Early Assessment Of Treatment Response Research Articles

Magnetic resonance imaging techniques for monitoring glioma response to chemoradiotherapy.

Treatment response assessment for gliomas currently uses changes in tumour size as measured with T1- and T2-weighted MRI. However, changes in tumour size may occur many weeks after therapy completion and are confounded by radiation treatment effects. Advanced MRI techniques sensitive to tumour physiology may provide complementary information to evaluate tumour response at early timepoints during therapy. The objective of this review is to provide a summary of the history and current knowledge regarding advanced MRI techniques for early treatment response evaluation in glioma. The literature survey included perfusion MRI, diffusion-weighted imaging, quantitative magnetization transfer imaging, and chemical exchange transfer MRI. Select articles spanning the history of each technique as applied to treatment response evaluation in glioma were chosen. This report is a narrative review, not formally systematic. Chemical exchange saturation transfer imaging potentially offers the earliest method to detect tumour response due to changes in metabolism. Diffusion-weighted imaging is sensitive to changes in tumour cellularity later during radiotherapy and is prognostic for progression-free and overall survival. Substantial evidence suggests that perfusion MRI can differentiate between tumour recurrence and treatment effect, but consensus regarding acquisition, processing, and interpretation is still lacking. Magnetization transfer imaging shows promise for detecting subtle white matter damage which could indicate tumour invasion, but more research in this area is needed. Advanced MRI techniques show potential for early treatment response assessment, but each technique alone lacks specificity. Multiparametric imaging may be necessary to aid biological interpretation and enable treatment guidance.

Evaluation of arterial spin labeling in the diagnosis and monitoring of myelin oligodendrocyte glycoprotein-associated cerebral cortical encephalitis.

Myelin oligodendrocyte glycoprotein (MOG)-associated disorders are inflammatory demyelinating diseases of the CNS. Cerebral cortical encephalitis (CCE) is characterized by cortical fluid-attenuated inversion recovery hyperintensity with seizures and headaches. We report two cases of MOG antibody-associated CCE (MOG-CCE) evaluated using serial MRI sequences, including arterial spin labeling (ASL), pre- and posttreatment. In both patients, ASL demonstrated hyperperfusion correlating with disease activity, which normalized following steroid therapy. Our cases highlight the usefulness of ASL in early detection, monitoring, and assessment of treatment response in MOG-CCE.

Early treatment response assessment with [177Lu]PSMA whole-body-scintigraphy compared to interim PSMA-PET

BackgroundProstate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS.MethodsMen with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders.ResultsA total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P < 0.001, n = 188). The median follow-up time was 14.7 months (range: 3–63 months; 125 deaths occurred). Median overall survival (OS) time was 14.5 months (95% CI: 11.9–15.9). In terms of OS analysis, early progression during therapy revealed a significantly higher likelihood of death: e.g. second cycle WBS (15 vs. 25 months, P < 0.001) with a HR of 2.81 (P < 0.001) or at PET timepoint after 2 cycles of RLT (11 vs. 24 months, P < 0.001) with a HR of 3.5 (P < 0.001). For early biochemical response, a PSA decline of at least 50% after two cycles of RLT indicates a significantly lower likelihood of death (26 vs. 17 months, P < 0.001) with a HR of 0.5 (P < 0.001).ConclusionResponse assessment of RLT by WBS and interim PET after two cycles of RLT have high congruence and can identify patients at risk of poor outcome. This indicates that interim PET might be omitted for response assessment, but future trials corroborating these findings are warranted.

Harnessing the Power of Radiotherapy for Lung Cancer: A Narrative Review of the Evolving Role of Magnetic Resonance Imaging Guidance.

Compared with computed tomography (CT), magnetic resonance imaging (MRI) traditionally plays a very limited role in lung cancer management, although there is plenty of room for improvement in the current CT-based workflow, for example, in structures such as the brachial plexus and chest wall invasion, which are difficult to visualize with CT alone. Furthermore, in the treatment of high-risk tumors such as ultracentral lung cancer, treatment-associated toxicity currently still outweighs its benefits. The advent of MR-Linac, an MRI-guided radiotherapy (RT) that combines MRI with a linear accelerator, could potentially address these limitations. Compared with CT-based technologies, MR-Linac could offer superior soft tissue visualization, daily adaptive capability, real-time target tracking, and an early assessment of treatment response. Clinically, it could be especially advantageous in the treatment of central/ultracentral lung cancer, early-stage lung cancer, and locally advanced lung cancer. Increasing demands for stereotactic body radiotherapy (SBRT) for lung cancer have led to MR-Linac adoption in some cancer centers. In this review, a broad overview of the latest research on imaging-guided radiotherapy (IGRT) with MR-Linac for lung cancer management is provided, and development pertaining to artificial intelligence is also highlighted. New avenues of research are also discussed.

Differential impact of asparaginase discontinuation on outcomes of children with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma.

Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL. The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable. In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60). The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.

Repeatability quantification of brain diffusion-weighted imaging for future clinical implementation at a low-field MR-linac

BackgroundLongitudinal assessments of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) during intracranial radiotherapy at magnetic resonance imaging-guided linear accelerators (MR-linacs) could enable early response assessment by tracking tumor diffusivity changes. However, DWI pulse sequences are currently unavailable in clinical practice at low-field MR-linacs. Quantifying the in vivo repeatability of ADC measurements is a crucial step towards clinical implementation of DWI sequences but has not yet been reported on for low-field MR-linacs. This study assessed ADC measurement repeatability in a phantom and in vivo at a 0.35 T MR-linac.MethodsEleven volunteers and a diffusion phantom were imaged on a 0.35 T MR-linac. Two echo-planar imaging DWI sequence variants, emphasizing high spatial resolution (“highRes”) and signal-to-noise ratio (“highSNR”), were investigated. A test–retest study with an intermediate outside-scanner-break was performed to assess repeatability in the phantom and volunteers’ brains. Mean ADCs within phantom vials, cerebrospinal fluid (CSF), and four brain tissue regions were compared to literature values. Absolute relative differences of mean ADCs in pre- and post-break scans were calculated for the diffusion phantom, and repeatability coefficients (RC) and relative RC (relRC) with 95% confidence intervals were determined for each region-of-interest (ROI) in volunteers.ResultsBoth DWI sequence variants demonstrated high repeatability, with absolute relative deviations below 1% for water, dimethyl sulfoxide, and polyethylene glycol in the diffusion phantom. RelRCs were 7% [5%, 12%] (CSF; highRes), 12% [9%, 22%] (CSF; highSNR), 9% [8%, 12%] (brain tissue ROIs; highRes), and 6% [5%, 7%] (brain tissue ROIs; highSNR), respectively. ADCs measured with the highSNR variant were consistent with literature values for volunteers, while smaller mean values were measured for the diffusion phantom. Conversely, the highRes variant underestimated ADCs compared to literature values, indicating systematic deviations.ConclusionsHigh repeatability of ADC measurements in a diffusion phantom and volunteers’ brains were measured at a low-field MR-linac. The highSNR variant outperformed the highRes variant in accuracy and repeatability, at the expense of an approximately doubled voxel volume. The observed high in vivo repeatability confirms the potential utility of DWI at low-field MR-linacs for early treatment response assessment.

A statistical framework for planning and analysing test-retest studies of repeatability.

There is an increasing number of potential quantitative biomarkers that could allow for early assessment of treatment response or disease progression. However, measurements of such biomarkers are subject to random variability. Hence, differences of a biomarker in longitudinal measurements do not necessarily represent real change but might be caused by this random measurement variability. Before utilizing a quantitative biomarker in longitudinal studies, it is therefore essential to assess the measurement repeatability. Measurement repeatability obtained from test-retest studies can be quantified by the repeatability coefficient, which is then used in the subsequent longitudinal study to determine if a measured difference represents real change or is within the range of expected random measurement variability. The quality of the point estimate of the repeatability coefficient, therefore, directly governs the assessment quality of the longitudinal study. Repeatability coefficient estimation accuracy depends on the case number in the test-retest study, but despite its pivotal role, no comprehensive framework for sample size calculation of test-retest studies exists. To address this issue, we have established such a framework, which allows for flexible sample size calculation of test-retest studies, based upon newly introduced criteria concerning assessment quality in the longitudinal study. This also permits retrospective assessment of prior test-retest studies.

Biomarkers for Hepatocellular Carcinoma: Diagnosis, Prognosis, and Treatment Response Assessment - A Systematic Review

Background: Hepatocellular carcinoma (HCC) is a significant global health concern due to its high mortality rates, highlighting the urgent need for improved diagnostic, prognostic, and therapeutic markers. Biomarkers hold potential for enhancing the early detection, prognostic evaluation, and treatment response assessment of HCC. Methods: A systematic review was conducted to evaluate the utility of various biomarkers in the diagnosis, prognosis, and prediction of treatment responses in HCC. A comprehensive search was performed in electronic databases, including PubMed, Embase, Scopus, and the Cochrane Library, up to January 2024. Studies that assessed biomarkers for HCC in terms of diagnostic accuracy, prognostic value, or their role in predicting treatment responses were included. Data extraction and quality assessment were performed for all eligible studies. Results: The search initially identified 78 articles, of which 41 met the inclusion criteria. The review evaluated biomarkers from genomic, epigenomic, transcriptomic, proteomic, and metabolomic sources. The diagnostic accuracy of these biomarkers ranged from 70% to 90%, with alpha-fetoprotein (AFP) being the most frequently studied and widely utilized biomarker. Prognostic biomarkers were found to have significant associations with overall survival and disease-free survival. Biomarkers predicting treatment responses, particularly to sorafenib and immunotherapy, exhibited varying levels of sensitivity and specificity. Conclusion: Biomarkers play a critical role in the management of HCC, offering promising potential for early diagnosis, prognostic assessment, and prediction of treatment responses. However, further validation and standardization of these biomarkers are required before they can be implemented clinically. Future research should aim to identify and integrate novel biomarkers within a multidisciplinary framework to enable personalized management of HCC.

Is System xc- a Suitable Target for Tumour Detection and Response Assessment with Imaging?

System xc- is upregulated in cancer cells and can be imaged using novel radiotracers, most commonly with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid (18F-FSPG). The aim of this review was to summarise the use of 18F-FSPG in humans, explore the benefits and limitations of 18F-FSPG, and assess the potential for further use of 18F-FSPG in cancer patients. To date, ten papers have described the use of 18F-FSPG in human cancers. These studies involved small numbers of patients (range 1-26) and assessed the use of 18F-FSPG as a general oncological diagnostic agent across different cancer types. These clinical trials were contrasting in their findings, limiting the scope of 18F-FSPG PET/CT as a purely diagnostic agent, primarily due to heterogeneity of 18F-FSPG retention both between cancer types and patients. Despite these limitations, a potential further application for 18F-FSPG is in the assessment of early treatment response and prediction of treatment resistance. Animal models of cancer have shown that changes in 18F-FSPG retention following effective therapy precede glycolytic changes, as indicated by 18F-FDG, and changes in tumour volume, as measured by CT. If these results could be replicated in human clinical trials, imaging with 18F-FSPG PET/CT would offer an exciting route towards addressing the currently unmet clinical needs of treatment resistance prediction and early imaging assessment of therapy response.

The potential role of combined shear wave elastography and superb microvascular imaging for early prediction the pathological response to neoadjuvant chemotherapy in breast cancer.

The potential role of shear wave elastography (SWE) and superb microvascular imaging (SMI) for early assessment of treatment response to neoadjuvant chemotherapy (NAC) in breast cancer remains unexplored. This study aimed to identify potential factors associated with the pathological response to NAC using these advanced ultrasound techniques. Between August 2021 and October 2022, 68 patients with breast cancer undergoing NAC were recruited. Patients underwent conventional ultrasonography, SMI, and SWE examinations at baseline and post-2nd cycle of NAC. Maximum tumor diameter (Dmax), maximum elastic value (Emax), peak systolic velocity (PSV), and resistance index (RI) at baseline and the rate of change of these parameters post-2nd cycle were recorded. After chemotherapy, all patients underwent surgery. Using the Miller-Payne's grade, patients were categorized into response (grades 3, 4, or 5) and non-response (grades 1 or 2) group. Parameters were compared using t-tests at baseline and post-2nd cycle. Binary logistic regression analysis was used to identify variables and their odds ratios (ORs) related to responses and a prediction model was established. ROC curves were drawn to analyze the efficacy of each parameter and their combined model for early NAC response prediction. Among the 68 patients, 15(22.06%) were categorized into the non-response group, whereas 53(77.94%) were categorized into the response group. At baseline, no significant differences were observed between the two groups (p>0.05). Post-2nd cycle of NAC, rates of change of Emax, PSV and RI (ΔEmax, ΔPSV and ΔRI) were higher in responders than non-responders (p<0.05). Binary logistic regression analysis revealed that ΔEmax (OR 0.797 95% CI, 0.683-0.929), ΔPSV (OR 0.926, 95%CI, 0.860-0.998), and ΔRI (OR 0.841, 95%CI, 0.736-0.960) were independently associated with the pathological response of breast cancer after NAC. The combined prediction model exhibited higher accuracy in the early evaluation of the response to NAC (AUC 0.945, 95%CI, 0.873-1.000). SWE and SMI techniques enable early identification of tumor characteristics associated with the pathological response to NAC and may be potentially indicative of an effective response. These factors may eventually be used for the early assessment of NAC treatment for clinical management.

Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.

The highly aggressive nature of glioblastoma carries a dismal prognosis despite aggressive multimodal therapy. Alternative treatment regimens, such as immunotherapies, are known to intensify the inflammatory response in the treatment field. Follow-up imaging in these scenarios often mimics disease progression on conventional MRI, making accurate evaluation extremely challenging. To this end, revised criteria for assessment of treatment response in high-grade gliomas were successfully proposed by the RANO Working Group to distinguish pseudoprogression from true progression, with intrinsic constraints related to the postcontrast T1-weighted MRI sequence. To address these existing limitations, our group proposes a more objective and quantifiable "treatment agnostic" model, integrating into the RANO criteria advanced multimodal neuroimaging techniques, such as diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI), dynamic contrast enhanced (DCE)-MRI, MR spectroscopy, and amino acid-based positron emission tomography (PET) imaging tracers, along with artificial intelligence (AI) tools (radiomics, radiogenomics, and radiopathomics) and molecular information to address this complex issue of treatment-related changes versus tumor progression in "real-time", particularly in the early posttreatment window. Our perspective delineates the potential of incorporating multimodal neuroimaging techniques to improve consistency and automation for the assessment of early treatment response in neuro-oncology.

Abstract 5573: Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with non-small cell lung cancer (NSCLC): A real-world (RW) analysis incorporating baseline ctDNA level and molecular response

Abstract Background: Data suggests that changes in ctDNA quantity correlate with response to therapy in patients with advanced solid malignancies. Furthermore, absolute baseline (pre-treatment) ctDNA level has been shown to be associated with patient prognosis. However, there is little information on how these variables can be combined to better interpret ctDNA results and enhance predictive power of treatment response. Here, we develop a model that incorporates the effects of both baseline ctDNA level as well as linear and nonlinear relative ctDNA change. Methods: We queried the Guardant INFORM database, which comprises aggregated commercial payer health claims and de-identified records from over 225,000 individuals with comprehensive ctDNA testing via Guardant360 (G360). From September 2018-March 2022, patients with NSCLC treated with immune checkpoint inhibitors (ICI) (monotherapy or in combination) who received a ctDNA test within 15 weeks prior to treatment initiation and a second test 3-15 weeks after treatment initiation were retrospectively evaluated. Cox proportional hazards (CPH) were used for RW time to next treatment (TTNT) and time to treatment discontinuation (TTD) analyses. Gender, age, line of therapy (LOT) and comorbidities were included as covariates. ctDNA change from baseline to on-treatment (using the Guardant360 Response algorithm) was modeled as a continuous variable using a regularized cubic spline and baseline ctDNA level (using maximum variant allele fraction) was modeled as an interaction effect. Model validation and calibration were carried out via bootstrap resampling, ANOVA was used for multiple design hypothesis testing. Results: 82 patients met the study criteria. 31 patients with large ctDNA decrease (e.g. &amp;gt=50% decrease), also known as molecular responders, had significantly longer TTNT and TTD compared to other patients, regardless of baseline ctDNA level. 51 patients with small ctDNA decrease or ctDNA increase showed ctDNA level dependent trends in TTNT and TTD, with decreased risk for shorter TTNT and TTD for lower baseline ctDNA level. We found that the interaction between baseline ctDNA level and ctDNA change was significant (TTNT: p = .0069, TTD: p = .0236), and that ctDNA change had a nonlinear effect on both TTNT and TTD (TTNT: p = .0014, TTD: p = .0349). TTNT (TTD) bootstrap-adjusted concordance indices were 0.69 (0.65) and hazard ratios [95% CI] were 5.36 [1.79, 16.10] (2.37 [1.13, 4.98]). Conclusions: These data demonstrate a statistically significant interaction between baseline ctDNA level and treatment-induced ctDNA level change in association with RW clinical outcomes. This facilitates the development of patient-based models incorporating baseline ctDNA level with ctDNA molecular response for association with RW clinical outcomes. Citation Format: Sean Gordon, Bojan Losic, Katie Quinn, Kyle Chang, Jiemin Liao, Han-Yu Chuang. Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with non-small cell lung cancer (NSCLC): A real-world (RW) analysis incorporating baseline ctDNA level and molecular response. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5573.

Ventilation and perfusion MRI at a 0.35 T MR-Linac: feasibility and reproducibility study

BackgroundHybrid devices that combine radiation therapy and MR-imaging have been introduced in the clinical routine for the treatment of lung cancer. This opened up not only possibilities in terms of accurate tumor tracking, dose delivery and adapted treatment planning, but also functional lung imaging. The aim of this study was to show the feasibility of Non-uniform Fourier Decomposition (NuFD) MRI at a 0.35 T MR-Linac as a potential treatment response assessment tool, and propose two signal normalization strategies for enhancing the reproducibility of the results.MethodsTen healthy volunteers (median age 28 ± 8 years, five female, five male) were repeatedly scanned at a 0.35 T MR-Linac using an optimized 2D+t balanced steady-state free precession (bSSFP) sequence for two coronal slice positions. Image series were acquired in normal free breathing with breaks inside and outside the scanner as well as deep and shallow breathing. Ventilation- and perfusion-weighted maps were generated for each image series using NuFD. For intra-volunteer ventilation map reproducibility, a normalization factor was defined based on the linear correlation of the ventilation signal and diaphragm position of each scan as well as the diaphragm motion amplitude of a reference scan. This allowed for the correction of signal dependency on the diaphragm motion amplitude, which varies with breathing patterns. The second strategy, which can be used for ventilation and perfusion, eliminates the dependency on the signal amplitude by normalizing the ventilation/perfusion maps with the average ventilation/perfusion signal within a selected region-of-interest (ROI). The position and size dependency of this ROI was analyzed. To evaluate the performance of both approaches, the normalized ventilation/perfusion-weighted maps were compared and the deviation of the mean ventilation/perfusion signal from the reference was calculated for each scan. Wilcoxon signed-rank tests were performed to test whether the normalization methods can significantly improve the reproducibility of the ventilation/perfusion maps.ResultsThe ventilation- and perfusion-weighted maps generated with the NuFD algorithm demonstrated a mostly homogenous distribution of signal intensity as expected for healthy volunteers regardless of the breathing maneuver and slice position. Evaluation of the ROI’s size and position dependency showed small differences in the performance. Applying both normalization strategies improved the reproducibility of the ventilation by reducing the median deviation of all scans to 9.1%, 5.7% and 8.6% for the diaphragm-based, the best and worst performing ROI-based normalization, respectively, compared to 29.5% for the non-normalized scans. The significance of this improvement was confirmed by the Wilcoxon signed rank test with p, <, 0.01 at alpha , =, 0.05. A comparison of the techniques against each other revealed a significant difference in the performance between best ROI-based normalization and worst ROI (p, =, 0.01) and between best ROI-based normalization and scaling factor (p, =, 0.02), but not between scaling factor and worst ROI (p, =, 0.71). Using the ROI-based approach for the perfusion-maps, the uncorrected deviation of 10.2% was reduced to 5.3%, which was shown to be significant (p, <, 0.01).ConclusionsUsing NuFD for non-contrast enhanced functional lung MRI at a 0.35 T MR-Linac is feasible and produces plausible ventilation- and perfusion-weighted maps for volunteers without history of chronic pulmonary diseases utilizing different breathing patterns. The reproducibility of the results in repeated scans significantly benefits from the introduction of the two normalization strategies, making NuFD a potential candidate for fast and robust early treatment response assessment of lung cancer patients during MR-guided radiotherapy.

Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with advanced colorectal cancer (aCRC): A real-world (RW) analysis.

246 Background: Data suggests that changes in ctDNA quantity correlate with response to therapy in patients with advanced solid malignancies. However, there is little consistency on how to calculate and interpret such changes. Here, we apply a clinically-validated molecular response algorithm to a RW cohort of patients with aCRC to further evaluate its ability to assess treatment outcomes. Methods: We queried the Guardant INFORM database, which comprises aggregated commercial payer health claims and de-identified records from patients with comprehensive ctDNA testing via Guardant360 (G360) from September 2018-March 2022. Patients with aCRC who received G360 within 15 weeks prior to new treatment initiation (any line of therapy) and a second test 3-15 weeks after treatment initiation were retrospectively evaluated using the G360 Response algorithm. Cox proportional hazards (CPH) were used for RW time to next treatment (TTNT), time to treatment discontinuation (TTD), and overall survival (rwOS) analyses. Patients categorized as molecular responders had a &gt;50% decrease in mean variant allele fraction (VAF) ratio from pre-treatment to on-treatment. Gender, age, line of therapy (LOT) and comorbidities were included as covariates. Median TTNT, TTD, and rwOS were calculated by Kaplan Meier. Results: Of 185 aCRC patients with eligible MR results, 65% received chemotherapy +/- VEGF, 21% received regimens containing anti-EGFR monoclonal antibodies, and 14% received other therapies. 43% of aCRC patients were classified as molecular responders, 42% were non-responders, and 15% were not evaluable by the algorithm due to no/low ctDNA at one or both timepoints. 16% of patients cleared their ctDNA on treatment (i.e., ctDNA became undetectable). Molecular responders had significantly longer TTNT (median 10.1 months vs 6.1 months; HR p &lt; 0.005), TTD (median 5.2 Months vs 3.9 months, HR p=0.041), and rwOS (not reached vs 17.8 months, HR p=0.017). Conclusions: Patients with aCRC classified as molecular responders, as calculated by this algorithm, had prolonged time on treatment and overall survival. Compared to tumor markers, ctDNA has a short half-life, which can allow for early response assessment, as shown by our study. These findings are relevant for clinical care, with future potential to allow for adaptive clinical trial design. [Table: see text]

The Emerging Role of Circular RNA Homeodomain Interacting Protein Kinase 3 and Circular RNA 0046367 through Wnt/Beta-Catenin Pathway on the Pathogenesis of Nonalcoholic Steatohepatitis in Egyptian Patients.

Non-alcoholic fatty liver disease is a major problem worldwide that needs non-invasive biomarkers for early diagnosis and treatment response assessment. We aimed to assess the correlation between circRNA-HIPK3 and miRNA-29a expression and its role as miRNA-29a sponge, as well as the correlation between circRNA-0046367 and miRNA-34a expression and its role as miRNA-34a sponge and their effect on regulation of the Wnt/β catenin pathway, which may provide a new target for treatment of non-alcoholic steatohepatitis. the research was performed on 110 participants: group (I): fifty-five healthy donors served as controls and group (II): fifty-five patients with fatty liver pattern on abdominal ultrasound. Lipid profile and liver functions were assessed. RT-PCR was performed to assess the RNAs: circRNA-HIPK3, circRNA-0046367, miRNA-29a, miRNA-34a and Wnt mRNA gene expression. ELISA was performed to determine β-catenin protein levels. miRNA-34a and circRNA-HIPK3 expression were significantly greater, while miRNA-29a and circRNA-0046367 expression were significantly less, in patients than in controls. Wnt/β-catenin regulated by miRNA-29a and miRNA-34a showed a significant decrease that leads to its abnormal effect on lipid metabolism. our results imply that miRNA-29a can be investigated as a target for circRNA-HIPK3, while miRNA-34a can be investigated as a target for circRNA-0046367, and that circRNA-HIPK3 and circRNA-0046367 may have emerging roles that can affect the pathogenesis of nonalcoholic steatohepatitis through the Wnt/β-catenin pathway and thus be used as therapeutic targets for the disease.

Monitoring Plasma Cells and Clonal Emergence through Genome Sequencing of Circulating Tumor Cells for Minimally Invasive Molecular Characterization of Multiple Myeloma

Introduction Multiple Myeloma (MM) develops from well-defined precursor stages, however, bone marrow (BM) biopsy limits screening and monitoring strategies for patients. Precursor conditions are incidentally diagnosed and require invasive BM biopsies for complete characterization, highlighting the need for improved early detection methods. Minimally invasive blood biopsies to measure circulating tumor cells (CTCs) as markers of MM disease development are a promising solution to this need. CTCs are amenable to repeatable enrichment, enumeration, and molecular characterization for early detection, real-time monitoring, and assessment of treatment response and clonal evolution. We present our novel method, MinimuMM-seq, for enumeration and whole genome sequencing (WGS) of CTCs that enables genomic profiling and WGS-based cytogenetic analyses from enriched liquid biopsy samples. CTCs were enumerated from 241 patients, with 50 patients undergoing WGS that revealed that CTCs were of tumor origin and could faithfully match BM sequencing results, detecting 100% of clinically reported events. Longitudinal sampling of CTCs tracked clonal dynamics over time and detected the emergence of high-risk genetic subclones. Methods Peripheral blood from 241 precursor patients (82 MGUS, 159 SMM) from the PCROWD observational study (IRB #14-174) was collected in CellRescuepreservation tubes and processed on the CellSearch® system (Menarini Silicon Biosystems) using the Circulating Multiple Myeloma Cell (CMMC) assay kit with 4mL of blood. Enrichment and enumeration of CTCs was based on CD138+38+CD45-19- immunophenotype. Nucleated cells were identified using DAPI staining. In 50 patients, CTCs were sorted for library construction, quantification, and WGS on Illumina NovaSeq6000. Mutation analyses were performed with the cancer genome analysis pipelines of the Broad Institute. Tumor phylogeny was reconstructed with the PhylogicNDT algorithm in patients with matched CTC and BM sequencing (n=27), as well as serial CTCs derived from PB only (n=10). Results CTCs were detected in 75% of MGUS and 86% of SMM patients enrolled in the study, with a median count of 2.5 (range 0 to 1328) and 13 CTCs (range 0 to 43836), respectively. An increased number of CTCs correlated with progressive disease staging from MGUS, to low, intermediate and high-risk SMM defined by IMWG 2/20/20 risk stratification. MinimuMM-seq yielded a median tumor purity of 98% (range 45 to 100%) in CTCs. Our method detected 100% of clinically reported BM biopsy events by fluorescence in situ hybridization (FISH), including translocations and copy number abnormalities. It could replace molecular cytogenetics for diagnostic yield and risk classification in patients with paired BM and CTC samples (n=27). Additional diagnostic yield compared to clinical BM FISH was found in 88% of patients. Our method detected novel events and unknown/cryptic translocations, such as t(8;14) and t(14;20), and MM driver mutations, including KRAS, NRAS, and TP53. As peripheral blood continuously circulates, liquid biopsy sampling may be affected by the phenomena of spatial and temporal heterogeneity in CTC burden. In 10 patients longitudinal CTC sampling was carried out to monitor clonal evolution of disease. We validated stability of the major clone and described shifting dynamics of subclones over time with the emergence of potentially high-risk CTC subclones. Expansion of subclones harboring MM events (such as 13q deletion) and driver mutations (such as KRAS and DIS3) was observed, indicating their potential to confer selective advantage for clonal fitness and independence for circulation. Anecdotally, one SMM patient received early interventional treatment, and we identified the emergence of the new fittest clone (bearing KRAS p.G12S) before any potential resistance was clinically observed. Conclusion We have established an approach for WGS of CTCs that can replace standard molecular cytogenetics. CTCs harbored the same pathognomonic MM abnormalities as BM plasma cells. We tracked clonal dynamics over time and detected the emergence of high-risk CTC subclones. Our findings show that capture and genomic profiling of CTCs could be a robust surrogate for BM biopsy, allowing minimally invasive detection and monitoring of disease and unlocking the clinical potential of liquid biopsies for MM diagnostics.

NIMG-62. RADIOMIC-BASED PROGRESSION-FREE SURVIVAL STRATIFICATION OF PEDIATRIC LOW-GRADE GLIOMA IS ASSOCIATED WITH MOLECULAR ALTERATIONS

Abstract Pediatric low-grade glioma (pLGG) encompasses a variety of tumor subtypes with heterogeneous treatment response and relatively long progression-free survival (PFS). Radiomics may serve as a non-invasive and in-vivo tool for early prediction of PFS as a surrogate marker for treatment response and to objectively gauge the efficacy of novel treatment strategies. Here, we present a multivariate model based on radiomic features and clinical variables for risk stratification of pLGGs in terms of PFS and seek associations of the predicted risk groups and mutations in key molecular markers using data from PedCBioportal. Pre-operative multi-parametric MRI scans (T1-pre, T1-post, T2, T2-FLAIR) of 129 patients with newly diagnosed pLGG (median age, 7.76, range, 0.35-19.58 years; median PFS, 28.5, range, 1.1-124.8 months) were collected and quantitative radiomic features (n = 881) were extracted. A multivariate Cox proportional hazard’s (Cox-PH) regression model was fitted based on clinical (age, sex, and extent of tumor resection) and radiomic variables using 4-fold cross-validation. A subset of radiomic features (n = 27) that were most predictive of PFS was selected by applying Elastic Net regularization penalty during Cox-PH model fitting. High-, medium- and low-risk groups were determined based on model predictions. Cox-PH modeling showed excellent performance for prediction of PFS as suggested by the concordance index of 0.78. Radiogenomic assessment (data available in 94/129 patients) showed more enrichment of mutations in NF1 and RB1 genes in the high-risk group, as compared to the low- and medium-risk groups. We showed the potential value of radiomics in providing upfront prediction of PFS, which may further be used as an added treatment arm for early assessment of treatment response of the pLGG patients enrolled in the clinical trials. In the next step of this work, we will expand the cohort and cross-validate these results in an external cohort.

Update on Disease-Specific Biomarkers in Transthyretin Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy and an increasingly recognized cause of morbidity and mortality. There remains substantial delay between initial symptoms and diagnosis. With the recent emergence of various targeted therapies proven to reduce morbidity and mortality, there is an imperative to diagnose subclinical disease. Biomarkers may be well-suited for this role. Conventional markers of heart failure, such as natriuretic peptides and cardiac troponins, and estimated glomerular filtration rate are associated with risk in ATTR-CM. Circulating transthyretin (TTR) levels parallel TTR kinetic stability, correlate with disease severity, and may serve as indirect markers of ATTR-CM disease activity and response to targeted treatment. There is also growing evidence for the correlation of TTR to retinol-binding protein 4, a biomarker which independently associates with this disease. The rate-limiting step for ATTR pathogenesis is dissociation of the TTR homotetramer, which may be quantified using subunit exchange to allow for early risk assessment, prognostication, and assessment of treatment response. The protein species that result from the dissociation and misfolding of TTR are known as nonnative transthyretin (NNTTR). NNTTR is quantifiable via peptide probes and is a specific biomarker whose reduction is positively correlated with improvement in neuropathic ATTR amyloidosis. Neurofilament light chain (NfL) is released into the blood after axonal damage and correlates with neuropathic ATTR amyloidosis, but its clinical use in ATTR-CM is uncertain. Conventional markers of heart failure, transthyretin, retinol-binding protein 4, transthyretin kinetic stability, nonnative transthyretin, peptide probes, and neurofilament light chain have potential as biomarkers to enable early, subclinical diagnosis in patients with transthyretin cardiac amyloidosis.

IMG-16. Non-invasive metabolic imaging of response to therapy in diffuse midline gliomas

Abstract Diffuse midline gliomas (DMGs) are universally lethal pediatric tumors that are defined by the presence of histone H3K27 alterations. The infiltrative nature and anatomical location of these tumors prohibit surgical resection. Radiotherapy, which is standard of care, does not significantly enhance long-term outcome. Novel therapies are sorely needed for DMG patients. Imipridone drugs ONC201 and ONC206 have demonstrated anti-tumor activity in preclinical cancer models, including DMGs and have shown promise in pilot studies in DMG patients. Successful clinical deployment of imipridones requires the identification of companion imaging biomarkers that report on response to therapy. Magnetic resonance spectroscopy (MRS) is a safe, non-radioactive, non-invasive method of imaging metabolism in vivo. 1H-MRS assesses steady-state metabolite levels and is used in clinics. 2H-MRS following administration of 2H-labeled substrates is a novel, clinically translatable method of imaging metabolic pathway activity. Our results indicate that treatment of SF7761 DMG cells with ONC206 causes a significant reduction in 1H-MRS-detectable lactate, glutamate, glutathione and phosphocholine, pointing to inhibition of glycolysis, oxidative phosphorylation, redox and phosphatidylcholine biosynthesis respectively. Examination of [6,6’-2H]-glucose metabolism using 2H-MRS indicates that lactate production from [6,6’-2H]-glucose is significantly reduced in ONC206-treated SF7761 cells relative to controls. We then investigated the effect of ONC206 on mice bearing orthotopic SF8628 DMG tumors. At day 7 following the treatment onset, at a timepoint when no change in tumor volume can be observed by anatomical imaging, in vivo1H-MRS-detectable lactate and total choline are reduced relative to day 0. Collectively, our studies indicate that imipridones induce alterations in DMG metabolism that can be leveraged for non-invasive 1H- and 2H-MRS-based imaging of response to therapy. By providing clinicians with an early readout of treatment response prior to anatomical changes, our biomarkers will enable early assessment of treatment response and, thereby, clinical translation of these promising therapeutics.

Abstract No. 265 Differentiation of irreversible electroporation regions through interpretation of MRI texture

Irreversible electroporation (IRE) ablation has demonstrated promising outcomes for the treatment of hepatocellular carcinoma (HCC) patients who are not suitable for curative treatments such as surgical resection or liver transplantation. Immediate differentiation of IRE ablation regions holds great importance for the early assessment of treatment response and enables potential adjustments. Earlier studies have demonstrated that IRE ablation regions can be identified via transcatheter intra-arterial perfusion (TRIP) MRI. Yet the availability of the centers offering TRIP MRI capabilities is limited. In this study, we have investigated the potential benefits of radiomics analysis to identify IRE ablative regions using T1w MRI data.