Pretreatment Risk Research Articles

A novel scoring system for better management of small bowel obstruction.

Due to the lack of a comprehensive evaluation of the prognosis of small bowel obstruction (SBO), recent clinical strategies have remained subjective and controversial. The recognition of pretreatment risk factors and tailored treatment could improve SBO outcomes. A series of posttreatment laboratory tests were integrated into a two-step clustering (TSC) analysis. The TSC outcome was determined according to different predictor importance (PI). A risk score (RS) system for the TSC outcome model was constructed by multivariable analysis. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were calculated to assess prediction accuracy. Of the 355 patients, 66 (18.6%) were sorted into the better prognosis group (BPG), 149 (42.0%) were sorted into the poor prognosis group (PPG), and 140 (39.4%) were sorted into the severe prognosis group (SPG) by TSC analysis. For the TSC outcome, four variables with higher PI were identified, namely, Ca (PI = 1), albumin (PI = 0.62), WBC count (PI = 0.5) and NE% (PI = 0.45). Compared with the SPG, the BPG presented better outcomes after surgery events. The TSC outcome model was efficient in distinguishing the duration of bowel function recovery and hospital stay by Kaplan‒Meier curves. Via multivariate analysis, a RS consisting of four risk factors, namely, constipation duration (OR = 1.002), APTT (OR = 0.923), PT (OR = 1.449) and PCT (OR = 1.540), was identified. The AUC of the RS on the TSC outcome model was 0.719 (95% CI, 0.635-0.804). A novel TSC outcome model and RS system was constructed to comprehensively reflect the tailored treatment, surgical events and posttreatment recovery for SBO patients.

Evaluating risk factors for Trastuzumab-Deruxtecan Pneumonitis in patients with metastatic breast cancer

BackgroundTrastuzumab deruxtecan (T-DXd) is FDA-approved for treatment of patients with HER2 positive and HER2-low metastatic breast cancer. Currently, there is limited understanding of pre-treatment risk factors for pneumonitis associated with T-DXd.MethodsConsecutive breast cancer patients who received at least one dose of T-DXd at a single academic cancer study between January 1, 2019, and February 20, 2024, were identified for analysis. Pneumonitis was documented by the treating oncologist at the time of toxicity and retrospectively independently confirmed by a member of the study team through chart and radiologic review. Pre-treatment variables of interest were collected, including patient demographics, radiation dosimetry variables, and chest imaging abnormalities.ResultsOf 179 total patients, 23 (12.8%) had pneumonitis after T-DXd exposure. Patients with pneumonitis had lower baseline oxygen saturation (98% vs. 97%, p = 0.02) and were more likely to have received abemaciclib (26.1% vs. 9.6%, p = 0.03) before T-DXd. Multiple pre-treatment variables were not found to be associated with T-DXd pneumonitis, including chest imaging abnormalities (41.9% vs. 47.8%, p = 0.59), prior immune checkpoint inhibitor treatment (16.0% vs. 8.7%, p = 0.50) and prior chest or breast radiation (61.5% vs. 47.8%, p = 0.20). On multivariate analysis, prior treatment with abemaciclib remained significantly associated with T-DXd pneumonitis (OR 3.25 [1.07–9.11], p = 0.04), while neither pre-treatment chest imaging abnormalities nor prior chest or breast radiation were associated (OR 1.60 [0.62–4.20], p = 0.33); OR 0.51 [0.20–1.33], p = 0.17).ConclusionsIn this cohort, prior treatment with abemaciclib may be a risk factor for T-DXd pneumonitis. Conversely, pre-treatment chest imaging abnormalities, prior immune checkpoint inhibitor treatment, and prior chest or breast radiation did not increase the risk of T-DXd pneumonitis. Larger studies are warranted to validate these findings toward an improved understanding of risk factors for pneumonitis after T-DXd exposure.

P0787 A large-scale comparison of clinical response to IBD therapies in white and non-white ethnicities

Abstract Background IBD phenotypes differ between non-White (NW) and White (WH) populations. Ethnic differences can influence the effectiveness of non-IBD medications, and IBD therapies differ by IBD phenotype. An unanswered question is whether IBD therapies are equally efficacious, with a similar side effect profile, for all ethnic groups. This multi-centre cohort study sought to compare the effectiveness and adverse events (AEs) of IBD therapies in WH and NW patients. Methods Phenotypic and outcome data were extracted from the UK IBD BioResource, a large-scale IBD database enrolling patients across the UK. Response and AEs to 5-ASAs, thiopurines, anti-TNFs and anti-integrins were assessed. Treatment effectiveness was defined as treatment persistence free of discontinuation or failure, and evaluated using Kaplan-Meier survival and Cox regression analysis. The risk of experiencing any AE (and individual AEs with a given treatment) was assessed using Cox regression analysis. Models were adjusted for sex, smoking status, IBD subtype, disease duration, disease location/extent, disease behaviour (CD), perianal disease (CD), co-morbidities, presence of extra-intestinal manifestations, age at commencing therapy, steroid and concomitant immunomodulator use, and the occurrence of an AE (in treatment response models). Results In total 27,433 patients were included [51.1% females; median age at diagnosis 30 years (IQR 21-43); 94.7% WH, 5.3% NW (71.3% South Asian)]. NW were diagnosed at a younger age, exhibited different disease phenotypes, and were younger at treatment initiation therapy than WH. However, no differences in treatment persistence between WH and NW were identified for all therapies analysed, in either CD or UC (Table 1). NW were at significantly increased risk of AEs when treated with thiopurines [HR 1.16 (95% CI 1.00-1.35), p=0.046] and a similar trend was observed for anti-TNFs [HR 1.25 (95% CI 0.99-1.56), p=0.057]; Table 2]. Specifically, NW were at increased risk of developing leucopenia [HR 1.66 (95% CI 1.10-2.42), p=0.01] and pancreatitis [ p=0.009] with thiopurines, and renal dysfunction with anti-TNFs [HR 2.33 (95% CI 1.11-4.38), p=0.02]. Conclusion This is the first large-scale study focussing on ethnic differences in IBD treatment response. No differences were observed in treatment response, but we have shown that thiopurines are associated with increased risks of leucopenia and pancreatitis, whilst anti-TNFs are associated with a higher risk of renal dysfunction in NW patients. These findings underscore the importance of thorough pre-treatment risk assessment and patient counselling by clinicians, and the need for more diverse patient representation in research.

Variance in development of early and late cardiotoxicities in patients with lymphoma and myeloma receiving CAR T-cell therapies

Cardiovascular adverse events (CVAEs) are recognized complications of chimeric antigen receptor (CAR) T-cell therapies. However, data are lacking regarding subtypes of adverse events that develop in patients with different malignancies, and little is known about the timeframe in which different cardiotoxicities are most likely to occur post-CAR T-cell therapies. In this study, 211 patients, including 138 lymphoma patients and 66 myeloma patients who received CAR T-cell therapies were retrospectively identified. Of these, 42 patients (19.9%) developed CVAEs post-treatment. Myeloma patients predominantly experienced heart failure while lymphoma patients predominantly experienced arrhythmia. Severe CVAEs were observed even at >12 months post-treatment. Lower baseline global longitudinal strain was significantly associated with development of post-CAR T-cell therapy CVAEs in both lymphoma and myeloma patients. These findings highlight the spectra of post-CAR T-cell cardiotoxicities in lymphoma and myeloma patients and the importance of echocardiography for pretreatment risk stratification and long-term surveillance.

High correlation between Ki-67 expression and a novel perfusion MRI biomarker diffusion-derived vessel density (DDVD) in endometrial carcinoma.

This study aimed to investigate the feasibility of diffusion-derived vessel density (DDVD) in characterizing tumor microvasculature in endometrial carcinoma (EC), and to explore the correlations with Ki-67 proliferation status and histological type based on DDVD values. There were in total 81 EC patients. There were 64 cases of non-aggressive histological type, and 17 cases of aggressive histological type. Ki-67 labeling index was low (<50%) in 35 cases and high (≥50%) in 46 cases. DDVD(b0b20) is calculated according to: DDVD(b0b20)=Sb0/ROIarea0 - Sb20/ROIarea20, where Sb0 and Sb20 refer to the tissue signal when b is 0 or 20s/mm2. Intraclass correlation coefficient (ICC); two-tailed independent samples t-test and Mann-Whitney U test, and Receiver operating characteristic area under the curve (AUC) were applied for statistical analysis. Endometrial carcinoma showed lower DDVD(b0b20) values (34.9±21.2, au/pixel) compared with myometrium (65.3±37.4, P<0.001). Tumors with Ki-67 high-proliferation or aggressive histological type had higher DDVD values than those with Ki-67 low-proliferation (44.17 (median) vs. 16.08, P<0.001]] or non-aggressive histological type (47.92 vs. 30.77, P=0.002). DDVD(b0b20) ROC curve analysis shows AUC of 0.842 for distinguishing between Ki-67 low- and high-expression, and AUC of 0.771 for distinguishing between non-aggressive and aggressive histological types. DDVD(b0b20)>32.9 and DDVD(b0b20)>50.1 provided a specificity of 85% for identifying Ki67 high expression (sensitivity 78.3%) and histological aggressive type (sensitivity 47.1%), respectively. DDVD can act as an imaging marker reflecting Ki-67 proliferation and histological aggressiveness of EC, thus helping pretreatment risk assessment in EC.

Current and Evolving Biomarkers in the Diagnosis and Management of Testicular Germ Cell Tumors.

Testicular cancer is the most common cancer among young adult men and has favorable outcomes, with survival rates approaching 99% and over 80% for those with early and advanced stage disease, respectively. Biomarkers play a critical role in the diagnosis, pre-treatment risk stratification, surveillance, and assessment of post-treatment disease response in these men. Traditional serum tumor markers (STMs), which include alpha fetoprotein (AFP), beta subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), are limited by low sensitivity (approximately 50%) during initial diagnosis; false-positive elevations as a result of other benign and malignant conditions; and negative levels in low-stage disease and in certain histologies such as teratoma and seminoma. As a result, novel biomarkers with potentially better performance characteristics, including microRNA (miRNA), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs), are being investigated. MicroRNAs are small noncoding RNA involved in transcription and translation and regulate the expression of almost one-third of human genes that regulate the cell cycle, differentiation, proliferation, and apoptosis. In germ cell tumor (GCT) patients, miR371a-3p has been identified as a promising biomarker with sensitivity and specificity of approximately 90-92% and 84-86%, respectively. The use of this new biomarker could aid in several clinical scenarios, such as predicting the presence of micrometastases in chemotherapy-naïve patients with clinical stage I-II disease, thereby guiding decisions on treatment versus surveillance and predicting the presence of viable GCT in patients with residual disease post chemotherapy. Clinical trials are ongoing to validate the use of miRNA 371 as a biomarker and to define its performance characteristics. Though promising, miRNAs are limited by their inability to detect teratoma. ctDNA and CTCs are two other emerging biomarkers, though further studies are needed to clarify their role in managing patients with GCT.

Court-ordered forensic psychiatry treatment in prison: determinants of outcome and risk mitigation.

Court-ordered forensic psychiatry treatments (COT) are specifically designed to reduce the risk of violence in mentally disordered offenders. Given their high costs and ethical issues, mental health professionals need admission criteria to be able to select those candidates with optimal benefit. This study analyses offender-related and treatment-related determinants of COT outcome and risk mitigation. This two-year longitudinal study assessed the evolution of 117 adult offenders admitted to a specialized medium-security forensic psychiatry clinic. Treatment outcome included court-ordered discharge locations and the Historical Clinical Risk Management (HCR) score evolution. Treatment progress was assessed every six months across five time-points including measures of protective factors, work rehabilitation and security. Outcome determinants included psychiatric diagnosis and type of offence. Discharge locations are predicted by pre-treatment risk level. Lower HCR scores are associated with discharge into low-security psychiatry wards independently of the psychiatric diagnosis. Risk reduction follows diagnosis-specific and offense-related patterns and reveals that mentally disordered offenders with Cluster B personality disorders or those sentenced for drug crimes are significantly less prone to benefit from COT. Our findings indicate that criminological characteristics at baseline as well as diagnosis of personality disorders are the main determinants of treatment outcome in our care setting. Inmates with concomitant higher violence risk at baseline and presence of Cluster B personality disorders might benefit the least from court-ordered forensic inpatient psychiatric care in prison.

1972P Pre-treatment (Tx) risk factors for enfortumab vedotin-induced peripheral neuropathy (EVIPN) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of UNITE

1972P Pre-treatment (Tx) risk factors for enfortumab vedotin-induced peripheral neuropathy (EVIPN) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of UNITE

Prediction of Response to FDA-Approved Targeted Therapy and Immunotherapy in Acute Lymphoblastic Leukemia (ALL).

Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.

Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.

#932 Obinutuzumab for the treatment of refractory PLA2R-associated membranous nephropathy: a single-center cohort study

Abstract Background and Aims The established first-line immunosuppressive treatment for membranous nephropathy, rituximab, is met with resistance in some cases of refractory disease. Obinutuzumab, a Type II humanized CD20 monoclonal antibody, has been documented in international case reports as a potential treatment for refractory membranous nephropathy, yet application in China is in its infancy. This study aims to investigate the preliminary short-term efficacy and safety profile of obinutuzumab in such challenging cases. Method We assessed six adult patients with PLA2R-associated membranous nephropathy unresponsive to rituximab, prednisone combined with cyclophosphamide, and calcineurin inhibitors. Obinutuzumab was administered intravenously at 1000 mg, preceded by prophylactic dexamethasone and diphenhydramine to mitigate infusion reactions. Immunological remission was defined as a reduction of anti-PLA2R antibodies to titers below 2RU/ml. Results Baseline characteristics at the initiation of obinutuzumab treatment included an average disease duration of 3.6 ± 2.1 years and a median patient age of 54 years, with a male predominance (3:1 ratio). Laboratory findings at baseline revealed serum albumin at 22 ± 4 g/L, serum creatinine at 133 ± 68 μmol/L, and a significant 24-hour urinary protein quantification (24 hUP) at 7.1 ± 2.9 g/d. The median baseline anti-PLA2R antibody titer was substantial at 90 (range 50-671) RU/ml. At follow-up (9.1 ± 3.7 months), immunological remission rates post-obinutuzumab at 1, 3, and 6 months were 33.3%, 50%, and 50%, respectively. By the end of the study, CD19+ B-cells were depleted (&amp;lt; 5 cells/μL) for an average duration of 6.8 ± 2.6 months. At this juncture, improvements were noted with increased serum albumin (33 ± 8 g/L) and decreased serum creatinine (125 ± 80 μmol/L), along with a reduction in 24 hUP to 4.7 ± 6.2 g/L. Clinical evaluations indicated two cases of complete remission and two of partial remission. In the remaining two patients, 24 hUP was halved compared to baseline. Prednisone dosage was reduced to 7 ± 7 mg/day, with a corresponding reduction in cyclosporine and tacrolimus dosages, and cessation of cyclophosphamide and Tripterygium wilfordii polyglycosides. There were no acute infusion reactions, but two patients suffered severe infections, including one fatality, related to COVID-19 during the pandemic. Conclusion Obinutuzumab emerges as a novel agent in the immunosuppressive armamentarium against refractory PLA2R-associated membranous nephropathy, warranting further long-term study. The enduring B-cell depletion necessitates a careful pre-treatment risk assessment for opportunistic infections, particularly during the ongoing COVID-19 pandemic.

Pre-first-line chemotherapy risk stratification for overall survival in advanced urothelial carcinoma in sequential therapy era.

To explore pre-treatment risk factors for overall survival (OS) in advanced urothelial carcinoma (UC) patients treated with first-line (1L) chemotherapy in sequential therapy (ST) era. Additionally, to evaluate the proportion of patients who were not able to undergo subsequent immune checkpoint inhibitor (ICI) therapy according to the subgroups stratified by the risk factors. A multicenter retrospective study was conducted. Metastatic or locally advanced UC patients treated between 2017 and 2022 were included. The Kaplan-Meier method with the log-rank test and multivariate Cox regression models were used to address OS. Three hundred and fourteen patients treated with 1L chemotherapy were included in the study and 57 (18.2%) patients were not able to proceed to subsequent ICI therapy. Pre-chemotherapy risk factors for OS in 314 patients were ECOG-PS 1 or more, having no primary site resection, C-reactive protein (CRP) level of 3mg/dL or more, and non-cisplatin-based regimen. Patients having 3 or 4 risk factors had higher risk for not being able to receive ST (Mann-Whitney U test, P < 0.001). As risk factors for OS in 230 patients who were able to receive ST, having no primary site resection, a neutrophil to lymphocyte ratio of 3 or more, and the presence of liver metastasis were identified. We reported the risk factors for OS in advanced UC patients treated with 1L chemotherapy in ST era. Patients with high risk for OS may not be able to proceed to subsequent ICI therapy even in the ST era.

Interferon-Gamma Secretion Is Significantly Decreased in Stage III Breast Cancer Patients.

Even though some studies have shown possible clinical relationship between molecular subtypes and tumor infiltrating natural killer (NK) cells around tumors, there are few studies showing the clinical relevance of peripheral NK cell activity at diagnosis in female patients with invasive breast cancer. A total of 396 female invasive breast cancer patients who received curative surgical treatment from March 2017 to July 2021 were retrospectively analyzed. NK cell activation-induced interferon-gamma (IFN-γ) secretion measured by enzyme-linked immunosorbent assay was used to measure the activity of peripheral NK cells. Statistical analyses were performed to determine clinical relationships with major clinicopathologic parameters. Quadripartite NK cell activity measured by induced interferon-gamma showed significant relevance with staging and body mass index, and some of the inflammatory serological markers, namely N/L (neutrophil/lymphocyte), P/N (platelet/neutrophil), and P/L (platelet/lymphocyte), showed significantly different NK activity in each interval by univariate analysis. A binary subgroup analysis, setting the IFN-γ secretion cut-off at 100 pg/mL, showed that stage III was significantly increased and axillary lymph node metastasis positivity was increased in the group of IFN-γ < 100 pg/mL, and IFN-γ secretion decreased with an increasing N stage, increased BMI (body mass index), and decreased production of IFN-γ. Following this, the same binary analysis, but with the IFN-γ secretion cut-off at 250 pg/mL, also showed that secretion in stage III was increased in those concentrations with <250 pg/mL, axillary lymph node positivity appeared to be correlated, and BMI ≥ 30 increased in prevalence. Additional ANOVA post hoc tests (Bonferroni) were performed on some serological markers that tended to be somewhat inconsistent. By subgroup analysis with Bonferroni adjustment between the IFN-γ secretion and TNM stage, no significant difference in IFN-γ secretion could be identified at stages I, II, and IV, but at stage III, the IFN-γ secretion < 100 pg/mL was significantly higher than 250 ≤ IFN-γ secretion < 500 pg/mL or IFN-γ secretion ≥ 500 pg/mL. According to this study, stage III was significantly associated with the lowest IFN-γ secretion. Compared to a higher level of IFN-γ secretion, a lower level of IFN-γ secretion seemed to be associated with increased body mass index. Unlike when IFN-γ secretion was analyzed in quartiles, as the IFN-γ secretion fell below 100 pg/mL, the correlation between axillary lymph node positivity and increased N stage, increased BMI, and increased N/L and P/L, which are suggested poor prognostic factors, became more pronounced. We think a peripheral IFN-γ secretion test might be convenient and useful tool for pretreatment risk assessment and selecting probable candidates for further treatment such as immunotherapy in some curable but high-risk invasive breast cancer patients, compared to other costly assaying of tissue NK cell activity at diagnosis.

Pre-treatment risk predictors of valproic acid-induced dyslipidemia in pediatric patients with epilepsy.

Background: Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within therapeutic range, prolonged VPA usage may result in metabolic disturbances including insulin resistance and dyslipidemia. These metabolic dysregulations in childhood are notably linked to heightened cardiovascular risk in adulthood. Therefore, identification and effective management of dyslipidemia in children hold paramount significance. Methods: In this retrospective cohort study, we explored the potential associations between physiological factors, medication situation, biochemical parameters before the first dose of VPA (baseline) and VPA-induced dyslipidemia (VID) in pediatric patients. Binary logistic regression was utilized to construct a predictive model for blood lipid disorders, aiming to identify independent pre-treatment risk factors. Additionally, The Receiver Operating Characteristic (ROC) curve was used to evaluate the performance of the model. Results: Through binary logistic regression analysis, we identified for the first time that direct bilirubin (DBIL) (odds ratios (OR) = 0.511, p = 0.01), duration of medication (OR = 0.357, p = 0.009), serum albumin (ALB) (OR = 0.913, p = 0.043), BMI (OR = 1.140, p = 0.045), and aspartate aminotransferase (AST) (OR = 1.038, p = 0.026) at baseline were independent risk factors for VID in pediatric patients with epilepsy. Notably, the predictive ability of DBIL (AUC = 0.690, p < 0.0001) surpassed that of other individual factors. Furthermore, when combined into a predictive model, incorporating all five risk factors, the predictive capacity significantly increased (AUC = 0.777, p < 0.0001), enabling the forecast of 77.7% of dyslipidemia events. Conclusion: DBIL emerges as the most potent predictor, and in conjunction with the other four factors, can effectively forecast VID in pediatric patients with epilepsy. This insight can guide the formulation of individualized strategies for the clinical administration of VPA in children.

Biomarkers for Pre-Treatment Risk Stratification of Prostate Cancer Patients: A Systematic Review.

Prostate cancer (PCa) is one of the most frequently occurring malignancies. Although most cases are not life-threatening, approximately 20% endure an unfavorable outcome. PSA-based screening reduced mortality but at the cost of an increased overdiagnosis/overtreatment of low-risk (lrPCa) and favorable intermediate-risk (firPCa) PCa. PCa risk-groups are usually identified based on serum Prostate-Specific Antigen (PSA), the Gleason score, and clinical T stage, which have consistent although variable specificity or subjectivity. Thus, more effective and specific tools for risk assessment are needed, ideally making use of minimally invasive methods such as liquid biopsies. In this systematic review we assessed the clinical potential and analytical performance of liquid biopsy-based biomarkers for pre-treatment risk stratification of PCa patients. Studies that assessed PCa pre-treatment risk were retrieved from PubMed, Scopus, and MedLine. PCa risk biomarkers were analyzed, and the studies' quality was assessed using the QUADAS-2 tool. The final analysis comprised 24 full-text articles, in which case-control studies predominated, mostly reporting urine-based biomarkers (54.2%) and biomarker quantification by qPCR (41.7%). Categorization into risk groups was heterogeneous, predominantly making use of the Gleason score. This systematic review unveils the substantial clinical promise of using circulating biomarkers in assessing the risk for prostate cancer patients. However, the standardization of groups, categories, and biomarker validation are mandatory before this technique can be implemented. Circulating biomarkers might represent a viable alternative to currently available tools, obviating the need for tissue biopsies, and allowing for faster and more cost-effective testing, with superior analytical performance, specificity, and reproducibility.

Heart failure related to contemporary breast cancer treatment.

This article addresses cardiotoxicity in patients with breast cancer who are treated with anthracyclines and/or anti-human epidermal growth factor 2 (HER2) therapy, namely doxorubicin and trastuzumab. Development of concise clinical guidelines for chemotherapy-induced heart failure is ongoing. Through identification of specific risk factors and clinical predictors of cardiotoxicity, clinicians are able to better understand and define effective monitoring strategies and optimize patient care. Close cardiac monitoring is recommended for patients throughout treatment with anthracyclines and anti-HER2 therapy. Pretreatment risk assessment with echocardiography and evaluation of cardiovascular risk factors aid in predicting the development of left ventricular (LV) dysfunction. Further clinical trials are needed to increase understanding and optimize treatment guidelines for LV dysfunction in patients taking anthracyclines or anti-HER2 therapy.

Abstract 1167: Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity

Abstract Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, significantly improving outcomes. Nevertheless, too many melanoma patients undergoing ICI treatment experience severe and often debilitating immune-related adverse events (irAEs). In a retrospective melanoma cohort treated with ICIs, we previously found that elevated baseline levels of circulating CD4 effector memory T (TEM) cells were associated with the development of severe irAEs, irrespective of the affected organ system (Lozano et al., Nature Medicine, 2022). Here, we present data from an extended prospective validation cohort from 47 patients across two academic medical centers. Methods: Of 47 patients, 26 received combination anti-PD1/anti-CTLA4 ICIs, 3 combination anti-PD1/anti-LAG3 ICIs, 17 anti-PD1 ICI, and 1 anti-CTLA4 ICI. Peripheral blood mononuclear cells (PBMCs) were prepared from pretreatment (Cycle 1 Day 1) blood samples obtained from all patients. We performed mass cytometry (CyTOF) on PBMCs using a 38-marker panel to deeply profile immune subsets. We further leveraged bulk RNA-seq from 24 patients to (i) deconvolve CD4 memory T cell abundance using CIBERSORTx and (ii) determine T cell receptor (TCR) diversity using Shannon entropy following MiXCR clonotype assembly. irAEs were graded on a 5-point scale using the Common Terminology Criteria for Adverse Events v5. Results: After treatment initiation, 14 patients experienced severe irAEs (grade 3+) at a median of 12.1 weeks (range 4-54), including 4 with life-threatening (grade 4) irAEs. CyTOF revealed elevated circulating CD4 TEM cells in patients that developed severe irAEs (P&amp;lt;0.0001; AUC=0.87), including those treated with combination ICIs (P=0.0001; AUC=0.89). We further observed a continuous relationship between increasing CD4 TEM levels and irAE grade (P=3e-6, Jonckheere-Terpstra test). We then combined CD4 memory T cell abundance and TCR diversity derived from bulk RNA-seq on 24 of these patients using logistic regression (trained on data from Lozano et al.) to yield a composite model score. The pretreatment composite model score was strongly associated with severe irAE development (P=0.0009, AUC=0.88), and in a median split, identified patients with shorter time to severe irAE development (3 months vs. not reached; P=0.006; HR=10.5). Notably, composite model features and the overall score had no significant association with immunotherapy benefit. Conclusion: In this prospective study, both circulating CD4 TEM levels determined by CyTOF and a composite model score measured by RNA-seq were strongly associated with severe irAE development, independent of response status. These findings hold promise for future pretreatment risk stratification of ICI therapy. Citation Format: Abul Usmani, Noah Earland, Wubing Zhang, Peter K. Harris, Antonietta Bacchiocchi, Chloe M. Sachs, Aishwarya Nene, David Y. Chen, Mario Sznol, Ruth Halaban, Aaron M. Newman, Aadel A. Chaudhuri. Prospective analysis of pretreatment circulating CD4 memory T cell features associated with severe immunotherapy toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1167.

Acute kidney injury following treatment with CD19-specific CAR T-cell therapy in children, adolescent, and young adult patients with B-cell acute lymphoblastic leukemia.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. However, its use may be related to complications such as immune-mediated complications, infections, and end-organ dysfunction. The incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent, and young adult (CAYA) patient population is largely unreported. The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. We conducted a retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution. There was a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n = 7), with four cases being severe AKI (stages 2-3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and cytokine release syndrome and neurotoxicity. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. Frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population.

Chemoembolization as first-line treatment for hepatocellular carcinoma invading segmental portal vein with tumour burden limited to a monosegmental level.

To evaluate the safety and effectiveness of chemoembolization for hepatocellular carcinoma (HCC) with portal vein tumour thrombosis (PVTT) confined to a monosegment of the liver. A total of 192 treatment-naive patients who received chemoembolization between March 2008 and January 2023 as a first-line treatment for locally advanced HCC with PVTT limited to a monosegment were retrospectively analysed. Overall survival (OS) and the identification of pretreatment risk factors related to OS were investigated using Cox regression analysis. Complications, radiologic tumour response, and progression-free survival (PFS) following chemoembolization were investigated. After chemoembolization, the 1-, 3-, and 5-year OS rates were 86%, 48%, and 39%, respectively, and the median OS was 33 months. Multivariable analyses revealed four significant pretreatment risk factors: infiltrative HCC (P = .02; HR, 1.60), beyond the up-to-11 criteria (P = .002; HR, 2.26), Child-Pugh class B (P = .01; HR, 2.35), and serum AFP ≥400 ng/mL (P = .01; HR, 1.69). The major complication rate was 5%. Of the 192 patients, 1 month after chemoembolization, 35% achieved a complete response, 47% achieved a partial response, 11% had stable disease, and 7% showed progressive disease. The median PFS after chemoembolization was 12 months. Chemoembolization shows high safety and efficiency, and contributes to improved survival in patients with HCC with PVTT confined to a monosegment. Four risk factors were found to be significantly associated with improved survival rates after chemoembolization in patients with HCC with PVTT confined to a monosegment. (1) Although systemic therapy with a combination of atezolizumab and bevacizumab (Atezo-Bev) is recommended as the first-line treatment when HCC invades the portal vein, chemoembolization is not infrequently performed in HCC cases in which tumour burden is limited. (2) Our study cohort (n=192) had a median OS of 33 months and a 5% major complication rate following chemoembolization, findings in the range of candidates typically accepted as ideal for chemoembolization. Thus, patients with HCC with PVTT confined to a monosegment may be good candidates for first-line chemoembolization.

Scoring system for diagnosis and pretreatment risk assessment of neuroblastoma using urinary biomarker combinations.

The urinary catecholamine metabolites, homovanillic acid (HVA) and vanillylmandelic acid (VMA), are used for the adjunctive diagnosis of neuroblastomas. We aimed to develop a scoring system for the diagnosis and pretreatment risk assessment of neuroblastoma, incorporating age and other urinary catecholamine metabolite combinations. Urine samples from 227 controls (227 samples) and 68 patients with neuroblastoma (228 samples) were evaluated. First, the catecholamine metabolites vanillactic acid (VLA) and 3-methoxytyramine sulfate (MTS) were identified as urinary marker candidates through comprehensive analysis using liquid chromatography-mass spectrometry. The concentrations of these marker candidates and conventional markers were then compared among controls, patients, and numerous risk groups to develop a scoring system. Participants were classified into four groups: control, low risk, intermediate risk, and high risk, and the proportional odds model was fitted using the L2-penalized maximum likelihood method, incorporating age on a monthly scale for adjustment. This scoring model using the novel urine catecholamine metabolite combinations, VLA and MTS, had greater area under the curve values than the model using HVA and VMA for diagnosis (0.978 vs. 0.964), pretreatment risk assessment (low and intermediate risk vs. high risk: 0.866 vs. 0.724; low risk vs. intermediate and high risk: 0.871 vs. 0.680), and prognostic factors (MYCN status: 0.741 vs. 0.369, histology: 0.932 vs. 0.747). The new system also had greater accuracy in detecting missing high-risk neuroblastomas, and in predicting the pretreatment risk at the time of screening. The new scoring system employing VLA and MTS has the potential to replace the conventional adjunctive diagnostic method using HVA and VMA.