin, Nataniel Hernan Lester-Coll, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2024)

54 Background: Approximately 5-10% of men with prostate cancer (PC) are eligible for treatment with PARP inhibitors. As an estimated 120,000 men living in the US have metastatic PC, between 6,000-12,000 men may be eligible for treatment with PARP inhibitors. Recently, several PARP inhibitors have been approved as single or combination therapies in the first-line castrate-resistant (CR) setting and later-line setting including: olaparib, olaparib plus abiraterone (AAP), and talazoparib plus enzalutamide. It is unclear if these newly approved therapies may be cost prohibitive for patients and/or health care systems. Methods: Using average sale price data from UpToDate for PARP inhibitors and novel hormone therapies (NHTs), we calculated the total cost of treatment for each single or combination therapy regimen. We used phase II/III clinical trial data to determine the median duration of treatment for each regimen. Results: The three approved PARP inhibitors have total costs in descending order as follows: AAP plus olaparib ($689,813.77), talazoparib plus enzalutamide ($388,390.46), and olaparib ($202,845.22). In comparison, in the PROfound trial, the cost of AAP alone was $192,140.37 and in the TALAPRO-2 trial, the cost of enzalutamide alone was $ 253,780.80. The difference in estimated cost between olaparib plus AAP versus talazoparib plus enzalutamide per patient is $37,970.29. Conclusions: Despite several new approved therapies in BRCA mutated and HRR mutated mPC, the total costs for PARP inhibitors remain prohibitive for health care institutions. The estimated difference between two newly approved PARP plus NHT regimens could translate in a difference of $455,643,480 in healthcare system costs if all eligible U.S. men received treatment with olaparib plus AAP over talazoparib plus enzalutamide. [Table: see text]
Response evaluation criteria in PSMA PET/CT (RECIP 1.0) in metastatic castration-resistant prostate cancer.
Authors: Andrei Gafita, Loic Djaileb, Isabel Rauscher, Wolfgang P. Fendler, Boris A. Hadaschik, Steven P. Rowe, Ken Herrmann, Jeremie Calais, Matthew Rettig, Matthias Eiber, Manuel Weber, Matthias R. Benz, Andrea Farolfi
Journal: Journal of Clinical Oncology (2024)

45 Background: Response Evaluation Criteria in Prostate-Specific Membrane Antigen (PSMA) PET/CT (RECIP 1.0) initially integrated software-based quantitative assessment of PSMA-positive total tumor volume (PSMA-VOL). Clinical implementation of such software is not expected soon, limiting the use of RECIP in practice. This study aimed to assess the agreement of RECIP determined using tumor segmentation software (quantitative RECIP) with RECIP determined by qualitative reads by nuclear medicine physicians (visual RECIP) for response evaluation in metastatic castration-resistant prostate cancer. Methods: This multicenter retrospective study at three academic centers included patients who received lutetium-177 ( 177 Lu) PSMA treatment between December 2014 and July 2019. PSMA PET/CT images at baseline and 12 weeks were assessed qualitatively by five nuclear medicine physicians for changes in PSMA-VOL and for new lesions. Quantitative changes in PSMA-VOL were also measured using tumor segmentation software. The status of new lesions was combined with qualitative changes in PSMA-VOL to determine visual RECIP and with quantitative changes in PSMA-VOL to determine quantitative RECIP. The primary outcomes were the agreement between visual and quantitative RECIP and the interreader reliability of visual RECIP according to the Fleiss κ. The secondary outcome was the association of visual RECIP with overall survival according to Cox regression. Results: A total of 124 patients (median age, 73 years [IQR, 67–76 years]) were included. Forty (32%) and 84 (68%) patients had quantitative RECIP progressive disease (PD) and non-PD, respectively. Agreement between visual versus quantitative RECIP was excellent (κ=0.89; 118 of 124 patients [95%]). Agreement among readers in classifying visual RECIP PD versus non-PD was excellent (κ=0.81; 103 of 124 patients [83%]). RECIP-PD was associated with significantly shorter overall survival compared with RECIP-nonPD (hazard ratio, 2.6 [95%CI: 1.7, 3.8]; P &lt;.001). Conclusions: Qualitatively assessed RECIP demonstrated excellent agreement with quantitative RECIP and excellent interreader reliability, and can be readily implemented in clinical practice for response evaluation in patients with metastatic castration-resistant prostate cancer undergoing 177 Lu-PSMA therapy and possible other systemic therapies.
Patterns of PSMA PET/CT scan usage for initial staging and recurrence in a multi-centered hospital system.
Authors: Richard Bennett, Eric Li, Austin Y. Ho, Jonathan Aguiar, Ashorne Krithiesh Mahenthiran, Sai Kumar, Chalairat Suk-ouichai, Clayton Neill, Hiten Dilip Patel, Edward M. Schaeffer, Hatice Savas, Ashley Ross
Journal: Journal of Clinical Oncology (2024)

36 Background: PET PSMA-based imaging for prostate cancer staging has been approved since late 2020 and was widely available in our medical system by July 2021. We sought to examine the patterns of use of PSMA PET/CT and conventional imaging for staging since this time. Methods: We retrospectively identified men who were diagnosed with presumptive NCCN unfavorable intermediate risk (UIR), high risk, or very high risk (VHR) and men who underwent staging work-up for biochemical recurrence (BCR) from July 2021 – June 2023. Patient clinical, pathological, and imaging variables were collected. Sufficient conventional imaging for initial staging was defined as the use of a bone scan and one or more of an MRI or CT scan. The date of staging was determined by the initiation of staging with conventional imaging or the date of PSMA scan if used. Results: In the study period, 899 men were diagnosed with presumptive NCCN UIR-VHR disease. Among these individuals 32% (290/899) underwent no or insufficient staging, 26% (230/899) underwent staging with conventional imaging only, and 42% (379/899) underwent initial staging evaluations that included PET PSMA. The frequency of PET PSMA used for initial staging increased from 24% (20/82) to 80% (167/208) over the 2-year study period. 1173 men with biochemical recurrence who underwent a staging work-up were identified. Median PSA of these men was 1.37 ng/mL (IQR 0.23, 6.59 ng/mL). The frequency of PET PSMA imaging increased in these men from 91% (225/246) to 98% (296/303) over the 2-year study period. When ordering both PSMA and conventional imaging for initial staging, providers tended to order PSMA scans after initial conventional imaging orders (72%) rather than before (18%) or on the same day (11%). Conclusions: The use of PSMA PET/CT imaging rose since its implementation in our system in July 2021 with PSMA PET being utilized in 80% of patients being initially staged and 98% of those staged at BCR. Conventional imaging and Axumin PET are rarely used in BCR. If both PET PSMA and conventional imaging were ordered for initial staging, PET PSMA was typically performed after conventional imaging. Growing data may inform best sequencing and use of conventional imaging in the PSMA-PET era.
Differences between whole body magnetic resonance imaging (WB-MRI) and chest/abdomen/pelvis computed tomography (CT)/bone scan (CT/B) in patients staged as having metastatic hormone-sensitive prostate cancer (mHSPC): A retrospective comparative study within a single trust in the UK.
Authors: Mona Hassan, Shobana Anpalakhan, Akash Maniam, Aruni Ghose, Utku Lokman, Tomasz Olejnik, Giuseppe Luigi Banna
Journal: Journal of Clinical Oncology (2024)

37 Background: Diagnostic imaging for metastases detection in HSPC varies across different countries with increasing use of WB-MRI and PSMA-PET. However, CT/B has still been the most used modality in the real world and recent registration clinical trials in this disease setting. Methods: We performed a cross-sectional retrospective descriptive study comparing WB-MRI with CT/B used as baseline staging modalities in patients diagnosed with mHSPC between February 2017 and August 2023 in two hospitals belonging to the same NHS trust in the UK routinely using one of the two. The study aimed at the detection of differences between the two modalities in the identification of metastatic sites and CHAARTED volume/LATITUDE risk, and the relative impact on patients’ received therapies and outcomes. Results: Of 213 patients diagnosed with mHSPC, 121 had baseline WB-MRI, 86 CT/B and 7 choline or PSMA PET. Compared to CT/B, patients staged by WB-MRI were diagnosed with significantly higher bone-only (47 vs 24%, p=0.002) and lower lymph-node only disease (11 vs 27%, p=0.005); higher high-volume (49 vs 21%, p&lt;0.001) and -risk disease (48 vs 17%, p&lt;0.001); higher de-novo metastatic disease (91 vs 66%, p&lt;0.001); had previously received less radical surgery (2 vs 13%, p=0.003) or radiotherapy (7 vs 24%, p&lt;0.001); received more frequently ADT plus Docetaxel (65 vs 44%, p=0.005). Treatment and outcome results in the overall cohorts’ populations and according to disease volume/risk will be presented. Conclusions: In a homogenous cohort of patients, we found a relevant discrepancy between the use of WB-MRI and CT/B in the identification of high-volume/risk and de-novo disease in mHSPC related to a higher detection rate of bone-only disease by the WB-MRI. This may prompt clinicians to offer different systemic therapies according to the disease burden and could also have a role in avoiding overtreatments for the under-staged disease.
A convolutional neural network model using intraprostatic patterns of [F18]DCFPyL uptake in PSMA PET images to predict synchronous metastases.
Authors: Jesus Eduardo Juarez, Cecil Mayra Benitez, Kamil Rzechowski, Karl Sjöstrand, Aseem Anand, Ida Sonni, Gholam Reza Berenji, Sai Duriseti, Matthew Rettig, Nicholas George Nickols
Journal: Journal of Clinical Oncology (2024)

46 Background: [F18]DCFPyL (PyL) is a PSMA targeted imaging agent that provides whole-body staging of prostate cancer. Image analysis of the primary tumor using deep learning algorithms might offer additional insight into disease biology, including co-existing metastatic disease. We developed convolutional neural network (CNN) models using inputs from the entire prostate on PyL images along with auto-segmented hot spots within the of primary prostate cancer tumor to predict synchronous metastases and compared the models against established models built from clinico-pathologic data. Methods: 91 Veterans with de novo prostate cancer were imaged with PyL PSMA PET/CT for initial staging (46% with metastatic disease). The PyL images of the prostate were analyzed using aPROMISE, which autosegments, localizes, and quantifies disease on PSMA PET. The segmentations of the prostate were used to map the PyL PET image of the prostate. Both the entire prostate, as well as aPROMISE defined hot spots were used as inputs for the CNN, where, according to attention map analysis, the hotspot information helps the network understand the location and extent of tumors. The CNN model architecture was based on SqueezeNet v2. The dataset was split into training, validation and test sets using stratified random sampling. The area under ROC curve (AUC) was computed to determine the performance of the model in predicting the presence of metastases and the test predictions were compared with ground truth (M1). Training was repeated 50 times and the best performing experiment was identified. Prediction scores from UCSF-CAPRA and UCLA PSMA risk calculator were used as comparators. Results: The best CNN model had an AUC of 0.89 for prediction of metastatic disease (median 0.72, ICR 0.64 and 0.8). For comparison, the AUC from the UCSF-CAPRA score and UCLA-PSMA risk calculator (any upstaging on PET), which rely on clinicopathologic information, had AUCs of 0.729 and 0.754 in this dataset, respectively. Conclusions: The CNN based model using PyL imaging demonstrates that synchronous metastases can be predicted from intraprostatic PyL uptake patterns alone with a predictive accuracy in this dataset that is at least comparable to published prediction models based on clinicopathologic features. This study raises the hypothesis that PyL CNN-based models could be developed to prognosticate metastatic progression.
Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials
Authors: Elias Jabbour, Jane Apperley, Jorge Cortes, Delphine Rea, Michael Deininger, Elisabetta Abruzzese, Charles Chuah, Daniel J. DeAngelo, Andreas Hochhaus, Jeffrey H. Lipton, Michael Mauro, Franck Nicolini, Javier Pinilla-Ibarz, Gianantonio Rosti, Philippe Rousselot, Neil P. Shah, Moshe Talpaz, Alexander Vorog, Xiaowei Ren, Hagop Kantarjian
Journal: Leukemia (2024)

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1
Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease
Authors: Parker C. Wilson, Amit Verma, Yasuhiro Yoshimura, Yoshiharu Muto, Haikuo Li, Nicole P. Malvin, Eryn E. Dixon, Benjamin D. Humphreys
Journal: Genome biology (2024)

Abstract Background Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single-cell RNA and ATAC sequencing to show that LOY is present in the kidney and increases with age and chronic kidney disease. Results The likelihood of a cell having LOY varies depending on its location in the nephron. Cortical epithelial cell types have a greater proportion of LOY than medullary or glomerular cell types, which may reflect their proliferative history. Proximal tubule cells are the most abundant cell type in the cortex and are susceptible to hypoxic injury. A subset of these cells acquires a pro-inflammatory transcription and chromatin accessibility profile associated with expression of HAVCR1 , VCAM1 , and PROM1 . These injured epithelial cells have the greatest proportion of LOY and their presence predicts future kidney function decline. Moreover, proximal tubule cells with LOY are more likely to harbor additional large chromosomal gains and express pro-survival pathways. Spatial transcriptomics localizes injured proximal tubule cells to a pro-fibrotic microenvironment where they adopt a secretory phenotype and likely communicate with infiltrating immune cells. Conclusions We hypothesize that LOY is an indicator of increased DNA damage and potential marker of cellular senescence that can be applied to single-cell datasets in other tissues.
Neo-adjuvant tislelizumab combined with lenvatinib treatment for resectable, recurrent hepatocellular carcinoma.
Authors: Kuang Ming, Wenxuan Xie, Jingying Chen, Shuling Chen, Yuanqi Wang, Shunli Shen, Sui Peng
Journal: Journal of Clinical Oncology (2024)

517 Background: The persistent challenge of elevated re-recurrence rates following secondary hepatectomy complicates the prospects for improving survival in recurrent hepatocellular carcinoma (rHCC) patients. Immunotherapy combined with targeted drugs have been the first-line therapy for advanced HCC and shown good response rate in neoadjuvant situation. However, the effectiveness and safety of the combination treatment has not been reported in rHCC patients. To address this, we conducted the present phase 2 clinical trial of neoadjuvant treatments using tislelizumab in combination with lenvatinib for rHCC patients. Methods: Patients with resectable rHCC patients who had previously undergone curative treatment were enrolled. Enrolled patients were treated with 2 neoadjuvant cycles of a combination of tislelizumab 200mg intravenously every 3 weeks and lenvatinib 8mg every day (12mg for patients over 60kg) for 4 weeks. Hepatectomy was conducted in six weeks after enrollment. One month after surgery, adjuvant combination of tislelizumab and lenvatinib was started for at least one year or until disease progression or intolerance of adverse reactions. The primary objective of the trial is to evaluate one-year disease-free survival (DFS) rate, and secondary endpoints include objective response rate (ORR) as assessed by RECIST 1.1, major pathologic response (defined as over 90% tumor necrosis), and safety considerations. Results: Until Sep 30 th , 2023, a total of 14 patients have been enrolled. All participants underwent the complete neoadjuvant therapy with a combination of tislelizumab and lenvatinib before proceeding to hepatectomy. Throughout the neoadjuvant phase, 14.3% (2/14) of patients occurred adverse events below grade 3, with no severe adverse events occurring. The most common adverse events were fatigue (in 2 patients), hypertension (in 1 patient) and reduced appetite (in 1 patient). In 14 patients, 12 patients underwent R0 resection and 2 were waiting for hepatectomy. The average time from the initiation of the neoadjuvant therapy to hepatectomy was approximately 40.42 days. On the radiological front, one patient (8.3%) exhibited a partial response, while 11/12 (91.7%) displayed stable disease with 8 patients had tumor shrinkage. In terms of pathological outcomes, 25% of patients (3/12) achieved a complete response, whereas the remaining patients showed varying degrees of pathologic response, ranging from 5% to 85%. Conclusions: In summary, the dual therapy of tislelizumab and lenvatinib demonstrates encouraging safety and effectiveness as a neoadjuvant intervention for patients with rHCC. The long-term results of this combined treatment approach are eagerly anticipated. Clinical trial information: NCT04615143 .
Id2 epigenetically controls CD8+ T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex
Authors: Yiming Li, Mingwei Han, Haolin Wei, Wan Huang, Zhinan Chen, Tianjiao Zhang, Meirui Qian, Lin Jing, Gang Nan, Xiuxuan Sun, Shuhui Dai, Kun Wang, Jianli Jiang, Ping Zhu, Liang Chen
Journal: Cellular and Molecular Immunology (2024)

Abstract CD8 + T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6 + progenitor exhausted (Tex prog ) and Tim-3 + terminally exhausted (Tex term ) subpopulations. Inhibitor of DNA binding protein 2 (Id2) has been shown to play important roles in T-cell development and CD8 + T-cell immunity. However, the role of Id2 in CD8 + T-cell exhaustion is unclear. Here, we found that Id2 transcriptionally and epigenetically regulates the generation of Tex prog cells and their conversion to Tex term cells. Genetic deletion of Id2 dampens CD8 + T-cell-mediated immune responses and the maintenance of stem-like CD8 + T-cell subpopulations, suppresses PD-1 blockade and increases tumor susceptibility. Mechanistically, through its HLH domain, Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex, and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1. Therefore, Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter, modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6 + Tex prog cells. An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6 + Tim-3 − Tex prog cells in tumors and the expression level of Tcf1 in Id2-deleted CD8 + T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8 + T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.
KDM5C-mediated recruitment of BRD4 to chromatin regulates enhancer activation and BET inhibitor sensitivity
Authors: Yulong Qiang, Jiachen Fan, Chuanshuai Xie, Leilei Yan, Xiaofei Song, Nan Zhang, Yan Lin, Jie Xiong, Wei Zhang, Yu Liu, Lei Wei, Yu Li, Shizhen Chen, Kaiwei Liang, Feng Li
Journal: Cancer Research (2024)

Abstract The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy. Significance: BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer.