Dynamic Risk Stratification Research Articles

Abstract IA018: Liquid biopsy in head and neck cancers: A model for tissue-agnostic MRD detection

Abstract Head and neck cancer (HNC) is a molecularly heterogenous disease with a variable clinical course. Current treatment decisions rely primarily on pre-treatment prognostic factors without consideration of treatment response. This presentation will introduce liquid biopsy biomarkers that can be repeated in HNC patients for the purpose of dynamic risk stratification, treatment adaptation, and post-treatment surveillance. Novel approaches to measuring circulating tumor DNA (ctDNA) will be described, with particular attention to viral-associated and non-viral- associated subtypes of HNC. Detection of molecular residual disease (MRD) using ctDNA will be discussed. As HNC is often treated by non-surgical means, there is a pressing need for tissue- agnostic methods for ctDNA-based MRD detection. Analysis of tumor-specific genetic and epigenetic aberrations within ctDNA each present distinct opportunities and challenges for tissue-agnostic characterization of ctDNA. Viral ctDNA has emerged as a convenient target for MRD detection in viral-associated HNC, while ctDNA methylome profiling offers a versatile approach for tissue-agnostic MRD detection across HNC subtypes. Future applications of these methods may improve individualized management of HNC patients without requiring access to precious tumor tissue samples. Citation Format: Scott V Bratman. Liquid biopsy in head and neck cancers: A model for tissue-agnostic MRD detection [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA018.

Evaluation of repeated machine learning-based phenotyping in patients with cardiogenic shock

Abstract Background Cardiogenic shock (CS) is a highly mortal disease with variable clinical manifestations, severity, and in-hospital trajectories. Multiple clinical trials have failed to show an impact of therapies on outcomes, partly because they focus on etiology as a classifier, failing to capture the clinical heterogeneity. A phenotype-based approach to CS allows for a dynamic risk stratification based on disease severity. We have previously presented three CS phenotypes at baseline using machine learning-based algorithms: phenotype I (non-congested), II (cardiorenal), and III (cardiometabolic). However, little is known about the clinical course of these CS phenotypes during hospitalization and whether repeated phenotyping may provide additional insights. Purpose To assess relevance and prognostic impact of repetitive reassessment of CS phenotypes and their trajectories during the first 72h after CS diagnosis. Methods We included all-cause CS patients from the multi-center, multinational Cardiogenic Shock Working Group (CSWG) V3 and V4 registries (Yr. 2022-2023). Phenotypes were assigned by nearest centroid classification based on the centroids from the initial CSWG V1 (Yr. 2019) registry derivation cohort. Missing values required for phenotype assignment were imputed for all patients, but imputed values were only used for phenotype assignment and not reported as outcomes. Results A total of 4308 patients were included, of which 928 had CS due to myocardial infarction (MI-CS) and 2164 had CS due to heart failure (HF-CS). At time of diagnosis/ baseline, 1627 (37.8%), 1832 (42.5%), and 849 (19.7%) of patients were in phenotype I (non-congested), II (cardiorenal) and III (cardiometabolic), respectively. In MI-CS, patients were evenly distributed between the three phenotypes (35.5%, 34.4%, and 30.2%, respectively), whereas in HF-CS, non-congested and cardiorenal CS were more common than cardiometabolic shock (38.8%, 48.9%, and 12.3%, respectively). Within the first 12 hours, most patients in cardiorenal and cardiometabolic CS shifted to non-congested CS (Figure 1). In-hospital mortality in admission phenotype I, II, and III was 21.7%, 32.1%, and 50.1% (p<0.0001 for difference), respectively, in concordance with previous reports. When assessed at different time points, phenotypes II and III were associated with higher odds of mortality than phenotype I at 24h, 48h, and 72h after initial shock diagnosis (p≤0.03 for all, Figure 2). Conclusion Beyond baseline, re-assessment of machine learning-based CS phenotypes within the first 72h after CS diagnosis may provide additional prognostic insights. These data may inform future clinical trial design to tailor interventions to specific CS phenotypes.Figure 1Figure 2

Consideration of Early Dynamic Risk Stratification to Guide Discharge from Oncologic Follow-Up in Patients with Differentiated Thyroid Cancer.

Background: The current dogma is a life-long follow-up for patients treated for follicular-derived differentiated thyroid cancers (DTC). Our primary objective was to determine the time to recurrence in a series of DTC patients with an excellent response to therapy 6 months after total thyroidectomy and radioiodine therapy. The secondary objectives were to determine the time to suspicion of recurrence and to identify factors associated with recurrence. Methods: This retrospective cohort study included patients treated for DTC between 2008 and 2012 and in remission 6 months after total thyroidectomy and radioiodine treatment. The criteria for remission were negative imaging and suppressed thyroglobulin (Tg) <0.2 ng/mL or rh-TSH-(recombinant human TSH) stimulated Tg <1 ng/mL according to the 2015 ATA (American Thyroid Association) guidelines. Recurrence was defined by cytologically and/or histologically proven cervical lymph node metastasis or the administration of a second radioiodine treatment. Results: Among 721 patients treated for DTC, 158 were excluded because of persistent disease at 6 months, 71 because of missing follow-up data, and 492 were included. The mean and median follow-up time were 7.0 and 7.9 years (interquartile range IQR [2.1-11.3]). Recurrence occurred for 7 patients (1.4%), 1 initially classified as high recurrence risk, 3 as intermediate, and 3 as low risk according to the 2015 ATA guidelines. All relapses occurred within 10 years after initial management (4 within the first 5 years). For patients with recurrence, rise in Tg and/or suspicious lymph nodes were detected in six out of seven cases in the first 8 years and for the last case 10 years after initial surgery. Conclusion: Low and intermediate recurrence risk DTC patients with excellent response 6 months after total thyroidectomy and radioiodine and in remission 10 years later have an extremely low recurrence risk. Follow-up might be undertaken by primary care providers from this time point. These discharge recommendations should be confirmed by further prospective studies.

8549 A Pre-ablative Stimulated Thyroglobulin Value That Predicts ATA High Risk Patients and Their Treatment Response

Abstract Disclosure: H. Gondaliya: None. N. Nangadda: None. D. Bhat: None. K.S. Khadilkar: None. S. Kumbenahalli Siddegowda: None. B.G. Sooragonda: None. A. Shetty: None. S. Kannan: None. In ATA risk stratification system for differentiated thyroid cancer (DTC), one of the variables placing patients in ATA high risk category is thyroglobulin (Tg) suggestive of distant metastases. However there is no defined cut-off Tg level for guiding the clinicians. We aimed to determine pre-ablative stimulated Tg (psTg) value that predicts ATA high risk patients (based on non-Tg parameters) and their treatment response on follow up. This was an ambispective observational study of 285 patients with DTC treated at our centre from April 2017 to November 2022. psTg was measured in all patients 3-4 weeks after surgery and they were subjected to RAIA depending on clinician’s discretion and followed up using the ATA dynamic risk stratification every 6 months. The cohort was divided into two groups: ATA high risk and ATA non-high risk (Low and intermediate risk). Patients among high risk group were divided based on response to treatment into structural incomplete group and non-structural incomplete group (Excellent, Indeterminate and Biochemically incomplete response). The mean age of the study population was 41±15 years and 68% (n=194) were female and 87% (n=249) were papillary thyroid cancer (PTC) and 13% (n=36) were Follicular Thyroid Cancer (FTC). Median duration of follow up was 2.95 years (IQR: 1.42 - 5.12). Among those with PTC, 75% were Classic, 15% Follicular variant and 10% aggressive variants that included tall cell, hobnail, diffuse sclerosing and columnar variant. On ATA risk stratification, 81.75% (n=233) patients were in non-high risk group with median psTg 3.4 ng/ml (IQR 0.5-12.2) and 18.25% (n=52) were in high-risk group with median psTg 150.5 ng/ml (IQR 7.15-439.5). On ROC analysis of all the patients, a psTg value &amp;gt;53.3 ng/ml was predictive of ATA high risk group with PPV of 64%; NPV of 93.5% and AUC 0.81. In ATA high-risk group, there were 73% (n=38) of patients with structural incomplete response on follow up and their median psTg was 287 ng/ml (IQR 95-500) and there were 27% (n=14) with non-structural incomplete response and their median psTg level of 6.2 ng/ml (IQR 2.3-110). A psTg value &amp;gt;53 ng/ml discriminated structural incomplete from non-structural incomplete response with PPV of 77%; NPV 87% and AUC 0.83. A psTg value &amp;gt;53 ng/ml not only predicts ATA high risk patients but also indicates those who are likely to remain with structural residual disease at follow up of 3 years. Presentation: 6/1/2024

Significance of longitudinal Epstein–Barr virus DNA combined with multipoint tumor response for dynamic risk stratification and treatment adaptation in nasopharyngeal carcinoma

Dynamic therapy response is strongly associated with cancer outcomes. This study aimed to evaluate the significance of longitudinal Epstein–Barr virus (EBV) DNA and radiological tumor regression in risk stratification and response-adaptive treatment in locally-advanced nasopharyngeal carcinoma (LA-NPC). In total, 1312 patients from two centers were assigned to the training and validation cohorts. Based on the multipoint examination of EBV-DNA and tumor response, four post-induction chemotherapy, four mid-radiotherapy, and four post-radiotherapy subgroups were established. Then seven phenotypes were further generated according to different permutations and combinations. These phenotypes were subsequently congregated into four response clusters, which reflect distinct biological treatment responses. The four response clusters correlated with an evident 5-year progression-free survival in both the training and external validation cohorts (5-year: training cohort 91.1 %, 82.8 %, 30.6 %, and 10.0 %; external validation 94.4 %, 55.6 %, 40.0 %, and 12.7 %) had superior prognostic performance compared to TNM staging and nomogram model (concordance index: training cohort—0.825 vs. 0.603 vs. 0.756 and external validation—0.834 vs. 0.606 vs. 0.789). Importantly, the response clusters exhibited an excellent capability in selecting candidates who can benefit from adjuvant chemotherapy. In conclusion, risk stratification based on the dynamic assessment of both radiological and biological responses can significantly enhance prognostic insights and shed light on individualized treatment modifications in LA-NPCs.

Pediatric Papillary Thyroid Carcinoma: Outcomes After Surgery Without Adjuvant Radioactive Iodine.

Pediatric papillary thyroid carcinoma (PTC) is usually treated with total thyroidectomy followed by radioactive iodine (RAI). Recently, RAI is being used more selectively based on surgical pathology and postoperative dynamic risk stratification (DRS). To describe patients with pediatric PTC not initially treated with RAI and their disease outcomes. This was an ambispective study at a tertiary cancer center of patients < 19 years diagnosed from 1/1/1990 to 12/31/2021 with stage I PTC who intentionally were not treated with RAI within a year of diagnosis. We assessed clinical characteristics, management, and disease outcomes using DRS. Of 490 PTC patients, we identified 93 eligible patients (median age at diagnosis 16y; 87% female), including 46 (49%) with cervical lymph node metastases. Initial management included: total thyroidectomy ± neck dissection (n=69, 75%), lobectomy ± neck dissection (n=20, 21%), or a Sistrunk procedure for ectopic PTC (n=4, 4%). After a median follow-up of 5.5 years (range 1-26), most patients (85/93; 91%) remained disease-free with no further therapy. Persistent (n=5) or recurrent (n=3) disease was found in 9% of the entire cohort. Four patients ultimately received RAI, of which only one clearly benefited, and additional surgery was performed or planned in four patients, two of whom had an excellent response at last follow-up. Selected pediatric PTC patients, even those with lymph node metastases, may not require therapeutic 131I and can avoid the unnecessary risks of RAI while still benefitting from the excellent long-term outcomes that are well-described for this disease.

Tracking dynamic evolution of low- and intermediate-risk differentiated thyroid cancer: Identification of individuals at risk of recurrence.

The generally good prognosis of low- and intermediate-risk differentiated thyroid cancer (DTC) underscored the need to identify those few patients who relapse. Records of 299 low- or intermediate-risk DTC patients (mean follow-up 8.2 ± 6.2 years) were retrospectively reviewed. The sample was classified following the American Thyroid Association (ATA) dynamic risk stratification (DRS) system. After classifying patients according to DRS at the first visit following initial therapy (FU1), structural recurrence occurred in 2/181 (1.1%), 5/81 (6.2%) and 13/26 (50.0%) with excellent, indeterminate and biochemical incomplete response to treatment, respectively. All relapses but one happened within 5 years from FU1. Univariate analysis comparing excellent, indeterminate and biochemical incomplete with structural incomplete responses at the end of the follow-up, identified tumour size (p < .001), T status (<0.001), positive lymph nodes (N) (p < .01), multifocality (p < .004), need of additional radioactive iodine (RAI) (p < .0001) and first DRS status (p < .0003) as risk factors of recurrence. In the multivariate analysis, only RAI remained statistically significant (p < .02). Comparison between excellent and indeterminate with biochemical and structural incomplete responses, identified tumour size (p < .0004), T (p < .01), N (p < .0001), bilaterality (p < .03), first DRS status (p < .0001) and RAI (p < .001) as recurrence risk factors. T (p < .01) and first DRS (p < .0006) were confirmed in the multivariate analysis. Patients with DTC classified as low- or intermediate-risk of recurrence with excellent response to treatment at FU1 rarely develop structural disease and this occurs almost exclusively in the first 5 years. Initial DRS status is an accurate tool for determining the risk of recurrence.

Treatment and management of medullary thyroid microcarcinoma: a 10-year retrospective study from a single center.

To explore individualized treatment and management methods for medullary thyroid microcarcinoma (MTMC). Clinical data of patients with medullary thyroid carcinoma with a diameter ≤1 cm admitted to the First Affiliated Hospital of Kunming Medical University from June 2013 to June 20× were collected. Combined with different treatment guidelines for medullary thyroid carcinoma, factors affecting lymph node metastasis and postoperative disease status were analyzed. Twenty-nine patients with MTMC were included in the analysis, including 24 patients who underwent total thyroidectomy, 5 who underwent thyroid gland lobectomy, and 13 who experienced postoperative lymph node metastasis. Multifocal tumor and calcitonin (Ctn) were the influencing factors, while multifocal tumor, Ctn, lymph node metastasis, and AJCC stage affected the dynamic risk stratification of postoperative disease. Calcitonin detection is an important method for detecting MTMC. A tumor diameter ≤1 cm does not indicate that the tumor is in the early stage. The presence of multifocal tumors and Ctn should be used as important indicators for preoperative evaluation. Dynamic stratified risk assessment is critical in postoperative follow-up.

Prognostic implications of preoperative, postoperative, and dynamic changes of alpha-fetoprotein and des-gamma (γ)-carboxy prothrombin expression pattern for hepatocellular carcinoma after hepatic resection: a multicenter observational study.

The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated. From a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns. Preoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both P < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers. AFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies.

Clinical inertia in thyrotropin suppressive therapy for low-risk differentiated thyroid cancer: A real-world experience at an endocrine center in Bangkok.

The management of low-risk differentiated thyroid cancer (DTC) has evolved over time toward treatment de-escalation. However, overtreatment with supraphysiological dose of levothyroxine (LT4) continues to be observed despite current clinical guideline. This study aimed to assess the actual thyrotropin suppressive therapy for low-risk DTC patients at an endocrine center in Bangkok. This retrospective study included patients with low-risk DTC who were regularly follow-up for at least 18 months at Theptarin Hospital between 2016 and 2022. The serum thyroid stimulating hormone (TSH) levels were stratified as TSH < 0.1 mIU/L; TSH 0.1 to 0.5 mIU/L; TSH 0.5 to 2.0 mIU/L; and TSH > 2.0 mIU/L. The initial risk stratification (IRS) and dynamic risk stratification were determined at 12 months of follow-up after completing the initial treatment and at the last visit. The clinical factors associated with overtreatment with LT4 were analyzed. A total of 102 patients (83.3% female, age at diagnosis 41.8 ± 13.6 years, mean tumor size 1.6 ± 1.0 cm) were evaluated with a mean follow-up of 5.9 years. The IRS classified 92.2% of patients after the initial treatment and 93.1% of patients at the last follow-up visit into the excellent response category. The mean LT4 daily dosage at the last follow-up was 121.3 ± 44.8 µg/day. Serum TSH levels were in an appropriate target range according to IRS in only 8.8% (9/102) of the patients and then improved to 19.6% (20/102) at the last follow-up visit. Further analysis showed that treating physicians with ≥10 years of practice was associated with severe TSH suppression therapy (TSH < 0.1 mIU/L). Despite the current clinical guideline recommendations and scientific evidences, less than one-fifth of low-risk DTC patients achieved the appropriate serum TSH target. While the proportion of an optimum LT4 suppressive had improved during the study period, further efforts are needed to overcome this clinical inertia.

Dynamic risk stratification of worsening heart failure using a deep learning-enabled implanted ambulatory single-lead electrocardiogram.

Implantable loop recorders (ILRs) provide continuous single-lead ambulatory electrocardiogram (aECG) monitoring. Whether these aECGs could be used to identify worsening heart failure (HF) is unknown. We linked ILR aECG from Medtronic device database to the left ventricular ejection fraction (LVEF) measurements in Optum® de-identified electronic health record dataset. We trained an artificial intelligence (AI) algorithm [aECG-convolutional neural network (CNN)] on a dataset of 35 741 aECGs from 2247 patients to identify LVEF ≤ 40% and assessed its performance using the area under the receiver operating characteristic curve. Ambulatory electrocardiogram-CNN was then used to identify patients with increasing risk of HF hospitalization in a real-world cohort of 909 patients with prior HF diagnosis. This dataset provided 12 467 follow-up monthly evaluations, with 201 HF hospitalizations. For every month, time-series features from these predictions were used to categorize patients into high- and low-risk groups and predict HF hospitalization in the next month. The risk of HF hospitalization in the next 30 days was significantly higher in the cohort that aECG-CNN identified as high risk [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.28-2.79; P = 0.001] compared with low risk, even after adjusting patient demographics (HR 1.88; 95% CI 1.27-2.79 P = 0.002). An AI algorithm trained to detect LVEF ≤40% using ILR aECGs can also readily identify patients at increased risk of HF hospitalizations by monitoring changes in the probability of HF over 30 days.

Predictors of recurrence after total thyroidectomy in 1,611 patients with papillary thyroid carcinoma: postoperative stimulated serum thyroglobulin and ATA initial and dynamic risk assessment.

Despite a favorable prognosis, some patients with papillary thyroid carcinoma (PTC) develop recurrence. The objective of this study was to examine the impact of the combination of initial American Thyroid Association (ATA) risk stratification with serum level of postoperative stimulated thyroglobulin (s-Tg) in predicting recurrence in patients with PTC and compare the results with an assessment of response to initial therapy (dynamic risk stratification). We retrospectively analyzed 1,611 patients who had undergone total thyroidectomy for PTC, followed in most cases (87.3%) by radioactive iodine (RAI) administration. Clinicopathological features and s-Tg levels obtained 3 months postoperatively were evaluated. The patients were stratified according to ATA risk categories. Nonstimulated thyroglobulin levels and imaging studies obtained during the first year of follow-up were used to restage the patients based on response to initial therapy. After a mean follow-up of 61.5 months (range 12-246 months), tumor recurrence was diagnosed in 99 (6.1%) patients. According to ATA risk, recurrence was identified in 2.3% of the low-risk, 9% of the intermediate-risk, and 25% of the high-risk patients (p < 0.001). Using a receiver operating characteristic curve approach, a postoperative s-Tg level of 10 ng/mL emerged as the ideal cutoff value, with positive and negative predictive values of 24% and 97.8%, respectively (p < 0.001). Patients with low to intermediate ATA risk with postoperative s-Tg levels < 10 ng/mL and excellent response to treatment had a very low recurrence rate (<0.8%). In contrast, higher recurrence rates were observed in intermediate-riskto high-risk patients with postoperative s-Tg > 10 ng/mL and indeterminate response (25%) and in those with incomplete response regardless of ATA category or postoperative s-Tg value (38.5-87.5%). Using proportion of variance explained (PVE), the predicted recurrence using the ATA initial risk assessment alone was 12.7% and increased to 29.9% when postoperative s-Tg was added to the logistic regression model and 49.1% with dynamic risk stratification. The combination of ATA staging system and postoperative s-Tg can better predict the risk of PTC recurrence. Initial risk estimates can be refined based ondynamic risk assessment following response to therapy, thus providing a useful guide for follow-up recommendations.

Chapter 6: Risk Stratification and Surveillance in Differentiated Thyroid Cancers

ABSTRACT Surveillance strategies in differentiated thyroid cancers (DTCs) differ from other head-and-neck subsites by virtue of their excellent prognosis. Guidelines in this chapter are based on a comprehensive literature review, particularly in the Indian setting concurred upon by experts in the field. Key recommendations include serial measurement of thyroglobulin values, thyroglobulin antibodies, and risk-based suppression of thyroid-stimulating hormone during follow-up of treated DTCs, with radioactive iodine scan and structural imaging based on dynamic risk stratification. These recommendations take into consideration prevailing Indian scenario related to reliability of follow-up, insurance coverage, as well as burden on health-care systems.

Chapter 11: Pediatric Differentiated Thyroid Cancers

ABSTRACT The document discusses pediatric differentiated thyroid cancer (DTC), focusing on papillary thyroid carcinoma (PTC), which is increasingly prevalent globally, including in India. Despite a more aggressive initial presentation in children, the long-term prognosis is generally positive. Key differences between pediatric and adult DTC are highlighted, such as a higher risk of malignancy in children with thyroid nodules and common RET/PTC gene rearrangements. There is a debate on the age cutoff for defining pediatric DTC, but the document suggests that 18 years is considered appropriate in the Indian context. Diagnostic methods, including ultrasonography-guided fine needle aspirate (FNA) and the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), are emphasized. The importance of genomic analysis for indeterminate cytology is also proposed. Treatment approaches involve total thyroidectomy due to higher multifocality in children, with consideration of potential complications. Post-operative risk stratification, utilizing the TNM staging system, is seen as crucial and correlates with disease-free survival. Post-operative staging includes TSH-stimulated thyroglobulin (Tg) and anti-thyroglobulin antibody (ATg) levels, along with a diagnostic whole-body 131I scan to assess surgical completeness. Radioactive iodine therapy (RAI) is recommended for iodine-avid persistent/metastatic disease, with an empirical activity of 30 mCi for remnant ablation and adjustments based on age or weight. Regular follow-ups include monitoring TSH-suppressed Tg, Anti-Tg levels, and neck ultrasound. Dynamic risk stratification at 2 years refines risk based on treatment responses. Genetic considerations reveal prevalent RET fusion oncogene and less common BRAF mutations, which are associated with RAI refractoriness. In summary, the document provides a comprehensive understanding of pediatric DTC, emphasizing the need for tailored guidelines in the Indian context. It covers various aspects of diagnosis, surgery, and post-operative care, with a focus on age-appropriate management and ongoing research in this specialized field.

Survival Outcomes, Efficacy and Tolerability of a Pediatric-Inspired Regimen (MASPORE) for Philadelphia-Negative Acute Lymphoblastic Leukemia in Young Adults at a Tertiary Hospital in Singapore

Introduction: Recent evidence has emerged to support the use of pediatric-inspired regimen as a standard of care in Adolescents and Young Adults (AYA) patients diagnosed with Philadelphia-negative acute lymphoblastic leukemia (Ph- ALL). The backbone of the pediatric regimen is high cumulative doses of steroids, asparaginase, vincristine and more intensive CNS prophylaxis. Most literature, however, has been in the western population, with few data reported in Asia. MASPORE protocol is a locally designed pediatric-inspired regimen for treatment of ALL in AYA. The protocol uses a 3- or 4-drugs induction regimen (L-asparaginase, Vincristine, Dexamethasone +/- Daunorubicin) based on standard or high-risk disease. PCR-based measurable residual disease (MRD) marker was utilized for disease monitoring and dynamic risk stratification, which led to subsequent intensification of regimen as needed. Methods: In this IRB approved retrospective analysis, patients aged 18-39 years old with Ph- ALL who received MASPORE regimen from January 2009 to December 2021 at the National University Hospital Singapore were identified via our institution database. Treatment outcomes, including measurable residual disease (MRD) monitoring, and toxicity profile were analyzed. Survival outcomes were estimated using Kaplan-Meier method. High risk disease at diagnosis was defined as high white blood cell (&amp;gt;30x10 9/L for B-ALL, &amp;gt;100x10 9/L for T-ALL), hypodiploidy, t(4;11) and other MLL gene rearrangement. Results: 32 patients were identified during the study period; 3 patients were excluded due to incomplete data. The median age was 23 years old (range 18-33 years) with majority being male (86.2%). 16 patients (55.2%) had B-ALL and 13 (44.8%) had T-ALL. High risk disease was present in 7 (43.8%) B-ALL patients and 8 (61.5%) in T-ALL patients. 2 patients in B-ALL group had CNS involvement at diagnosis. The majority (96.5%) achieved complete remission after the induction phase. 1 patient died within first 1 month of treatment due to pancreatitis. 5 patients in high risk group received allogenic stem cell transplantation (alloSCT), whereas 2 patients with standard risk required alloSCT due to relapse and persistent MRD positivity. MRD result was available for 26 patients. In the entire cohort, MRD negativity was achieved in 22 patients (75.9%). Subtype was not associated with achievement of MRD negativity (80% in B-ALL vs 90.9% in T-ALL). High risk patients however had a lower odds of achieving MRD negativity after induction (OR 0.114 95% CI 0.017-0.742, p=0.021). The median follow-up for survivors was 41 months (range 27 to 89 months). Relapse and mortality rate was low at 13.8% each. 5-year OS for patients with B-ALL and T-ALL were 92.3% and 75.2%, respectively (Figure 1a). 5-year OS for patients with standard and high-risk disease were 84.4% and 84.0%, respectively (Figure 1b). Delayed achievement of MRD negativity (i.e. after induction) was not associated with inferior survival outcomes, albeit our sample size was small. In terms of adverse events, Asparaginase-related toxicities included 11 patients (37.9%) with thrombotic events (4 cerebral venous thrombosis and 7 deep vein thrombosis), and 5 patients (17.2%) with grade 2 or more pancreatitis. 7 patients (24.1%) had at least 1 episode of grade 3 or 4 transaminitis. 7 patients (24.1%) had grade 3 or 4 sepsis during the course of treatment. 2 patients developed osteonecrosis of the hip requiring operation and cessation of steroids. Conclusion: Our locally designed MASPORE protocol tailored in accordance to risk stratification demonstrated promising survival outcomes. Similar outcomes observed in standard and high-risk disease suggests the benefit of such an approach. Toxicities were mainly related to L-asparaginase use. Individualized dosing based on drug level monitoring will help to further optimize the treatment intensity with reduced toxicities.

Risk Stratification of Differentiated Thyroid Cancer: A Single-Center Study in Basrah.

Background Differentiated thyroid cancer is a common endocrine cancer; most of it has an indolent course and favorable outcomes, with a subset of patients having the risk of disease recurrence, which can be assessed using the fixed American Thyroid Association (ATA) risk stratification system or the dynamic response to therapy risk stratification that can be modified during patients follow-up. Aim The aim of this article is to assess the risk stratification of patients having differentiated thyroid cancer. Methods This is aretrospective cross-sectional study in which we evaluated medical records of 75 patients having differentiated thyroid cancer to assess the baseline ATA risk of recurrence and compared it to the results of dynamic risk stratification in response to therapy at 6-12 months post-surgery and at the last visit. Thyroglobulin level, anti-thyroglobulin antibody, thyroid ultrasound, and cytopathological examination were used to determine dynamic response to therapy and divided subjects into four groups: excellent response (ER), biochemical incomplete response (BIR), structural incomplete response (SIR), and indeterminate response (IR). Results At baseline, 55 patients had low risk, 14 patients had intermediate risk, and six patients had high risk. At 6-12 months post-surgery, in the low-risk group, ER, BIR, and IR responses were observed in 56.4%, 5.5%, and 38.2% of patients, respectively, and none of them exhibited SIR. In the intermediate-risk group, ER, BIR, and IR responses were observed in 57.1%, 21.4%, and 21.4% of patients, respectively, and none exhibited SIR. Among the high-risk group, two patients had ER, two patients had BIR, one patient had IR, and one patient had SIR. At the last visit, ER, BIR, and IR were observed in 65.5%, 9.1%, and 25.5% of low-risk patients, respectively, and no patient developed SIR. In the intermediate-risk group, ER, BIR, and IR were observed in 50%, 21.4%, and 28.6% of patients, respectively, and no patients developed SIR. Among the high-risk group, three patients achieved ER, one had BIR, one had IR, and one had SIR. Conclusion Most of the differentiated thyroid cancers in this study are low-risk. Dynamic risk stratification appears to be an effective tool in the follow-up of this population of patients having differentiated thyroid cancer.

Prognostic Factors Improving ATA Risk System and Dynamic Risk Stratification in Low- and Intermediate-Risk DTC Patients.

American Thyroid Association (ATA) guidelines do not consider age at diagnosis as a prognostic factor on the estimation of the risk of persistent/recurrent disease in differentiated thyroid carcinoma (DTC) patients. While age at diagnosis has already been assessed in high-risk patients, it remains to be established in low- and intermediate-risk patients. The aim of our study was to investigate the role of age as a prognostic factor in the short- and long-term outcome of DTC patients classified at low and intermediate risk according to the ATA stratification risk system. We retrospectively evaluated 863 DTC patients (mean follow-up: 10 ± 6.2 years) 52% classified as low (449/863) and 48% as intermediate risk (414/863). For each ATA-risk class patients were divided into subgroups based on age at diagnosis (<55 or ≥55 years). In the intermediate-risk group, patients aged 55 years or older had a higher rate of structural disease (11.6% vs 8.9%), recurrent disease (4.1% vs 0.7%), and death (4.1% vs 1%) when compared with younger patients (<55 years) (P = .007). Multivariate analysis confirmed that older age at diagnosis (odds ratio [OR] = 3.9; 95% CI, 1.9-8.6; P < .001) was an independent risk factor for worse long-term outcome together with response to initial therapy (OR = 13.0; 95% CI, 6.3-27.9; P < .001), and T (OR = 32; 95% CI, 1.4-7.1; P = .005) and N category (OR = 2.3; 95% CI, 1.1-5.0; P = .03). Nevertheless, a negative effect of older age was documented only in the subgroup of intermediate DTC patients with persistent structural disease after initial therapy. Indeed, the rate of worse long-term outcome rose from 13.3% in the whole population of intermediate DTC patients to 47.8% in patients with persistent structural disease after initial therapy (P < .001) and to 80% in patients older than 55 years and persistent structural disease after initial therapy (P = .02). Our results suggest that age at diagnosis further predict individual outcomes in Intermediate-Risk DTC allowing ongoing management to be tailored accordingly.

SAT526 Limited Utility of Routine Neck Ultrasound Follow-up in Advanced Stage Differentiated Thyroid Cancer

Abstract Disclosure: V. Munro: None. S. Mustafa: None. F.S. Siddiqi: None. M. Rajaraman: None. S.A. Imran: None. Background: Most guidelines recommend periodic cervical ultrasound (US) for ongoing surveillance of differentiated thyroid cancer (DTC). While recent studies do not support routine US surveillance in low-risk DTC, to date, no study has assessed the clinical utility of cervical US in advanced DTC. Methods: We conducted a retrospective study of our hospital DTC registry using the following criteria: a) AJCC stage III and IV, b) minimum follow-up of &amp;gt;4 years since total thyroidectomy +/-I-131 ablation, and c) at least one US per 3 years of follow-up. Patients with hemithyroidectomy only or positive anti-thyroglobulin antibody at the initial visit were excluded. Two years after initial treatment, patients were categorized by Dynamic Risk Stratification (DRS) as excellent, indeterminate, biochemically incomplete, or structurally incomplete response. Data obtained at each visit included: treatment response, thyroglobulin (TG) level, and US findings. Results: A total of 114 patients (85 AJCC stage III and 29 stage IV patients) met the inclusion criteria. Mean age (yrs) at diagnosis was 59, and 67% were female. Mean duration of follow-up was 8.5 years. Based on DRS, 73 patients had excellent response, 28 indeterminate, 8 biochemically incomplete, and 5 structurally incomplete. Recurrence or progression was detected in 20 patients (17.5%): 5 excellent response, 6 indeterminate, 5 biochemically incomplete, and 4 structurally incomplete. Recurrence sites included cervical region (14), distant metastases (5) and both (1). The TG rose from a mean of 4.76 ng/mL at baseline to 40.37 ng/mL at time of recurrence/progression. In those with structurally incomplete disease, US demonstrated progression in all 4 patients. However in other DRS categories, only 5/10 had definite US abnormalities. Of those without recurrence, 4 patients (4.3%) had false positive TG (mean baseline TG 0.08 rose to 11.8 ng/ml) without clinical/radiologic recurrence whereas the rate of false positive US abnormalities was 32% (37/114). The sensitivity and specificity of US vs. TG in diagnosing recurrence was 45% and 60% vs 100% and 95.7%, respectively. Conclusion: Our study suggests that routine cervical US surveillance after initial DRS does not improve the detection of recurrence in patients with excellent, indeterminate, or biochemically incomplete disease, and has a high false positive rate. Therefore, we suggest TG should be considered the mainstay of surveillance and any further imaging guided by DRS status and change in TG. Presentation Date: Saturday, June 17, 2023

Dynamic Risk Stratification Integrated with ATA Risk System for Predicting Long-Term Outcome in Papillary Thyroid Cancer.

In recent years, there has been a renewed interest in thyroid cancer management paradigms that use individualized risk assessments as the basis for treatment and follow-up recommendations. In this study, we assumed that the long-term follow-up of differentiated thyroid cancer patients might be better tailored by integrating the response to initial therapy with the America Thyroid Association (ATA) risk classes. This retrospective study included low- and intermediate-risk papillary thyroid cancer (PTC) patients followed up for a median time of 8 years and classified according to the response to initial therapy assessed 6-12 months after initial treatment. After a median follow-up of 8 years, in the initial excellent response subgroup of PTC patients (n = 522), the rate of recurrent disease was significantly higher in intermediate-risk patients than in low-risk PTC patients (6.9% versus 1.2%, p = 0.0005). Similarly, in the initial biochemical incomplete response subgroup (n = 82), the rate of excellent response was significantly higher in low-risk PTC patients (58.0%) than in intermediate-risk PTC patients (33.3%) (p = 0.007). Finally, in the initial structural incomplete response subgroup (n = 66), the rate of excellent response was higher in low-risk patients (80.0%) than in intermediate-risk patients (46.4%) (p = 0.08). Moreover, all patients with initial indeterminate response had an excellent response at the last follow-up visit. ATA risk classes were independently associated with long-term outcome in each subgroup of patients classified dynamically after initial therapy and the overall prognostic performance, defined via ROC curve analysis, of response to initial therapy integrated with the ATA risk system (AUC: 0.89; 95% CI: 0.86-0.92) was significantly higher compared to the ATA risk stratification (AUC 0.69; 95% CI: 0.65-0.74, p < 0.001) or the dynamic risk stratification (DRS) systems alone (AUC: 0.86 95% CI: 0.82-0.90, p = 0.007). This study of a large cohort of PTC patients showed that the initial ATA risk criteria may be useful for improving the risk-adapted management of PTC patients based on the response to initial therapy.

Follow-up strategy of radiofrequency ablation for papillary thyroid microcarcinoma: defining a response-to-ablation system.

To define a response-to-ablation system based on dynamic risk stratification proposed by the 2015 American Thyroid Association guidelines for predicting clinical outcomes and guiding follow-up strategies for patients with low-risk papillary thyroid microcarcinoma (PTMC) who underwent radiofrequency ablation (RFA). This retrospective study reviewed patients with low-risk PTMC who underwent RFA between 2014 and 2018. We classified patients into three groups based on their response to therapy at the 1-year follow-up: complete, indeterminate, and incomplete. The primary endpoints were local tumor progression (LTP) and disease-free survival (DFS). Among the 748 patients (mean age, 43.7 years ± 9.8; 586 women), 4.0% (30/748) had LTP during a median follow-up of 5 years. The response was complete in 80.2% (600/748) of the patients, indeterminate in 18.1% (135/748), and incomplete in 1.7% (13/748). The LTP rate in the final follow-up was 1% (6/600), 8.1% (11/135), and 100% (13/13), respectively. The risk of LTP was significantly different in the incomplete response group (HR, 1825.82; 95% CI: 458.27, 7274.36; p< 0.001) and indeterminate response group (HR, 8.12; 95% CI: 2.99, 22.09; p< 0.001) than in the complete response group. There were significant differences in DFS among groups (p< 0.001). The proportion of variation explained and C-index of the system was high (27.66% and 0.79, respectively). We defined a response-to-ablation system that provides a new paradigm for the management of patients with PTMC who underwent RFA. Our data confirm that the system can effectively predict the risk of LTP and guide ongoing follow-up recommendations. • The response-to-ablation system can classify patients with low-risk PTMC who underwent RFA into complete, indeterminate, or incomplete response categories. • Results suggest that, in this population, this system can identify three separate cohorts of patients who have significantly different clinical outcomes. • The response-to-ablation system will help better tailor the ongoing follow-up recommendations.