Komel, Aqsa

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

e20629 Background: Concomitant inhibition of the vascular endothelial growth factor (VEGF) pathway together with PD-1 or PD-L1 immune checkpoint blockade has demonstrated synergistic activity in non-small cell lung cancer (NSCLC). However, comparative evidence across individual immune checkpoint inhibitor (ICI) and anti-VEGF combinations remains limited. This network meta-analysis (NMA) aimed to evaluate and compare the efficacy of available ICI plus anti-VEGF combination strategies in NSCLC. Methods: A systematic search of three electronic databases and two clinical trial registries was conducted to identify randomized controlled trials evaluating combinations of ICIs with anti-VEGF agents. A frequentist NMA framework was applied using the netmeta package in R. Hazard ratios (HRs) were used for overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were used for objective response rate (ORR). Treatment ranking was performed using P scores. Results: A total of 24 randomized controlled trials were included in the network. For survival outcomes, the combination of nivolumab plus bevacizumab demonstrated significantly improved OS (HR = 0.66, 95% CI 0.50–0.88) and PFS (HR = 0.46, 95% CI 0.27–0.81) compared with standard chemotherapy. In addition, atezolizumab plus bevacizumab was associated with a significant OS benefit over chemotherapy (HR = 0.79, 95% CI 0.65–0.95). Indirect comparisons showed that nivolumab plus bevacizumab significantly improved PFS compared with pembrolizumab monotherapy, as well as pembrolizumab combined with lenvatinib or chemotherapy. Furthermore, nivolumab combined with sitravatinib demonstrated significantly superior OS and PFS compared with ramucirumab and chemotherapy. For ORR assessed using RECIST 1.1, nivolumab-based combinations could not be incorporated into the network due to insufficient data, and no other combination demonstrated a statistically significant advantage over chemotherapy. However, indirect comparisons showed that pembrolizumab plus lenvatinib was superior to lenvatinib monotherapy (OR = 4.76, 95% CI 1.04–25.0). P-score rankings identified nivolumab plus bevacizumab as the top-ranked regimen for survival outcomes, followed by atezolizumab plus bevacizumab. For ORR, pembrolizumab plus lenvatinib ranked highest, followed by atezolizumab plus bevacizumab. Conclusions: Nivolumab-based ICI and anti-VEGF combinations, particularly with bevacizumab and sitravatinib, demonstrate the most favorable survival outcomes in NSCLC. Evidence for ORR remains limited, and further randomized comparisons are required to better define the relative efficacy of these combinations.

e17594 Background: Cardiovascular disease (CVD) is the leading cause of death among women with ovarian cancer. This study investigates cardiovascular mortality in women with ovarian cancer across the United States, assessing trends by geography and urbanization. Methods: Mortality data from the CDC WONDER database (1999–2020) were analyzed. Females with ovarian cancer listed on the death certificate and cardiovascular disease as the cause of death were identified using ICD-10 codes. Age-adjusted mortality rates (per 100,000) were calculated and stratified by census region and urbanization. Trends were evaluated using Average Annual Percent Change (AAPC) calculated by the Joinpoint Regression Program V5.4.0. Results: From 1999 to 2018, cardiovascular mortality in ovarian cancer patients declined, with an APC of –2.09%, consistent across regions and urbanization levels. However, from 2018 to 2020, a concerning reversal occurred, with mortality increasing by +3.79% per year. The abrupt rise in mortality is observed in the Midwest region, with an APC of +3.99, and in small and medium metro regions, with APCs of +7.38 and +6.46, respectively. This reversal in cardiovascular mortality in ovarian cancer from 2018 to 2020 is likely due to the COVID-19 pandemic that disrupted screening and treatment. Conclusions: This 21-year analysis demonstrates a long-term decline in cardiovascular mortality among women with ovarian cancer, followed by a sharp reversal from 2018 to 2020. This increase suggests the urgent need for public health interventions to reduce cardiovascular risk among ovarian cancer patients.

e17524 Background: Cervical cancer remains one of the leading causes of female cancer mortality, while heart failure drives chronic disease burden. Their coexistence complicates outcomes through shared risk factors, cardiotoxicity, and mortality. This study examined cervical cancer mortality trends in patients with heart failure, assessed disparities, and aimed to inform integrated management strategies. Methods: We analyzed death certificates from CDC WONDER Database (1999–2020), using ICD-10 C53 (cervical cancer) and I50 (heart failure). Female mortality was stratified by race and urbanization. Joinpoint Regression Program V5.4.0 calculated Annual Percent Change (APC) and Average Annual Percent Change (AAPC). Results: A total of 5,534 deaths were identified. Age-adjusted mortality rates (AAMR) declined overall, but trends varied. Among females, mortality fell from 0.1102 per 100,000 in 1999 to 0.076 in 2020 (AAPC -1.28%). Three phases emerged: a modest decline (1999-2006, APC -1.45%), a rapid decline (2006-2009, APC -17.6%), and a concerning reversal (2009-2020, APC +3.27%). The latter increase may reflect reduced screening, declining vaccination rates, or COVID-19 disruptions.By urbanization, large central metropolitan areas showed a steady decline (APC -4.13%). By race, White women demonstrated a consistent reduction (APC -2.61%), indicating sustained benefits of screening and vaccination. Conclusions: Cervical cancer mortality in heart failure patients declined from 1999-2020, reflecting prevention and healthcare advances. However, disparities persist, with notable increases among women since 2009. These findings highlight successes but stress the urgent need for vaccination and screening.

e17104 Background: Prostate cancer is a commonly diagnosed malignancy among men. Sepsis continues to pose a significant threat to outcomes. Patients with are particularly vulnerable to sepsis due to immunosuppression from the malignancy itself, advanced age, and treatment-related factors including catheter use. Sepsis is associated with high short-term mortality, and worsened overall outcomes, underscoring the need for epidemiological and clinical evaluation. Methods: We analyzed death certificates from 1990-2023 from CDC Wonder Database. We used ICD-10 codes, C61 for malignant neoplasm of prostate and C56 for sepsis to identify related deaths. Mortality rates were compared by urbanization, sex and census region. Joinpoint Regression Program V5.4.0 computed Annual Percent Change with 95% CIs. p value < 0.05 was considered statistically significant. Results: Between 1999 and 2023, 39,801 deaths were recorded. Overall age-adjusted mortality rates (AAMRs) changed little over time, remaining near 2 deaths per 100,000 population (2.02 in 1999 and 2.00 in the most recent year). Clear differences were seen across demographic groups.In 1999, AAMRs among Black or African American was highest with value of 6.80 compared to white and hispanic or latino individual with AAMR vales 1.67 and 1.89 respectively.In 2023, mortality among Black individuals fell to 5.06; however, rates were still higher than those seen among White (1.76) and Hispanic/Latino (1.92) populations. Geographic differences were also evident.The mortality rate in the South, decreasing from 2.43 in 1999 to 2.16 in 2023, was highest among all the other census regions.Mortality rates declined across both metropolitan and nonmetropolitan areas, falling from 2.02 to 1.84 in metropolitan regions and from 2.05 to 1.73 in nonmetropolitan regions in year 2020. Conclusions: Overall sepsis-related mortality has remained relatively unchanged over the two decades, with significant racial and geographic disparities. Black individuals continue to experience disproportionately higher mortality, and Southern region showed consistently elevated rates. Both metropolitan and non-metropolitan areas saw modest declines. These findings highlight the continued need for targeted preventive measures and management strategies to reduce mortality and improve outcomes. Prostate cancer with sepsis AAMRs. variable AAMR 1999 AAMR 2023 Overall / Male 2.02 (1.91-2.14) 2.00 (1.92-2.09) Race Black or African American 6.80 (6.04-7.56) 5.06 (4.60-5.53) White 1.67 (1.56-1.78) 1.76 (1.67-1.85) Hispanic or Latino 1.89 (1.39-2.50) 1.92 (1.65-2.20) Census Region Northeast 2.25 (2.00-2.51) 1.99 (1.80-2.18) Midwest 1.71 (1.50-1.92) 1.65 (1.49-1.81) South 2.43 (2.22-2.63) 2.16 (2.02-2.30) West 1.54 (1.33-1.76) 2.12 (1.94-2.30) Urbanization AAMR 2020 Metro 2.02 (1.90-2.15) 1.84 (1.75-1.93) Non-metro 2.05 (1.79-2.30) 1.73 (1.54-1.92)

e16067 Background: Gastric carcinoma remains a significant cause of cancer mortality in the United States. Although overall mortality rates have declined, persistent disparities exist across racial, age, and geographic groups. For cancer patients, sepsis—a life-threatening infection response—is a major fatal complication. Analyzing linked mortality data is crucial for identifying high-risk populations, understanding the burden of cancer-associated infections, and guiding targeted prevention and treatment strategies to improve outcomes and achieve health. Methods: This cross-sectional study used CDC WONDER mortality data from 1999–2020 for adults aged 25 years and older. Causes of death were identified using ICD-10 codes, and age-adjusted mortality rates (AAMRs) were calculated across sex, race/ethnicity, age, census regions, and urban–rural categories. Mortality trends were assessed using Joinpoint regression to estimate average annual percentage changes (AAPC) with 95% confidence intervals (CIs) and statistical significance. Results: From 1999 to 2020, U.S. stomach cancer mortality declined overall, with AAMRs decreasing from 0.29 to 0.22 per 100,000 (AAPC = –0.8%, 95% CI: –1.64 to 0.04). Significant declines occurred among adults aged 65–74 (APC = –1.7%, 95% CI: –2.32 to –1.05), 75–84 (APC = –1.9%, 95% CI: –2.65 to –1.05), and ≥85 years (APC = –3.0%, 95% CI: –4.02 to –1.99). Adults 45–54 years experienced increasing mortality after 2005 (APC = 5.1%, 95% CI: 2.82 to 7.46), while rates among 55–64 years remained stable. Male mortality declined significantly (AAPC = –1.24%, 95% CI: –1.93 to –0.54), whereas female mortality showed no significant long term change (AAPC = –0.93%, 95% CI: –2.44 to 0.60). Black (AAPC = –2.25%, 95% CI: –3.02 to –1.47) and Hispanic/Latino populations (AAPC = –1.50%, 95% CI: –2.26 to –0.74) experienced significant declines. Regionally, the Northeast showed the largest decline (AAPC = –2.30%, 95% CI: –3.52 to –1.07), while the Midwest, South, and West demonstrated no significant long term trends. Metropolitan areas declined from 1999–2011 (APC = –2.80%, 95% CI: –4.44 to –1.14). Conclusions: While overall U.S. gastric cancer mortality declined from 1999–2020, this progress is uneven. Significant increases among adults aged 45–54 and stable rates for those 55–64 highlight an emerging concern. Furthermore, declining trends are concentrated in specific demographic groups and regions, such as the Northeast, revealing persistent disparities. These findings underscore the need for targeted prevention and research focused on younger adults and lagging geographic areas.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone-marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures. Lay Summary Radiotherapy as part of cancer treatment is correlated with an acute increase in senescent cells. Here we show that the pro-inflammatory senescence associated secretory phenotype (SASP) becomes much more prominent soon after radiotherapy in both patients and mice. Suppression of the SASP using a Janus kinase inhibitor, ruxolitinib, reduced the overall senescent cell burden, improved bone architecture by promoting bone formation, reduced bone marrow adiposity, and mitigated radiation-induced lymphatic impairment. Overall, these findings suggest that early inhibition of the SASP may help mitigate several bone anomalies and prevent long-term bone loss and fractures after radiotherapy. Graphical Abstract

ABSTRACT Background Lung cancer (LC) and respiratory failure (RF) are leading causes of adult mortality worldwide. Analyzing long‐term mortality trends across demographic, racial, geographic, and socioeconomic groups is essential to address disparities and enhance outcomes. This study investigates US national mortality patterns for LC and RF from 1999 to 2023, focusing on changes in age‐adjusted mortality rates (AAMRs) and key disparities. Methods Mortality data from the CDC WONDER database (1999–2023) for adults aged 25+ with LC (ICD‐10: C34) or RF (ICD‐10: J96) were analyzed. AAMRs per 100,000 were calculated, stratified by gender, race/ethnicity, region, state, and urban–rural status. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes (APCs) with 95% confidence intervals (CIs), with significance at p < 0.05. Results Over 1999–2023, 456,325 deaths from LC and RF were recorded. AAMRs declined from 1999 to 2010 (APC = −1.2, 95% CI: −1.6 to −0.9) but rose from 2010 to 2023 (APC = 1.4, 95% CI: 1.1–1.7). Men's AAMRs steadily decreased, whereas women's dropped initially, then increased from 2011 to 2023 (APC = 2.0, 95% CI: 1.7 to 2.5). Non‐Hispanic Whites saw a sharp AAMR rise from 2014 to 2017 (APC = 2.7, 95% CI: 0.9 to 3.3), with other racial/ethnic groups showing mixed trends. Regionally, the Northeast had the highest AAMRs (8.6, 95% CI: 8.5 to 8.7), and the Midwest the lowest (7.1, 95% CI: 7.0 to 7.1). Metropolitan areas saw increases post‐2006, whereas nonmetropolitan areas rose after 2009 (APC = 2.3, 95% CI: 1.8–3.1). Mississippi had the highest state AAMR (14.0, 95% CI: 13.7–14.4), Wisconsin the lowest (3.7, 95% CI: 3.5–3.8). Conclusion LC and RF mortality declined until 2010, then increased, revealing significant disparities. Targeted interventions are critical to address these trends and reduce inequities.

Abstract Disclosure: A. Ullah: None. R. Haider: None. M. Khawar: None. M. Abid: None. M. Hadeed Khawar: None. M. Shaukat: None. M. Asad Cheema: None. A. Komel: None. M. Ahmed Khan: None. R. Noureen: None. A. Batool: None. M. Mubashir: None. A. Qadeer: None. R. W. Kirchoff: None. Background: The role of dissecting the right paraesophageal lymph node (RPELN) in managing papillary thyroid carcinoma (PTC) remains a subject of debate. This meta-analysis examines both established and novel risk factors associated with RPELN metastasis. Methods: Relevant studies published up to December 2024 were retrieved using PubMed, Embase, Ovid, and Scopus search engines. Data were extracted and evaluated using the Newcastle-Ottawa scale. Statistical analysis was performed using Review Manager 5.4, with heterogeneity assessed through the Q-test and I²-test. Sensitivity analysis was conducted using the leave-one-out method, and the Egger regression test was used to generate a funnel plot for publication bias assessment. Results: Out of 2,444 articles screened, 26 studies involving 16,427 patients were included in the meta-analysis. The overall RPELN metastasis rate was 12.98% (2,133/16,427). The pooled analysis revealed significant associations between RPELN metastasis and the following factors: age under 55 years (P &lt; 0.00001), male gender (P &lt; 0.00001), tumor size &gt;1 cm (P &lt; 0.00001), multifocality (P &lt; 0.00001), capsular invasion (P &lt; 0.00001), vascular invasion (P &lt; 0.00001), extra-thyroidal extension (P &lt; 0.0001), central lymph node metastasis (P &lt; 0.00001), lateral lymph node metastasis (P &lt; 0.00001), Hashimoto’s thyroiditis (P = 0.002), micro-calcifications (P = 0.01), and altered echogenicity (P = 0.03). Conversely, no significant associations were observed for tumor location in the right lobe (P = 0.07), superior pole (P = 0.08), middle pole (P = 1.00), inferior pole (P = 0.28), or tumor margins (P = 0.93) (all P &gt; 0.05). Conclusion: Factors such as age &lt;55, male sex, tumor size &gt;1 cm, multifocality, capsular invasion, vascular invasion, extra-thyroidal extension, central lymph node metastasis, lateral lymph node metastasis, and Hashimoto’s thyroiditis are significantly associated with RPELN metastasis. These should be carefully considered during RPELN dissection in PTC management. Presentation: Sunday, July 13, 2025

e20520 Background: Cancer and respiratory failure (RF) are amongst leading causes of mortality in adults. This study investigates national trends in age-adjusted mortality rates (AAMRs) for cancer and RF in the United States from 1999 to 2023, focusing on disparities by gender, race, region, and rural-urban residence to inform public health strategies. Methods: This descriptive study analyzed data from the CDC WONDER database, of adults aged 25 and older. Mortality data were identified using ICD-10 codes C00–C97 (cancer) and J96 (RF). AAMRs per 100,000 population were calculated and stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Temporal trends were analyzed using Joinpoint regression to estimate annual percent changes (APCs) with 95% confidence intervals (CIs). Statistical significance was set at p < 0.05. Results: From 1999 to 2023, total deaths of 1,263,368 attributed to cancer and RF (682,141 men, 581,227 women). AAMRs declined from 1999 to 2004 (APC = -1.5, 95% CI: -4.0 to -0.4), stabilized from 2004 to 2012 (APC = 0.8, 95% CI: 0.1 to 2.4), and increased from 2012 to 2023 (APC = 3.2, 95% CI: 2.9 to 3.8). Men experienced a greater initial decline (APC = -2.1, 1999–2004) but significant increases thereafter (APC = 3.0, 2012–2023), while women showed a slower decline followed by sharper increases (APC = 3.5, 2013–2023). Non-Hispanic Black populations initially declined (APC = -1.7, 1999–2003) but later increased significantly (APC = 3.0, 2014–2020). Hispanic/Latino populations declined (APC = -1.2, 1999–2009) before rising sharply (APC = 3.1, 2009–2020). American Indian or Alaska Native populations showed consistent increases (APC = 1.7, 1999–2020). Urban areas experienced initial declines (APC = -1.7, 1999–2004), followed by increases (APC = 2.4, 2011–2020). Non-metropolitan areas exhibited steeper increases (APC = 4.6, 2014–2020). Regionally, the West recorded the highest AAMR (24.0), followed by the Northeast (23.6), South (20.9), and Midwest (18.0). Mississippi had the highest state-level AAMR (36.3), while Wisconsin had the lowest (10.0). States in the top 90th percentile included Mississippi, Arkansas, and California, while Wisconsin, Minnesota, and Oregon were among the lowest. Conclusions: Cancer and RF mortality declined initially but have significantly increased in recent years. Disparities persist across gender, racial, and regional groups, underscoring the need for focused public health efforts and equitable resource distribution to address these trends.