Methods Of Assessing Response Research Articles

BIOM-50. SERIAL INTRACRANIAL CEREBROSPINAL CELL-FREE DNA FOR DISEASE MONITORING IN PATIENTS WITH GLIOMAS

Abstract Improved response assessment methods are needed for patients with gliomas. Intracranial cerebrospinal fluid (CSF) is longitudinally accessible and provides an abundance source of candidate biomarkers, such as cell-free DNA (cfDNA), for disease monitoring. To evaluate the clinical feasibility of molecular profiling from longitudinal intracranial CSF, CSF was acquired from patients with CSF access devices, including Ommaya reservoirs and ventriculoperitoneal shunts. cfDNA was extracted and analyzed via PredicineCARE (Next Generation sequencing) or PredicineSCORE (low pass whole genome sequencing). Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, forty-eight CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL), with 39 samples (81.3%) yielding sufficient cfDNA for variant profiling. Our initial findings suggest that tumor fraction increased by 6.28x, 2.87x, and 8.31x with radiographic progression in three patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased a patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. In conclusion, longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course toward evaluating candidate monitoring biomarkers.

Structural response and damage assessment method for subsea pipe-in-pipe subjected to anchor impact

The pipe-in-pipe system is widely used in the development and transportation of offshore oil and gas resources. The damage caused by anchor impacts on the pipe-in-pipe system has long been a focal point and challenge in both engineering and academic fields. Numerical simulation method is employed to investigate the impact process of anchors on pipe-in-pipe systems, revealing the variation patterns of pipeline deformation response over time. The structural response of the pipe-in-pipe system to dropped anchor impacts is studied from multiple perspectives, including deformation, energy, and load transfer. The influence of pipe-in-pipe characteristic parameters, anchor characteristic parameters, centralizers, and bulkheads on the extent of impact damage is analyzed, establishing a relationship between the absorbed energy and the damage to the pipe-in-pipe. The results indicate that the impact energy primarily depends on the mass and velocity of the anchor. Energy is conserved during the impact process. It is found that even with different anchor masses and velocities, the extent of damage to the pipe-in-pipe system remains the same if the impact energy is identical. High-strength steel, large diameter, and thick-walled pipelines exhibit better resistance to impact loads. Additionally, centralizers and bulkheads mitigate the impact damage to the pipe-in-pipe system. Finally, an evaluation method for pipe-in-pipe impact damage due to dropped anchors is proposed. It is discovered that the assessment method for pipelines impacted by dropped anchors in the DNV-RP-F107 standard tends to be conservative when the impact energy is high. The findings of this study provide technical support for the integrity management of pipe-in-pipe systems.

Effect of think-pair-share and choral response assessment methods on academic achievement of prospective science teachers

Effect of think-pair-share and choral response assessment methods on academic achievement of prospective science teachers

Uncertain seismic response and robustness analysis of isolated continuous girder bridges

When calculating the seismic response of structures, conventional methods often neglect uncertainty and suffer from excessive computation. Although robustness metrics have been effective in evaluating structural safety, they are not suitable for isolated continuous girder bridges (ICGB). To address this issue, this paper introduces an uncertain seismic response and robustness assessment method tailored to ICGB: Firstly, the method considers uncertainty in material parameters and ground motion by constructing a data set using Monte Carlo simulation. Secondly, a genetic algorithm for parallel optimisation of radial basis function neural network (GAPO-RBFNN) is trained to predict the seismic responses of the bridges. Thirdly, a robustness metric specifically designed for bridges is derived and applied to bridge. Finally, the proposed robustness metric is validated on lead rubber bearing (LRB) and shape memory alloy-lead rubber bearing (SMA-LRB) bridges. Results indicate that the GAPO-RBFNN model accurately approximates the mapping relationship between structural parameters and seismic response, with an average error of only 0.32% and a 70% reduction in computation time compared with traditional methods. Moreover, the new robustness metric overcomes the limitations of the dismantled member method and is applicable to bridge. The robustness of the SMA-LRB-ICGB, strengthened by SMA, is improved, providing evidence of the effectiveness of the proposed robustness metric.

Tumor response assessment in hepatocellular carcinoma treated with immunotherapy: imaging biomarkers for clinical decision-making.

To compare the performance of 1D and 3D tumor response assessment for predicting median overall survival (mOS) in patients who underwent immunotherapy for hepatocellular carcinoma (HCC). Patients with HCC who underwent immunotherapy between 2017 and 2023 and received multi-phasic contrast-enhanced MRIs pre- and post-treatment were included in this retrospective study. Tumor response was measured using 1D, RECIST 1.1, and mRECIST, and 3D, volumetric, and percentage quantitative EASL (vqEASL and %qEASL). Patients were grouped into disease control vs progression and responders vs non-responders. Kaplan-Meier curves analyzed with log-rank tests assessed the predictive value for mOS. Cox regression modeling evaluated the association of clinical baseline parameters with mOS. This study included 37 patients (mean age, 69.1 years [SD, 8.0]; 33 men). The mOS was 16.9 months. 3D vqEASL and %qEASL successfully stratified patients into disease control and progression (vqEASL: HR 0.21, CI: 0.55-0.08, p < 0.001; %qEASL: HR 0.18, CI: 0.83-0.04, p = 0.013), as well as responder and nonresponder (vqEASL: HR 0.25, CI: 0.08-0.74, p = 0.007; %qEASL: HR 0.17, CI: 0.04-0.72, p = 0.007) for predicting mOS. The 1D criteria, mRECIST stratified into disease control and progression only (HR 0.24, CI: 0.65-0.09, p = 0.002), and RECIST 1.1 showed no predictive value in either stratification. Multivariate Cox regression identified alpha-fetoprotein > 500 ng/mL as a predictor for poor mOS (p = 0.04). The 3D quantitative enhancement-based response assessment tool qEASL can predict overall survival in patients undergoing immunotherapy for HCC and could identify non-responders. Using 3D quantitative enhancement-based tumor response criteria (qEASL), radiologists' predictions of tumor response in patients undergoing immunotherapy for HCC can be further improved. MRI-based tumor response criteria predict immunotherapy survival benefits in HCC patients. 3D tumor response assessment methods surpass current evaluation criteria in predicting overall survival during HCC immunotherapy. Enhancement-based 3D tumor response criteria are robust prognosticators of survival for HCC patients on immunotherapy.

Glioma monitoring via longitudinal intracranial cerebrospinal fluid cell-free DNA.

2053 Background: Current methods for glioma treatment response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using intracranial CSF from patients with gliomas during their disease course. Methods: Adults with gliomas were recruited for longitudinal intracranial CSF collection using 1) Ommaya reservoirs, from which CSF would be sampled on at least two separate occasions, or 2) CSF collection from other clinically indicated CSF access devices, such as ventriculoperitoneal (VP) shunts. Patients were followed until their last visit or present time for ongoing participants. For this initial cfDNA feasibility study, CSF was collected from Ommaya reservoirs in four patients and from an existing VP shunt in one patient. cfDNA was then extracted and analyzed using two sequencing platforms, PredicineCARE for cancer variant profiling and PredicineSCORE for low-pass whole genome sequencing (LP-WGS). This analysis generated genomic aberration profiles and genome-wide copy number burden (CNB) score. Results: Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, thirty-five CSF samples were obtained (median volume: 3.80 mL; 0.5-5 mL), with 30 samples (85.7%) yielding sufficient cfDNA for variant profiling and LP-WGS. Our initial findings suggest that tumor fraction increased by 6.28x and 2.87x with radiographic progression in two patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased in the patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. Conclusions: Longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Ongoing studies will evaluate hypotheses generated in this case series regarding how longitudinal CSF cfDNA could be utilized to sensitively detect changes in disease burden. Clinical trial information: NCT04692337 ; NCT04692324 .

Translational risk-adapted approaches to de-escalated radiation for human papillomavirus-positive oropharyngeal cancer: Past, present, and future

Interest in the use of de-escalated radiation to treat patients with newly diagnosed human papillomavirus (HPV)-positive oropharyngeal cancer has grown dramatically with the publication of prospective trials demonstrating the efficacy of such an approach. While the rationale for de-escalation--- namely to decrease treatment-related toxicity while maintaining the excellent rates of disease control historically observed in patients with this disease—is inherently obvious, uncertainty exists regarding how to best select patients for de-escalation. Consequently, risk-adapted strategies using a variety of translational and clinical platforms have been increasingly popularized to better refine treatment. These have integrated contemporary methods of mid-treatment response assessment using advanced technologies and molecular assays to customize the radiation dose. By monitoring the response as patients actively proceed through treatment, risk-adapted protocols have the potential to provide insight into the biological behavior of tumors and make individualized therapy possible. The purpose of this review is to summarize the evidence to date on risk-adapted approaches to de-escalated radiation-- highlighting the clinical, radiological, and biological data which may ultimately help usher the principles of precision medicine into practice for patients with HPV-positive oropharyngeal cancer.

Abstract 3759: First clinical evidence of the tissue nanomechanical signature as a novel diagnostic and prognostic tool in patients with non-small-cell lung cancer

Abstract Introduction: Complex structural remodelling of cells and extracellular matrix during cancer initiation and progression elicit substantial biomechanical alterations, which can be measured by Atomic Force Microscopy (AFM) at the nanoscale level. Clinical and translational evidence indicates that tissue nanomechanical signature (NS) can be a useful tool for rapid cancer diagnosis, and assessment of cancer aggressiveness. We demonstrated that the AFM-based Automated and Reliable Tissue Diagnostics (ARTIDIS) platform represents a valid method for rapid diagnosis, prognosis, and treatment response assessment in patients with breast cancer. Here we aimed to use this platform to examine tumour biopsies from non-small cell lung cancer (NSCLC) patients for the first time. Methods: This is an ongoing, single center study at the Hospital Clinic of Barcelona and University of Barcelona (UHB) Spain, aiming to enroll 75 patients by January 2024 in the first phase, followed by 200 patients in the expansion phase. To date, 54 matching tumor and non-tumor fresh tissue biopsies were taken by experienced pathologists from fresh surgical resection specimens from 27 patients with previously diagnosed NSCLC. Tissue biopsies were measured with the ARTIDIS device in a blinded manner, without knowing the malignancy status of the biopsy. Routine clinico-pathologic parameters have been collected. The multiparametric nanomechanical signature has been analyzed in an automated manner using the proprietary AI-based ARTIDISNET software platform together with available clinico-pathologic parameters. Results: In total, the NSCLC tissue samples included 16 squamous cell carcinoma (SCC), 6 Adenocarcinoma (ADC), 1 large cell carcinoma (LCC) and 4 other histological subtypes. Non-tumor tissues exhibited significantly varied composition, including normal lung parenchyma, bronchial tissues, fibrosis and inflammatory changes. Among the 27 patients, 5 patients developed distant progression within 12 months after ARTIDIS measurements. Results analysis showed that the ARTIDIS NS can reliably differentiate malignant NSCLC lesions from non-tumor lung tissue, with a sensitivity of 0.84, specificity of 0.81, positive predictive value (PPV) of 0.79, negative predictive value (NPV) of 0.86 and accuracy of 0.82. In addition, the ARTIDIS NS can differentiate patients with and without distant progression with a sensitivity of 0.62, specificity of 0.81, PPV of 0.42, NPV of 0.90 and accuracy of 0.77. Conclusions: Here we demonstrated first clinical evidence of the ARTIDIS tissue NS as a novel diagnostic and prognostic tool in patients with NSCLC. This study aims to establish the diagnostic, prognostic, and predictive NS in patients NSCLC. In addition to local expansion at the UHB, study results will be further validated in ARTIDIS clinical program at MD Anderson Cancer Centre, USA. Citation Format: Jordi Alcaraz, Héctor Sanz-Fraile, Elba Marin, Paula Gausa Busquets, Kate Neal, Marselina Arshakyan, Marc Rico, Marc Boada, David Sanchez, Reinier Oropesa Nunez, Gitika Srivastava, Ahmed Jizawi, Sara Nizzero, Tobias Appenzeller, Mariam Gachechiladze, Marko Loparic, Marija Plodinec, Noemi Reguart. First clinical evidence of the tissue nanomechanical signature as a novel diagnostic and prognostic tool in patients with non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3759.

A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer

BackgroundNeoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI).MethodsIn this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size.ResultsOur results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0–80); radiological-TS by USS 9 (0–31); by MRI: 12 (0–60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value.ConclusionOur findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation.

The review delves into the methods for the quantitative assessment of intracellular effectors and cellular response of Receptor for Advanced Glycation End products (RAGE), a vital transmembrane receptor involved in a range of physiological and pathological processes. RAGE bind to Advanced Glycation End products (AGEs) and other ligands, which in turn activate diverse downstream signaling pathways that impact cellular responses such as inflammation, oxidative stress, and immune reactions. The review article discusses the intracellular signaling pathways activated by RAGE followed by differential activation of RAGE signaling across various diseases. This will ultimately guide researchers in developing targeted and effective interventions for diseases associated with RAGE activation. Further, we have discussed how PCR, western blotting, and microscopic examination of various molecules involved in downstream signaling can be leveraged to monitor, diagnose, and explore diseases involving proteins with unique post-translational modifications. This review article underscores the pressing need for advancements in molecular approaches for disease detection and management involving RAGE.

A Novel Method for Evaluating Early Tumor Response Based on Daily CBCT Images for Lung SBRT.

We aimed to develop a new tumor response assessment method for lung SBRT. In total, 132 lung cancer patients with 134 tumors who received SBRT treatment with daily CBCT were included in this study. The information about tumor size (area), contrast (contrast-to-noise ratio (CNR)), and density/attenuation (μ) was derived from the CBCT images for the first and the last fractions. The ratios of tumor area, CNR, and μ (RA, RCNR, Rμ) between the last and first fractions were calculated for comparison. The product of the three rations was defined as a new parameter (R) for assessment. Tumor response was independently assessed by a radiologist based on a comprehensive analysis of the CBCT images. R ranged from 0.27 to 1.67 with a mean value of 0.95. Based on the radiologic assessment results, a receiver operation characteristic (ROC) curve with the area under the curve (AUC) of 95% was obtained and the optimal cutoff value (RC) was determined as 1.1. The results based on RC achieved a 94% accuracy, 94% specificity, and 90% sensitivity. The results show that R was correlated with early tumor response to lung SBRT and that using R for evaluating tumor response to SBRT would be viable and efficient.

Nuclear medicine techniques in paediatric body oncology: Present and future

Modern nuclear medicine techniques combining anatomical and functional imaging have transformed our ability to diagnose, stage and prognosticate in paediatric oncology. Progress in the use of positron emission tomography (PET) in children with cancer has been relatively restrained compared to adults due to radiation concerns, limited research, availability, and the practical challenges associated with imaging young children. However, there have been several developments in the last decade and the role of molecular imaging in paediatric oncology will only broaden with forthcoming novel tracers and molecular radiotherapy. This review article summarises the practical aspects of nuclear imaging in paediatric oncology, discusses the main imaging methods including PET and single photon emission computed tomography (SPECT), appraises the available established and novel tracers, and summarises the evidence behind molecular imaging in paediatric lymphoma, neuroblastoma, sarcomas, thyroid cancer and other tumours. 18F-FDG PET/CT is the established method for staging and response assessment after induction chemotherapy in paediatric Hodgkin lymphoma and has high sensitivity for the detection of bone marrow disease, reducing the need for bone marrow biopsy in some cases. 123I-mIBG planar with SPECT imaging remains the mainstay for neuroblastoma imaging, however there is a well-established role for 18F-FDG PET/CT in mIBG non-avid disease, and 18F-DOPA and 68Ga-DOTA PET tracers have shown promising results as upcoming alternatives. 18F-FDG PET/CT is advocated in the staging assessment of rhabdomyosarcoma and has been shown to have excellent sensitivity in the detection of bone metastases in osteosarcoma and Ewing sarcoma, although standard chest CT is still recommended for the detection of lung metastases. The role of PET in germ cell tumours, hepatoblastoma, Wilms tumour and Langerhans cell histiocytosis is complementary to standard techniques.

Size and depth of residual tumor after neoadjuvant chemoradiotherapy in rectal cancer - implications for the development of new imaging modalities for response assessment.

With the shift towards organ preserving treatment strategies in rectal cancer it has become increasingly important to accurately discriminate between a complete and good clinical response after neoadjuvant chemoradiotherapy (CRT). Standard of care imaging techniques such as CT and MRI are well equipped for initial staging of rectal tumors, but discrimination between a good clinical and complete response remains difficult due to their limited ability to detect small residual vital tumor fragments. To identify new promising imaging techniques that could fill this gap, it is crucial to know the size and invasion depth of residual vital tumor tissue since this determines the requirements with regard to the resolution and imaging depth of potential new optical imaging techniques. We analyzed 198 pathology slides from 30 rectal cancer patients with a Mandard tumor regression grade 2 or 3 after CRT that underwent surgery. For each patient we determined response pattern, size of the largest vital tumor fragment or bulk and the shortest distance from the vital tumor to the luminal surface. The response pattern was shrinkage in 14 patients and fragmentation in 16 patients. For both groups combined, the largest vital tumor fragment per patient was smaller than 1mm for 38% of patients, below 0.2mm for 12% of patients and for one patient as small as 0.06mm. For 29% of patients the vital tumor remnant was present within the first 0.01mm from the luminal surface and for 87% within 0.5mm. Our results explain why it is difficult to differentiate between a good clinical and complete response in rectal cancer patients using endoscopy and MRI, since in many patients submillimeter tumor fragments remain below the luminal surface. To detect residual vital tumor tissue in all patients included in this study a technique with a spatial resolution of 0.06mm and an imaging depth of 8.9mm would have been required. Optical imaging techniques offer the possibility of detecting majority of these cases due to the potential of both high-resolution imaging and enhanced contrast between tissue types. These techniques could thus serve as a complimentary tool to conventional methods for rectal cancer response assessment.

Radiomics of magnetic resonance imaging for assessment of pathological complete response to neoadjuvant therapy and long-term survival in breast cancer

Breast cancer (BC) is the most common malignant disease. The use of neoadjuvant drug therapy increases the likelihood of achieving a complete pathomorphological response (pCR), leads to an increase in resectability and ablation; helps to determine the sensitivity of tumor cells to chemopreventive agents, thereby improving the patient’s prognosis. Since pathomorphological assessment occurs aſter surgery, it is necessary to develop methods for non-invasive response assessment for timely correction of the volume of treatment. One such method is magnetic resonance imaging (MRI). Assessment of the obtained images using texture analysis allows to increase the accuracy of the method both in the control of neoadjuvant treatment and in the assessment of the response to neoadjuvant therapy during preoperative planning.This article provides an analysis of the literature data on the potential to improve the prognostic value of breast MRI in assessing the complete pathomorphological response to neoadjuvant drug treatment of breast cancer using texture analysis of data.

Real-world response endpoints in patients with mNSCLC treated with chemotherapy across real-world datasets.

6595 Background: Response Evaluation Criteria in Solid Tumors (RECIST) based response rate (RR) is used for efficacy evaluation in clinical trials and relies on imaging data collected at specified timepoints for uniform assessment. In routine clinical practice, the method and timing of response assessment can vary, and imaging data from electronic health records (EHR) and other real world (rw) sources may not be available, making RECIST-based assessment of rw-response rate (rwRR) using rw data (RWD) challenging. Friends of Cancer Research formed a multi-stakeholder partnership to assess available data attributes to measure response across RWD sources to inform development of a consistent method for measurement. Methods: The study included seven EHR data partners who identified and analyzed a cohort of 1,380 patients (pts) with metastatic non-small cell lung cancer (mNSCLC) treated with first-line platinum doublet chemotherapy, following a common protocol and statistical analysis plan. The availability and frequency of data components to assess response including raw images, radiology imaging reports, and clinician response assessments from provider notes were assessed. Response endpoints measured included rwRR, rw-duration of response (rwDOR), and the association of rwR with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). Results: The availability of data components varied across RWD sources (Table). Images were not widely accessible, thus response was analyzed using clinician response assessments (median proportion of pts evaluable, 77.5%). Of these assessments, the majority relied on imaging interpretation. The median rwRR was 46% with a median rwDOR of 119 days. The table provides median rwTTD, rwTTNT, and rwOS across data sources. Conclusions: The rwRR among pts with mNSCLC calculated using the clinician assessment was relatively consistent across all RWD sources, with consistent trends in time to event endpoints. While variability in the availability of data components to assess response was observed, the demonstrated feasibility of response endpoints based on clinician assessment suggests further exploration may inform drug effectiveness evaluation with RWD. [Table: see text]

Abstract PD16-04: To monitor or not to monitor? MRI monitoring of neoadjuvant chemotherapy effect and its benefit on breast cancer patients’ pathological complete response rate

Abstract Introduction: Neoadjuvant chemotherapy (NACT) represents an essential tool for the treatment of selected breast cancer patients aimed to reduce the tumor size for a more conservative resection and to gain early information about the sensitivity to applied treatment. An effective early response assessment helps both to change the therapeutic strategy for patients nonresponding to the treatment used and to avoid the toxicity related to ineffective treatment. We assumed that changing the chemotherapy regimen might avoid the residual cancer burden (RCB) III outcome and lead to the highest possible rate of pathological complete response (pCR) achieved. We examined the benefit of MRI as a preferred method for interim response assessment to NACT with a primary focus on the relation between the pattern of responses to NACT within the MRI- monitored and non-monitored patients and the pattern of final outcomes on the RCB scale. Methods We present a real-life data-based retrospective analysis of 124 female patients with locally advanced breast carcinoma. All patients received NACT (anthracycline-based regimen followed by taxane-based regimen/early switch to taxanes after the 2nd cycle in nonresponders, and antiHER2 therapy if indicated) prior to surgery (mastectomy/breast-conserving surgery, sentinel lymph node biopsy/axillary dissection). Postoperative histopathological analysis of tumor specimens categorised 120 patients according to the RCB scale 0 – III. Four patients had surgery ex muros and were lost to follow-up. Patients were divided into two cohorts. Group A covered monitored patients with pre-treatment MRI and follow-up MRI after the 2nd cycle of NACT. If no response was detected, another follow-up MRI was indicated after the 2nd cycle of a new treatment. Group B comprised patients with no/incomplete MRI monitoring and patients without the change of therapy even though no response was detected by MRI after the 2nd cycle of NACT. Association between categorical variables was tested using chi-square tests. Statistical analysis was performed using StatsDirect® 3.3.5 (StatsDirect Ltd., Cheshire, UK). The data analysis was supported by a grant from the Cultural and Educational Grant Agency of the Ministry of Education, Science, Research, and Sport of the Slovak Republic (KEGA 041UK-4/2020). Results MRI-monitored patients had two times the odds of being RBC 0 (OR = 2.02, P = 0.122) and almost three times the odds of being RCB 0 or RCB I (OR = 2.83, P = 0.0206) than patients with no monitoring. Changing the NACT after the 2nd cycle in the cohort of monitored patients with no response to initial therapy was significantly associated with better outcomes on the RCB scale (P = 0.0042). This result was confirmed by comparing the pattern of results in patients with no response within the group of incompletely monitored patients with known MRI results after the 2nd cycle (P = 0.0257). Changing the ineffective NACT after the 2nd cycle significantly increased the proportion of RCB 0-I by 23.4%, confirming the benefit of response monitoring by MRI. Conclusion Breast cancer constitutes a heterogeneity of tumor subtypes and it is acknowledged that their behaviour during NACT is highly variable and often unpredictable. MRI represents an effective tool for the assessment of tumor response to applied NACT. To achieve the most clinically meaningful impact of the selected treatment it is critical to monitor the tumor response within the first 3 cycles. Our data clearly confirmed that clinical decisions related to the detection of early response or no response (resulting in the change of NACT) lead to better treatment outcomes and less toxicity. The rate of pCR defines the applied treatment efficacy. Every single patient with results different from RCB III has a better prognosis, reduced need for further expensive treatment and also a more favourable quality of life. These key facts need to be carefully considered when discussing the cost and benefits of MRI monitoring. Citation Format: Lucia Vanovcanova, Iveta Waszulikova, Bibiana Vertakova Krakovska. To monitor or not to monitor? MRI monitoring of neoadjuvant chemotherapy effect and its benefit on breast cancer patients’ pathological complete response rate [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD16-04.

Assesment of specific T-cell immunity to SARS-CoV-2 virus antigens in COVID-19 reconvalescents

The development of the COVID-19 pandemic has stimulated the scientific research aimed at studying of the mechanisms of formation the immunity against SARS-CoV-2. Currently, there is a need to develop a domestic simple and cost-effective specific method suitable for monitoring of T-cell response against SARS-CoV-2 in reconvalescents and vaccinated individuals. Development of a screening method for evaluation specific T-cell immunity against SARS-CoV-2. Total 40 individuals who had mild to moderate COVID-19 and 20 healthy volunteers who did not have a history of this disease were examined. The presence and levels of IgG and IgM antibodies to SARS-CoV-2 were identified in participants sera by ELISA using the diagnostic kits from JSC Vector-Best (Novosibirsk, Russian Federation). Antigenic stimulation of mononuclear cells was carried out on commercial plates with adsorbed whole-virion inactivated SARS-CoV-2 antigen (State Research Center of Virology and Biotechnology VECTOR Novosibirsk, Russian Federation). The concentration of IFN- was measured in ELISA using the test systems from JSC Vector-Best (Novosibirsk, Russian Federation). The immunophenotyping of lymphocytes was performed on a flow cytometer Cytomics FC500 (Beckman Coulter, USA). Statistical data processing was carried out using the Microsoft Excel and STATISTICA 10 software package. Stimulation of mononuclear cells isolated from the peripheral blood with whole-virion inactivated SARS-CoV-2 antigen fixed at the bottom of the wells of a polystyrene plate showed a significantly higher median response in terms of IFN- production in 40 people who had history of COVID-19 compared to 20 healthy blood donors (172.1 [34.3575.1] pg/ml versus 15.4 [6.925.8] pg/ml, p 0.0001). There was no difference in median IFN- levels in supernatants collected from unstimulated mononuclear cells from COVID-19 reconvalescents and healthy donors (2.7 [0.411.4] pg/ml versus 0.8 [0.023.3] pg/ml, p 0.05). The overall sensitivity and specificity of this method were 73% (95% CI 5888%) and 100% (95% CI 100100%), respectively, at a cut-off of 50 pg/ml. The developed method for assessment of the cellular immune response to SARS-CoV-2 can be used as a screening method for monitoring the T-cell response in a population against a new coronavirus infection in recovered people.

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

BackgroundBreast cancer neoadjuvant chemotherapy (NACT) allows for assessing tumor sensitivity to systemic treatment, planning adjuvant treatment and follow-up. However, a sufficiently large number of patients fail to achieve the desired level of pathological tumor response while optimal early response assessment methods have not been established now. In our study, we simultaneously assessed the early chemotherapy-induced changes in the tumor volume by ultrasound (US), the tumor oxygenation by diffuse optical spectroscopy imaging (DOSI), and the state of the tumor vascular bed by Doppler US to elaborate the predictive criteria of breast tumor response to treatment.MethodsA total of 133 patients with a confirmed diagnosis of invasive breast cancer stage II to III admitted to NACT following definitive breast surgery were enrolled, of those 103 were included in the final analysis. Tumor oxygenation by DOSI, tumor volume by US, and tumor vascularization by Doppler US were determined before the first and second cycle of NACT. After NACT completion, patients underwent surgery followed by pathological examination and assessment of the pathological tumor response. On the basis of these, data regression predictive models were created.ResultsWe observed changes in all three parameters 3 weeks after the start of the treatment. However, a high predictive potential for early assessment of tumor sensitivity to NACT demonstrated only the level of oxygenation, ΔStO2, (ρ = 0.802, p ≤ 0.01). The regression model predicts the tumor response with a high probability of a correct conclusion (89.3%). The “Tumor volume” model and the “Vascularization index” model did not accurately predict the absence of a pathological tumor response to treatment (60.9% and 58.7%, respectively), while predicting a positive response to treatment was relatively better (78.9% and 75.4%, respectively).ConclusionsDiffuse optical spectroscopy imaging appeared to be a robust tool for early predicting breast cancer response to chemotherapy. It may help identify patients who need additional molecular genetic study of the tumor in order to find the source of resistance to treatment, as well as to correct the treatment regimen.

Oxidative stress coping capacity (OSC) value: Development and validation of an in vitro measurement method for blood plasma using electron paramagnetic resonance spectroscopy (EPR) and vitamin C.

Oxidative stress as a driver of disease is reinforcing the trend towards supplementation with antioxidants. While antioxidants positively influence the redox status when applied at physiological doses, higher concentrations may have pro-oxidative effects. Precise assessment methods for testing the supply of antioxidants are lacking. Using in-situ-irradiation as stressor and electron paramagnetic resonance (EPR) spectroscopy as readout system for formed radicals, a stress response assessment method was developed, using protein solutions and plasma samples from transfusion medicine. The method was validated in a double-blind placebo-controlled in vivo cross-over pilot study in blood plasma samples of individuals before and after vitamin C supplementation. Reference measurements were performed for the exogenous antioxidants β-carotene and vitamin C, and glutathione as an endogenous representative. Malondialdehyde was studied for oxidative stress indication. Protein solutions without antioxidants showed a linear increase in radical concentration during irradiation. The in-vitro-addition of vitamin C or plasma samples from subjects displayed two slopes (m1, m2) for radical production, whereby m1 represented the amount of antioxidants and proteins, m2 only the protein content. These two slopes in combination with the intervening transition area (T) were used to calculate the oxidative stress coping capacity (OSC), which correlated positively with vitamin C concentration in blood plasma, while oxidative stress biomarkers showed only fluctuations within their reference ranges. Furthermore, a selective radical quenching mechanism for vitamin C was observed: the proportion of reactive oxygen species (ROS) in the plasma samples was degraded in dependence to the vitamin C concentration ingested. The proportion of lipid oxygen species (LOS) remained stable while the ascorbyl radical increased with higher vitamin C intake. OSC may represent a sensitive method to detect treatment effects on the redox status in vivo in future validation and treatment studies, and potentially in clinical routine.

Prompt Assessment of Tumor Load and Treatment Response in Patients with Lymphoma By a Blood-Based Multi-Omics Approach

Introduction Lymphoma is a class of highly heterogeneous hematological malignancy derived from malignant clonal proliferation of lymphocytes. Periodic imaging examinations are the current standard for clinical assessment of lymphoma treatment response. Liquid biopsy is an emerging, non-invasive method for quantitative assessment of cancer treatment response. In this prospective study, we applied a noninvasive multi-omics assay named SeekInClarity to assess lymphoma treatment response and predict patient outcomes. Methods 149 patients meeting the WHO diagnosis criteria of lymphoid neoplasm were prospectively recruited from two clinical sites. The study is in progress, and 114 patients were included in the current interim analysis. 8.8% of patients who were lost to follow-up or quickly died were excluded. SeekInClarity assay integrates the analysis of genomic feature and common plasma tumor protein markers (PTMs, including AFP, CEA, CA153, CA125, CA199, CYFRA21-1 and CA724). Genomic features including copy number aberration (CNA) and the fragment size (FS) that are pan-cancer hallmarks were analyzed by shallow whole genome sequencing. Patients received SeekInClarity test before and after 1, 2, 4 and 6 cycles of treatment to generate the molecular tumor burden score (MTB). MTB positive/negative suggests that molecular signal of tumor is detectable/undetectable. Results The value of each dimension (protein marker, CNA and FS) in the prior-treatment (baseline) lymphoma samples were significantly higher than that in healthy control samples (Mann-Whitney test: P<0.001). 72.8% base line samples were MTB positive. After 2 cycles of treatment, the samples from patients who experienced disease progression showed higher MTB positivity rate than that from those without disease progression (85.7% vs. 26.7). MTB- patients showed a significantly longer progression free survival (PFS) time than MTB+ patients [HR: 12.6, 95% CI:4.1-38.6, P<0.0001] regardless of tumor stage and lymphoma subtype. Patients with reduced sample MTB values compared to baseline sample MTB values after two cycles of treatment had significantly better disease-free survival than patients with increased sample MTB values after treatment [HR: 5.0, 95% CI:0.48-52.5; P<0.0001]. We further divided the patients into two groups according to the degree of reduction in MTB values in the pre- and post-treatment samples (>50% & <50%), and we found that patients with higher MTB decrease (>50%) showed a better PFS than those with lower MTB decrease (<50%, P < 0.001). Conclusions This prospective study demonstrated that SeekInClarity, a non-invasive, multidimensional blood-based assay, can promptly evaluate the treatment response of lymphoma patients, and the MTB status showed an excellent correlation with clinical outcome. The dynamic change of MTB exhibited a good prognostic power of lymphoma. It challenged the status quo of employing imaging as a sole standard for evaluating early treatment response.