Poor Survival Outcomes Research Articles

Effects of Viral Infections Like COVID-19 on Head and Neck Cancers: The Role of Neutrophil-Lymphocyte Counts and Ratios.

Over the last three years, the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a global impact. COVID-19 has led to diagnostic and treatment delays in head and neck squamous cell cancers (HNSCCs). Both cancer and COVID-19 trigger systemic inflammatory responses that can result in cytokine storms, creating a favorable tumor microenvironment that supports tumor growth. Various studies have shown a positive association between increasing neutrophil-to-lymphocyte ratio (NLR) and disease severity in COVID-19. Studies have also shown that high NLR is associated with poor survival outcomes in cancer patients. Our aim is to investigate whether an increased NLRis linked to rapid tumor progression in patients with HNSCCwho have also been affected by infections like COVID-19 in the pre-operative period. This was a retrospective analysis of patients of HNSCC who were scheduled for surgery and had contracted COVID-19 in their pre-operative period between April 2021 and May 2021.The study analyzed pre- and post-COVID NLR in relation to disease progression in HNSCC.Statistical analysis was presented as an interquartile range and numbered with the percentage. StatisticalPackage for the Social Sciences (IBMSPSSStatisticsforWindows,IBMCorp., Version 26.0, Armonk,NY) was utilized for the analysis. We evaluated 200 operable cases of which 38/200 (20%) patients with HNSCC were COVID-19 positive. Out of those COVID-19-positive patients, 27/38 (71%) patients got operated. Around, 11/38 (28.9%) patients were inoperable. And, 14/27 (53.8%) operated patients also had a change in treatment plan. The mean duration from the joint clinic treatment plan to the date of surgery was 25.18 days.Patients who had contracted COVID-19 and had a change in their treatment plan due to disease progression exhibited mean NLR values of 3.84 (pre-COVID) and 11.11 (post-COVID), with respective medians of 3.04 and 10.50. These differences showed a statistically significant p-value of 0.000. In contrast, patients who had no change in treatment plan displayed mean NLR values of 4.51 (pre-COVID) and 9.70 (post-COVID), with respective medians of 3.47 and 3.42, resulting in with a non-significant p-value of 0.082. This is a one-of-its-kind study that has evaluated the role of elevated NLR in patients with a COVID-19 virus infection and its relationship with the clinical progression of the disease. The findings suggest that elevated NLR in patients with HNSCC, along with concurrent SARS-CoV2 infection, may contribute to accelerated disease progression with an increase in tumor burden and nodal metastasis.

Integrated Bioinformatic Analysis Reveals the Oncogenic, Survival, and Prognostic Characteristics of TPX2 in Hepatocellular Carcinoma.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.

Expanding multiple features of extracranial metastasis to predict survival for patients with breast cancer brain metastasis: A population-based retrospective analysis.

e13038 Background: Breast cancer brain metastasis (BCBM) is associated with poor survival outcomes and reduced quality of life. The Graded Prognostic Assessment (GPA) score model serves as a well-established tool for predicting the prognosis of BCBM. Notably, the presence of extracranial metastasis (ECM) is considered as a significant prognostic factor in the breast GPA. This study aims to further refine this factor to enhance the prognostic prediction for BCBM. Methods: This study included all inpatients diagnosed with BCBM at the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS), from January 2010 to July 2021. The subsets were categorized by the presence, number, location, and control status of ECM. Baseline clinicopathological characteristics were documented and compared among subgroups. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. We used the Kaplan–Meier method with log-rank test to compare the survival outcomes. Cox regression analyses were conducted to identify significant prognostic factors, which were then incorporated into a new Breast-GPA model. Results: A total of 286 patients with BCBM were included in the study. Kaplan–Meier survival curves suggested that patients without ECM when diagnosed with BCBM showed better survival (p=0.0068). In the subgroups with ECM, more than 3 organs involved, both bone and visceral metastasis and progressive ECM portended dismal OS (p=0.0032, 0.0014 and 0.00054). Multivariate analysis (MVA) demonstrated that the presence, number, and control status of ECM significantly influenced OS after BCBM (p=0.01, 0.03, and 0.048, respectively). The specific location of ECM also had a significant impact on the long-term survival (p=0.0014). By modifying the current GPA model to include categories for '3 or fewer controlled ECM', the predictive accuracy of the newly established GPA model was further enhanced. Conclusions: More extracranial sites, both bone and visceral invasion and uncontrolled ECM were independent prognostic factors for dismal survival outcomes of BCBM patients.

Predictors of time to brain metastasis and survival in patients diagnosed with breast cancer.

e13122 Background: Patients with breast cancer (BC) who develop brain metastases (BM) have poor survival outcomes. We aimed to identify significant predictors of time to develop BM and survival after diagnosis. Methods: Patient records were retrospectively reviewed from the Cleveland Clinic database between 2010-2020. Patients with a BC and a BM diagnosis were included for analysis. One way ANOVA was used to compare mean time to BM across subgroups (mean ± SE), and Kaplan-Meier method was used to compute median overall survival (mOS) after BM diagnosis (95% CI). Results: N=109 patients were included in the analysis with a mean age of 52 ± 13 years, mean time to developing BM of 42 ± 35 months, and mOS after BM of 12.00 months (8.99-15.01). The patients’ characteristics were as follows: female (98.2%), white (83.5%), married (56%), privately insured (43.1%), had a Karnofsky Performance Status (KPS) >80 (61.7%), and 21% had stage IV at initial diagnosis. In terms of BC characteristics, 80.4% of cases were ductal, 63.7% were Grade III, 52.3% were HR+, and 31.5% were HER2+, and 32.4% were triple negative. Most patients had extracranial metastases (ECM) at the time of BM diagnosis (67.8%), had at least 2 sites of BM (71.6%), parenchymal only BM (75%), and 10-30 mm BM (44.2%). 15.8% of patients underwent craniotomy and 86.2% received at least one form of radiotherapy (RT) for BM. The HR+/HER2- group had the longest time to BM compared to the shortest in the triple negative group (61.29 ± 6.95 vs 28.59 months ± 4.80, p<0.001). Patients receiving hormonal therapy had longer time to BM compared to those who didn’t (50.83 ± 5.04 vs 35.98 ± 4.67 months, p=0.034). Patients with Stage I disease had the longest time to develop BM (68.50 ± 13.66 months, p=0.009), while grade III status had the shortest time to BM (34.46 ± 3.46 months, p=0.002). Uninsured patients had the shortest time to BM (22.92 ± 4.09 months, p=0.003). After BM diagnosis, the HR+/HER2+ group achieved the best mOS at 35.00 months (14.20-55.80, p=0.040). Patients receiving Gamma Knife Radiosurgery (GKRS) achieved longer mOS than the other RT modalities at 30.00 months (11.46-48.51) vs 20.00 (1.26-38.74) in GKRS + Whole Brain RT (WBRT), 9.00 (3.43-14.57) in the WBRT, and 2.00 (1.12-2.88) in no RT group (p=0.022). Patients with a KPS of <80 had a shorter mOS compared to those with a KPS of >80 [5.00 (2.02-7.98) vs 17.00 (9.41-24.6), p=0.002]. Patients receiving hormonal therapy had longer mOS compared to those who did not [17.00 (6.58-27.43) vs 9.00 (3.72-14.28), p=0.016]. Patients with stage I disease had longer mOS compared to those with stage II-IV disease [41.00 (22.70-59.30) vs 10.00 (6.60-13.40), p=0.025]. Conclusions: This study identifies significant clinical predictors for BM development and survival in patients with BC including Hormone receptor status, treatment modalities, stage, and KPS. These findings emphasize the need for early BM screening in high-risk patients to improve survival.

Clinical profile and response to adjuvant treatments in patients with follicular dendritic cell sarcoma in the United States: Insights from SEER analysis.

e23537 Background: Follicular Dendritic Cell Sarcoma (FDCS) is a rare, indolent, low-grade sarcoma known for local recurrences managed primarily by surgery. The role for adjuvant therapy has not been established for either radiation or chemotherapy. We aimed to comprehensively analyze clinical and epidemiological profiles and responses to treatment in these patients. Methods: This is a retrospective study using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Result (SEER) database. Cases of FDCS between 2001 to 2022 were identified utilizing the International Classification of Diseases for Oncology edition 3 (ICD-O-3) code 9758/3. Only adults > 18 years of age and diagnosed by positive histology or cytology were included. Descriptive statistics were used to describe demographic and tumor characteristics. Logistic regression was used to identify the factors influencing survival. Kaplan-Meier method was used to plot survival based on different treatment regimens and stages. Results: A total of 168 patients with FDCS were identified, with more than 50% of the patients ≥ 50 years of age. The mean age at diagnosis was 52.6 years, 56% were female, and 74.4% were white. Most of the patients had localized disease (63.7%), 17.9% had distant disease, and the remaining had unknown stages. About 90% of the patients underwent surgery, with 41% receiving local tumor excision. In Univariate analysis, older age, and distant disease were found to have poor outcomes. Surgery, irrespective of stage, was found to improve overall Survival (Table 1). While chemotherapy and distant disease had poor outcomes in univariate analysis, they were not statistically significant in multivariate analysis. The majority of the patients who received chemotherapy alone without surgical intervention had distant disease, explaining the poor outcome seen in univariate analysis. Among 107 patients with localized disease, 41 patients (41.1%) underwent only surgery and 43 patients (40.1%) received adjuvant therapy (either chemotherapy or radiation vs both) along with surgery. 5-year overall survival was significantly lower in patients who received adjuvant therapy. (88.4% vs 68.4%, p = 0.001). Conclusions: In conclusion, FDCS has a fair overall 5-year survival with surgery alone. Patients with localized disease, who received adjuvant therapies had poor survival outcomes as compared to the surgery-only group owing to disease burden. Large prospective studies are required to properly evaluate the benefit of adding chemotherapy or radiotherapy in resectable disease.

Lysosome-Related Genes and RNF19B as Prognostic Markers for Survival and Immunotherapy Efficacy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a considerable worldwide health concern due to its associated high risk of death. The heterogeneity of HCC poses challenges in developing practical risk stratification tools and identifying prognostic markers for personalized targeted treatments. Recently, lysosomes were shown to be crucial contributors to numerous cellular activities, including tumor initiation and immune response regulation. We aimed to construct a reliable prognostic signature based on lysosome-related genes and determine its association with the immune microenvironment. We comprehensively analyzed lysosome-related genes in HCC to investigate their influence on patient survival and the tumor immune microenvironment. A prognostic signature comprising 14 genes associated with lysosomes was created to estimate the survival outcomes of individuals with HCC. In addition, we verified the prognostic importance of Ring Finger Protein 19B (RNF19B) in patients with HCC through multiplex immunohistochemistry analysis. Our constructed lysosome-related prediction model could significantly discriminate between HCC patients with good and poor survival outcomes ( P < 0.05). We also found that elevated RNF19B expression was linked to unfavorable prognostic outcomes and showed a connection with specific clinicopathological characteristics. Moreover, it was observed that RNF19B could facilitate the transformation of macrophages into M2-polarized macrophages and showed a significant positive correlation with PD-1 and CTLA-4. In summary, our study proposes that the expression of lysosome-related genes is associated with the immune microenvironment, serving as a predictor for HCC patient survival. Meanwhile, RNF19B was identified as a novel prognostic marker for predicting overall survival and immunotherapy effects in patients with HCC.

Galectin-3-Binding Protein Inhibits Extracellular Heparan 6-O-Endosulfatase Sulf-2

Human extracellular 6-O-endosulfatases Sulf-1 and Sulf-2 are the only enzymes that post-synthetically alter the 6-O sulfation of heparan sulfate proteoglycans (HSPG), which regulates interactions of HSPG with many proteins. Oncogenicity of Sulf-2 in different cancers has been documented, and we have shown that Sulf-2 is associated with poor survival outcomes in head and neck squamous cell carcinoma (HNSCC). Despite its importance, limited information is available on direct protein–protein interactions of the Sulf-2 protein in the tumor microenvironment. In this study, we used monoclonal antibody (mAb) affinity purification and mass spectrometry to identify galectin-3-binding protein (LG3BP) as a highly specific binding partner of Sulf-2 in the conditioned media of HNSCC cell lines. We validated their direct interaction in vitro using recombinant proteins and have shown that the chondroitin sulfate (CS) covalently bound to the Sulf-2 influences the binding to LG3BP. We confirmed the importance of the CS chain for the interaction by generating a mutant Sulf-2 protein that lacks the CS. Importantly, we have shown that the LG3BP inhibits Sulf-2 activity in vitro in a concentration-dependent manner. As a consequence, the addition of LG3BP to a spheroid cell culture inhibited the invasion of the HNSCC cells into Matrigel. Thus, Sulf-2 interaction with LG3BP may regulate the physiological activity of the Sulf-2 enzyme as well as its activity in the tumor microenvironment.

Survival outcomes in patients with stage IV gastric cancer with Krukenberg tumors: A systematic review and meta-analysis.

e16020 Background: Stage IV gastric cancer patients with Krukenberg tumors tend to have poor survival outcomes, usually less than 2 years. The management of such tumor groups remains unstandardized, and whether oophorectomy improves survival is unknown. In this study, we systematically analyze the survival outcomes in gastric cancer patients with ovarian metastases who received either standard chemotherapy, surgical resection of ovarian metastases, or combined chemotherapy and surgery. Methods: We synthesized randomized controlled trials and observational studies, which were retrieved by systematically searching MEDLINE (PubMed), Embase, and the Cochrane Library through January 25, 2024, using the Boolean logic. Participants included individuals with pathologically and radiologically confirmed ovarian metastasis or clinically symptomatic cases with imaging evidence. Statistical analyses were conducted using R (v.4.3.2., Vienna) (PROSPERO ID-CRD42023488373). Results: A total of 1502 patients from 17 retrospective studies were pooled for differential overall survival (OS) outcomes ( Table). The OS in the standard chemotherapy cohort using the random effects model was 6.708 months (95% CI: 3.867 to 9.548). Heterogeneity was non-significant (P = 0.3854) with I2 of 5.5%. In the surgical resection cohort, OS was 12.786 months (95% CI: 6.9 to 18.671). I2 was 0%, and heterogeneity was low (P = 0.6013). In the combined chemotherapy and surgical resection cohort, OS was 16.228 months (95% CI: 12.254 to 20.202). I2 was 0%, and heterogeneity was insignificant (P = 0.9632). Conclusions: This meta-analysis provides novel insights into survival outcomes associated with distinct therapeutic modalities in gastric cancer with krukenberg metastases, contributing valuable evidence for clinical decision-making and future research directions. While the combined approach of chemotherapy and surgery demonstrates the highest effect size for OS, judicious consideration of patient-centric approaches is imperative in the oncological care landscape. [Table: see text]

Impact of boarding time on in-hospital mortality in patients with cancer presenting to the emergency department.

11036 Background: Longer emergency department (ED) boarding times for admitted patients is associated with increased morbidity and mortality.1 While research over the years has shown an association between boarding time to mortality in a variety of patient demographics, no specific research has been explored in a cancer population. Patients with cancer visit the emergency department frequently and have a high rate of admission compared to other patients.2 This study evaluates boarding times and mortality rates in patients presenting to an oncologic ED. Methods: A retrospective analysis was performed on 183,524 ED visits located at a comprehensive cancer center between March 2016 and December 2022. Eligibility criteria included patients 19 years and older admitted to the hospital excluding direct intensive care unit admission. Boarding time was defined from the time the physician made an order to admit to the hospital to the time of ED departure. Demographics and clinical characteristics were examined using descriptive statistics. Categorical data was analyzed using chi-square test and continuous variables employed the nonparametric Mann–Whitney U test. Boarding time was grouped into quartiles. Univariate and multivariable logistic regression analyses examined clinical factors, including boarding time and in-hospital mortality. Results: The eligible number of visits supporting the study equaled 83,629. Overall median boarding time was 2.7 hours (interquartile range: 1.5–5.1 hours) and in-hospital mortality was 5.5% (n=4607). Longer boarding time was significantly associated with in-hospital mortality. Patients with boarding time ≥5.1 hours had 1.19 (95% confidence interval [95%CI]: 1.09-1.30; P&lt;0.001) odds of in-hospital mortality when compared to the reference group (boarding time &lt;1.5 hours) when controlling for other risk factors including comorbidities and emergency severity index (ESI) between 1 through 5. Similar results were observed for patients with boarding times of ≥1.5- &lt;2.7 hours and ≥2.7- &lt;5.1 hours with odds ratio of 1.12 (95%CI: 1.02-1.22; P=0.013) and 1.11 (95%CI: 1.02-1.21; P=0.020), respectively. Higher Charlson comorbidity index and levels 1 and 2 ESI were also associated with poor survival outcome (P&lt;0.001 for both). Conclusions: This study found an association between boarding time and in-hospital mortality in cancer patients presenting to the ED. Patients with longer boarding times were likely to experience mortality during their hospital admission. High comorbidity score and high-risk ESI were also identified as risk factors for poor survival outcome. These results emphasize the need for improved strategies to expedite the admission process and optimize care for cancer patients in the ED to reduce mortality rates. Further research and interventions targeting reduction in boarding times are warranted to improve outcomes for this vulnerable population.

Role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in unresectable hepatocellular carcinoma (uHCC): Subgroup analysis of patients treated with camrelizumab (cam) + rivoceranib (rivo) in the CARES-310 trial.

e16197 Background: CARES-310 (NCT03764293) evaluated the combination of the PD-1 inhibitor, cam, and the VEGFR-2 tyrosine kinase inhibitor, rivo, compared to sorafenib (sor) for the treatment of 543 patients (pts) with uHCC. Cam + rivo significantly improved mOS (22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p &lt; 0.0001) and mPFS (5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.54 [95% CI 0.44-0.67]; one-sided p &lt; 0.0001) compared to sor. The most common (≥20%) grade ≥3 treatment-related adverse events (TRAEs) for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. An elevated level of inflammation, including NLR and PLR, have been associated with poor survival outcomes in pts with HCC (Lin S, et al. Trans Cancer Res. 2021). Here, we present a subgroup analysis of the CARES-310 trial evaluating the impact of baseline (BL) NLR and PLR status on pt outcomes. Methods: The subgroup of pts treated with cam+rivo and BL NLR &lt; 5 or ≥5 and PLR &lt; 300 or ≥300 were evaluated for mOS, mPFS, overall response rate (ORR), disease control rate (DCR), and safety. Results: Of 272 pts treated with cam+rivo, 64.3% of pts had extrahepatic spread, median AFP was 84.1 ng/mL, 86.8% were Child-Pugh (CP) class A5, 13.2% were CP class A6, 73.5% were ALBI grade 1, 26.5% were ALBI grade 2. Additionally, 249 pts had NLR &lt; 5, 10 pts had NLR ≥5, 252 pts had PLR &lt; 300, and 7 pts had PLR ≥300. Pts with BL NLR &lt; 5 and PLR &lt; 300 demonstrated improved outcomes in mOS, mPFS, ORR, and DCR vs pts with BL NLR ≥5 and PLR ≥300 (Table). Rates of any grade TRAEs and grade ≥ 3 TRAEs were comparable between pts with BL NLR &lt; 5 and ≥5 and PLR &lt; 300 and ≥300 (Table). Conclusions: These results suggest that NLR and PLR may serve as a prognostic marker in patients with uHCC, but larger studies are needed to validate these findings. Clinical trial information: NCT03764293 . [Table: see text]

Characteristics, treatment, and outcomes of cutaneous mantle cell lymphoma: A decade-long study at MD Anderson Cancer Center.

e19037 Background: Mantle cell lymphoma (MCL) is a rare B cell neoplasm that accounts for 6% of all non-Hodgkin lymphomas and affects predominantly older Caucasian males. Cutaneous involvement is rare in MCL, but more commonly occurs in the advanced or terminal stages of the disease and lacks a standardized approach. Here we report our center’s experience with cutaneous MCL. Methods: We conducted a retrospective chart review of all MCL patients treated at the University of Texas MD Anderson Cancer Center from January 2013 to December 2023 and identified 20 MCL patients with cutaneous involvement. Demographic data, disease characteristics, imaging findings, therapies, and survival outcomes were collected. The study was performed in accordance with the guidelines of the institutional review board. Results: Among the 20 MCL patients with cutaneous involvement (Table), nearly all were Caucasian (n=19/20, 95%), and most were male (n=14/20, 70%). The median age at cutaneous MCL diagnosis was 63.5 years (range: 50-83). All patients had advanced stage disease. The median interval from MCL diagnosis to the emergence of cutaneous symptoms was 2.2 years (range 0-9.3). Most had relapsed/refractory disease (n=17/20, 85%). Most patients had blastoid (n=13/19) or pleomorphic (n=4/19) cytology with a Ki-67 proliferative index ≥50% (n=19/20, median 90%). Several patients had p53 expression (n=11/14) and/or TP53 aberrations (n=4/16). Immediate subsequent systemic therapy, most commonly immunochemotherapy (n=9/20), led to frequent responses (overall response rate: 61%). Most patients received low-dose radiotherapy (RT) for their cutaneous disease (n=19/20) achieving high rates of local control (n=16/18). Of those who are alive and in complete response (n=3) at data cutoff, 2 received chimeric antigen receptor (CAR) T cell therapy as their last MCL-directed treatment. The median survival time from MCL diagnosis to death was 6.83 years (95% confidence interval (CI):4.20-not estimable (NE)). The median survival time from the diagnosis of cutaneous involvement to death was 3.16 years (95%CI: 1.93-NE). The median follow-up duration from MCL diagnosis was 8.22 years. Conclusions: Cutaneous involvement in MCL is associated with aggressive disease biology and poor survival outcomes. Low-dose RT with concurrent immunochemotherapy should be considered the current standard therapeutic approach. CAR T cell therapy and/or bispecific T cell engagers may further improve outcomes in these high-risk patients. [Table: see text]

Identification and Construction of a Disulfidptosis-Mediated Diagnostic Model and Associated Immune Microenvironment of Osteoarthritis from the Perspective of PPPM.

Osteoarthritis (OA) is a major cause of human disability. Despite receiving treatment, patients with the middle and late stage of OA have poor survival outcomes. Therefore, within the framework of predictive, preventive, and personalized medicine (PPPM/3PM), early personalized diagnosis of OA is particularly prominent. PPPM aims to accurately identify disease by integrating multiple omic techniques; however, the efficiency of currently available methods and biomarkers in predicting and diagnosing OA should be improved. Disulfidptosis, a novel programmed cell death mechanism and appeared in particular metabolic status, plays a mysterious characteristic in the occurrence and development of OA, which warrants further investigation. In this study, we integrated three public datasets from the Gene Expression Omnibus (GEO) database, including 26 OA samples and 20 normal samples. Via a series of bioinformatic analysis and machine learning, we identified the diagnostic biomarkers and several subtypes of OA. Moreover, the expression of these biomarkers were verified in our in-house cohort and the single cell dataset. Three significant regulators of disulfidptosis (NCKAP1, OXSM, and SLC3A2) were identified through differential expression analysis and machine learning. And a nomogram constructed based on these three regulators exhibited ideal efficiency in predicting early- and late-stage OA. Furthermore, based on the expression of three regulators, we identified two disulfidptosis-related subtypes of OA with different infiltration of immune cells and personalized expression level of immune checkpoints. Notably, the expression of the three regulators was demonstrated in a single-cell RNA profile and verified in the synovial tissue in our in-house cohort including 6 OA patients and 6 normal people. Finally, an efficient disulfidptosis-mediated diagnostic model was constructed for OA, with the AUC value of 97.6923% in the training set and 93.3333% and 100% in two validation sets. Overall, with regard to PPPM, this study provided novel insights into the role of disulfidptosis regulators in the personalized diagnosis and treatment of OA.

Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and lung cancer metastasis.

e20520 Background: The evolutionarily conserved protein FBXO9 acts as a substrate receptor for the SKP1-cullin-1-RBX1 ubiquitin ligase and is implicated in cancer, exhibiting either tumor-suppressive or oncogenic effects depending on the specific tumor type. However, their role in lung cancer metastasis remains unclear. Methods: Lentiviral vectors carrying miRNA-based shRNA sequences for gene-specific knockdown were generated, and Lenti-CRISPR-Cas9 vectors containing gene-specific sgRNA sequences were designed. Gene overexpression was achieved using doxycycline-inducible lentiviral constructs, while gene knockdown or knockout cells were generated using shRNA and CRISPR-Cas9, respectively. Functional assays included migration, clonogenic survival assays, tumor sphere assays, and protein interaction studies using mass spectrometry, immunoprecipitation, and immunoblot analysis. Results: This study identified FBXO9 as a crucial regulator that suppresses lung cancer cell migration, tumor sphere growth and restricts metastasis. We showed that FBXO9 facilitates the ubiquitination of the catalytic subunit A (ATP6V1A) of the Vacuolar-type H+-ATPase (V-ATPase), resulting in its interaction with the cytoplasmic chaperone HSPA8 and subsequent sequestration within the cytoplasm. This process hinders the assembly of functional V-ATPase, resulting in reduced vesicular acidification. In contrast, depletion of FBXO9 reduced ATP6V1A ubiquitination, resulting in increased V-ATPase assembly and vesicular acidification, thus promoting pro-metastatic Wnt signaling and metastasis of lung cancer cells. Furthermore, we demonstrated the effectiveness of inhibitors targeting V-ATPase in inhibiting lung cancer metastasis in a mouse model. Finally, we established a correlation between lower FBXO9 levels and poorer survival outcomes in patients with lung cancer. Conclusions: These findings collectively elucidate the critical role of FBXO9 in regulating V-ATPase assembly and provide a molecular basis for FBXO9's function in inhibiting lung cancer metastasis. This highlights the potential therapeutic opportunities of FBXO9 supplementation.

Characterizing the impact of sarcopenia on treatment response and survival in previously treated recurrent or metastatic nasopharyngeal carcinoma: Insights from a secondary analysis of the KL-A167 randomized trial.

6046 Background: The relationship between sarcopenia and adverse outcomes among patients with recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) undergoing immunotherapy remains underexplored. This secondary analysis of the KL-A167 clinical trial data aims to elucidate the impact of sarcopenia on treatment efficacy and prognosis in this cohort, while also identifying potential mediating hematological biomarkers. Methods: A cohort of 148 patients enrolled in the KL-A167 clinical trial was analyzed. Logistic and Cox regression models were applied to assess the association between sarcopenia and treatment response, overall survival (OS), and progression-free survival (PFS), with adjustment for clinical prognostic factors. Counterfactual causal mediation analysis was conducted to identify hematological biomarkers potentially mediating the relationship between sarcopenia and prognosis in R/M NPC patients. Results: The presence of sarcopenia was significantly associated with reduced objective response rate (ORR: OR = 0.25, 95% CI = 0.08–0.81, p = 0.020) and disease control rate (DCR: OR = 0.23, 95% CI = 0.07–0.70, p = 0.010). Furthermore, sarcopenia was linked to inferior OS (HR = 2.07, 95% CI = 1.12–3.81, p = 0.020) and PFS (HR = 2.59, 95% CI = 1.48–4.54, p = 0.001). Notably, sarcopenia was characterized by elevated levels of neutrophil count, fibrinogen, and white blood cell count, alongside decreased creatine kinase levels. Fibrinogen emerged as the sole elevated biomarker significantly associated with both OS and PFS. Causal mediation analysis indicated that fibrinogen accounted for 23.5% of the association between sarcopenia and OS and 15.7% of PFS. Conclusions: Sarcopenia significantly correlates with poor treatment response and survival outcomes in patients with R/M NPC receiving immunotherapy. Targeting fibrinogen may offer a novel strategy to mitigate the negative impact of sarcopenia on patient survival.

A single center analysis of long-term outcomes and survival related risk factors in liver retransplantation.

Liver retransplant is the only option to save a patient with liver graft failure. However, it is controversial due to its poor survival outcome compared to primary transplantation. Insufficient deceased organ donation in Taiwan leads to high waitlist mortality. Hence, living-donor grafts offer a valuable alternative for retransplantation. This study aims to analyze the single center's outcome in living donor liver retransplantation (re-LDLT) and deceased donor liver retransplantation (re-DDLT) as well as the survival related confounding risk factors. This is a single center retrospective study including 32 adults who underwent liver retransplantation (re-LT) from June 2002 to April 2020. The cohort was divided into a re-LDLT and a re-DDLT group and survival outcomes were analyzed. Patient outcomes over different periods, the effect of timing on survival, and multivariate analysis for risk factors were also demonstrated. Of the 32 retransplantations, the re-LDLT group (n=11) received grafts from younger donors (31.3 vs. 43.75 years, P=0.016), with lower graft weights (688 vs. 1,457.2 g, P<0.001) and shorter cold ischemia time (CIT) (45 vs. 313 min, P<0.001). The 5-year survival was significantly better in the re-LDLT group than in the re-DDLT group (100% vs. 70.8%, P=0.02). This difference was adjusted when only retransplantation after 2010 was analyzed. Further analysis showed that the timing of retransplantation (early vs. late) did not affect patient survival. Multivariate analysis revealed that prolonged warm ischemia time (WIT) and intraoperative blood transfusion were related to poor long-term survival. Retransplantation with living donor graft demonstrated good long-term outcomes with acceptable complications to both recipient and donor. It may serve as a choice in areas lacking deceased donors. The timing of retransplantation did not affect the long-term survival. Further effort should be made to reduce WIT and massive blood transfusion as they contributed to poor survival after retransplantation.

Germline NQO1c.559C&gt;T as a biomarker of genetic susceptibility to immune checkpoint blockade resistance.

8537 Background: Tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop cancer while others do at young ages. The study of cancer immunology has led to the surge of immune checkpoint blockade (ICB), which transformed the treatment landscape of cancer pts. NQO1 has been associated with extreme phenotypes of high risk for the development of tobacco-induced NSCLC and with poor survival outcomes for xerographs. Development of biomarkers for ICB has been mainly focused on tumor-related factors while genetic susceptibility of the host has been poorly explored to date and some evidence suggests that genetic dysregulation may enables immune escape. Methods: From June 2016 to January 2023, 326 NSCLC pts from two main University Hospitals of Malaga (Spain) receiving ICB were prospectively enrolled, blood samples were gathered. We selected a representative set of 60 consecutive pts for exome sequencing to characterize the germline contribution to resistance (progression within the first 6 months of treatment). PBMC DNA was extracted and prepared for exome sequencing. Raw sequencing data was processed and aligned to a reference genome using BWA. Base recalibration, germline variant calling and variant filtering was performed through GATK. Survival probabilities were estimated with the Kaplan-Meier method and compared using the log-rank test. We explored the lung cancer related genes among our results. Results: Median age at diagnosis of 64 (54-85). 76,6% were men. 44/60 (73,3%) were adenocarcinoma (ADC), PD-L1≥1% in 55% of patients, 22% shown PD-L≥50%. 78% had advanced disease at diagnosis. 65% received ICB in combination with chemotherapy. We found NQO1c.559C&gt;T in 46,6% of pts (28/60). The variation was not associated with survival outcomes in the multivariant analysis (p&gt;0.05) but with poor OS for non-ADC histology (19.7m vs 6m for mutated and WT, respectively; p&lt;0.01). In addition, we found 26 germline variants associated with OS and PFS, and 52 variants with response to ICB. The variants were missense or involved a stop gain/loss. Conclusions: Exome sequencing analysis of germline variants could be a suitable methodology to identify subrogated biomarkers of immune resistance in NSCLC patients. NQO1c.559C&gt;T might help to identify poor prognosis non-ADC pts in the ICB setting.

SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer.

TPS3640 Background: Patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Second-line treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAFV600E mCRC. In preclinical models of MSS, BRAFV600E CRC, inhibition of BRAF and EGFR induces loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAFV600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAFV600E mCRC. Methods: In this prospective phase II clinical trial (N=84), patients with previously treated MSS, BRAFV600E mCRC are randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients receive E (300 mg PO daily) and C (500 mg/m2 IV every 14 days), and patients in the experimental arm receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months (hazard ratio 0.57). Additional patient specimens will be collected for exploratory correlative research. As of 2/2024, 50 of 84 planned participants have been enrolled. Clinical trial information: NCT05308446 .

Health disparities in acute myeloid leukemia: A decade-long analysis of Afro-Caribbean patients in a safety net New York City hospital.

e18515 Background: Acute Myeloid Leukemia (AML) in the Afro-Caribbean population is associated with poor outcomes due to disparities in health insurance and access to healthcare resources, among other factors, when compared to survival data in the national SEER database. This study reviews clinical characteristics and treatment outcomes of a cohort of 51 Afro-Caribbean patients who were diagnosed with AML and treated in the past 10 years in a urban safety net hospital in Brooklyn, New York. Methods: This is a retrospective review of patients diagnosed and treated for AML at New York City Health and Hospitals/Kings County from 2012 to 2022. Electronic Health Data was reviewed for clinicopathologic data and treatment outcomes. Analysis was performed through descriptive statistics with specific focus on insurance status and survival outcomes. Results: Our AML patient cohort had a mean age of 66, with 84% of patients identifying as Afro-Caribbean, and 51% being female. In this cohort, the AML risk stratification distribution based on 2022 European LeukemiaNet Risk classification includes 21 (41%) patients in the adverse-risk group, 23 (45%) patients in the intermediate-risk group, and 7 (14%) patients in the favorable-risk group. Of the 36 patients with molecular analysis data, 9 (25%) harbored a mutation in FLT3-ITD. Healthcare disparities are evident in insurance coverage, as 58% of patients lacked medical insurance, 19% had Medicare/Medicaid, and 23% had private insurance. At the time of this retrospective chart review, 35% of patients lacked any follow-up information, including appointments or status updates regarding their condition, vital status, or engagement with healthcare, possibly due to missed appointments, transfers, mortality, or other reasons. Of the 27 patients who were deemed transplant eligible, three (11%) successfully completed allogeneic bone marrow transplant. Reasons for non-transplantation include lack of a compatible donor, inadequate social support, insurance-related challenges, or patient refusal. Patients who completed induction and consolidation treatment with documented follow-up had a 23% survival rate at the five-year mark, compared to 31.7% overall survival rate reported in SEER data from 2013 to 2019. Conclusions: Our study highlights persistent healthcare disparities in Afro-Caribbean AML patients leading to poor survival outcomes. Despite treatment advancements, challenges related to insurance coverage, social support, follow-up care, and access to restricted, advanced care remain. Addressing these disparities calls for targeted interventions to enhance access and support systems for this vulnerable population.

Patient (pt) experience with and perceptions of transfusion-dependent (TD) and transfusion-independent (TI) myelofibrosis (MF): A qualitative interview study.

e23110 Background: MF is a rare myeloproliferative neoplasm for which Janus kinase inhibitors are the standard of care. Some Janus kinase inhibitors can exacerbate anemia, a hallmark feature of MF that increases in severity with disease progression. Red blood cell transfusions are an important component of anemia management, but transfusion dependence is an independent predictor of poor survival outcomes and is inversely correlated with quality of life (QOL). The current study aimed to elicit the perceived direct and indirect burden of transfusion dependence and its impact on pts with MF. Methods: Concept elicitation interviews were conducted remotely with Janus kinase inhibitor–experienced and symptomatic (MF Symptom Assessment Form v4.0 Total Symptom Score [TSS] ≥10) pts with MF across the US, UK, Germany, Italy, Spain, and Poland (N = 20). Five TD pts (≥2 blood transfusions in any 1 mo over the last 3 mo) and 15 TI pts (≤1 blood transfusion in any 1 mo over the last 3 mo) participated in 60-minute interviews, which followed a semistructured guide including open-ended questions and completion of ranking exercises and sociodemographic and clinical forms. Results: Of 20 pts, mean age was 59 years, 50% were male, and85% received a diagnosis of anemia after their MF diagnosis. Pts with anemia experienced a range of related symptoms, including fatigue (94%), weakness (53%), and night sweats (29%). These symptoms impacted several QOL domains, including emotional (88%) and physical (71%) health and social life (71%). Most pts (18 of 20) had received a transfusion in the past, of whom 5 were TD. In addition to higher transfusion burden, TD pts had higher symptom burden than TI pts (mean TSS, 30.8 vs 27.9).TD pts endorsed challenges with frequent transfusions relating to clinical concerns/safety (100%), convenience (100%), and travel (80%), all of which remained concerns when thinking about being TD in the future (40% each). These challenges resulted in emotional (80%) and physical (60%) impacts and impacts to activities of daily living (60%). Four of 5 (80%) reported that going ≥12 weeks without a transfusion would be helpful and positively impact their QOL. Similarly, TI pts felt it was important to remain TI, with 73% expressing concerns about becoming TD in the future. Regarding the most important MF treatment outcomes, MF symptom reduction and overall survival were the most common (40% each) among TD pts, and reduction/avoidance of transfusion was the most common (40%) among TI pts. Conclusions: These interviews characterize the substantial negative experiences with and perceptions of anemia and transfusions in pts with MF who are TD and those who are TI but concerned about becoming TD in the future. These findings highlight the value of treatment options that reduce/eliminate transfusion burden and prevent future transfusions in improving the experiences of pts with MF.

Complex immune microenvironment of chordoma: a road map for future treatment

BackgroundChordoma, a rare bone tumor, presents limited treatment options and patients typically exhibit poor survival outcomes. While immunotherapy has shown promising results in treating various tumors, research on the immune...