Detection Of Disease Progression Research Articles

Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression. The GENCOMS method relies on robust natural history data and/or placebo arm data from DMT trials. Validated scales that are core to the disease process have been identified, and item level data obtained to standardize the response outcomes from 0 (best possible score) to 1 (worst possible score). A partial least squares regression analysis was conducted with temporal change as the dependent variable and change scores in standardized items as the explanatory variables. The derived model coefficients constitute a weighted sum of items that most effectively measure disease progression. The resultant composite scale was optimized to detect disease progression and can be examined in a range of slow or fast progressing populations. The scale can be used in studies with comparable patient populations as an endpoint optimized to measure disease progression and therefore ideally suited to assess treatment effects in DMTs. The methodology presented here provides a generalizable framework for developing composite scales in the assessment of neurodegenerative disease progression and evaluation of DMT effects. By objectively selecting and weighting items from previously validated measures based solely on their sensitivity to disease progression, this methodology allows for the creation of a more responsive measurement of clinical decline. This heightened sensitivity to clinical decline can be utilized to detect modest yet meaningful treatment effects in the early stages of neurogenerative diseases, when it is optimal to begin a DMT.

Changes in saccadic intrusions over time as an objective biomarker to follow ALS disease progression

Objective: Saccadic Intrusions (SIs) are abnormal eye movements during gaze fixation. Studies have indicated the clinical relevance of SIs, especially of square wave jerks (SWJ) in ALS. We used a software-based platform to extract SIs as a part of an interventional drug trial. The objective was to examine SIs’ change over time as a potential biomarker of ALS disease progression. Methods: 28 ALS patients (61.95 ± 8.6 years) were assessed with the revised ALS Functional Rating Scale (ALSFRS-R) and with an oculometric test. Changes of SIs over time and correlations with ALSFRS-R and its bulbar subscale were calculated. A power calculation was conducted to understand the practical implications of results. Results: A significant increase of SWJ over trial duration was observed, with an increase in frequency (mean rise of 0.14 ± 0.28, p < 0.01), amplitude (0.001 ± 0.0016 degrees, p < 0.005), overall duration of SWJ (0.13 ± 0.25, in %, p < 0.01), and in their relative part out of all intrusions (0.18 ± 0.32, in %, p < 0.005). Negative correlations were found with the bulbar subscale (R=-0.43, −0.41, −0.39 and −0.47, respectively, p < 0.001). The required sample size for observing a 40% reduction in bulbar aspects when using the oculometric test (α = 0.05 and β = 0.8), was found to be 150 patients per arm, compared with 200 patients using the bulbar subscale. Conclusions: Evaluation of saccadic intrusions during fixation was able to detect disease progression over time, correlated with ALSFRS-R bulbar subscale. Eye movements can potentially serve as an objective biomarker in ALS clinical trials and reduce the required sample size to show clinical effect of therapies.

Accuracy of glomerular filtration rate estimation using creatinine and cystatin C for identifying and monitoring moderate chronic kidney disease: the eGFR-C study.

Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Primary, secondary and tertiary care. Adults (≥ 18 years) with stage 3 chronic kidney disease. Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. This trial is registered as ISRCTN42955626. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

METRADS-P vs. RECIST/PCWG criteria to detect disease progression in metastatic castration-resistant prostate cancer (mCRPC).

5070 Background: Radiographic Progression-free survival (rPFS) derived from Computer Tomography (CT) and Bone Scan (BS) using Prostate Cancer Working Group (PCWG) criteria is utilized as an intermediate clinical endpoint for overall survival (OS) benefit in mCRPC. Whole Body MRI (WBMRI) is emerging as a potentially superior response biomarker, allowing a more accurate assessment of bone marrow and soft tissue disease. We have now compared the performance of previously reported WBMRI criteria (MET-RADS-P) with PCWG criteria as a response biomarker for mCRPC, and this with overall survival (OS). Methods: We retrospectively analysed imaging data from mCRPC patients that 1) discontinued therapy based on PCWG criteria; 2) had contemporaneous WBMRI, CT, and BS at time-points according to PCWG. Soft tissue lesions were classified according to RECIST1.1 both on CT and WBMRI; bone lesions were classified on BS using PCWG criteria as non-PD (non-progressive disease), PD-U (PD unknown) &amp; PD (progressive disease) and on WBMRI using MET-RADS-P as non–PD (subclassified as partial response-PR &amp; stable disease-SD) &amp; PD, for each imaging time-point. We calculated % agreement between MET-RADS-P and PCWG across all time-points. Median PFS as per PCWG (rPFS) and METRADS-P (mPFS) and median OS according to METRADS-P response at 12 weeks was estimated by Kaplan Meier. Results: 100 cases (91 subjects received 100 lines of treatment, 100 baseline imaging &amp; 216 follow-up imaging assessments). For soft tissue disease, RECIST 1.1 and WBMRI assessments were concordant at 201 of 216 time-points (93.1%); the discordance was related to superior detection of local disease and liver metastases on WBMRI. Bone metastases assessments showed agreement in 37.5% time-points, with details as follows (% over BS category): 1) Negative BS (13 time-points): WBMRI 69.2% negative, 15.4% PR, 15.4% as PD; 2) Non-PD BS (154 time-points): WBMRI non-PD 51% (34.4% PR, 17.5% SD), 48.1% PD; 3) PD-U BS (40 time-points): WBMRI PD 90%; Non-PD 10% (1pt FLARE &amp; 3pt with subsequent concordant PD). At time of PD-U, 30 out of 40 pt (75%) discontinued treatment due to RECIST PD (24/40) &amp; clinical progression (6/40). 4) PD confirmatory BS (9 time-points) : WBMRI 100%PD. Median rPFS by PCWG was 4.9 months (m) (95%CI: 3.8-5.7); the median mPFS by MET-RADS-P was 2.8 months (2.6-3.9), with overall progression rate of 70% and 94% respectively. Non-PD by WBMRI at 12-weeks associated with longer OS when compared with PD by MRI (median OS: 17.9m (14.2-22.6) vs 14.4m (9.6-17.0) (crude log-rank test 0.0059). Conclusions: Regarding soft-tissue disease, MET-RADS-P detects progression earlier than RECIST in 4.2% time-points, while for bone metastases it detects progression earlier than PCWG at 51.9% of timepoints. WBMRI can better classify BS non-PD patients in PR, SD and PD. Response evaluation based on WBMRI is a prognostic factor in mCRPC.

Plasma-Derived Cell-Free DNA as a Biomarker for Early Detection, Prognostication, and Personalized Treatment of Urothelial Carcinoma.

Bladder cancer (BC) is one of the most common malignancies in the United States, with over 80,000 new cases and 16,000 deaths each year. Urothelial carcinoma (UC) is the most common histology and accounts for 90% of cases. BC management is complicated by recurrence rates of over 50% in both muscle-invasive and non-muscle-invasive bladder cancer. As such, the American Urological Association (AUA) recommends that patients undergo close surveillance during and after treatment. This surveillance is in the form of cystoscopy or imaging tests, which can be invasive and costly tests. Considering this, there have been recent pushes to find complements to bladder cancer surveillance. Cell-free DNA (CfDNA), or DNA released from dying cells, and circulating tumor DNA (ctDNA), or mutated DNA released from tumor cells, can be analyzed to detect and characterize the molecular characteristics of tumors. Research has shown promising results for ctDNA use in the BC care realm. A PubMed literature review was performed finding studies discussing cfDNA and ctDNA in BC detection, prognostication, and monitoring for recurrence. Keywords used included bladder cancer, cell-free DNA, circulating tumor DNA, urothelial carcinoma, and liquid biopsy. Studies show that ctDNA can serve as prognostic indicators of both early- and late-stage BC, aid in risk stratification prior to major surgery, assist in detection of disease progression and metastatic relapse, and can assess patients who may respond to immunotherapy. The benefit of ctDNA is not confined to BC, as studies have also suggested its promise as a biomarker for neoadjuvant chemotherapy in upper-tract UC. However, there are some limitations to ctDNA that require improvements in ctDNA-specific detection methods and BC-specific mutations before widespread utilization can be achieved. Further prospective, randomized trials are needed to elucidate the true potential ctDNA has in advancements in BC care.

Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis

BackgroundTransthyretin cardiac amyloidosis (ATTR-CA) is a progressive cardiomyopathy. The clinical course varies among individuals and there are no established measures to assess disease progression. ObjectivesThe goal of this study was to assess the prognostic importance of an increase in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and outpatient diuretic intensification (ODI) as markers of disease progression in a large cohort of patients with ATTR-CA. MethodsWe evaluated landmark survival analysis based on worsening of NT-proBNP and requirement for ODI between time of diagnosis and a 1-year visit, and subsequent mortality in 2,275 patients with ATTR-CA from 7 specialist centers. The variables were developed in the National Amyloidosis Centre (NAC) cohort (n = 1,598) and validated in the external cohort from the remaining centers (n = 677). ResultsBetween baseline and 1-year visits, 551 (34.5%) NAC patients and 204 (30.1%) patients in the external validation cohort experienced NT-proBNP progression (NT-proBNP increase >700 ng/L and >30%), which was associated with mortality (NAC cohort: HR: 1.82; 95% CI: 1.57-2.10; P < 0.001; validation cohort: HR: 1.75; 95% CI: 1.32-2.33; P < 0.001). At 1 year, 451 (28.2%) NAC patients and 301 (44.5%) patients in the external validation cohort experienced ODI, which was associated with mortality (NAC cohort: HR: 1.88; 95% CI: 1.62-2.18; P < 0.001; validation cohort: HR: 2.05; 95% CI: 1.53-2.74; P < 0.001). When compared with patients with a stable NT-proBNP and stable diuretic dose, a higher risk of mortality was observed in those experiencing either NT-proBNP progression or ODI (NAC cohort: HR: 1.93; 95% CI: 1.65-2.27; P < 0.001; validation cohort: HR: 1.94; 95% CI: 1.36-2.77; P < 0.001), and those experiencing both NT-proBNP progression and ODI (NAC cohort: HR: 2.98; 95% CI: 2.42-3.67; P < 0.001; validation cohort: HR: 3.23; 95% CI: 2.17-4.79; P < 0.001). ConclusionsNT-proBNP progression and ODI are frequent and consistently associated with an increased risk of mortality. Combining both variables produces a simple, universally applicable model that detects disease progression in ATTR-CA.

Identifying patients at risk for myasthenic crisis with hemogram and inflammation-related laboratory parameters - a pilot study.

Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG. We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit. 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02-1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14-1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99-1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99-2.38) may indicate increased risk for a myasthenic crisis. This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. To develop a new composite score to improve the prediction of outcome change. We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

Transcriptomic Signature of 3D Hierarchical Porous Chip Enriched Exosomes for Early Detection and Progression Monitoring of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor, and the current non-invasive diagnosis method based on serum markers, such as α-fetoprotein (AFP), and des-γ-carboxy-prothrombin (DCP), has limited efficacy in detecting it. Therefore, there is a critical need to develop novel biomarkers for HCC. Recent studies have highlighted the potential of exosomes as biomarkers. To enhance exosome enrichment, a silicon dioxide (SiO2) microsphere-coated three-dimensional (3D) hierarchical porous chip, named a SiO2-chip is designed. The features of the chip, including its continuous porous 3D scaffold, large surface area, and nanopores between the SiO2 microspheres, synergistically improved the exosome capture efficiency. Exosomes from both non-HCC and HCC subjects are enriched using an SiO2-chip and performed RNA sequencing to identify HCC-related long non-coding RNAs (lncRNAs) in the exosomes. This study analysis reveales that LUCAT-1 and EGFR-AS-1 are two HCC-related lncRNAs. To further detect dual lncRNAs in exosomes, quantitative real time polymerase chain reaction (qRT-PCR) is employed. The integration of dual lncRNAs with AFP and DCP significantly improves the diagnostic accuracy. Furthermore, the integration of dual lncRNAs with DCP effectively monitors the prognosis of patients with HCC and detects disease progression. In this study, a liquid biopsy-based approach for noninvasive and reliable HCC detection is developed.

Sequential or up-front triple combination with durvalumab, tremelimumab, and bevacizumab for patients with unresectable hepatocellular carcinoma (HCC): MONTBLANC.

TPS574 Background: Escalation of treatment from one to two combined immune checkpoint inhibitors (CPI) has dramatically increased objective and clinical response in advanced hepatocellular carcinoma (HCC) patients. Establishing strategies with more than two CPI agents to further increase response while maintaining a manageable toxicity is therefore a top priority. The upfront simultaneous use of three or more CPI can yield a strong initial response to treatment, but it may also increase treatment-related toxicity. An alternative approach, which prioritizes safety over immediate response, involves utilizing different CPI doublets in a sequential manner. However, this design entails switching to a different combination only after radiological progression is observed, and recurrent progressions may lead to deteriorating liver function and treatment resistance. Trials of immunotherapy of HCC conducted in recent years showed that the efficacy of CPI, when used simultaneously, outweighs the drawbacks of their combined toxicity and that early radiological response to treatment, or the lack thereof, is a predictor of clinical outcome. In addition, failure of trials using broad-spectrum tyrosine kinase inhibitors (TKI) and CPI suggest that antibodies or narrow-spectrum TKI should be used for future CPI-based combinations in HCC studies. Based on these considerations, the MONTBLANC study is the first trial to assess the effectiveness of up-front triple treatment with a combination of the three currently approved immunological agents for HCC and to implement the concept of treatment escalation determined by lack of early radiological response (as opposed to treatment progression). Methods: The MONTBLANC study is a randomized, 2-arm phase II study on the efficacy of combinations of durvalumab, tremelimumab, and bevacizumab in patients with advanced HCC. Patients with preserved liver function (Child-Pugh A) with unresectable tumors or not amenable to local or locoregional treatment are randomized to an early escalation arm (A) or a triple treatment arm (B). Patients in arm A receive combined durvalumab and tremelimumab (STRIDE regimen). Treatment is escalated by the addition of bevacizumab upon detection of disease progression or in the absence of radiological response by the 4th month of treatment. Patients in arm B receive up-front STRIDE and bevacizumab. Treatment will continue until unacceptable toxicity or progression under the Bev-containing regimen. The primary endpoint is overall response rate (ORR). Clinical trial information: NCT05844046 .

Machine Learning-Based Prediction Models for Cognitive Decline Progression: A Comparative Study in Multilingual Settings Using Speech Analysis.

Mild cognitive impairment (MCI) is a condition commonly associated with dementia. Therefore, early prediction of progression from MCI to dementia is essential for preventing or alleviating cognitive decline. Given that dementia affects cognitive functions like language and speech, detecting disease progression through speech analysis can provide a cost-effective solution for patients and caregivers. In our study, we examined spontaneous speech (SS) and written Mini Mental Status Examination (MMSE) scores from a 60-patient dataset obtained from the Mugla University Dementia Outpatient Clinic (MUDC) and a 153-patient dataset from the Alzheimer's Dementia Recognition through Spontaneous Speech (ADRess) challenge. Our study, for the first time, analyzed the impact of audio features extracted from SS in distinguishing between different degrees of cognitive impairment using both an Indo-European language and a Turkic language, which exhibit distinct word order, agglutination, noun cases, and grammatical markers. When each machine learning model was tested on its respective trained language, we attained a 95% accuracy using the random forest classifier on the ADRess dataset and a 94% accuracy on the MUDC dataset employing the multilayer perceptron (MLP) neural network algorithm. In our second experiment, we evaluated the effectiveness of each language-specific machine learning model on the dataset of the other language. We achieved accuracies of 72% for English and 76% for Turkish, respectively. These findings underscore the cross-language potential of audio features for automated tracking of cognitive impairment progression in MCI patients, offering a convenient and cost-effective option for clinicians or patients.

Progression of retinitis pigmentosa on static perimetry, optical coherence tomography, and fundus autofluorescence

In retinitis pigmentosa (RP), photoreceptor degeneration leads to progressive visual field loss and visual impairment. Several therapeutic trials are ongoing aiming to establish effective treatments. Although functional evaluations are commonly used in clinical trials, residual ellipsoid zone (EZ) measurement on optical coherence tomography has been shown to be more sensitive to detect disease progression. Establishment of sensitive outcome measurement is essential to develop new therapeutic strategies. In the current study, we evaluated the progression rates of the disease in 76 eyes of 76 patients with RP, using the residual EZ length, ring-shaped macular hyperautofluorescent (AF), and visual field. Decrease rates measured by the residual EZ area and by the hyper-AF ring area were strongly positively correlated (P < 0.0001, r = 0.71). The reduction rates of the residual EZ length and hyper-AF ring radius were constant regardless of their baseline measurements. Faster annual reduction rates of the hyper-AF ring area or radius were significantly correlated with faster visual field progression (P = 0.03, r = 0.25 and P = 0.004, r = 0.33, respectively). These findings support the usage of morphological measurements such as EZ or hyper-AF ring measurements as outcome measurement for future clinical trials for RP.

Remote Monitoring of Visual Function in Patients with Maculopathy: The Aphelion Study.

Remote monitoring of vision, using tools such as the shape discrimination hyperacuity (SDH) test, can detect disease activity in patients with maculopathy. We determined the in-clinic accuracy and repeatability of three myVisionTrack expanded version (mVTx) tests for self-testing of visual acuity (VA) and contrast sensitivity. Aphelion, a single-arm, prospective study conducted at two sites in the USA, included adults with any maculopathy and a baseline VA of 0.7 log of minimum angle of resolution (logMAR) (Snellen 20/100) or better. Participants completed the mVTx tests (tumblingE, LandoltC, contrast sensitivity, and SDH) and standard clinical tests (near and distance Early Treatment Diabetic Retinopathy Study [ETDRS] charts and the Pelli-Robson contrast sensitivity chart). Test-retest repeatability and agreement between the mVTx tests and the corresponding clinical test were assessed by Bland-Altman analyses. Participants also completed a usability survey. The mean age of the 122 participants was 67years. The most common diagnosis was age-related macular degeneration (42% of patients). The tumblingE test had a test-retest 95% limit of agreement (LoA) of ± 0.18logMAR; the LandoltC test, ± 0.23logMAR; the SDH test, ± 0.24logMAR; and the contrast sensitivity test, ± 0.32 log contrast threshold (logCT). Compared with the distance ETDRS chart, the LoA was ± 0.35logMAR for the tumblingE test (mean difference, - 0.07logMAR) and ± 0.39logMAR for the LandoltC test (mean difference, 0.03logMAR). For the contrast sensitivity test, the LoA compared with the Pelli-Robson chart was ± 0.30 logCT (mean difference, - 0.25logCT). Most participants (85%) reported that they learned the tests quickly. The tumblingE test scored the highest on ease of use. The mVTx tests of VA are accurate and repeatable, supporting their potential use alongside the SDH test to detect disease progression remotely between clinic visits.

Results of complex treatment of anaplastic glioma

Anaplastic glioma is a rare disease with an unfavorable prognosis. Currently, guidelines do not provide clear recommendations for the optimal treatment of patients with anaplastic glioma, necessitating the use of individual case series to guide clinical decisionmaking. Therefore, this study aimed to review the clinical management of anaplastic gliomas, including long-term follow-up (catamnesis) and complications. Using a retrospective approach, we analyzed patients with anaplastic glioma who were treated in our institution, either with or without concomitant chemotherapy, from early 2000 until 2021. Overall survival and progressionfree survival were calculated from the time of diagnosis until death and from the initiation of radiation therapy until the detection of disease progression through MRI. Our findings indicate that the combination of surgery, radiotherapy, and chemotherapy yielded the maximum benefit in the treatment of anaplastic glioma. However, managing this aggressive tumor remains challenging, despite continuous advancements in therapeutic options. Optimal management necessitates a multidisciplinary approach and a comprehensive understanding of potential complications arising from both the disease itself and its treatment.

Additional measures of macular function beyond visual acuity.

Visual function is a complex process in which external visual stimuli are interpreted. Patients with retinal diseases and prolonged follow-up times may experience changes in their visual function that are not detected by the standard visual acuity measure, as they are a result of other alterations in visual function. With the advancement of different methods to evaluate visual function, additional measurements have become available, and further standardization suggests that some methods may be promising for use in clinical trials or routine clinical practice. The objectives of this article are to review these additional measurements and to provide guidance on their application. The Vision Academy's membership of international retinal disease experts reviewed the literature and developed consensus recommendations for the application of additional measures of visual function in routine clinical practice or clinical trials. Measures such as low-luminance visual acuity, contrast sensitivity, retinal fixation and microperimetry, and reading performance are measures which can complement visual acuity measurements to provide an assessment of overall visual function, including impact on patients' quality of life. Measures such as dark adaptation, color vision testing, binocular vision testing, visual recognition testing, and shape discrimination require further optimization and validation before they can be implemented in everyday clinical practice. Additional measurements of visual function may help identify patients who could benefit from earlier diagnosis, detection of disease progression, and therapeutic intervention. New and additional functional clinical trial endpoints are required to fully understand the early stages of macular disease, its progression, and the response to treatment.

Use of 3-Dimensional Stereophotogrammetry to Detect Disease Progression in Craniofacial Morphea

Objectively determining disease progression in craniofacial morphea (CM) is challenging, as clinical findings of disease activity are often lacking. To evaluate the utility of 3-dimensional (3D) stereophotogrammetry in detecting disease progression in CM over time. This prospective cohort study included 27 pediatric and adult patients with CM from 2 hospitals in Boston (Boston Children's Hospital and Brigham & Women's Hospital) consecutively enrolled from April 1, 2019, to March 1, 2023. Review of 3D stereophotogrammetry images and data analysis occurred from March 1 to April 1, 2023. Clinical and 3D stereophotogrammetry assessments were performed at 2- to 12-month intervals, depending on the clinical context. The 3D stereophotogrammetry images were then qualitatively rated as demonstrating no progression or definitive progression by an expert (board-certified plastic craniofacial surgeon) and nonexpert (board-certified dermatologist) in 3D stereophotogrammetry. In addition, κ coefficients were calculated for interrater reliability. Of 27 patients with CM (19 female; median age, 14 [range, 5-40] years) and 3D stereophotogrammetry images obtained from a minimum of 2 time points (median, 4 [range, 2-10] images) spaced a median of 3 (range, 2-12) months apart, 10 experienced progression of their disease based on clinical assessments performed during the study period. In all cases in which clinical progression was favored, blinded qualitative assessment of 3D stereophotogrammetry images also favored progression with substantial interrater reliability (κ = 0.80 [95% CI, 0.61-0.99]). Furthermore, review of 3D stereophotogrammetry detected occult progression of asymmetry not noted on clinical examination in 3 additional patients. In this prospective cohort study, blinded assessment of sequential 3D stereophotogrammetry images in patients with CM not only corroborated clinical assessment of disease progression but also detected occult progression of facial asymmetry not appreciable on clinical examination alone. Therefore, 3D stereophotogrammetry may serve as a useful adjunct to clinical examination of patients with CM over time. Future investigations are warranted to validate 3D stereophotogrammetry as an outcome measure in CM.

Impact of Surveillance Imaging in Patients with HPV-Associated Oropharyngeal Carcinomas Treated with Definitive Radiation and Chemotherapy

Post-treatment surveillance imaging for HPV-associated oropharyngeal carcinomas (OPCs) differs among physicians and institutions. Surveillance imaging can detect disease progression earlier, but can also contribute to anxiety and cost, without proven disease-free or survival benefit. We sought to determine the number of surveillance scans needed to detect a recurrence in patients with HPV-associated OPCs. We included consecutive patients with locally advanced HPV-associated OPC that received definitive concurrent chemoradiotherapy (CRT) with 70 Gy between March 1, 2017 to July 31, 2019. First post-treatment scans were defined as the first scans following the end of CRT. Surveillance scans were defined as body FDG PET/CTs, neck or chest CTs, and neck MRIs taken after the first post-treatment scans showed no evidence of disease. Any scans ordered to follow suspicious lesions on first post-treatment scans were not counted as surveillance scans. Recurrences were classified as detected by first post-treatment scans, surveillance scans, clinical exam, or incidental findings. The number of surveillance scans needed to detect 1 recurrence was determined by dividing the number of surveillance scans by the number of recurrences detected by surveillance scans. There were a total of 275 patients with median follow-up of 39.8 months (Interquartile Range (IQR), 34.9-47.8). Surveillance scans were first taken at a median of 12.1 months (IQR, 9.2-16) post-CRT. There were 27 (9.8%) patients who had a recurrence: 7 (2.5%) had locoregional recurrence (LR), 19 (6.9%) had distant metastasis (DM), and 1 (0.4%) had both LR and DM. LR was detected at a median of 5.8 months (IQR, 3.4-10.6) post-CRT and DM was detected at a median of 9.5 months (IQR, 4.8-14.3) post-CRT. Of all recurrences, 11/27 (40.7%) were first post-treatment scan detected, 10 (37.0%) were surveillance scan detected, 5 (18.5%) were clinical exam detected, and 1 (3.7%) was incidentally detected on lung cancer screening. Four (50%) LRs were first post-treatment detected (median time to detection, MTD: 4.2 months), 3 (37.5%) were clinical exam detected (MTD: 6.7 months), and 1 (12.5%) was surveillance detected (MTD: 9.0 months). For DM, 9 (45%) were surveillance detected (MTD: 12.7 months), 8 (40%) were first post-treatment detected (MTD: 4.1 months), 2 (10%) were clinical exam detected (MTD: 18.9 months), and 1 (5%) was incidentally detected (MTD: 12.1 months). A total of 702 surveillance scans were taken during the follow-up period. The number of surveillance scans needed to detect 1 LR/DM was 71 overall, 50 within 2 years and 254 beyond 2 years from CRT. First post treatment scans detect most recurrences for HPV-associated OPC. A high burden of surveillance scans is needed to detect one recurrence, especially beyond 2 years from CRT.

B-368 Non-invasive Longitudinal Analysis of Cancer Signal to Monitor Disease Progression and Responses to Treatment

Abstract Background Multi-cancer early detection products are poised to change cancer treatment and survival. However, current applications lack the ability to translate analytical findings to clinical outcomes. Quantitatively tracking cancer signals is the next frontier for early cancer detection and data-driven intervention. Harbinger Health has pioneered a platform that combines novel epigenomic insights with artificial intelligence to detect cancer and monitor signal over time to track disease progression and/or response to treatment. Methods We designed a comprehensive enrichment panel (17.8 Mb) which provides simultaneous methylation and mutational state for cancer and tissue-of-origin informative regions as well as a panel of tumor suppressor genes and oncogenic drivers. We also defined the most significant methylation motifs (MMs) that contribute to pan-cancer signal and developed an algorithm to estimate the amount of tumor-derived reads in a cell-free DNA (cfDNA) sample. To verify our methodology, we performed whole exome sequencing (WES) for a cohort of 46 patients with matched FFPE and cfDNA and compared variant allele frequency of somatic mutations to tumor content estimates from MMs. We used this tumor content (%TC) estimate to quantify signal over time and monitor dynamic changes in the tumor. Simultaneously, we tracked orthogonal mutations across treatment. To clinically assess our quantitative analysis, we sourced longitudinal samples of 21 cancer patients over the course of treatment with four timepoints, averaging 38 days apart. Timepoint 0 (TP0) was before any treatment, while TP1, TP2, and TP3 were taken before subsequent treatment. For most timepoints, we had endpoint RECIST data which identified n = 8 samples as progressive disease (PD), n = 1 as stable disease (SD), n = 9 as partial response (PR), and n = 3 as complete response (CR). We also sourced 21 non-cancer subjects with two timepoints, 60 days apart. All samples across these timepoints were captured with the 17.8 Mb panel and analysis was done to assess longitudinal tracking—predict prognosis, identify minimal residual disease (MRD), and/or detect disease progression. Results We confirmed that our %TC estimates derived using MMs were highly correlated to estimates derived using WES. We therefore utilized our methylation data to estimate %TC for all timepoints across treatment. The %TC ranged from 0.02% to 60%, with Stage IV disease showing the greatest tumor burden, as expected. Notably, %TC showed dynamic fold-changes during treatment, with differential levels between response groups and non-cancers. In a small subset that included three Stage IV prostate cancer patients with high initial %TC, our biomarkers were able to identify one patient that was reported PR but showed an increase of 18.9% tumor content, indicating disease progression. This patient was deceased at last follow-up. [Additional data to be reported.] Conclusion Our analytical approach of identifying %TC based on Harbinger Health’s proprietary enrichment panel was successful in quantitatively monitoring cancer patients through treatment and disease progression. Our data can provide valuable insights to help clinicians make more informed decisions (e.g. increased monitoring or interventions) about patient care. Further development of techniques enriching specifically for these MMs are in progress.

Discussion to: Delayed-enhancement cardiac magnetic resonance imaging detects disease progression in patients with mitral valve disease and atrial fibrillation

Discussion to: Delayed-enhancement cardiac magnetic resonance imaging detects disease progression in patients with mitral valve disease and atrial fibrillation

Circulating tumour DNA testing in metastatic breast cancer: Integration with tissue testing.

Breast cancer biomarker profiling predominantly relies on tissue testing (surgical and/or biopsy samples). However, the field of liquid biopsy, particularly the analysis of circulating tumour DNA (ctDNA), has witnessed remarkable progress and continues to evolve rapidly. The incorporation of ctDNA-based testing into clinical practice is creating new opportunities for patients with metastatic breast cancer (MBC). ctDNA offers advantages over conventional tissue analyses, as it reflects tumour heterogeneity and enables multiple serial biopsies in a minimally invasive manner. Thus, it serves as a valuable complement to standard tumour tissues and, in certain instances, may even present a potential alternative approach. In the context of MBC, ctDNA testing proves highly informative in the detection of disease progression, monitoring treatment response, assessing actionable biomarkers, and identifying mechanisms of resistance. Nevertheless, ctDNA does exhibit inherent limitations, including its generally low abundance, necessitating timely blood samplings and rigorous management of the pre-analytical phase. The development of highly sensitive assays and robust bioinformatic tools has paved the way for reliable ctDNA analyses. The time has now come to establish how ctDNA and tissue analyses can be effectively integrated into the diagnostic workflow of MBC to provide patients with the most comprehensive and accurate profiling. In this manuscript, we comprehensively analyse the current methodologies employed in ctDNA analysis and explore the potential benefits arising from the integration of tissue and ctDNA testing for patients diagnosed with MBC.