Evaluation Of Treatment Response Research Articles

NEUROFILAMENTS AS A POTENTIAL BIOMARKER IN PATIENTS WITH MULTIPLE SCLEROSIS: A REVIEW OF LITERATURE

Background: Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) characterized by demyelination, axonal damage and loss of neurons. Its growing incidence has determined the need for more intensive research towards effective models for managing disease progression and evaluation of treatment response. Finding clinically relevant biomarkers has been a significant challenge. Purpose: This review aims to summarize the findings from current relevant literature sources on neurofilaments as a potential biomarker of diagnostic and prognostic value in patients with MS. Results: Recently, neurofilaments have been identified as the most promising and informative biomarkers of axonal damage and loss. Neurofilament concentration demonstrates a strong association with the disease course, activity and progression, disability accumulation and response to disease-modifying treatment. A significant correlation with future relapse rates, symptom worsening and risk of conversion from clinically isolated syndrome (CIS) to definite MS has also been established. Several MS therapies have demonstrated a substantial reduction in neurofilament levels upon treatment initiation. Conclusion: The results available from real-world studies and clinical trials regarding neurofilaments as a reliable predictor and indicator of MS disease course are encouraging. They have consistently proven to be of utility if integrated into the diagnostic and therapeutic algorithm of MS patients. This review encompasses undeniable data confirming the considerable potential of neurofilaments for becoming the first globally verified biomarker for MS. The accessibility, safety, low cost and possibility for serial evaluation make the neurofilaments the perfect component to be implemented in routine clinical tests for MS.

Treatment benefit of electrochemotherapy for superficial squamous cell carcinoma: a systematic review and single-arm meta-analysis.

Treating aggressive superficial squamous cell carcinoma (SCC) poses challenges due to invasiveness. Palliative care is recommended for inoperable cases with extensive tumors near vital organs, risking disfigurement or functional impairment. Electrochemotherapy (ECT) is an emerging cutaneous tumor treatment, but its efficacy against superficial SCC remains uncertain. This study conducts a systematic review and single-arm meta-analysis to evaluate ECT's effectiveness against superficial SCC and provide current evidence for clinical practice. Embase, PubMed and Cochrane Library were searched for studies up to May 2023. The random effects model analyzed complete response (CR) and partial response (PR), with subgroup assessment based on drug dosage, treatment response evaluation, tumor size, primary/recurrent status, and tumor location. Ten studies involving 162 patients and 208 tumors were included. Pooled CR and PR rates for ECT-treated superficial SCC were 66.5% (95% CI 48.4%-82.5%; I2 = 84%) and 20.3% (95% CI 10.5%-32.3%; I2 = 70%), respectively. Subgroup analysis indicated ECT's superiority in treating primary tumors (PR: 70%, CR: 30%) and tumors ≤ 3cm (PR: 81.3%, CR: 10.1%) compared to recurrent tumors (PR: 56.7%, CR: 36.5%) and tumors > 3cm (PR: 45.2%, CR: 34.4%). This single-arm meta-analysis confirms ECT's efficacy against superficial SCC, especially in primary tumors and those ≤ 3cm in diameter. The study highlights the impact of tumor location and response evaluation on ECT's benefits, warranting further investigation through additional research.

The prognostic role of 18F-FDG PET/CT-based response evaluation in children with stage 4 neuroblastoma.

To evaluate the association between metabolic response on 18F-FDG PET/CT and long-term survival in children with neuroblastoma (NB). A total of 39 consecutive children with newly diagnosed stage 4 NB undergoing both 18F-FDG PET/CT imaging at baseline and after chemotherapy were retrospectively analyzed. The associations between metabolic parameters, including SUVmax of the lesion with the most intense 18F-FDG uptake at baseline (SUVb), after chemotherapy (SUVe), and the percentage change between SUVb and SUVe, and long-term survival were evaluated. With a median follow-up of 56 months, 22 patients who had achieved complete resolution on PET (no residual 18F-FDG uptake higher than the surrounding backgrounds) after chemotherapy had superior 5-year overall survival (OS) (73.6% vs. 39.0%, p = 0.044). SUVb > 6.9 indicated significantly poorer 5-year event-free survival (EFS) (12.5% vs. 59.3%, p = 0.005), as did SUVe > 1.2 (18.8% vs. 41.7%, p = 0.041). Children with SUVe > 1.2 had shorter 5-year OS (33.9% vs. 75.0%, p = 0.018). Multivariate analysis identified SUVe > 1.2 as an independent predictor for both EFS [hazard ratio (HR), 3.479, 95% CI, 1.381-8.761, p = 0.008] and OS (HR, 6.948, 95% CI, 1.663-29.025, p = 0.008), while SUVb > 6.9 was a predictor for EFS (HR, 2.889, 95% CI, 1.064-7.842, p = 0.037). Among 11 children with both SUVb > 6.9 and SUVe > 1.2, all experienced disease progression or relapse within 2 years since diagnosis. 18F-FDG PET/CT could be of useful to evaluate treatment response in children with stage 4 NB. 18F-FDG PET/CT after chemotherapy exhibits prognostic significance in neuroblastoma and holds potential as an alternative imaging modality for response evaluation, especially in cases with metaiodobenzylguanidine-nonavid or persistent avid disease. The prognostic value of chemotherapy response on 18F-FDG PET/CT in advanced neuroblastoma is unknown. Higher 18F-FDG uptake after chemotherapy was associated with worse long-term event-free survival and overall survival. 18F-FDG PET/CT after chemotherapy holds prognostic significance in children with stage 4 neuroblastoma.

Abstract PS05-04: [89Zr]Trastuzumab-PET/MRI to Characterize HER2+ Breast Cancer: A Quantitative Approach on Tumor Heterogeneity

Abstract Introduction: Molecular imaging of human epidermal receptor 2 (HER2) aims to overcome limitations of traditional HER2 assessment through biopsy, including invasiveness and inability to detect intra and inter-tumoral spatial heterogeneity. Prior human studies suggest that [89Zr]Trastuzumab-positron emission tomography (PET) imaging can effectively differentiate HER2 lesions (Dehdashti et al, Breast Cancer Res. Treat. 2018). Commonly, CT complements PET for anatomical reference, however, integrating MRI enables the sensitivity of soft-tissue contrast required for anatomic and morphological breast imaging and can provide for quantitative multiparametric characterization. Diffusion weighted-MRI (DW-MRI) contributes to tumor characterization by assessing intratumoral cellularity via the apparent diffusion coefficient (ADC), and can be combined with molecular expression from HER2-PET. We present preliminary results in 13 patients with HER2 PET/MRI to define tumor and normal tissue imaging metrics. Methods: A phase II clinical trial assessing the feasibility of [89Zr]trastuzumab-PET with simultaneous quantitative DW-MRI to enhance understanding of tumor heterogeneity in patients with HER2-positive metastatic breast cancer. 13 patients (ages 40-70; mean 60) with HER2-positive breast cancer based on prior biopsy underwent whole-body [89Zr]trastuzumab-PET/MR imaging (5 ± 1 days post-injection of radiopharmaceutical) during the course of HER2-directed therapy. Normal organ and tumor regions of interest (ROI) were identified on concurrently acquired whole-body T1-weighted MRI for ADC (cellularity) and standardized uptake value (SUV, PET uptake) mean quantification. Tumor presence was confirmed via bone scintigraphy, FDG-PET/CT, or contrast-enhanced MRI. Non-parametric T-tests compared lesions to normal organs. Lesions greater than 30 mm in diameter underwent multiparametric intratumoral habitat analysis. Using the median HER2 values, tumors were evaluated for heterogeneity of high and low HER2 expression in conjunction with ADC. Long-term treatment response evaluation is ongoing. Results: Mean [89Zr]trastuzumab uptake, SUV, and ADC values for normal tissue were summarized in Table 1. All tumors demonstrated higher overall uptake of [89Zr]trastuzumab (bone: p=0.019, brain: p=0.014, breast: p=0.069, juxtapulmonary: p=0.026) and increased ADCmean values (bone: p=0.002, brain: p=0.5, breast: p=0.03, juxtapulmonary: p=0.037), in comparison to matched normal organs. Notably, one of five patients with a breast lesion, who completely responded to HER2 targeted therapy, exhibited the highest breast lesion SUVmean. Brain and lymph node lesions demonstrated intratumoral heterogeneity of HER2 expression. Conclusion: Our study demonstrates the potential value of quantitative MRI along with molecular imaging to characterize metastatic HER2+ breast cancer and evaluate intratumoral heterogeneity. We underscore the importance of standardizing processing techniques and contribute to this effort by summarizing [89Zr]trastuzumab uptake and cellularity values of normal physiological uptake. Higher SUVmean and ADC mean values observed in lesions, compared to normal tissue, highlight their potential roles in intratumoral classification. While studies have shown the utility of [89 Zr]trastuzumab-PET/CT, our findings demonstrate that integrated DW-MRI can aid in tumor classification. Table 1: Physiological 89Zr-Trastuzumab Uptake (SUVmean) and Apparent Diffusion Coefficient (ADCmean) in Healthy Tissues Citation Format: Ameer Mansur, Moozhan Nikpanah, Johnathan McConathy, Erica Stringer-Reasor, Gabrielle Rocque, Ahmed Elkhanany, Katia Khoury, Nusrat Jahan, Suzanne Lapi, Anna Sorace. [89Zr]Trastuzumab-PET/MRI to Characterize HER2+ Breast Cancer: A Quantitative Approach on Tumor Heterogeneity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-04.

Central sensitization significantly deteriorates functionality and the interpretation of self-reported disease activity in primary Sjögren's syndrome.

Central sensitization has a major role in health-related parameters in musculoskeletal conditions. There is still a lack of understanding regarding the impact of central sensitization on the interpretation of disease activity and functional disability in primary Sjögren's syndrome (pSS). The Central Sensitization Inventory (CSI) was used to screen for central sensitization. Disease-related parameters, including objective tests, medication use, the EULAR SS Patient Reported Index (ESSPRI), and the EULAR SS Disease Activity Index (ESSDAI), were assessed. Functionality, quality of life, sleep, and mental health were evaluated by the Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Jenkins Sleep Evaluation Scale (JSS), and Hospital Anxiety and Depression Scale (HADS), respectively. The effect of central sensitization on functionality and disease activity measures was assessed by regression analyses. The frequency of central sensitization was 65% in patients with pSS (n = 60). Patients with central sensitization had higher HAQ-DI, ESSPRI, HADS, and JSS and lower SF-36 subdomain scores (p < 0.05 for all). A significant positive correlation was observed between the CSI scoreand theESSPRI, JSS, HAQ-DI, and HADS scores (Spearman's rho ranging from 0.342 to 0.739). The multiple regression analysis indicated that CSI was independently associated with HAQ-DI (adjusted R2 = 0.19, B = 0.01) and ESSPRI (adjusted R2 = 0.45, B = 0.08) (p < 0.001 for all). This study confirms that central sensitization has a major impact on functionality and the interpretation of self-reported disease activity in pSS. When devising strategies for the management of patients with pSS, it is crucial to consider these close relationships. Key Points • The frequency of central sensitization accompanying primary Sjögren's syndrome is considerable. • Central sensitization was independently associated with functionality and self-reported disease activity assessment. • This close association leads to challenges in functionality, evaluating treatment response, and planning or switching between therapies in primary Sjögren's syndrome.

Abnormalities in subcortical function and their treatment response in Wilson’s disease

Extensive neuroimaging abnormalities in subcortical regions build the pathophysiological basis of Wilson’s disease (WD). Yet, subcortical topographic organization fails to articulate, leaving a huge gap in understanding the neural mechanism of WD. Thus, how functional abnormalities of WD subcortical regions influence complex clinical symptoms and response to treatment remain unknown. Using resting-state functional MRI data from 232 participants (including 130 WD patients and 102 healthy controls), we applied a connectivity-based parcellation technique to develop a subcortical atlas for WD. The atlas was further used to investigate abnormalities in subcortical function (ASF) by exploring intrasubcortical functional connectivity (FC) and topographic organization of cortico-subcortical FC. We further used support vector machine (SVM) to integrate these functional abnormalities into the ASF score, which serves as a biomarker for characterizing individual subcortical dysfunction for WD. Finally, the baseline ASF score and one-year treatment data of the follow-up WD patients were used to assess treatment response. A group set of subcortical parcellations was evaluated, in which 26 bilateral regions well recapitulated the anatomical nuclei of the subcortical areas of WD. The results of cortico-subcortical FC and intrasubcortical FC reveal that dysfunction of the somatomotor networks-lenticular nucleus-thalamic pathways is involved in complex symptoms of WD. The ASF score was able to characterize disease progression and was significantly associated with treatment response of WD. Our findings provide a comprehensive elaboration of functional abnormalities of WD subcortical regions and reveal their association with clinical presentations, improving our understanding of the functional neural underpinnings in WD. Furthermore, abnormalities in subcortical function could serve as a potential biomarker for understanding the disease progression and evaluating treatment response of WD.

P134 Developing a potential composite pharmacodynamic serum marker of skin severity in systemic sclerosis

Abstract Background/Aims Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients. Methods COMP (DCMP0, R&amp;D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n = 33) and MODERNISE (n = 37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n = 36). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA results. Results Serum concentration positively correlated with mRSS for COMP and TNC, particularly in early dcSSc patients (COMP, r = 0.10, p = 0.05; TNC, r = 0.13, p = 0.03). No significant correlation was observed for COL4A1 (r = 0.03, p = 0.34). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Confirming previous results multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins (r = 0.15, p = 0.009). mRSS = 9.896 + 0.01719(COMP) - 0.006481(COL4A1) - 0.002318(TNC). Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p = 0.16), COL4A1 (p = 0.32), TNC (p = 0.15) and a lower composite biomarker score (p = 0.22) with increasing treatment duration in early dcSSc cases (Table 1). Conclusion Our results confirm this novel three-protein composite serum marker predicts skin severity in SSc better than each individual analyte. After further validation, this blood-based approach may help evaluate treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker. Disclosure E. Roblin: None. K.E.N. Clark: None. C. Beesley: None. V.H. Ong: None. C.P. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

A novel immunogenic cell death-related classification indicates the immune landscape and predicts clinical outcome and treatment response in acute myeloid leukemia

BackgroundImmunogenic cell death (ICD) is closely related to anti-tumor therapy and regulates the tumor microenvironment (TME). This study aims to explore the molecular characteristics of ICD in acute myeloid leukemia (AML) and to analyze the value of ICD-related biomarkers in TME indication, prognosis prediction, and treatment response evaluation in AML.MethodsSingle-sample gene set enrichment analysis was used to calculate the ICD score. LASSO regression was used to construct a prognostic risk score model. We also analyzed differences in clinical characteristics, immune landscape, immunotherapy response, and chemotherapy sensitivity between high-risk and low-risk patients.ResultsThis study identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune landscape between different ICD subtypes. Subsequently, a novel ICD-related prognostic risk score model was developed, which accurately predicted the prognosis of AML patients and was validated in nine AML cohorts. Moreover, there were significant correlations between risk scores and clinicopathological factors, somatic mutations, TME characteristics, immune cell infiltration, immunotherapy response, and chemosensitivity. We further validated the model gene expression in a clinically real-world cohort.ConclusionsThe novel ICD-related signatures identified and validated by us can serve as promising biomarkers for predicting clinical outcomes, chemotherapy sensitivity, and immunotherapy response in AML patients, guiding the establishment of personalized and accurate treatment strategies for AML.Graphical

Measurement of metabolite levels and treatment-induced changes in hepatic metastases of gastro-esophageal cancer using 7-T phosphorus magnetic resonance spectroscopic imaging.

Methods for early treatment response evaluation to systemic therapy of liver metastases are lacking. Tumor tissue often exhibits an increased ratio of phosphomonoesters to phosphodiesters (PME/PDE), which can be noninvasively measured by phosphorus magnetic resonance spectroscopy (31P MRS), and may be a marker for early therapy response assessment in liver metastases. However, with commonly used 31P surface coils for liver 31P MRS, the liver is not fully covered, and metastases may be missed. The objective of this study was to demonstrate the feasibility of 31P MRS imaging (31P MRSI) with full liver coverage to assess 31P metabolite levels and chemotherapy-induced changes in liver metastases of gastro-esophageal cancer, using a 31P whole-body birdcage transmit coil in combination with a 31P body receive array at 7 T. 3D 31P MRSI data were acquired in two patients with hepatic metastases of esophageal cancer, before the start of chemotherapy and after 2 (and 9 in patient 2) weeks of chemotherapy. 3D 31P MRSI acquisitions were performed using an integrated 31P whole-body transmit coil in combination with a 16-channel body receive array at 7 T, with a field of view covering the full abdomen and a nominal voxel size of 20-mm isotropic. From the 31P MRSI data, 12 31P metabolite signals were quantified. Prior to chemotherapy initiation, both PMEs, that is, phosphocholine (PC) and phosphoethanolamine (PE), were significantly higher in all metastases compared with the levels previously determined in the liver of healthy volunteers. After 2 weeks of chemotherapy, PC and PE levels remained high or even increased further, resulting in increased PME/PDE ratios compared with healthy liver tissue, in correspondence with the clinical assessment of progressive disease after 2 months of chemotherapy. The suggested approach may present a viable tool for early therapy (non)response assessment of tumor metabolism in patients with liver metastases.

Application of PET/MRI in Gynecologic Malignancies.

The diagnosis, treatment, and management of gynecologic malignancies benefit from both positron emission tomography/computed tomography (PET/CT) and MRI. PET/CT provides important information on the local extent of disease as well as diffuse metastatic involvement. MRI offers soft tissue delineation and loco-regional disease involvement. The combination of these two technologies is key in diagnosis, treatment planning, and evaluating treatment response in gynecological malignancies. This review aims to assess the performance of PET/MRI in gynecologic cancer patients and outlines the technical challenges and clinical advantages of PET/MR systems when specifically applied to gynecologic malignancies.

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib.

Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

Innovation in Non-Invasive Diagnosis and Disease Monitoring for Meningiomas.

Meningiomas are tumors of the central nervous system that vary in their presentation, ranging from benign and slow-growing to highly aggressive. The standard method for diagnosing and classifying meningiomas involves invasive surgery and can fail to provide accurate prognostic information. Liquid biopsy methods, which exploit circulating tumor biomarkers such as DNA, extracellular vesicles, micro-RNA, proteins, and more, offer a non-invasive and dynamic approach for tumor classification, prognostication, and evaluating treatment response. Currently, a clinically approved liquid biopsy test for meningiomas does not exist. This review provides a discussion of current research and the challenges of implementing liquid biopsy techniques for advancing meningioma patient care.

Pathology of Surgically Resected Lung Cancers Following Neoadjuvant Therapy.

In around 30% of patients, non-small cell lung cancer is diagnosed at an advanced but resectable stage. Adding systemic therapy has shown clear benefit over surgery alone in locally advanced disease, and currently, chemo-immunotherapy in the adjuvant or neoadjuvant setting is the new standard for patients without targetable mutations. One major advantage of the neoadjuvant approach is the possibility of an immediate evaluation of the treatment effect, highlighting the role of pathology as an important contributor at the forefront of clinical decision-making and research. This review provides a summary and an update on current guidelines for histological evaluation of treatment effect after neoadjuvant therapy, also known as regression grading, and discusses newer data focusing on areas of evolving questions and controversies, such as the gross examination of the tumor and tumor bed, weighted versus unweighted evaluation approaches, discussion of histologic tumor type-specific cut-offs for major pathologic response, assessment of lymph nodes and regression grading after immunotherapy and targeted therapy. As no data or recommendations exist on regression grading of multiple tumor nodules, a practical approach is recommended. Lastly, we will touch on additional tissue biomarkers and summarize recent advances in the ardently discussed field of using circulating tumor DNA for the evaluation of treatment response.

Splenosis imaging with 99mTc nano-colloid as a different mimicker in a lymphoma patient on 18F- FDG PET/CT

Fluorodeoxyglucose (FDG) 18F-FDG PET/CT plays an important role in lymphoma staging and evaluation of treatment response. Mimics should be considered when evaluating 18F-FDG PET/CT images to perform correct staging and correct treatment response evaluation. Splenosis is one of the causes that may cause misinterpretation by mixing with lymph nodes in lymphoma patients. In our case report, we visualized splenosis mimicking lymph node in a 50-year-old lymphoma patient with 99mTc nano-colloid scintigraphy.

Additive Value of Magnetic Resonance Simulation Before Chemoradiation in Evaluating Treatment Response and Pseudoprogression in High-Grade Gliomas

BackgroundA dedicated MRI Simulation(MRsim) for radiation treatment(RT) planning in high-grade glioma(HGG) patients can detect early radiological changes, including tumor progression after surgery and before standard of care chemoradiation. This study aimed to determine the impact of using post-op MRI vs. MRsim as the baseline for response assessment and reporting pseudo-progression on follow-up imaging at one month(FU1) after chemoradiation. MethodsHistologically confirmed HGG patients were planned for six weeks of RT in a prospective study for adaptive RT planning. All patients underwent post-op MRI, MRsim, and follow-up MRI scans every 2-3 months. Tumor response was assessed by three independent blinded reviewers using Response Assessment in Neuro-Oncology(RANO) criteria when baseline was either post-op MRI or MRsim. Interobserver agreement was calculated using light's kappa. Results30 patients (median age 60.5 years; IQR 54.5-66.3) were included. Median interval between surgery and RT was 34 days (IQR 27–41). Response assessment at FU1 differed in 17 patients (57%) when the baseline was post-op MRI vs. MRsim, including true progression vs. partial response(PR) or stable disease(SD) in 11 (37%) and SD vs. PR in 6 (20%) patients. True progression was reported in 19 patients (63.3%) on FU1 when the baseline was post-op MRI vs 8 patients (26.7%) when the baseline was MRsim (p=.004). Pseudo-progression was observed at FU1 in 12 (40%) vs. 4 (13%) patients, when the baseline was post-op MRI vs. MRsim (p=.019). Interobserver agreement between observers was moderate (κ = 0.579; p<0.001). ConclusionsOur study demonstrates the value of acquiring an updated MR closer to RT in patients with HGG to improve response assessment, and accuracy in evaluation of pseudo-progression even at the early time point of first follow-up after RT. Earlier identification of patients with true progression would enable more timely salvage treatments including potential clinical trial enrolment to improve patient outcomes.

Inflammatory and subtype-dependent serum protein signatures predict survival beyond the ctDNA in aggressive B cell lymphomas.

Biological heterogeneity of large B cell lymphomas (LBCLs) is poorly captured by current prognostic tools, hampering optimal treatment decisions. We dissected the levels of 1,463 serum proteins in a uniformly treated trial cohort of 109 patients with high-risk primary LBCL (ClinicalTrials.gov: NCT01325194) and correlated the profiles with molecular data from tumor tissue and circulating tumor DNA (ctDNA) together with clinical data. We discovered clinically and biologically relevant associations beyond established clinical estimates and ctDNA. We identified an inflamed serum protein profile, which reflected host response to lymphoma, associated with inflamed and exhausted tumor microenvironment features and high ctDNA burden, and translated to poor outcome. We composed an inflammation score based on the identified inflammatory proteins and used the score to predict survival in an independent LBCL trial cohort (ClinicalTrials.gov: NCT03293173). Furthermore, joint analyses with ctDNA uncovered multiple serum proteins that correlate with tumor burden. We found that SERPINA9, TACI, and TARC complement minimally invasive subtype profiling and that TACI and TARC can be used to evaluate treatment response in a subtype-dependent manner in the liquid biopsy. Altogether, we discovered distinct serum protein landscapes that dissect the heterogeneity of LBCLs and provide agile, minimally invasive tools for precision oncology. This research was funded by grants from the Research Council of Finland, Finnish Cancer Organizations, Sigrid Juselius Foundation, University of Helsinki, iCAN Digital Precision Cancer Medicine Flagship, Orion Research Foundation sr, and Helsinki University Hospital.

472 Utility of [89Zr]Trastuzumab-PET/MRI Imaging for Quantitative Assessment of Tumor Heterogeneity In HER2+ Breast Cancer

OBJECTIVES/GOALS: This study was performed to explore the capabilities of simultaneous [89 Zr]trastuzumab-PET/MRI acquisition in a cohort of metastatic HER2+ breast cancer. The insights derived provide additional noninvasive characterization and precise intratumoral analysis tools for healthcare providers. METHODS/STUDY POPULATION: A total of 13 patients, aged between 40 and 70, diagnosed with HER2-positive breast cancer, were selected to participate in this study. Whole-body [89 Zr]trastuzumab-PET/MR imaging was performed 5 ± 1 days post-injection of the radiopharmaceutical during ongoing HER2-directed therapy. Concurrently acquired T1-weighted MRI facilitated the identification of normal organ and tumor regions of interest, which were further analyzed for mean ADC and mean standardized uptake value. Multiparametric intratumoral habitat analysis was performed. Utilizing the median metric values, tumors were evaluated for heterogeneity, specifically assessing high and low HER2 expression through an image processing framework in conjunction with ADC metrics. Long-term treatment response evaluation is ongoing. RESULTS/ANTICIPATED RESULTS: Initial analysis indicate all tumors exhibited higher overall uptake of [89 Zr]trastuzumab across various sites including the bone (p=0.019), brain (p=0.014), and breast (p=0.069), when compared to corresponding normal organs. Additionally, increased ADCmean values were observed in all regions besides brain tumors (bone: p=0.002, brain: p=0.5, breast: p=0.03, juxtapulmonary: p=0.037), indicating distinct patterns of cellularity. Notably, one of five patients with a breast lesion, who exhibited a complete response to HER2-targeted therapy, exhibited the highest breast lesion SUVmean. Brain and lymph node lesions demonstrated intratumoral heterogeneity of HER2 expression. Qualification of multi parametric maps is anticipated to inform on intratumoral heterogeneity DISCUSSION/SIGNIFICANCE: Despite limitation in clinical applications of quantitative approaches due to lack of standardization of processing, initial investigations, in combining molecular imaging of HER2 and quantitative MRI demonstrate potential in characterizing metastatic HER2+ breast cancer for intratumoral classification and therapeutic stratification.

An evaluation of treatment response and remission definitions in adult obsessive-compulsive disorder: A systematic review and individual-patient data meta-analysis

IntroductionExpert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions. MethodsWe conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively. ResultsIndividual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses. ConclusionWhile the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions.

Erdheim-Chester Disease: Investigating the Correlation between Targeted Treatment Therapy and Disease Outcomes.

A retrospective analysis of 20 adult patients with histopathological and clinical diagnoses of ECD was conducted at a single institution over a twenty-year period (2002-2022). Clinical responses were compared on the basis of treatments rendered, which included chemotherapy, immunotherapy, systemic corticosteroids, surgery and radiation, or targeted agents, referring to any small molecular inhibitors. Treatment response evaluation varied by the anatomic site(s) of disease, the extent of disease at diagnosis, and the imaging modality employed. In this analysis, patients were treated with a combination of targeted agents, myelosuppressive therapies, and radiation at various points in their disease courses. Of these, the most common treatment modality rendered was targeted therapy, employed in 11 of 20 patients. Partial responses or better were observed in 15 of 20 patients. Rates of stable disease trended towards being more frequent with targeted therapy versus conventional therapy but did not reach significance (p = 0.2967). Complete response rates trended towards being more common with conventional therapy than molecular (p = 0.5) but were equivocal overall. Trends of peripheral blood absolute monocytes with relation to disease activity were reviewed as recent literature implied that monocyte levels surrounding disease progression were of potential prognostic significance in histiocytic diseases. Amongst the patients who progressed at any point during their treatment course, absolute monocyte count (in K/µL) was identified at the closest available timepoint prior to or following disease progression and at the lowest value (nadir) following re-institution of therapy prior to any additional agent(s) being employed. There was no statistically significant difference in either of these monocyte values nor in disease outcomes with respect to treatments rendered within our cohort. However, our cohort consists of a heterogenous population of patients with ECD with data that highlights several trends over a longitudinal period, spanning the advent of targeted therapy. Significant differences are anticipated in ongoing analyses.

A large language model-based generative natural language processing framework fine-tuned on clinical notes accurately extracts headache frequency from electronic health records.

To develop a natural language processing (NLP) algorithm that can accurately extract headache frequency from free-text clinical notes. Headache frequency, defined as the number of days with any headache in a month (or 4 weeks), remains a key parameter in the evaluation of treatment response to migraine preventive medications. However, due to the variations and inconsistencies in documentation by clinicians, significant challenges exist to accurately extract headache frequency from the electronic health record (EHR) by traditional NLP algorithms. This was a retrospective cross-sectional study with patients identified from two tertiary headache referral centers, Mayo Clinic Arizona and Mayo Clinic Rochester. All neurology consultation notes written by 15 specialized clinicians (11 headache specialists and 4 nurse practitioners) between 2012 and 2022 were extracted and 1915 notes were used for model fine-tuning (90%) and testing (10%). We employed four different NLP frameworks: (1) ClinicalBERT (Bidirectional Encoder Representations from Transformers) regression model, (2) Generative Pre-Trained Transformer-2 (GPT-2) Question Answering (QA) model zero-shot, (3) GPT-2 QA model few-shot training fine-tuned on clinical notes, and (4) GPT-2 generative model few-shot training fine-tuned on clinical notes to generate the answer by considering the context of included text. The mean (standard deviation) headache frequency of our training and testing datasets were 13.4 (10.9) and 14.4 (11.2), respectively. The GPT-2 generative model was the best-performing model with an accuracy of 0.92 (0.91, 0.93, 95% confidence interval [CI]) and R2 score of 0.89 (0.87, 0.90, 95% CI), and all GPT-2-based models outperformed the ClinicalBERT model in terms of exact matching accuracy. Although the ClinicalBERT regression model had the lowest accuracy of 0.27 (0.26, 0.28), it demonstrated a high R2 score of 0.88 (0.85, 0.89), suggesting the ClinicalBERT model can reasonably predict the headache frequency within a range of ≤ ± 3 days, and the R2 score was higher than the GPT-2 QA zero-shot model or GPT-2 QA model few-shot training fine-tuned model. We developed a robust information extraction model based on a state-of-the-art large language model, a GPT-2 generative model that can extract headache frequency from EHR free-text clinical notes with high accuracy and R2 score. It overcame several challenges related to different ways clinicians document headache frequency that were not easily achieved by traditional NLP models. We also showed that GPT-2-based frameworks outperformed ClinicalBERT in terms of accuracy in extracting headache frequency from clinical notes. To facilitate research in the field, we released the GPT-2 generative model and inference code with open-source license of community use in GitHub. Additional fine-tuning of the algorithm might be required when applied to different health-care systems for various clinical use cases.