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Frontiers in Oncology 2023This study aimed to elucidate the relationship between dynamic genomic mutation alteration and pseudoprogression (PsPD)/hyperprogressive disease (HPD) in...
INTRODUCTION
This study aimed to elucidate the relationship between dynamic genomic mutation alteration and pseudoprogression (PsPD)/hyperprogressive disease (HPD) in immunotherapy-treated advanced non-small-cell lung cancer (NSCLC), to provide clinical evidence for identifying and distinguishing between PsPD and HPD.
METHOD
Patients with advanced NSCLC who were treated with anti-PD1 were enrolled. Whole blood was collected at baseline and post image progression. Serum was separated and sequenced using 425-panel next-generation sequencing analysis (NGS).
RESULTS
NGS revealed that not only single gene mutations were associated with PsPD/HPD before treatment, dynamic monitoring of the whole-blood genome mutation spectrum also varied greatly. Mutational burden, allele frequency%, and relative circulating tumor DNA abundance indicated that the fold change after image progression was much higher in the HPD group.
DISCUSSION
The gene mutation profiles of PsPD and HPD not only differed before treatment, but higher genome mutation spectrum post image progression indicated true disease progression in patients with HPD. This suggests that dynamic whole-genome mutation profile monitoring as NGS can distinguish PsPD from HPD more effectively than single gene detection, providing a novel method for guiding clinical immune treatment.
PubMed: 38023206
DOI: 10.3389/fonc.2023.1231094 -
Cancers Oct 2023[F]-FDG positron emission tomography with computed tomography (PET/CT) imaging is widely used to enhance the quality of care in patients diagnosed with cancer....
Integrating [F]-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography with Radiation Therapy and Immunomodulation in Precision Therapy for Solid Tumors.
[F]-FDG positron emission tomography with computed tomography (PET/CT) imaging is widely used to enhance the quality of care in patients diagnosed with cancer. Furthermore, it holds the potential to offer insight into the synergic effect of combining radiation therapy (RT) with immuno-oncological (IO) agents. This is achieved by evaluating treatment responses both at the RT and distant tumor sites, thereby encompassing the phenomenon known as the abscopal effect. In this context, PET/CT can play an important role in establishing timelines for RT/IO administration and monitoring responses, including novel patterns such as hyperprogression, oligoprogression, and pseudoprogression, as well as immune-related adverse events. In this commentary, we explore the incremental value of PET/CT to enhance the combination of RT with IO in precision therapy for solid tumors, by offering supplementary insights to recently released joint guidelines.
PubMed: 37958353
DOI: 10.3390/cancers15215179 -
BMC Medical Imaging Nov 2023We focused on Differentiated pseudoprogression (PPN) of progression (PN) and the response to radiotherapy (RT) or chemoradiotherapy (CRT) using diffusion and metabolic...
BACKGROUND
We focused on Differentiated pseudoprogression (PPN) of progression (PN) and the response to radiotherapy (RT) or chemoradiotherapy (CRT) using diffusion and metabolic imaging.
METHODS
Seventy-five patients with glioma were included in this prospective study (approved by the Iranian Registry of Clinical Trials (IRCT) (IRCT20230904059352N1) in September 2023). Contrast-enhanced lesion volume (CELV), non-enhanced lesion volume (NELV), necrotic tumor volume (NTV), and quantitative values of apparent diffusion coefficient (ADC) and magnetic resonance spectroscopy (Cho/Cr, Cho/NAA and NAA/Cr) were calculated by a neuroradiologist using a semi-automatic method. All patients were followed at one and six months after CRT.
RESULTS
The results of the study showed statistically significant changes before and six months after RT-CRT for M-CELV in all glioma types (𝑝 < 0.05). In glioma cell types, the changes in M-ADC, M-Cho/Cr, and Cho/NAA indices for PN were incremental and greater for PPN patients. M-NAA/Cr ratio decreased after six months which was significant only on PN for GBM, and Epn (𝑝 < 0.05). A significant difference was observed between diffusion indices, metabolic ratios, and CELV changes after six months in all types (𝑝 < 0.05). None of the patients were suspected PPN one month after treatment. The DWI/ADC indices had higher sensitivity and specificity (98.25% and 96.57%, respectively).
CONCLUSION
The results of the present study showed that ADC values and Cho/Cr and Cho/NAA ratios can be used to differentiate between patients with PPN and PN, although ADC is more sensitive and specific.
Topics: Humans; Prospective Studies; Brain Neoplasms; Iran; Glioma; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Diffusion Magnetic Resonance Imaging; Chemoradiotherapy
PubMed: 37932656
DOI: 10.1186/s12880-023-01135-x -
Neuro-oncology Advances 2023Distinguishing true tumor progression (TP) from treatment-induced abnormalities (eg, pseudo-progression (PP) after radiotherapy) on conventional MRI scans remains...
BACKGROUND
Distinguishing true tumor progression (TP) from treatment-induced abnormalities (eg, pseudo-progression (PP) after radiotherapy) on conventional MRI scans remains challenging in patients with a glioblastoma. We aimed to establish brain MRI phenotypes of glioblastomas early after treatment by combined analysis of structural and perfusion tumor characteristics and assessed the relation with recurrence rate and overall survival time.
METHODS
Structural and perfusion MR images of 67 patients at 3 months post-radiotherapy were visually scored by a neuroradiologist. In total 23 parameters were predefined and used for hierarchical clustering analysis. Progression status was assessed based on the clinical course of each patient 9 months after radiotherapy (or latest available). Multivariable Cox regression models were used to determine the association between the phenotypes, recurrence rate, and overall survival.
RESULTS
We established 4 subgroups with significantly different tumor MRI characteristics, representing distinct MRI phenotypes of glioblastomas: TP and PP rates did not differ significantly between subgroups. Regression analysis showed that patients in subgroup 1 (characterized by having mostly small and ellipsoid nodular enhancing lesions with some hyper-perfusion) had a significant association with increased mortality at 9 months (HR: 2.6 (CI: 1.1-6.3); = .03) with a median survival time of 13 months (compared to 22 months of subgroup 2).
CONCLUSIONS
Our study suggests that distinct MRI phenotypes of glioblastomas at 3 months post-radiotherapy can be indicative of overall survival, but does not aid in differentiating TP from PP. The early prognostic information our method provides might in the future be informative for prognostication of glioblastoma patients.
PubMed: 37908765
DOI: 10.1093/noajnl/vdad133 -
European Journal of Nuclear Medicine... Mar 2024
Topics: Humans; Meningioma; Receptors, Somatostatin; Glioma; Brain Neoplasms; Meningeal Neoplasms; Positron-Emission Tomography; Tyrosine; Magnetic Resonance Imaging
PubMed: 37897618
DOI: 10.1007/s00259-023-06479-8 -
Cancers Oct 2023MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during...
MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, a reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy at 2-3 month intervals actually benefits patients and how it influences clinical decision making about the continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans post-chemoradiotherapy (post-CCRT), after three cycles of adjuvant chemotherapy [TMZ3/6], and after the completion of treatment [TMZ6/6]), and of unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in an early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; < 0.001). Perfusion MRI caused less diagnostic uncertainty ( = 0.021) but did not influence treatment consequences ( = 0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach.
PubMed: 37894340
DOI: 10.3390/cancers15204973 -
BMC Medicine Oct 2023GT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to...
BACKGROUND
GT90001 (also known as PF-03446962) is an anti-ALK-1 monoclonal antibody and has shown activity in hepatocellular carcinoma (HCC). This phase 1b/2 study was designed to determine the recommended phase 2 dose (RP2D) of GT90001 plus nivolumab, and assess the safety and anti-tumor activity in patients with advanced HCC.
METHODS
Patients with advanced HCC were recruited from 3 centers. Eligible patients in the dose de-escalation stage received the GT90001 on day 1 of a 14-day cycle in a rolling-six design with a fixed dose of nivolumab (3.0 mg/kg). Patients in dose-expansion stage received the RP2D of GT90001 plus nivolumab. Primary endpoint was safety. Key secondary endpoint was objective response rate (ORR) as per RECIST 1.1.
RESULTS
Between July 9, 2019, and August 8, 2022, 20 patients were treated (6 in phase 1b; 14 in phase 2) and evaluable for analysis. In phase 1b, no dose-limiting toxicities were observed, and GT90001 7.0 mg/kg was confirmed as the RP2D. Common grade 3/4 adverse events (AEs) were platelet count decreased (15%). No deaths due to AEs were reported. Confirmed ORR and disease control rate were 30% (95% CI, 14.6%-51.9%) and 40% (95% CI, 21.9%-61.3%), respectively. Median duration of response was not calculated (95% CI, 7.39 months to not calculated). Median progression-free survival (PFS) was 2.81 months (95% CI, 1.71-9.33), with 6-month and 12-month PFS rates of 35% and 25%, respectively. One patient with multiple intra- and extra-hepatic metastases was diagnosed with pseudo-progression upon GT90001 plus nivolumab exposure.
CONCLUSIONS
GT90001 plus nivolumab has a manageable safety profile and promising anti-tumor activity in patients with advanced HCC.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov identifier NCT03893695.
Topics: Humans; Nivolumab; Carcinoma, Hepatocellular; Liver Neoplasms; Progression-Free Survival; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37858184
DOI: 10.1186/s12916-023-03098-w -
Frontiers in Immunology 2023Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major...
BACKGROUND
Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC.
MATERIALS AND METHODS
A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[F]fluoro-D-glucose ([F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [Zr]-labeled anti-PD-1 antibody and measured as Zr tumor uptake.
RESULTS
Conventional [F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found ( = 0.8; = 0.001).
CONCLUSION
Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.
Topics: Humans; Mice; Animals; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Positron Emission Tomography Computed Tomography; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Fluorodeoxyglucose F18; B7-H1 Antigen
PubMed: 37841258
DOI: 10.3389/fimmu.2023.1272570 -
Translational Oncology Dec 2023The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they...
BACKGROUND
The biomarkers of immune checkpoint inhibitors (ICIs) efficacy and safety are still urgently needed. As cytokines are easily detected and monitored in circulation, they could be used as potential predictors of response and immune-related adverse events (irAEs) for ICIs therapy.
METHODS
The levels of TGF-β, IFN-γ, IL-6, IL-8, IL-10 were measured in sera and plasma by ELISA method of 30 healthy controls (HC) and 32 BRAF wild type (wt) MM patients before and after every 12 weeks of Pembrolizumab, PD-1 inhibitor, until one year or disease progression (DP).
RESULTS
Higher pretherapy levels of circulating TGF-β, IFN-γ, IL-6, and IL-10 were shown in MM patients compared to HC. In patients with disease control, TGF-β and IL-6 first decreased during the therapy, while then they started to successively increase reaching the initial values by the end of the follow up. Furthermore, in this group of patients IFN-γ increased, while IL-8 and IL-10 decreased at final points of the follow up. In patients with DP IL-6 increased at the time of progression, while IL-8 decreased when the best response was achieved. In patients with pseudoprogression IL-6 and IL-10 significantly increased compared to the pretreatment values. Melanoma patients with irAEs had increased baseline values of TGF-β, IFN-γ, IL-6, and IL-10 compared to HC. However, no significant changes in cytokines levels were found in these patients during therapy.
CONCLUSIONS
Inflammatory cytokines monitoring in circulation of BRAFwt MM patients could help in the selection of patients who will have the benefit from Pembrolizumab therapy.
PubMed: 37806113
DOI: 10.1016/j.tranon.2023.101799 -
Journal of Cancer Research and... 2023Systemic therapy in lung cancer is mainstay of treatment as most patients present in advanced stages, with rising importance of new immunotherapy agents.
BACKGROUND
Systemic therapy in lung cancer is mainstay of treatment as most patients present in advanced stages, with rising importance of new immunotherapy agents.
PURPOSE
To compare the RECIST 1.1 and the immunotherapy Response Evaluation Criteria in Solid Tumors (iRECISTs) criteria for response assessment in lung cancer patients on immunotherapy. To find the incidence of pseudoprogression and associated imaging patterns.
MATERIAL AND METHODS
Retrospective study in 28 patients treated with immunotherapy for advanced metastatic NSCLC. End points were progression-free survival (PFS) and overall survival (OS). Response assessments were separately tabulated according to RECIST 1.1 and iRECIST and classified into dichotomous groups of responders and nonresponders. Agreement in assessments between RECIST 1.0 and iRECIST examined using Cohen kappa (κ) coefficient with 95% confidence intervals. Kaplan-Meier survival analysis was done for PFS and OS. Differences between RECIST 1.1 and iRECIST for both responder and nonresponder were evaluated by the log rank test, Breslow (Generalized Wilcoxon) test, and Tarone-Ware test.
RESULTS
Incidence of pseudoprogression was 7% (2/28). The RECIST1.1 and iRECIST were in disagreement in two patients. The agreement between RECIST and iRECIST was almost perfect. The PFS and the OS are significantly longer in duration for responders in comparison to nonresponders for both RECIST and iRECIST and the difference between two assessment criteria is not significant.
CONCLUSION
Although iRECIST aims to monitor treatment more precisely than conventional response criteria, this must be weighed against how infrequent pseudoprogression is and the cost of this therapy, both financially and in the potential delay in changing to a more effective treatment.
Topics: Humans; Lung Neoplasms; Response Evaluation Criteria in Solid Tumors; Nivolumab; Retrospective Studies; Carcinoma, Non-Small-Cell Lung; Treatment Outcome
PubMed: 37787285
DOI: 10.4103/jcrt.jcrt_1456_21