Monitoring Treatment Response In Patients Research Articles

Longitudinal ctDNA measurements for treatment response monitoring in patients with metastatic colorectal cancer undergoing systemic therapy: The ORCA trial.

220 Background: Precise monitoring of treatment response may support and improve treatment decision-making in patients with metastatic colorectal cancer (mCRC). The PLCRC-ORCA study aimed to explore the clinical applicability of personalized ctDNA testing for treatment response monitoring in patients with mCRC. Methods: The prospective, observational ORCA study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). After informed consent, blood samples were collected before initiating first line of treatment (baseline) and subsequently every 8-9 weeks during routine clinical care. ctDNA levels were analyzed using a clinically validated, personalized, tumor-informed 16-plex PCR NGS assay (Signatera™, Natera, Inc). Results: The majority of patients (45/49) had blood samples collected at both baseline and the first on-treatment time point. At baseline, 43/45 (95.6%) patients were ctDNA-positive with a median concentration of 63.5 mean tumor molecules per mL (MTM/mL; range 0.08 to 16,200). In a multivariate linear regression model including metastatic site at baseline and resection status of the primary tumor, ctDNA levels at baseline were lower in patients with metastatic disease limited to the lung (n = 4; p < 0.001) or peritoneum (n = 6; p = 0.002) compared to patients with liver-limited metastases. Moreover, primary tumor resection was independently associated with lower levels of ctDNA at baseline (p = 0.05). At the first measurement on-treatment, 13/45 patients (28.9%) were ctDNA-negative and 32/45 (71.1%) patients were ctDNA-positive with ctDNA levels ranging from 0.04 to 318 MTM/mL. Reduction in ctDNA levels relative to baseline was observed in 42/45 (85.7%) patients while two patients exhibited increased ctDNA levels. One patient had undetectable ctDNA levels at baseline and on treatment. Among the 30 patients with detectable but reduced ctDNA levels on treatment, the median ctDNA levels decreased 55-fold (95% CI: 26–600). Conclusions: The levels of ctDNA in patients with mCRC are influenced by the metastatic site and are lowest among patients with metastases limited to the lung and peritoneum. Our data suggest that clinical applications of ctDNA testing for treatment response monitoring should take the baseline ctDNA levels into account when interpreting ctDNA dynamics. Correlation of ctDNA status with radiological treatment response is underway and will be reported during the conference.

Predictive Value of Circulating Tumor DNA (ctDNA) and Neutrophil To Lymphocyte Ratio (NLR) in Patients with Colon and Gastric Cancer: Case Reports

Monitoring disease progression and adjusting treatment based on biomarkers is essential in oncology. Circulating tumor DNA (ctDNA) is an emerging biomarker used for early detection of recurrence and monitoring response to treatment, while the neutrophil/lymphocyte ratio (NLR) is a recognized inflammatory marker for oncological prognosis. The aim of this study was to report two clinical cases and to assess the efficiency of ctDNA and NLR in guiding cancer treatments. These cases indicated that ctDNA testing may be more accurate than NLR assessment for monitoring treatment response in patients with colon or gastric cancer. Consequently, ctDNA may serve as a pivotal instrument in the surveillance and customization of oncological treatments, transcending the constraints of conventional inflammatory markers.

Pediatric Neuroimaging of Multiple Sclerosis and Neuroinflammatory Diseases.

Using a pediatric-focused lens, this review article briefly summarizes the presentation of several demyelinating and neuroinflammatory diseases using conventional magnetic resonance imaging (MRI) sequences, such as T1-weighted with and without an exogenous gadolinium-based contrast agent, T2-weighted, and fluid-attenuated inversion recovery (FLAIR). These conventional sequences exploit the intrinsic properties of tissue to provide a distinct signal contrast that is useful for evaluating disease features and monitoring treatment responses in patients by characterizing lesion involvement in the central nervous system and tracking temporal features with blood-brain barrier disruption. Illustrative examples are presented for pediatric-onset multiple sclerosis and neuroinflammatory diseases. This work also highlights findings from advanced MRI techniques, often infrequently employed due to the challenges involved in acquisition, post-processing, and interpretation, and identifies the need for future studies to extract the unique information, such as alterations in neurochemistry, disruptions of structural organization, or atypical functional connectivity, that may be relevant for the diagnosis and management of disease.

Abstract PO5-13-12: Personalized circulating tumor DNA testing for recurrence detection and treatment response monitoring in patients with metastatic invasive lobular carcinoma

Abstract Introduction Metastatic invasive lobular carcinoma (mILC) presents unique challenges during treatment response monitoring. A higher frequency of metastases to the bone, gastrointestinal tract, uterus, meninges, ovary, and diffuse serosal involvement is observed in mILC. The challenge with mILC is that they can be difficult to detect clinically and radiographically, and consequently clinical progression can be difficult to determine with conventional imaging modalities like CT Scans, thus precluding many patients with mILC from enrolling into clinical trials. Therefore more accurate biomarkers are needed to better assess response to treatment in real time. In this study, we demonstrate the feasibility of longitudinal ctDNA testing for treatment response monitoring in patients with mILC. Methods In this real-world study, longitudinal plasma samples (n=219) from 60 patients with mILC, treated across 52 independent clinics between 7/22/21 and 6/15/23, were analyzed. A personalized, tumor-informed ctDNA assay (SignateraTM bespoke, mPCR-NGS assay) was used for detection and quantification of ctDNA in plasma samples. Results In this cohort, the median patient age at diagnosis of metastatic disease (baseline) was 62.9 years (range: 32.2-79.7). Of the 60 patients, 41 (68%) had ER+PR+HER2-, 7 (12%) ER+PR-HER2-, 4 (7%) ER+PR+HER2+, 2 (3%) ER+PR-HER2+, 1 (2%) triple negative breast cancer; receptor status was not available for 5 (8%) patients. CDH1 (75%) and PIK3CA (42%) were observed to be the top two genes with somatic, nonsynonymous mutations. Mutations in TP53 and TBX3 were observed in 13% of patients, mutations in AKAP9, IGFN1, RBM26, and RFC3 in 10% of patients, and mutations in ESR1 in 6.7% of patients. At variant level, PIK3CA p.H1047R (22%) and RBM26 p.Q701Tfs*23 (10%) were the top two somatic variants identified. The most common CDH1 variant, p.Q23*, was found in 5% of the cases. Of the 60 patients, 37 (61.7%) were ctDNA-positive at all time points while on treatment (chemotherapy/endocrine therapy/targeted therapy) with the first time point collected at a median of 6.7 months (range: 2.5-2307 months) from baseline. Of these 37, imaging/biopsy results after baseline were available for 32 patients, 86% (27/32) of whom progressed. Thirty-two of 37 persistently ctDNA-positive patients had serial ctDNA measurements available, of which 14 (43%) had significant increase in ctDNA levels (average: 47-fold increase, standard deviation: 98) from first to last time points. At some point during their care ctDNA was detectable in all (n=51) patients with evidence of clinical progression. Of the 60 patients, 14 (23.3%) were ctDNA-negative at all time points tested. None of the 14 persistently ctDNA-negative patients had evidence of disease recurrence or progression at the time of initial testing or throughout ctDNA monitoring. The first ctDNA time point was collected at a median of 33.1 months (range: 0.68-92 months) from baseline for these patients,a median of 3 time points was tested per patient (1-12). Of the remaining 9/60 patients, 3 (33%) had sustained ctDNA clearance for a median of 46 days (range: 0-224 days) in response to treatment, and 2 (22%) were initially ctDNA-negative but turned positive 105 and 156 days later, indicating potential resistance to treatment and molecular progression. Additional 4/9 (44%) had ctDNA levels consistently low levels (average: 0.42 mean tumor molecules/mL) while on treatment for a median of 260 days (range: 217-442) and showed no evidence of progression. Conclusions ctDNA status and dynamics correlate well with clinical status of patients with mILC, as determined by conventional monitoring tools such as imaging and biopsy. Our results indicate that personalized, tumor-informed, longitudinal ctDNA testing may serve as a useful tool for detection of progression and monitoring treatment response in mILC patients. Citation Format: Steffi Oesterreich, Antony Tin, Samuel Rivero-Hinojosa, Janie Fielder, Jenifer Ferguson, Ekaterina Kalashnikova, Angel Rodriguez, Minetta Liu, Adrian Lee. Personalized circulating tumor DNA testing for recurrence detection and treatment response monitoring in patients with metastatic invasive lobular carcinoma [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 PO5-13-12.

Abstract PO4-15-12: Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer

Abstract Introduction Longitudinal ctDNA testing offers a minimally invasive approach for monitoring treatment response in patients with breast cancer (BC). In this study, we evaluated whether serial ctDNA testing during neoadjuvant therapy (NAT) can provide an early indication of treatment response or resistance and disease progression. Methods In this real world study, longitudinal blood samples collected from 159 patients with stage I-III BC were analyzed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS assay). Of the 159 patients, 157 received standard of care NAT; the remaining 2 patients were treated with endocrine therapy only in the neoadjuvant setting. Blood samples were collected at the time of diagnosis from 71 patients (baseline) and longitudinally during treatment from 159 patients (median time between time points: 1.5 months). ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes available at the time of data cut off. Results At baseline, ctDNA was detected in 72% (51/71) of patients. Baseline ctDNA detection rates varied based on histologic subtypes: 82% (28/34) in patients with triple negative breast cancer, 88% (15/17) in patients with HER2+ disease and 40% (8/20) in patients with ER+HER2- BC. ctDNA was detectable at baseline in 72% (26/36) of patients with clinical T1-2 disease and 92% (11/12) of patients with T3-4 disease. ctDNA was detected in 64% (16/25) of patients with clinical N0, whereas among patients with at least one positive lymph node, ctDNA was detected in 92% (22/24). At baseline, 65% (31/48) of patients with low/intermediate-grade disease were ctDNA-positive, while 81% (25/31) of patients with high-grade disease were ctDNA-positive. Similarly, 83% (24/29) of patients with high levels (>20%) of Ki67 expression had detectable ctDNA prior to treatment initiation, while only 22% (2/9) of those with low level (< 20%) of Ki67 expression had ctDNA detected. Surgical outcomes were available for 22 patients of whom 16 had achieved pathologic complete response (pCR). While 3/16 pts were ctDNA negative at baseline, all of the remaining cases except one patient with baseline ctDNA detection and serial measurements (11/12) became ctDNA negative by the end of two months of treatment. Despite achieving pCR, one patient with inflammatory ER+HER2+ BC remained ctDNA positive before and after the surgery, which informed a change in the adjuvant treatment strategy. Among those with residual disease (pT1c-T3), 28% (7/25) remained ctDNA positive after two months of NAT. Association between ctDNA dynamics and surgical outcomes of the remaining 137 patients will be presented at the time of the conference. Conclusions This real world study demonstrates the prevalence of ctDNA detection and dynamics in patients with eBC treated with NAT. ctDNA monitoring during NAT can facilitate real-time assessment of treatment response and serve as an early indicator of subsequent pCR to NAT. Citation Format: Mridula George, Trishala Meghal, Coral Omene, Ekaterina Kalashnikova, Janie Fielder, Nisha Ohri, Shicha Kumar, Valeria Burkovskaya, Preena Patel, Ashley Young, Melanie Racenstein, Tinamarie Bauman, Wassim Mchayleh, Deborah Toppmeyer, Shridar Ganesan, Barry Rosen, Angel Rodriguez, Minetta Liu. Personalized circulating tumor DNA monitoring to predict response to neoadjuvant therapy in patients with early-stage breast cancer [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 PO4-15-12.

Abstract 3673: Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial

Abstract Background: Accurate monitoring of treatment response in patients with metastatic colorectal cancer (mCRC) is important to decide when to adjust treatment regimen or to proceed to local therapy of metastases. At present, clinical response is determined by computed tomography (CT) imaging-based assessment of changes in tumor size. However, this monitoring approach is constrained by limited sensitivity in detecting lymph node and peritoneal metastases, as well as inter-reader variability. Detection of circulating tumor DNA (ctDNA) is indicative of the amount of neoplastic cells and may have added clinical value to CT imaging for assessment of treatment response and guidance in treatment decision making in mCRC patients. We recently developed a tumor mutation-independent ctDNA test that utilizes low-coverage whole genome sequencing to analyze the plasma cell-free DNA (cfDNA) fragmentome to measure the ctDNA tumor fraction: the DELFI-tumor fraction (DELFI-TF) score. Aim: The DOLPHIN study aims to investigate whether the DELFI-TF ctDNA assay can provide a sensitive, affordable and broadly applicable ctDNA test to monitor treatment response of mCRC patients. Methods: The prospective, observational, multi-center DOLPHIN study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). Clinical data, images and blood samples from 400 patients receiving systemic therapy in 8-10 Dutch hospitals will be collected. Blood samples will be drawn longitudinally in conjunction with regularly scheduled CT imaging. Plasma cfDNA will be analyzed for tumor-specific fragmentation patterns using the DELFI-TF score. Droplet digital PCR ctDNA-testing of RAS/RAF hotspot mutations will be performed as reference, when feasible. Primary endpoint is the association between ctDNA changes and clinical response. Secondary endpoints are the association between ctDNA changes and radiological response according to RECIST and to serum carcinoembryonic antigen (CEA) at various time points during systemic treatment, lead time of ctDNA-testing compared to CT imaging to detect progressive disease, and the prognostic value of longitudinal ctDNA-testing. Results: Since the inclusion of the first patient in March 2023, 117 patients have been included in the DOLPHIN study (November 2023). Seven hospitals throughout the Netherlands are currently open for patient inclusion and more sites have been approached to participate. Discussion: The DOLPHIN study will assess the added clinical value of longitudinal ctDNA-testing in treatment response monitoring of mCRC patients and whether imaging can be complemented and/or partly replaced by ctDNA-testing. The results of this study may lead to novel strategies for monitoring treatment response and to ctDNA-guided treatment decision making in mCRC patients. Citation Format: Denise E. van Steijn, Remond J. Fijneman, Geraldine R. Vink, Jeanine M. Roodhart, Miriam Koopman, Max J. Lahaye, Manon N.G. Braat, Veerle M. Coupé, Daan A. van den Broek, Gerrit A. Meijer, Haoyue Wang, Marjolein J. Greuter, Birgit I. Lissenberg-Witte, Lorenzo Rinaldi, E Peters, Alissa Konicki, Nicholas C. Dracopoli, Niels F. Kok, Victor E. Velculescu. Monitoring treatment response in patients with metastatic colorectal cancer using cfDNA fragmentomics testing: The DOLPHIN trial [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 3673.

1908P Utility of circulating tumor (ct)DNA testing for molecular residual disease (MRD) detection and treatment response monitoring in patients (pts) with renal cell carcinoma (RCC)

1908P Utility of circulating tumor (ct)DNA testing for molecular residual disease (MRD) detection and treatment response monitoring in patients (pts) with renal cell carcinoma (RCC)

Longitudinal Monitoring of Circulating Tumor DNA to Assess the Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Genitourinary Malignancies.

Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.

Prognostic value of the combined preoperative plasma fibrinogen and systemic inflammatory indexes in ESCC patients

The prognostic indexes based on the combination of preoperative fibrinogen and systemic inflammatory indexes may have greater predictive value in esophageal squamous cell carcinoma (ESCC). It was found that the predictive ability of F-NLR was more valuable than other systemic inflammatory indexes. The preoperative F-NLR score was closely related to the TNM stage, and could be used as an important independent prognostic index for patients with ESCC. Then the nomogram model constructed by F-NLR and TNM stage had higher prognostic ability than that of AJCC stage for ESCC patients. Preoperative F-NLR is a new independent prognostic index and a potential marker for treatment response monitoring in patients with ESCC.

Evaluation of the neurofilament light chain as a biomarker in children with spinal muscular atrophy treated with nusinersen

BackgroundThis study aimed to evaluate the neurofilament light chain (NfL) as a biomarker for treatment responses in children with a broad spectrum of spinal muscular atrophy (SMA) under nusinersen treatment. MethodWe measured NfL levels in serum (sNfL) and cerebrospinal fluid (cNfL) in nusinersen-treated patients with SMA and children without neurologic disorders. Correlations between cNfL and sNfL levels and motor function scores were analyzed. ResultssNfL and cNfL levels were measured in eight patients with SMA (SMA type 1, n = 3; SMA type 2, n = 5). sNfL levels were strongly correlated with cNfL levels regardless of the SMA subtype (r = 0.97, P < 0.001). Patients with SMA type 1 had higher baseline cNfL and sNfL levels before treatment initiation than those with SMA type 2 and neurologically healthy children. In patients with acute stage of SMA type 1 and 2, the NfL level rapidly decreased during the nusinersen treatment loading phase followed by stabilization at a lower plateau level. In contrast, in a patient with a chronic stage of SMA type 2, the NfL level remained within the normal range with no apparent downward trend. Motor function scores showed a tendency toward an inverse correlation with NfL levels in patients with acute stage although not in patients with chronic stage. ConclusionscNfL and sNfL levels can be promising biomarkers for monitoring treatment response in patients within their acute stage, particularly in SMA type 1, although not in patients with a chronic stage of SMA type 2.

Prognostic Value of Erythroblastic Leukemia Viral Oncogene Homolog 2 and Neuregulin 4 in Hepatocellular Carcinoma.

Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC.

Diagnostic Performance of 68Ga-PSMA-11 Positron Emission Tomography/Computed Tomography to Monitor Treatment Response in Patients with Metastatic Prostate Cancer: The Concordance Between Biochemical Response and Prostate-specific Membrane Antigen Results

BackgroundTreatment response is traditionally monitored using prostate-specific antigen (PSA) and conventional imaging in patients with metastatic prostate cancer (mPCa). ObjectiveTo assess the diagnostic performance of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) when monitoring mPCa patients receiving systemic treatment and also to investigate the concordance between PSMA PET response according to the PSMA PET progression (PPP) criteria and biochemical response. Design, setting, and participantsA total of 96 patients with 68Ga-PSMA-11 PET/CT-detected mPCa at baseline PSMA PET/CT (bPSMA) who underwent at least one follow-up scan after receiving systemic treatment were included in the study. PSA levels at bPSMA and follow-up PSMA PET (fPSMA) scans were recorded. The PPP criteria were used to define PSMA progression. Biochemical progression was defined as ≥25% increase in PSA. PSMA PET and PSA responses were dichotomized into progressive disease (PD) versus non-PD, and the concordance between PSA and PSMA responses was evaluated. Outcome measurements and statistical analysisThe concordance between PSA and PSMA PET responses was presented using frequencies, percentages, and Cohen’s kappa test. Results and limitationsA total of 345 serial PSMA PET/CT (96 bPSMA and 249 fPSMA) scans were evaluated. The positivity rates of PSMA PET scans for PSA levels of <0.01, 0.01–0.2, 0.2–4, and >4 ng/ml were 55.6%, 75.0%, 100%, and 98.8%, respectively. PSA and PSMA responses showed moderate-to-high concordance (Cohen’s κ = 0.623, p < 0.001). PSA-PSMA discordance was detected in 39 scans (17%). The most common cause of discordance was the discordant results between different metastatic lesions (16/28, 57.1%) in patients with PPP without PSA progression and local progression in prostate (n = 7/11, 63.6%) in patients with PSA progression without PPP. ConclusionsPSMA PET/CT showed very high detection rates of malignant lesions even at very low PSA values and showed significant concordance with PSA response when monitoring treatment response in patients receiving systemic treatment for mPCa. Patient summaryThis study describes that prostate-specific membrane antigen positron emission tomography (PSMA PET), a new sensitive imaging tool, can detect malignant lesions even at very low prostate-specific antigen values when monitoring metastatic prostate cancer. The PSMA PET response and biochemical response showed significant concordance, and the reason for discordant results seems to be the different responses of metastatic lesions and prostatic lesions to systemic treatment.

68GaPSMA-11 PET/CT to monitor treatment response in patients with metastatic prostate cancer: The concordance between biochemical response and PSMA response.

49 Background: The aim of this study was to assess whether PSMA PET is associated with flares, with discordant results in regard to biochemical response, and with positivity rates at low PSA values while monitoring metastatic prostate cancer (mPCa) receiving systemic treatment. Methods: A total of 96 patients with PSMA PET-detected mPCa who underwent at least one follow-up scan after receiving systemic treatment were included in the study. PSA levels at baseline PSMA PET-CT (bPSMA) and follow-up PSMA PET scans (fPSMA) were recorded. Any significant PSMA uptake at prostate and/or metastatic lesions were considered PSMA positivity. PSMA response were decided according to PSMA PET Progression (PPP) criteria . Biochemical progression was defined as ≥25% increase in PSA (1 ng/dL was the minimal starting value). PSMA PET and PSA response were dichotomized into progressive disease (PD) vs non-PD. Discordant responses among different metastases and prostate were defined as the condition when some metastatic lesions (or prostate) are responding (CR or PR) to systemic treatment while others had progressed. Results: A total of 346 serial PSMA PET/CT (96 bPSMA and 249 fPSMA) scans were evaluated. The median time between consecutive PSMA PET scans was 6.3 months (IQR: 4.7 – 10.6) Overall PSMA PET positivity rate of fPSMA scans was 88.4% (220/249). PSMA positivity rates according PSA levels were summarized. PPP was detected in 93 cases (37.8%) and biochemical progression was observed in 73 cases (30.2%). PSA and PSMA responses were highly concordant (Cohen’s K=0.623, p&lt;0.001). PSA-PSMA discordant responses were detected in 39 scans (17%). The possible causes could be identified in 34 of 39 scans (87%) while no obvious reason for discordance could be shown in the remaining 5. Conclusions: PSMA PET/CT showed very high detection rates of malignant lesions even in very low PSA values when monitoring treatment response in patients receiving systemic treatment for mPCa. PSA and PSMA responses were highly concordant. In cases with discordance, the reason seems to be the discordant behaviour of intraprostatic and metastatic lesions and not necessarily PSMA flares. PSMA PET is a promising biomarker to assess treatment response in patients with mPCa. [Table: see text]

Quantitative analysis of superb microvascular imaging for monitoring tumor response to chemoradiotherapy in locally advanced cervical cancer.

As an ultrasound (US) image processing method, superb microvascular imaging (SMI) extracts and visualizes flow signals from vessels through advanced clutter suppression technology. We investigated the feasibility of SMI in monitoring treatment response in patients with locally advanced cervical cancer (LACC) undergoing chemoradiotherapy (CRT). Forty-nine patients underwent CRT and received SMI examination at 3 time points: before therapy (baseline), 3 weeks during, and 1 month after CRT. The maximum tumor diameter (Dmax), vascularity index (VI), and their percentage changes (ΔDmax and ΔVI) were calculated. ΔDmax was compared with MRI results as the reference standard. Based on the MRI findings, 44 were classified as complete response (CR) group and 5 as partial response (PR) group. The Dmax and ΔDmax showed decrease in CR and PR groups at 3 weeks during CRT (P< 0.05), but no significant difference between the two groups (P > 0.05). Compared to the baseline, significant decrease in VI and ΔVI were observed at during and after treatment in the two groups (P< 0.05). Moreover, there were significant differences in VI and ΔVI at 3 weeks during CRT between the CR and PR groups (P< 0.05). ΔVI at 3 weeks during CRT showed a better predictive performance for responder prognosis than VI (AUC = 0.964, AUC = 0.950, respectively, P = 0.001), with a cut-off value of 41.6% yielding 100% sensitivity and 86.4% specificity. The SMI parameters (VI and ΔVI) have potential for monitoring treatment response in LACC.

Evaluation of the role of optical coherence tomography angiography in monitoring treatment response in patients with neovascular age-;1;related macular degeneration

Aim The aim was to assess the role of optical coherence tomography angiography (OCTA) in the diagnosis, assessment of activity, and monitoring the treatment response of choroidal neovascularization secondary to age-related macular degeneration (AMD). Methods Prospective, interventional case series of eyes that were diagnosed with active neovascular AMD. Spectral-domain optical coherence tomography (SD-OCT) and OCTA were done at baseline after intravitreal antivascular endothelial growth factor (anti-VEGF) treatment to determine OCTA sensitivity in the detection of activity in relation to SD-OCT findings and its specificity following intervention. Results Twenty-five eyes were included, of which 20 eyes were imaged successfully by OCTA. The diagnostic sensitivity of OCTA in those eyes was found to be 75%, and its sensitivity in the assessment of neovascular activity was 80 and 60%, before and after anti-VEGF therapy, respectively, whereas its specificity after anti-VEGFs therapy was 100%. Conclusion Although SD-OCT continues to be the gold-standard for noninvasively diagnosing and tracking neovascular AMD treatment response, OCTA may offer a noninvasive option that can support treatment selection throughout follow-up and guide efficient therapeutic approaches. Author contributions: All authors contributed to the construction of idea and question of the research with complete assessment and managements of all the study group. Hebatalla S. Makled: Assessment of the patients with follow-up, doing OCTA for the patients with interpretation, data collection and analysis, and manuscript writing and revision. Ahmad Almabrook Sahban: recruitment of patients with consent acquisition, doing OCTA for the patients, treatment with follow-up of the patients, collection and analysis of data, and manuscript writing. Ayman M Khattab: Patients assessment, decision making and follow-up of patients treatment, OCTA interpretation, collection and analysis of data, and manuscript writing and revision. Ashraf Ahmed Nossair: Patients assessment with follow-up, OCTA interpretation, data collection and analysis, and manuscript writing and revision.

Evaluation of the Feasibility of using Urine IP-10 as a Biomarker to Assess the Treatment Response to the Pharmacotherapy of Active Pulmonary Tuberculosis in the Intensive and Continuation Phase

Introduction: Tuberculosis is well known for its chronicity, treatment failures, and drug resistance. Interferon-gamma Inducible Protein 10 (INF IP-10) has been reported to be relatively specific for assessing the severity of tuberculosis, and it can be easily estimated in both urine and blood. Objective: To determine whether urinary IP-10 levels can be used as a biomarker for monitoring treatment response in patients with active Pulmonary Tuberculosis (PTb). Materials and Method: 40 participants were enrolled. Urine samples were collected at diagnosis, at the end of 1st, 2nd &amp; 6 months. Sputum smear and culture were done at diagnosis, end of 2nd and 6th month. IP-10 levels were estimated and correlated with treatment response. Results: All the patients were positive for Mycobacterium Tuberculosis (Mtb) at baseline. At the end of 2nd and 6 months, all of them became smear and culture-negative. The mean urine IP-10 values at diagnosis, end of 1st, 2nd and 6th month were 10.76 ± 2.76, 15.37 ± 3.09, 21.83 ± 4.10 and 8.38 ± 2.46 pg/dl. IP-10 levels increased following intensive therapy and decreased significantly towards the end of treatment. The mean values of IP-10 at baseline, at the end of 2nd and 6th month were correlated with mean scores of clinical symptoms at respective time points. Pearson’s linear correlation was done which showed that IP-10 values and clinical symptoms did not correlate with each other with p=0.836. Conclusion: Increase in IP-10 level during the intensive therapy indicates the response to treatment and bacterial clearance. Hence urinary IP-10 can be considered as biomarker for monitoring treatment response in PTb patients.

HLA-DR+ CD38high Expression in T Cells Is Excellent in Quantifying the Amplitude of T-Cell Activation in a Spectrum of Hyperinflammatory Disorders Including HLH

Introduction: T cell activation is the hallmark of several hyperinflammatory states such as HLH and immune dysregulation disorders like LRBA deficiency. Identifying T-cell activation and quantifying the amplitude of T-cell activation is critical for diagnosis, management, and monitoring treatment response in patients with hyperinflammatory and immune regulatory disorders. Soluble Interleukin 2 Receptor (sIL2R) is one of the established systemic T-cell activation markers for diagnosing and monitoring HLH and other hyperinflammatory disorders. However, the clinical availability of sIL2R testing is limited, and it may not be a reliable marker of T-cell activation in patients with eosinophilia and T-cell lymphoma. A recent study by Chaturvedi et.al has demonstrated the utility of flow-based T-cell activation assessment in differentiating HLH from sepsis. However, its utility in defining and quantifying T-cell activation across the hyperinflammatory spectrum and its correlation with sIL2R has not yet been established. Methods: A total of 125 samples were collected either at disease onset (n = 81) or at follow-up (n = 44) from 85 human subjects. Paired plasma sIL2R and T-cell activation markers were prospectively evaluated in patients with suspected HLH (n = 79) or immune dysregulation disorders (n = 46). Out of 85 patients, 21 patients were diagnosed with either primary HLH (p-HLH), Epstein-Barr virus infection-associated HLH (EBV-HLH), malignancy-associated HLH (m-HLH), or macrophage activation syndrome (MAS). The rest of the patients were diagnosed with either sepsis, multisystem inflammatory syndrome in children (MIS-C), hyperinflammatory conditions, hepatitis, or acute liver failure. Flow cytometry-based T-cell activation was evaluated in different T-cell sub-compartments by the co-expression of HLA-DR and CD38 surface markers. Plasma sIL2R levels and CXCL9 (a chemokine driven by IFN-g) were determined independently in CLIA certified clinical diagnostic laboratory. Research personnel who analyzed the flow cytometry data were blinded to the corresponding sIL2R test results and clinical diagnosis. Longitudinal follow-up was performed for a subset of patients with HLH or immune dysregulation with evidence of T-cell activation. We also evaluated T-cell activation in 30 healthy controls (HC) to establish a reference range. In addition, the correlation between T-cell activation markers with plasma levels of sIL2R and CXCL9 was also investigated. Results: Evaluation of T-cell activation measured by HLADR+CD38high in HCs and different hyperinflammatory/ immune regulatory disorders revealed that HCs have less than 8% of T-cell activation in CD8+ T effector memory (TEM) and less than 4% for activation in the CD4+ TEM compartments. In patients with suspected hyperinflammatory/ immune regulatory disorders, we identified significant correlation of direct T-cell activation with plasma sIL2R level in different T-cell subsets, CD3 (r = 0.44, p < 0.0001), CD4 (r = 0.41, p < 0.0001), CD8 (r = 0.45, p <0.001), CD4 TEM (T effector memory) (r =0.53, p < 0.001), and CD8 TEM (r =0.53, p < 0.0001). The strongest correlation between HLADR+CD38high with sIL2R level was noted in CD4+ TEM and CD8+ TEM compartments (Figure 1). The correlation is even more robust at disease onset (r = 0.69, p <0.0001 for CD4+ TEM and r = 0.64, p < 0.0001 for CD8+ TEM). However, at follow up, only activation in CD8+ TEM correlated with sIL2R levels (r = 0.4, p = 0.0069). Moreover, T-cell activation in CD8+ TEM correlated well with CXCL9 and ferritin levels. Among the cohort of patients with the confirmed final diagnosis, we found that both p-HLH and EBV-HLH have CD8+ TEM activation > 70%, whereas MAS and m-HLH have a median T cell activation of 37.8% (10.5-67) and 48.1% (4.9-80.6) respectively. Immune dysregulation patients had T-cell activation range from 8.0 to 46.0 % and sepsis group has 0% to 10.8% (Figure 2). A similar trend was also validated using corresponding plasma sIL2R levels in different hyperinflammatory states. Conclusions: Flow cytometry-based direct assessment of HLADR+CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulations disorders. If validated, this could be used as a real-time assessment of T-cell activation at disease onset and monitoring response to therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P055: Validation of the tumor cell-specific rearranged IgG-encoding circulating cell-free DNA for the treatment response monitoring in patients with classic Hodgkin lymphoma

Table 1: Clinical characteristics of patients Background: Detection and longitudinal monitoring of the cell-free circulating tumor-specific DNA (ctDNA) in plasma of cancer patients is a potent tool for treatment response assessment and detection of the early disease recurrence. There is a number of the next-generation sequencing (NGS) panels for analysis of the commonly mutated genes in tumors of classic Hodgkin lymphoma (cHL) patients, which are being validated for clinical use. The Cleveland Clinic team, in collaboration with Adaptive Biotechnologies, is exploring if longitudinal assessment of ctDNA encoding the patient- and tumor cell-specific rearranged heavy or light (kappa/lambda) chain IgG (r-IgH/r-IgK/L, could be used for the treatment response and early recurrence monitoring in cHL patients. Methods: Enrolled are patients (9–99 y) with newly diagnosed and previously untreated cHL. First, the diagnostic biopsy specimen and the pre-treatment plasma are tested for concordant presence of dominant r-IgH/r- IgK/L ctDNA sequences. Sequence dominance and suitability for tracking is determined according to the Adaptive Biotechnologies’ diagnostic algorithm validated for other B cell neoplasms. If dominant r-IgH/r-IgK/L sequence(s) is detected, the patient plasma is serially tested during and following completion of therapy. Results: Pilot results on first 4 patients are presented. Patients’ clinical characteristics are summarized in Table 1. P1 had a single dominant r-IgH ctDNA sequence; P2 had two dominant r-IgH ctDNA sequences; P3 had two r-IgH and one dominant IgK ctDNA sequences; the latter was chosen for serial tracking; P4 had a single dominant r-IgH ctDNA sequence. In P1 and P2, the concentration of ctDNA precipitously declined below detectable threshold following completion of the first two cycles of therapy, and remained undetectable through the end of treatment. These laboratory changes correlated well with the treatment response assessed by functional imaging. For P2 and P3, the in-treatment samples are in process of acquisition. Conclusion: The preliminary results of this pilot project demonstrate feasibility of establishing trackable ctDNA sequences encoding IgG heavy or light chain, with intra- and interpatient clonotypic heterogeneity of the dominant sequences. Correlation between results of the functional imaging treatment assessment and detectable quantity of ctDNA in plasma was observed. Further testing is underway.

CT-008 Relationship Between LDH and Mg in Monitoring of Hematological Malignant Diseases

Magnesium plays a key role in regulating many cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways. The objective of the study was to evaluate the correlation between the serum levels of lactate dehydrogenase (LDH) and magnesium (Mg) in patients diagnosed with hematological malignant diseases. We analyzed a cohort of patients (n=75) comprising men (n=36) and women (n=39), every group with a mean age of 57 years, who had blood cancer and were admitted to the oncology department in a 3-month period. We performed hematological and biochemical tests and determined LDH and serum Mg levels, which can serve as markers for monitoring the progression of malignancies. The complete blood count with differential count and biochemistry samples were used for the patients to establish the types of blood cancer diseases. An initial panel of monoclonal antibodies was used to determine the immune phenotypes of the subgroups of differentiated T cells and B cells by flow cytometry. Among the patients, 43 were diagnosed with chronic lymphocytic leukemia, 14 were diagnosed with acute promyelocytic leukemia, and 18 were diagnosed with chronic myelogenous leukemia. The biochemical parameters were measured by running a Vitros 250 dry chemistry analyzer (Johnson & Johnson, USA) using the slides for multi-layer spectrophotometry measurements. Normal levels of Mg with moderately increased LDH levels were observed in all patients who had cancer in the regression phase following good responses to a specific cancer therapy. In this study, 12 patients (16%) displayed high levels of serum Mg (range=2.6-3.27 mg/dL; mean value=2.89 mg/dL). The levels of serum LDH were also evaluated in patients newly diagnosed with cancer and in patients with unfavorable responses to the cancer therapy (range=240-1,330 U/L; mean value=787 U/L; SD=1.33; P=0.002). The total serum levels of LDH and Mg can be used as markers for monitoring treatment responses in patients with neoplasm with or without metastasis.

Evaluating the use of synthetic T1-w images in new T2 lesion detection in multiple sclerosis.

The assessment of disease activity using serial brain MRI scans is one of the most valuable strategies for monitoring treatment response in patients with multiple sclerosis (MS) receiving disease-modifying treatments. Recently, several deep learning approaches have been proposed to improve this analysis, obtaining a good trade-off between sensitivity and specificity, especially when using T1-w and T2-FLAIR images as inputs. However, the need to acquire two different types of images is time-consuming, costly and not always available in clinical practice. In this paper, we investigate an approach to generate synthetic T1-w images from T2-FLAIR images and subsequently analyse the impact of using original and synthetic T1-w images on the performance of a state-of-the-art approach for longitudinal MS lesion detection. We evaluate our approach on a dataset containing 136 images from MS patients, and 73 images with lesion activity (the appearance of new T2 lesions in follow-up scans). To evaluate the synthesis of the images, we analyse the structural similarity index metric and the median absolute error and obtain consistent results. To study the impact of synthetic T1-w images, we evaluate the performance of the new lesion detection approach when using (1) both T2-FLAIR and T1-w original images, (2) only T2-FLAIR images, and (3) both T2-FLAIR and synthetic T1-w images. Sensitivities of 0.75, 0.63, and 0.81, respectively, were obtained at the same false-positive rate (0.14) for all experiments. In addition, we also present the results obtained when using the data from the international MSSEG-2 challenge, showing also an improvement when including synthetic T1-w images. In conclusion, we show that the use of synthetic images can support the lack of data or even be used instead of the original image to homogenize the contrast of the different acquisitions in new T2 lesions detection algorithms.