Very-low Risk Research Articles

Performance of Computerised Self-Reported Medical History-Taking and HEAR Score for Safe Early Rule-Out of Cardiac Events in Acute Chest Pain Patients: The CLEOS-CPDS Prospective Cohort Study

Abstract Objective A simplified version of the History, ECG, Age, Risk factors, Troponin (HEART) score, excluding troponin, has been proposed to rule out major adverse cardiac events (MACE). Computerised history taking (CHT) provides a systematic and automated method to obtain information necessary to calculate the HEAR score. We aimed to evaluate the efficacy and diagnostic accuracy of CHT in calculating the HEAR score for predicting MACE. Methods Prospective study including clinically stable adults presenting with chest pain at the emergency department of Danderyd University Hospital (Stockholm, Sweden), in 2017-2019. Participants entered their medical histories on touchscreen tablets using CHT software. HEAR and HEART scores were calculated from CHT data. 30-day MACE and ACS outcomes were retrieved, and the diagnostic accuracy was assessed. Logistic regression was used to determine the most predictive components of the HEAR score. Results Among 1,000 patients, HEART and HEAR scores could be calculated from CHT data in 648 and 666 cases, respectively, with negative predictive values (95% CI) of 0.98 (0.97–0.99) and 0.99 (0.96–1.00). Two patients with HEAR score <2 experienced a 30-day MACE. The Age (OR 2.75, 95% CI 1.62–4.66) and History (OR 2.38, 95% CI 1.52–3.71) components of the HEAR score were most predictive of MACE. ACS outcomes provided similar results. Conclusions HEAR score acquired by CHT identifies very-low risk patients with chest pain in the ED, safely ruling out ACS and MACE. This highlights the value of computerised history-taking by patients, which may reduce unnecessary tests and hospital admissions. Trial Registration ClinicalTrials.gov NCT03439449.

Baseline Ga-68 PSMA PET-Derived Primary Tumor Parameters in Patients with Prostate Cancer and Their Association with Clinical Risk Stratification and Clinicopathologic Features

Abstract Aim This article evaluates whether parameters derived from the gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging studies of primary prostate cancer (PCa) lesions were associated with Gleason score (GS), D'Amico risk class, Candiolo nomograms, and the metastatic status of the disease. Methods We retrospectively evaluated newly diagnosed PCa patients who underwent 68Ga-PSMA PET/CT before therapy. Age, baseline serum prostate-specific antigen (PSA), and metastatic status were recorded. Maximal standardized uptake value (SUVmax), mean SUV (SUVmean), total lesion PSMA (TL-PSMA), and PSMA-derived tumor volume (PSMA-TV) were analyzed. The patients were grouped according to GS (GS ≤ 7 and GS ≥ 8), D'Amico risk classes (low intermediate and high-risk), and also based on their results with the Candiolo nomogram which normally creates five risk classes. For Candiolo classes, very-low risk and low-risk patients were pooled into the low-risk Candiolo (LRC) group, high and very high-risk patients were pooled into the high-risk Candiolo (HRC) group. The intermediate-risk Candiolo group was utilized as-is (IRC). Results Mean age was 67 ± 8 years, median PSA value was 14.3 (3–211). There were 82 patients with GS ≤ 7 and 38 patients with GS ≥ 8; intermediate D'Amico class comprised 32 patients, while the high D'Amico class comprised 88 patients. For Candiolo, there were 23 LRC, 40 IRC, and 57 HRC patients. PSMA-positive metastases were detected in 44 (36.7%) patients. The SUVmean, SUVmax, PSMA-TV, and TL-PSMA values of the primary tumor demonstrated significant differences when compared according to classifications for GS, D'Amico, LRC versus HRC, and metastatic versus nonmetastatic patients. Of note, TL-PSMA was the only parameter that varied significantly among all risk groups. Conclusion Primary tumor parameters obtained from baseline 68Ga-PSMA PET/CT are useful to distinguish PCa patients in terms of GS, D'Amico, Candiolo nomogram, and metastatic states. TL-PSMA appears to be the best parameter as it is the only parameter that can distinguish all risk groups from each other.

Contemporary Diagnosis of Very Low-risk Prostate Cancer in a Multihospital Health Care System

The National Comprehensive Cancer Network (NCCN) very low risk (VLR) category for prostate cancer (PCa) represents clinically insignificant disease, and detection of VLR PCa contributes to overdiagnosis. Greater use of magnetic resonance imaging (MRI) and biomarkers before patient selection for prostate biopsy (PBx) reduces unnecessary biopsies and may reduce the diagnosis of clinically insignificant PCa. We tested a hypothesis that the proportion of VLR diagnoses has decreased with greater use of MRI-informed PBx using data from our 11-hospital system. From 2018 to 2023, 351/3197 (11%) men diagnosed with PCa met the NCCN VLR criteria. The proportion of VLR diagnoses did not change from 2018 to 2023 (p = 0.8) despite an increase in the use of MRI-informed PBx (from 49% to 82%; p < 0.001). Of patients who underwent combined systematic and targeted PBx and were diagnosed with VLR disease, cancer was found in systematic PBx regions in 79% of cases and in targeted PBx regions in 31% of cases. When performing both systematic and targeted PBx, prebiopsy MRI-based risk calculators could limit VLR diagnosis by 41% using a risk threshold of >5% for Gleason grade group ≥3 PCa to recommend biopsy; the reduction would be 77% if performing targeted PBx only. These findings suggest that VLR disease continues to account for a significant minority of PCa diagnoses and could be limited by targeted PBx and risk stratification calculators. Patient summaryWe looked at recent trends for the diagnosis of very low-risk (VLR) prostate cancer. We found that VLR cancer still seems to be frequently diagnosed despite the use of MRI (magnetic resonance imaging) scans before biopsy. The use of risk calculators to identify men who could avoid biopsy and/or biopsy only for lesions that are visible on MRI could reduce the overdiagnosis of VLR prostate cancer.

Contemporary management and pathologic outcomes of men with low- and very low-risk prostate cancer.

297 Background: The very-low risk (VLR) substratification of prostate cancer has been called into question with the 2022 American Urological Association (AUA) guidelines dropping this designation. Historical data suggested men with VLR disease have a reduced risk of disease progression compared to other low risk (LR) men. In this study, we evaluate contemporary initial management, disease progression, and predictors of upgrading for VLR and LR patients in a multi-centered hospital system. Methods: We retrospectively identified men diagnosed with VLR or LR prostate cancer across our eleven-hospital system (January 2018-September 2022). Active surveillance (AS) was defined as no treatment within 1 year of diagnosis. Adverse pathology at surgery was defined as Gleason Grade (GG) 3-5 or pT3b. Clinical variables were compared with appropriate statistical tests (Wilcoxon rank sum, Chi square, Fisher’s exact). A multivariable logistic regression model evaluated predictors of upgrading (≥GG2). Results: 566 patients (305 VLR, 261 LR) were included. AS was the initial management for 85% and 78% of VLR and LR patients, respectively (p=0.029). With a median follow up time of 26 months, VLR patients were less likely receive treatment versus LR patients (24% vs. 38%, p&lt;0.001) or be reclassified to GG2-5 disease (24% vs. 39%, p&lt;0.001). VLR patients had less volume of disease at diagnosis by percentage of positive cores (7% vs. 16%, p&lt;0.001) and maximum core positivity (7% vs. 20%, p&lt;0.001). On multivariable regression analysis, only pre-biopsy PI-RADS (OR 1.88 for PI-RADS 4 (p=0.030); OR 4.53 for PI-RADS 5 (p&lt;0.001)) and percentage of positive cores (OR 1.02, p=0.039) were significant predictors of upgrading. Of men who receiving surgery, adverse pathology rates were similar for VLR and LR patients (14% vs. 19%, p=0.5). Conclusions: Men with VLR prostate cancer have lower treatment and upgrading rates than LR patients. VLR patients were more likely to be initially managed with AS and forgo definitive treatment, but rates of adverse pathology at surgery were similar. The findings support the AUA decision to drop the VLR substratification, but attention to high MRI PI-RADS and percentage of positive cores at diagnosis should be considered when evaluating risk of disease progression for men with GG1 prostate cancer.[Table: see text]

Reappraisals of biological behaviors of PDGFRA mutant gastrointestinal stromal tumor

Objective: To investigate the biological behavior spectrum of platelet-derived growth factor alpha receptor (PDGFRA)-mutant gastrointestinal stromal tumor (GIST), and to compare the clinical values of the Zhongshan method of benign and malignant evaluation with the modified National Institutes of Health (NIH) risk stratification. Methods: A total of 119 cases of GIST with PDGFRA mutation who underwent surgical resection at Zhongshan Hospital, Fudan University from 2009 to 2020 were collected. The clinicopathological data, follow-up records, and subsequent treatment were reviewed and analyzed statistically. Results: There were 79 males and 40 females. The patients ranged in age from 25 to 80 years, with a median age of 60 years. Among them, 115 patients were followed up for 1-154 months, and 13 patients progressed to disease. The 5-year disease-free survival (DFS) and overall survival (OS) were 90.1% and 94.1%, respectively. According to the modified NIH risk stratification, 8 cases, 32 cases, 38 cases, and 35 cases were very-low risk, low risk, intermediate risk, and high risk, and 5-year DFS were 100.0%, 95.6%, 94.3%, and 80.5%, respectively. There was no significant difference in prognosis among the non-high risk groups, only the difference between high risk and non-high risk groups was significant (P=0.029). However, the 5-year OS was 100.0%, 100.0%, 95.0% and 89.0%, and there was no difference (P=0.221). According to the benign and malignant evaluation Zhongshan method, 43 cases were non-malignant (37.4%), 56 cases were low-grade malignant (48.7%), 9 cases were moderately malignant (7.8%), and 7 cases were highly malignant (6.1%). The 5-year DFS were 100.0%, 91.7%, 77.8%, 38.1%, and the difference was significant (P<0.001). The 5-year OS were 100.0%, 97.5%, 77.8%, 66.7%, the difference was significant (P<0.001). Conclusions: GIST with PDGFRA gene mutation shows a broad range of biological behavior, ranging from benign to highly malignant. According to the Zhongshan method, non-malignant and low-grade malignant tumors are common, the prognosis after surgery is good, while the fewer medium-high malignant tumors showed poor prognosis after surgical resection. The overall biological behavior of this type of GIST is relatively inert, which is due to the low proportion of medium-high malignant GIST. The modified NIH risk stratification may not be effective in risk stratification for PDGFRA mutant GIST.

Establishing a Pathogenic Role for NK Cells As Drivers of Bone Marrow Failure in the Myelodysplastic Syndromes (MDS)

Background: Myelodysplastic syndromes (MDS) are characterized by aberrant bone-marrow (BM) morphology leading to a clonal impairment of hematopoiesis. Worsening BM failure (BMF) and increasing myeloblasts are observed as the predominant consequences of MDS disease progression from very low risk (VLR) to higher risk (HR) to acute myeloid leukemia (AML). Patients are stratified based on the degree of BMF and risk of AML transformation to help guide treatment decisions. Approximately 30% of MDS patients exhibit various autoimmune diseases that can include autoantibodies targeting neutrophils, erythrocytes, and/or platelets. Autoimmune phenomena play an important role in MDS yet are poorly characterized. We hypothesized that early in LR-MDS, dysregulated interactions between stromal cells and developing Natural Killer (NK)/T-cells promote rapid/unregulated development resulting in autoreactivity ( Fig. 1A). We predict dual effector mechanisms: CD16-mediated antibody-dependent cellular cytotoxicity (ADCC) and loss of HLA class I (HLA-I) expression by developing hematopoietic lineage cells making them targets for “missing-self” reactivity ( Fig. 1A). NK cells are important sentinel cells that recognize tumors and dysfunctional cells that lose expression of HLA class I. Such surveillance is guided by interactions between NK inhibitory receptors and HLA class I ligands that ‘train’ NK cells to distinguish diseased cells, exhibiting perturbed HLA expression, from healthy cells with normal expression. The effects of these interactions combined with expression of activating receptors (e.g. CD16, NKG2D, DNAM1, FasL, TRAIL) allow NK cells to engage a target cell through many activating mechanisms, importantly including antibodies eliciting an antibody-dependent cellular cytotoxicity (ADCC) reaction. Autoantibodies are well-established in MDS, yet no one has profiled whether they may trigger ADCC/complement. Further, no one has ever thoroughly characterized BMMCs from LR-MDS patients before. In our study, we observed a clear link between signatures of bone marrow failure at LR-MDS and a significant increase in BM CD57+NK and CD8 T cells expressing a highly activated and dysregulated phenotype. Method: Ex-vivo profiling of 19 MDS patients (N=10 LR/IR-MDS, N=9 HR-MDS) BM mononuclear cells (BMMCs) was performed by mass cytometry (CyTOF)( Fig.1B). Cells were stained with three different antibody panels each consisting of 44 antibodies focused on: specific markers of hematopoiesis and myeloid or lymphoid cell lineages; specific markers of development, effector function, homing, exhaustion, and T-cell memory and proliferation; expression of HLA class I and activating ligands which are critical regulators of NK inhibition. Results: In our study we observed that a major fraction of MDS patients present with clonal-like expansions of BM-derived CD57+CD8+T-cells and natural killer (NK) cells that strongly correlate with autoimmune-cytopenias and BMF-enriched in LR-MDS (Fig.#). We observed that NK-cells and non-classical T-cells were significantly expanded (&amp;gt;2-fold) in LR MDS compared to HR-MDS and healthy-control BM (p&amp;lt;0.01). These non-classical CD57+CD8+T-cells co-expressed HLA-I-reactive and inhibitory NKG2A/KIR receptors as well as activating CD16, NKG2C, NKG2D, NKp46, TRAIL, FasL. In cancers, these cells use innate-like, TCR-independent mechanisms (traditionally ascribed to NK-cells) to target HLA-I-deficient tumor cells. Strikingly, HLA-I was significantly elevated on myeloblasts in LR-MDS compared to HR-MDS (p=0.0007)( Fig.1B), demonstrating NK-evasion strategies, but strongly reduced on dendritic cells, granulocytes, and CD4+T-cells, suggesting susceptible immune targets for destruction by NK-cells (and innate-like CD8+T-cells) (p&amp;lt; 0.0001) ( Fig.1B). BM-derived CD57+NK and CD8+T-cells all co-express very high levels of CD16 making them particularly ADCC reactive. Conclusion: We identified novel innate-like CD8+CD57+ T-cell and NK-cell populations that may play a role in LR-MDS disease pathogenesis. We predict that a strategy to target these cells could help restore hematopoiesis early in the disease state. This may also reduce pressure on myeloblasts to increase HLA-I, permitting improved immune surveillance to control the blast burden and prevention MDS/AML progression. Further experiments are ongoing to validate our observations.

Analysis of active surveillance uptake for localized prostate cancer in Quebec in 2016: A Canadian bicentric study and comparison with 2010 data

IntroductionActive surveillance (AS) has emerged as a primary management strategy for low-risk prostate cancer (PC) patients. We aimed to assess AS uptake over a 1-year snapshot throughout Quebec and to compare it to 2010 multicentric Canadian data. MethodsA retrospective chart review and data collection was performed in 1 academic and 2 non-academic community centres from Quebec, among men identified in 2016 with localized T1c-T2c PC on biopsy, fulfilling NCCN criteria of low-risk (LR)-PC, including very-low-risk (VLR) and non-VLR-PC, and favourable-intermediate risk (FIR)-PC. AS adherence was defined when chosen as initial strategy, without any radical treatment within 6 months. ResultsOverall, 259 patients fulfilled the inclusion criteria with 50.2% of VLR-PC patients. At 6 months, 81% patients in the LR group and 65% in the FIR group were considered as adherent to AS, in both centres, but with an increased use of AS in the community centres compared to 2010 data. The rates of AS maintenance decreased at 12 months to respectively 69% and 58%. Among the VLR group, the rate of initiation was 98% and decreased to 85% at 12 months. ConclusionOur data suggest that the majority of low-risk PC patients indeed initiated an AS in 2016, with even a greater proportion of VLR-PC patients compared to 2010. This ideal strategy should be encouraged and improved at 12 months, and assessed with recent data and longer follow-up. Level of evidence4

O001 A novel molecular HLA mismatch algorithm to identify transplant patients at low risk of primary alloimmunity

Abstract Introduction There is an unmet need for prognostic biomarkers for alloimmune risk stratification to guide personalised recipient care kidney transplantation. Methods We used three molecular Mismatch (molMM) algorithms - Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and NetMHCIIpan in a dataset of patients receiving standardised donor lymphocyte injections to predict de-novo donor-specific-antibody (dnDSA) at the individual HLA level (n=665). Risk thresholds were derived for HLA-DR/DQ mismatch and algorithms combined. External validation was performed in two extensively-phenotyped kidney transplant cohorts (Manitoba, n=856, Denver n=404) and in the NHSBT kidney transplant registry (2000–2020, n=27,028). Results External validation (Manitoba cohort, 10-year follow-up) showed all algorithms predicted dnDSA development using experimentally derived HLA-DR/DQ molMM risk thresholds (HLA-DQ AUC: 0.78-0.80; HLA-DR AUC:0.76-0.81). AAMS and EMS3D had improved risk stratification (low-medium-high risk groups for HLA-DR+DQ dnDSA) vs NetMHCIIpan (p=NS). A combined AAMS+EMS3D molMM algorithm further improved discrimination and identified a large patient cohort (15.4% patients) at very-low risk of Class-II dnDSA (1.3% at 10 years). Multivariate analysis confirmed correlation with primary alloimmune events (dnDSA p&amp;lt;0.001, TCMR p&amp;lt;0.001, ABMR p=0.0049) and all-cause graft loss (p=0.0038). Further external validation of the combined molMM algorithm in an ethnically diverse cohort (Denver) confirmed the dnDSA risk association (p&amp;lt;0.0001), and in the UK registry cohort confirmed significant association with all-cause graft loss (p&amp;lt;0.001). Conclusion We developed and validated a novel molMM algorithm, incorporating information from HLA amino-acid sequence and tertiary structurebthat may be used as a prognostic biomarker of primary alloimmunity risk and to enrich prospective clinical trials in kidney transplantation.

Usefulness of the Vall d’Hebron Risk Score to stratify the risk of patients with ischemic cardiomyopathy

BackgroundTo evaluate the Vall d’Hebron-Risk-Score (VH-RS) to stratify the risk of patients with stable ischemic cardiomyopathy (ICM), and assess whether hemoglobin (Hb) and estimated glomerular filtration rate (eGFR) provide additional information to the VH-RS. Methods and resultsWe analysed 673 consecutive patients with ICM who underwent gated SPECT. According to VH-RS, we stratified patients into 4-risk-levels: very-low-risk (VLR), low-risk (LR), moderate-risk (MR), and high-risk (HRi). We considered as MACEs: non-fatal myocardial infarction (MI), heart failure hospitalization (HF), coronary revascularization (CR), and cardiac death (CD). Also the cardiac-resynchronization-therapy (CRT), and the implantable-cardioverter-defibrillator (ICD) were investigated. During the follow-up (4.8 ± 2.7 years), 379 patients had MACEs (0.18/patient/year). There were no patients in VLR and LR. All patients were reclassified in 3-risk-levels (MRi = 48; HRi = 121; VHRi[very high risk] = 504). Most patients with MACEs were in VHRi level (test-for-trend: MACEs ≥ 1 without CRT/ICD, P < .001; combined non-fatal MI, CD and CR, P < .001; MACEs ≥ 1 with CRT/ICD, P < .001). The Hb and eGFR values do not properly improve the risk stratification obtained by the VH-RS (global-NRI[net-reclassification-improvement] was: (MACEs ≥ 1 without CRT/ICD: − 10.6%; non-fatal MI, CD and CR: − 9.08%; and MACEs ≥ 1 with CRT/ICD: − 8.85%). ConclusionVH-RS is effective in evaluating risk of patients with stable ICM. In our population, adding Hb and eGFR variables do not improve the performance of the VH-RS.

Limited Relevance of the Very Low Risk Prostate Cancer Classification in the Modern Era: Results from a Large Institutional Active Surveillance Cohort

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05–1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. Patient summaryWe investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era.

An online tool for predicting ovarian responses in unselected patients using dynamic inhibin B and basal antimüllerian hormone levels.

Reliable predictive models for predicting excessive and poor ovarian response in controlled ovarian stimulation (COS) is currently lacking. The dynamic (Δ) inhibin B, which refers to increment of inhibin B responding to exogenous gonadotropin, has been indicated as a potential predictor of ovarian response. To establish mathematical models to predict ovarian response at the early phase of COS using Δinhibin B and other biomarkers. Prospective cohort study in a tertiary teaching hospital, including 669 cycles underwent standard gonadotropin releasing hormone (GnRH) antagonist ovarian stimulation between April 2020 and September 2020. Early Δinhibin B was defined as an increment in inhibin B from menstrual day 2 to day 6 through to the day of COS. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression with 5-fold cross-validation was applied to construct ovarian response prediction models. The area under the receiver operating characteristic curve (AUC), prevalence, sensitivity, and specificity were used for evaluating model performance. Early Δinhibin B and basal antimüllerian hormone (AMH) levels were the best measures in building models for predicting ovarian hypo- or hyper-responses, with AUCs and ranges of 0.948 (0.887-0.976) and 0.904 (0.836-0.945) in the validation set, respectively. The contribution of the early Δinhibin B was 67.7% in the poor response prediction model and 56.4% in the excessive response prediction model. The basal AMH level contributed 16.0% in the poor response prediction model and 25.0% in the excessive response prediction model. An online website-based tool (http://121.43.113.123:8001/) has been developed to make these complex algorithms available in clinical practice. Early Δinhibin B might be a novel biomarker for predicting ovarian response in IVF cycles. Limiting the two prediction models to the high and the very-low risk groups would achieve satisfactory performances and clinical significance. These novel models might help in counseling patients on their estimated ovarian response and reduce iatrogenic poor or excessive ovarian responses.

A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China.

Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited. We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021. A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%). Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Factors that influence treatment decisions: A qualitative study of racially and ethnically diverse patients with low- and very-low risk prostate cancer.

Factors that influence prostate cancer treatment decisions are complex, multifaceted, and personal, and may vary by race/ethnicity. Although research has been published to quantify factors involved in decision-making, these studies have been limited to primarily white, and to a lesser extent, Black patients, and quantitative studies are limited for discerning the cultural and contextual processes that shape decision-making. We conducted 43 semi-structured interviews with a racially and ethnically diverse sample of patients diagnosed with low- and very-low risk prostate cancer who had undergone treatment for their prostate cancer. Interviews were transcribed, independently coded, and analyzed to identify themes salient for decision-making, with attention to sociocultural differences. We found racial and ethnic differences in three areas. First, we found differences in how socialized masculinity influenced patient's feelings about different treatment options. Second, we found that for some men, religion and spirituality alleviated anxiety associated with the active surveillance protocol. Finally, for racially and ethnically minoritized patients, we found descriptions of how historic and social experiences within the healthcare system influenced decision-making. Our study adds to the current literature by expounding on racial and ethnic differences in the multidimensional, nuanced factors related to decision-making. Our findings suggest that factors associated with prostate cancer decision-making can manifest differently across racial and ethnic groups, and provide some guidance for future research.

Overall Survival and Progression-Free Survival of Patients Following Luspatercept Treatment in the MEDALIST Trial

Introduction: Overall survival (OS) is rarely assessed in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) despite a previous analysis highlighting the impact of treatment on factors influencing OS (Santini V, et al. Clin Lymphoma Myeloma Leuk 2022;doi.org/10.1016/j.clml.2022.05.001). Luspatercept is US FDA-approved to treat anemia in adults with Revised International Prognostic Scoring System (IPSS-R) Very low- to Intermediate (Int)-risk MDS with ring sideroblasts (RS) following erythropoiesis-stimulating agent (ESA) failure. Luspatercept promotes late-stage erythropoiesis and significantly reduced transfusion burden (TB) in pts with LR-MDS vs placebo (PBO) in the phase 3 MEDALIST trial (Fenaux P, et al. N Engl J Med 2020;382:140-151). However, the baseline (BL) pt characteristics predictive of the greatest survival benefit from luspatercept treatment have yet to be investigated. This study aimed to report the probability of greater OS and progression-free survival (PFS) benefit from luspatercept vs PBO in the MEDALIST trial. Methods: Pts were ≥ 18 years of age with IPSS-R Very low-, Low-, or Int-risk MDS-RS who received ≥ 2 red blood cell (RBC) units/8 weeks (wk) in the 16 wk before randomization and were unlikely to respond/refractory to ESAs. Pts in the intent-to-treat (ITT) population were randomly assigned to receive luspatercept (n = 153) at 1.0 mg/kg (titration up to 1.75 mg/kg) or PBO (n = 76) subcutaneously every 3 wk; no crossover was allowed at any point of the study. Responders were defined as pts who achieved transfusion independence ≥ 8 wk during the first 24 wk of treatment. OS was defined as time from randomization to death from any cause. PFS was defined as time from MDS diagnosis to acute myeloid leukemia progression. Kaplan-Meier method was used to evaluate ITT and responder OS (Jan 15, 2021 data cut), and ITT PFS (Jan 15, 2022 data cut). Analysis of BL characteristics associated with PFS and OS included pts who remained on treatment or discontinued before 36 months (mo; Jan 15, 2022 data cut). Results: Median OS (95% confidence interval [CI]) of the ITT population was not significantly different between luspatercept (not applicable [NA]; 46.1-NA mo) and PBO (NA; 43.1-NA mo; P < 0.9604). Luspatercept responders had statistically significantly longer OS than luspatercept non-responders at wk 25 (hazard ratio 0.319; P = 0.0003; Figure 1A). Probability of 36-mo OS was similar in luspatercept vs PBO pts when stratified by the BL RBC TB categories < 6 units/8 wk (50/87 [57.5%] vs 23/43 [53.5%] pts, respectively; odds ratio [OR] 1.18; P = 0.6680) and ≥ 6 units/8 wk (35/66 [53.0%] vs 20/33 [60.6%], respectively; OR 0.73; P = 0.4768). Probability of 36-mo OS was greater for pts diagnosed with IPSS-R Very-low risk MDS receiving luspatercept vs PBO (14/18 [77.8%] vs 1/6 [16.7%], respectively; OR 17.5; P = 0.0088). Of pts with a BL platelet count > 400 × 109/L, those receiving luspatercept also had a significantly higher 36-mo OS probability than those receiving PBO (13/17 [76.5%] vs 3/9 [33.3%], respectively; OR 6.5; P = 0.0349). BL serum erythropoietin (EPO) levels and time from MDS diagnosis did not impact 36-mo OS probability in the luspatercept vs PBO arms. Median PFS (95% CI) of the ITT population was not significantly different between the luspatercept (NA; 223.57-NA mo) and PBO (NA; 95% CI NA-NA) arms (P = 0.3514; Figure 1B). No significant PFS advantage was observed when comparing luspatercept vs PBO pts by BL RBC TB categories < 6 units/8 wk (81/87 [93.1%] vs 36/43 [83.7%], respectively; OR 2.62; P = 0.0947) and ≥ 6 units/8 wk (62/66 [93.9%] vs 32/33 [97.0%], respectively; OR 0.48; P = 0.5184). Probability of 36-mo PFS of pts with a BL serum EPO level of 100 to ≤ 200 U/L who received luspatercept was significantly higher than that of pts who received PBO (36/37 [97.3%] vs 15/19 [78.9%], respectively; OR 9.6; P = 0.0238). Conclusions: Although the MEDALIST trial was not specifically powered to assess OS or PFS, these data show that achieving response with luspatercept treatment increased OS probability. Luspatercept was associated with increased 36-mo OS probability for pts with IPSS-R Very low-risk MDS and 36-mo PFS probability in pts with a BL serum EPO level of 100 to ≤ 200 U/L. Therefore, pts with LR-MDS with these BL characteristics may derive greater survival benefit from luspatercept. Future studies with longer follow-up times will help to clarify the long-term impact of luspatercept therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic modeling of cutaneous melanoma stage I patients using cancer registry data identifies subsets with very-low melanoma mortality.

Evidence exists that escalating melanoma incidence is due in part to overdiagnosis, the diagnosis of lesions that will not lead to symptoms or death. The authors aimed to characterize subsets of melanoma patients with very-low risk of death that may be contributing to overdiagnosis. Melanoma patients diagnosed in 2010 and 2011 with stage I lesions ≤1.0mm thick and negative clinical lymph nodes from the Surveillance, Epidemiology, and End Results database were selected. Classification and regression tree and logistic regression models were developed and validated to identify patients with very-low risk of death from melanoma within 7years. Logistic models were also used to identify patients at higher risk of death among this group of stage I patients. Compared to an overall 7-year mortality from melanoma of 2.5% in these patients, a subset comprising 25% had a risk below 1%. Younger age at diagnosis and Clark level II were associated with low risk of death in all models. Breslow thickness below 0.4mm, absence of mitogenicity, absence of ulceration, and female sex were also associated with lower mortality. A small subset of high-risk patients with >20% risk of death was also identified. Patients with very-low risk of dying from melanoma within 7years of diagnosis were identified. Such cases warrant further study and consensus discussion to develop classification criteria, with the potential to be categorized using an alternative term such as "melanocytic neoplasms of low malignant potential." Although melanoma is the most serious skin cancer, most melanoma patients have high chances of survival. There is evidence that some lesions diagnosed as melanoma would never have caused symptoms or death, a phenomenon known as overdiagnosis. In this study, we used cancer registry data to identify a subset of early-stage melanoma patients with almost no melanoma deaths. Using two statistical approaches, we identified patients with <1% risk of dying from melanoma in 7 years. Such patients tended to be younger with minimal invasion into the skin. We also identified a very small patient subset with higher mortality risk.

Characterization of data-driven clusters in diabetes-free adults and their utility for risk stratification of type 2 diabetes

BackgroundThe prevention of type 2 diabetes is challenging due to the variable effects of risk factors at an individual level. Data-driven methods could be useful to detect more homogeneous groups based on risk factor variability. The aim of this study was to derive characteristic phenotypes using cluster analysis of common risk factors and to assess their utility to stratify the risk of type 2 diabetes.MethodsData on 7317 diabetes-free adults from Sweden were used in the main analysis and on 2332 diabetes-free adults from Mexico for external validation. Clusters were based on sex, family history of diabetes, educational attainment, fasting blood glucose and insulin levels, estimated insulin resistance and β-cell function, systolic and diastolic blood pressure, and BMI. The risk of type 2 diabetes was assessed using Cox proportional hazards models. The predictive accuracy and long-term stability of the clusters were then compared to different definitions of prediabetes.ResultsSix risk phenotypes were identified independently in both cohorts: very low-risk (VLR), low-risk low β-cell function (LRLB), low-risk high β-cell function (LRHB), high-risk high blood pressure (HRHBP), high-risk β-cell failure (HRBF), and high-risk insulin-resistant (HRIR). Compared to the LRHB cluster, the VLR and LRLB clusters showed a lower risk, while the HRHBP, HRBF, and HRIR clusters showed a higher risk of developing type 2 diabetes. The high-risk clusters, as a group, had a better predictive accuracy than prediabetes and adequate stability after 20 years.ConclusionsPhenotypes derived using cluster analysis were useful in stratifying the risk of type 2 diabetes among diabetes-free adults in two independent cohorts. These results could be used to develop more precise public health interventions.

S101: GENETIC AND EPIGENETIC FACTORS DRIVING PRIMARY MEDIASTINAL B-CELL LYMPHOMA PATHOGENESIS AND OUTCOME

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive lymphoma affecting predominantly young female patients. Previous studies in this rare entity have focused on single genes or were limited in cohort size. Aims: To unravel the underlying genetic pathogenesis and its impact on outcome, we embarked on a comprehensive large-scale genetic investigation. Methods: Specimens of 486 previously untreated PMBCL patients were analyzed by paired tumor/normal whole-genome (WGS, n=14), whole-exome (WES, n=78) and targeted sequencing (TS, n=486). To understand the consequences of highly recurrent mutations in the chromatin-modifying gene ZNF217, we conducted functional and multi-omics analyses in CRISPR/Cas9 engineered cell lines. Results: WGS/WES revealed a complex genomic landscape in PMBCL with a median of 85 structural variants, a mutational burden of 5 mutations/Mb, 12 mutated coding candidate driver genes (CDG) and 4 focal somatic copy-number aberrations per sample (Fig.1a). Besides known targets, significant breakpoints were identified in genes previously not implicated in B-lymphomagenesis such as TOX and TP73 (36% and 21%). In addition, non-coding mutations clustered within the PAX5 enhancer region. With the identification of 50 recurrently mutated CDGs, we significantly expand the repertoire of known PMBCL drivers. The 10 most frequently mutated CDGs were SOCS1 (86%), B2M (67%), ITPKB (64%), ACTB (58%), STAT6 (58%), IGLL5 (56%), TNFAIP3 (53%), NFKBIE (49%), GNA13 (47%), and ZNF217 (36%), respectively. The operative mutational processes were attributed to aging, AID/APOBEC activity, defective MMR, and an unexpected infidelity of DNA-Polymerase ε. Next, we performed TS in 486 samples using a PMBCL-specific 106-gene panel. Recurrent lesions in 25 epigenetic modifiers were found in >90%, with ZNF217 being among the most frequently mutated genes (Fig.1b). After knockdown of ZNF217 in Karpas1106P and L428 cells, we demonstrated altered proliferation, migration, and apoptosis. Using mass spectrometry, we showed that ZNF217 is acting in a LSD1, CoREST and HDAC containing histone modifier complex. Accordingly, knockout of ZNF217 led to global changes in chromatin accessibility with an enrichment of differentially accessible motifs for crucial lymphoma-associated transcription factors, especially of the NF-κB, BATF/AP1, and IRF family, but also of CTCF, a major regulator of global 3D chromatin architecture. Resulting gene expression was characterized by changes in interferon-responsive genes and inflammation-associated transcription (Fig 1c). Clinical data were available for 329 cases, including 84 cases from clinical trials. Multivariate analysis using an IPI-corrected Cox regression model was performed. The estimated 5-year PFS and OS were 77% and 86%. Among the genetic lesions with the strongest association for poor outcome, we identified patients with mutatedCD58 having a significantly shorter survival (PFS: HR 2.96; p<.001; OS: HR 2.55; p=.006). In contrast, mutated DUSP2 indicated longer survival (PFS: HR 0.28; p=.002; OS: HR 0.15; p=.011) (Fig1d). Notably, DUSP2 mutated patients (25%) showed a similar outcome for CR rate, PFS and OS when comparing CHOP-like and intensified treatment regimens, suggesting no further benefit from treatment intensification in this very-low risk patient population. Image:Summary/Conclusion: Here, we present the genetic landscape of PMBCL highlighting a previously underappreciated role of chromatin modifying genes, identify novel treatment targets and provide a solid basis for guiding precision medicine approaches.

Clinical and biological features prognostic of survival after relapse of INRGSS-stage MS pattern neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

10044 Background: Neuroblastoma (NB) presenting with INRGSS MS metastatic pattern highlights the extreme heterogeneity within NB and subsequent difficulty in risk assignment. Depending on tumor biology, patients with stage MS disease may be classified as very-low risk or as high-risk. While outcomes at initial diagnosis have been well-described, outcomes after relapse are less well defined. Methods: From the INRG Data Commons, we investigated clinical and biological characteristics of patients diagnosed 1984-2021 with stage MS pattern NB (INSS stage 4s, INSS stage 4 or INRG stage MS) who subsequently experienced disease relapse or progression, excluding patients whose first event was death. Using Kaplan-Meier methods, post-relapse overall survival (OS)± standard error (SE) was calculated from the time of first relapse/progression until death or last contact, overall and by era of diagnosis: &lt; 2000 vs ≥2001. Univariate Cox models were used to identify factors prognostic of post-relapse OS. Results: 209 patients met eligibility criteria,103 diagnosed &lt; 2001 and 106 ≥2001. Of patients diagnosed ≥2001, 89% (n = 94) were &lt; 365 days old at diagnosis; tumors were MYCN amplified in 21% (21/102) and diploid in 31% (20/64). Of this same cohort, time from initial diagnosis to relapse was &lt; 6 months in 40% (n = 42), 6-12 months in 25% (n = 26), and &gt; 12 months in 36% (n = 38) of patients. Of 60 patients with known site of relapse/progression diagnosed ≥2001, 73% (44) were metastatic (29) or primary plus metastatic (15). Among these, 16% (5/32) remained stage MS pattern while 84% (27/32) had metastatic sites beyond MS sites. Five-year post-relapse OS±SE was 53±3.5% overall (n = 209), and higher for those diagnosed ≥2001 (62±5.0%; n = 106) compared to those diagnosed &lt; 2001 (44±4.9%; n = 103) (p = 0.0046). In patients diagnosed ≥2001, factors prognostic of superior post-relapse OS included: age &lt; 365 days; not Hispanic; MYCN non-amplified; no 1p loss/aberration, hyperdiploidy; low/intermediate MKI; LDH &lt; 1400 U/L, favorable INPC histology; and &lt; 12 months from initial diagnosis to first relapse. Conclusions: Most patients with relapsed stage MS NB have metastatic relapse and these relapses more commonly occur at sites outside liver, skin, and bone marrow. Patients diagnosed ≥2001 with MS pattern NB have substantially better post-relapse OS compared to those diagnosed &lt; 2001. In the cohort of patients with MS pattern NB diagnosed ≥2001, most of the well-accepted prognostic factors for OS at diagnosis are also prognostic of post-relapse OS.

Distribution of NCCN risk classifications using MRI-ultrasound fusion versus systematic 12 core biopsies.

283 Background: The widely-used National Comprehensive Cancer Network (NCCN) risk criteria for prostate cancer are impactful for patient and clinicians, particularly when assessing suitability for initial active surveillance. However, in the era of MRI-guided biopsy, fewer patients may meet stringent “very-low risk” criteria due to improved sampling, which may lead to over-treatment of non-lethal cancers. We evaluated the distribution of prostate cancer risk classification obtained using MRI-ultrasound fusion versus systematic 12 core biopsy. Methods: We performed a retrospective study of patients who underwent prostate MRI-ultrasound fusion biopsy at a single institution from January 2017 to July 2021. The primary study objective was to characterize the proportion of patients meeting NCCN “very-low risk” designation within a contemporary biopsy cohort. We calculated NCCN risk classifications (very low, low, favorable intermediate, unfavorable intermediate, high, and very high) based on constituent components (PSA, PSA density, number of biopsy cores positive, greatest extent of core positivity). We conducted comparisons within patients based on findings obtained through MRI-ultrasound fusion biopsy versus systematic biopsy only. Results: We identified 1,132 patients, including 1,014 (89.5%) and 118 (10.5%) who underwent first-time biopsy and surveillance biopsies. The median PSA was 7.15 (interquartile range: 5.2-10.8). Using data obtained through systematic biopsy alone, 123 (10.9%) and 242 (21.4%) were classified as very-low and low NCCN risk, respectively. Incorporating data from MRI-ultrasound fusion biopsy, 86 (7.6%) and 255 (22.5%) were classified as very-low and low NCCN risk, respectively. Among patients initially electing active surveillance as management, 7.4%, 60.2%, 26.9% met very-low, low, and favorable-intermediate risk criteria, respectively. Conclusions: A small proportion of patients undergoing MRI-ultrasound fusion biopsy will be classified as ‘very-low risk’ by the NCCN definition, and the majority of patients managed initially with active surveillance fall outside of this criteria. These findings imply a need to broaden support for active surveillance outside of “very-low risk” criteria to promote greater uptake.[Table: see text]

Diagnostic Imaging in Low-Risk Prostate Cancer: More Harm Than Good?

Despite guidelines recommending that staging imaging is not needed in very low-risk (VLR) and low-risk (LR) prostate cancer (PCa), there is concern for overutilization in these risk groups. We investigate utilization of staging imaging and implications of findings in newly diagnosed VLR and LR PCa patients. A total of 493 patients diagnosed with PCa between 2011 and 2017 were stratified according to American Urological Association and National Comprehensive Cancer Network® VLR and LR groups. Computerized tomography (CT), magnetic resonance imaging and bone scan performed at diagnosis was captured and guidelines compliance was evaluated. The significance of radiologist interpreted imaging findings, by imaging type, were classified as normal, nonurological, nonsignificant urological and PCa significant. Greater than 75% of patients in the VLR and LR groups underwent imaging at time of diagnosis. Bone scan was performed in 30% of patients, none of which noted PCa-significant findings, and the majority were normal. CT was utilized in 38% of patients, with only 3 showing PCa-significant findings. Ten CTs showed nonurological/nonsignificant urological findings causing further evaluation. Magnetic resonance imaging was the most utilized scan in low-risk groups, occurring in 70% of patients. Although the majority were normal, 25 scans showed nonsignificant urological findings while only 7 showed PCa-significant findings. Among VLR and LR PCa patients, there is high overutilization of imaging with most studies yielding minimal PCa-significant findings and further evaluation for incidental observations. This exploratory analysis gives awareness that staging imaging in VLR and LR PCa patients may do more harm than good.