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Oncoimmunology 2024This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with...
Noninvasive radiomic biomarkers for predicting pseudoprogression and hyperprogression in patients with non-small cell lung cancer treated with immune checkpoint inhibition.
This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. We retrospectively analyzed 105 patients with NSCLC, from three institutions, treated with immune checkpoint inhibitors (ICIs) and categorized them into training and independent testing set. Subsequently, we processed CT scans with a series of image-preprocessing techniques, and 6008 radiomic features capturing intra- and peritumoral texture patterns were extracted. We used the least absolute shrinkage and selection operator logistic regression model to select radiomic features and construct machine learning models. To further differentiate between progressive disease (PD) and hyperprogressive disease (HPD), we developed a new radiomics model. The logistic regression (LR) model showed optimal performance in distinguishing PP from HPD, with areas under the receiver operating characteristic curve (AUC) of 0.95 (95% confidence interval [CI]: 0.91-0.99) and 0.88 (95% CI: 0.66-1) in the training and testing sets, respectively. Additionally, the support vector machine model showed optimal performance in distinguishing PD from HPD, with AUC of 0.97 (95% CI: 0.93-1) and 0.87 (95% CI: 0.72-1) in the training and testing sets, respectively. Kaplan‒Meier survival curves showed clear stratification between PP predicted by the radiomics model and true progression (HPD and PD) (hazard ratio = 0.337, 95% CI: 0.200-0.568, < 0.01) in overall survival. Our study demonstrates that radiomic features extracted from baseline CT scans are effective in predicting PP and HPD in patients with NSCLC treated with ICIs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Radiomics; Retrospective Studies; Disease Progression; Biomarkers
PubMed: 38343749
DOI: 10.1080/2162402X.2024.2312628 -
Frontiers in Oncology 2024There is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods...
OBJECTIVES
There is no theory to quantitatively describe the complex tumor ecosystem. At the same time, cancer immunotherapy is considered a revolution in oncology, but the methods used to describe tumors and the criteria used to evaluate efficacy are not keeping pace. The purpose of this study is to establish a new theory for quantitatively describing the tumor ecosystem, innovating the methods of tumor characterization, and establishing new efficacy evaluation criteria for cancer immunotherapy.
METHODS
Based on the mathematization of immune equilibrium theory and the establishment of immunodynamics in a previous study, the method of reverse immunodynamics was used, namely, the immune braking force was regarded as the tumor ecological force and the immune force was regarded as the tumor ecological braking force, and the concept of momentum in physics was applied to the tumor ecosystem to establish a series of tumor ecodynamic equations. These equations were used to solve the fundamental and applied problems of the complex tumor ecosystem.
RESULTS
A series of tumor ecodynamic equations were established. The tumor ecological momentum equations and their component factors could be used to distinguish disease progression, pseudoprogression, and hyperprogression in cancer immunotherapy. On this basis, the adjusted tumor momentum equations were established to achieve the equivalence of tumor activity (including immunosuppressive activity and metabolic activity) and tumor volume, which could be used to calculate individual disease remission rate and establish new efficacy evaluation criteria (ieRECIST) for immunotherapy of solid tumor based on tumor ecodynamics. At the same time, the concept of moving cube-to-force square ratio and its expression were proposed to calculate the area under the curve of tumor ecological braking force of blood required to achieve an individual disease remission rate when the adjusted tumor ecological momentum was known.
CONCLUSIONS
A new theory termed tumor ecodynamics emphasizing both tumor activity and tumor volume is established to solve a series of basic and applied problems in the complex tumor ecosystem. It can be predicted that the future will be the era of cancer immune ecotherapy that targets the entire tumor ecosystem.
PubMed: 38807760
DOI: 10.3389/fonc.2024.1335533 -
BMJ Open Aug 2023Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and...
INTRODUCTION
Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication.
METHODS AND ANALYSIS
The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival.
ETHICS AND DISSEMINATION
The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications.
TRIAL REGISTRATION NUMBER
ANZCTR ACTRN12619001735145.
Topics: Adult; Humans; Adolescent; Glioblastoma; Positron Emission Tomography Computed Tomography; Ficus; Tyrosine; Prospective Studies; Brain Neoplasms; Neoplasm Recurrence, Local; Australia; Positron-Emission Tomography; Magnetic Resonance Imaging; Clinical Trials, Phase II as Topic; Multicenter Studies as Topic
PubMed: 37541751
DOI: 10.1136/bmjopen-2022-071327 -
Frontiers in Oncology 2023
PubMed: 38162508
DOI: 10.3389/fonc.2023.1330225 -
Radiotherapy and Oncology : Journal of... Jul 2023The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast... (Review)
Review
OBJECTIVE
The interpretation of new enhancing lesions after radiotherapy for diffuse glioma remains a clinical challenge. We sought to characterize and classify new contrast enhancing lesions in a historical multicenter cohort of patients with IDH mutated grade 2 diffuse glioma treated with photon therapy.
METHODS
We reviewed all follow-up MRI's of all patients treated with radiotherapy for histologically confirmed, IDH mutated diffuse grade 2 glioma between 1-1-2007 and 31-12-2018 in two tertiary referral centers. Disease progression (PD) was defined in accordance with the RANO criteria for progressive disease in low grade glioma. Pseudoprogression (psPD) was defined as any transient contrast-enhancing lesion between the end of radiotherapy and PD, or any new contrast-enhancing lesion that remained stable over a period of 12 months in patients who did not exhibit PD.
RESULTS
A total of 860 MRI's of 106 patients were reviewed. psPD was identified in 24 patients (23%) on 76 MRI's. The cumulative incidence of psPD was 13% at 1 year, 22% at 5 years, and 28% at 10 years. The mean of the observed maximal volume of psPD was 2.4 cc. The median Dmin in psPD lesions was 50.1 Gy. The presence of an 1p/19q codeletion was associated with an increased risk of psPD (subhazard ratio 2.34, p = 0.048). psPD was asymptomatic in 83% of patients.
CONCLUSION
The cumulative incidence of psPD in grade 2 diffuse glioma increases over time. Consensus regarding event definition and statistical analysis is needed for comparisons between series investigating psPD.
Topics: Humans; Brain Neoplasms; Glioma; Magnetic Resonance Imaging; Disease Progression; Mutation; Isocitrate Dehydrogenase; Multicenter Studies as Topic
PubMed: 37084885
DOI: 10.1016/j.radonc.2023.109674 -
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 -
Discoveries (Craiova, Romania) 2023The incidence of tumor metastases in the brain is many times more frequent than primary brain tumors, affecting a very large share of patients suffering from systemic... (Review)
Review
The incidence of tumor metastases in the brain is many times more frequent than primary brain tumors, affecting a very large share of patients suffering from systemic cancer. Advanced malignant melanoma is well known for its ability to invade the brain space and current treatment options, such as surgery and radiation therapy, are not very efficient and cause notable complications and morbidity. The aim of this review is to explore the recent advances and future potential of using immunotherapy in the treatment of melanoma brain metastases. Several FDA approved immunotherapeutic drugs have shown to be able to at least double the overall survival rates in such patients. Clinical trials of varying phases are underway and available results are promising, significantly prolonging survival rates in patients with previously untreated melanoma brain metastases. Nevertheless, not all patients respond to these immunotherapies, facing a high percentage of resistant cases, without yet knowing the mechanisms and causes of resistance behind. Also, at the time of immunotherapy, a small percentage of patients is affected by pseudoprogression, which can be difficult to distinguish from true progression given the similarity of symptoms. Therefore, there is a pressing need for future research about treatment effectiveness in patients with brain metastases from melanoma, including outcomes from the perspective of patients.
PubMed: 37583899
DOI: 10.15190/d.2023.8 -
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 -
Therapeutic Advances in Medical Oncology 2024The microsatellite instability (MSI) phenotype is related to a deficiency of the DNA mismatch repair (dMMR) system and is observed in 5% of metastatic colorectal cancers... (Review)
Review
The microsatellite instability (MSI) phenotype is related to a deficiency of the DNA mismatch repair (dMMR) system and is observed in 5% of metastatic colorectal cancers (mCRCs). MSI/dMMR phenotype testing should be routine for all CRCs regardless of stage. Two complementary techniques with a high concordance (90-97%) allow us to determine the MSI/dMMR status of a tumor: immunohistochemistry and polymerase chain reaction. Since 2020 and the results of the phase III KEYNOTE 177 trial, pembrolizumab [anti-programmed cell death protein 1 (PD1)] is the new standard of care in first-line MSI/dMMR mCRC. To date, no combination of chemtotherapy ± targeted therapy with immune checkpoint inhibitors (ICIs) has been validated in the management of MSI/dMMR mCRC, and it is not known whether this combination would be beneficial. It is also unclear whether dual therapy with two ICIs is more effective than monotherapy. Several phase III trials are ongoing to answer these questions. Despite a high response rate and long-term benefit of a first line by anti-PD1, 30-50% of patients with MSI/dMMR mCRC experience an early or secondary progression. There are currently no validated predictive biomarkers of anti-PD1 ± anti-cytotoxic T lymphocyte antigen-4 resistance in patients with MSI/dMMR mCRC. In case of early progression on ICIs, the first two questions to consider are the possibility of pseudoprogression and the correct diagnosis of MSI/dMMR status. To date, there are no data on the use of adjuvant ICIs for MSI/dMMR resected colon cancers. By contrast, data are accumulating regarding the efficacy of neoadjuvant ICIs, with at least two-thirds of patients in the different trials in pathological complete response, making it possible to envisage 'Watch and wait' strategies in future.
PubMed: 38205076
DOI: 10.1177/17588359231170473 -
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