Improved Survival Outcomes Research Articles

Modeling optimal combination of breast and cervical cancer screening strategies in China

BackgroundBreast and cervical cancers are the commonest cancers among women. Secondary prevention of cancer through screening minimizes disease burden and improves survival outcomes. Optimizing screening strategies for breast and cervical cancers is a challenge in resource-limited settings with a high population density such as China. Therefore, we aimed at assessing the efficiency of different combined screening strategies for breast and cervical cancers under different budgets in China.MethodsMarkov cohort model was used to evaluate the cost-effectiveness of 36 strategy combinations for breast and cervical cancer screening with varying screening modality and intervals. The results were used as inputs in the Integer Programming (IP) model to determine the combination of the different screening options under different budgets.ResultsThe optimal combination strategy was biennial breast ultrasonography (BUS) and mammography (MAM) in parallel screening and quinquennial human papillomavirus (HPV) for breast and cervical cancer screening under the threshold of the annual per capita social cost investment (PCSCI) (18.80 USD) in China. Using this strategy, the total investment cost for 100,000 females was 1,877,984.50 USD, and the incremental life-years compared with no screening was 3,122 life-years. The optimal combination strategy included annual clinical breast examination (CBE), BUS and MAM in series screening, and biennial thin-layer liquid-based cytology (TCT) and HPV in series screening with the annual PCSCI reaching 37.60 USD. Thereafter, as the cost input continued to increase, the optimal combination strategy remained unchanged, and the sum of incremental life-years and actual input costs did not increase.ConclusionsFrom a social cost–benefit perspective, biennial BUS and MAM in parallel screening, and quinquennial HPV screening is the most efficient combination strategy with limited budget, while annual CBE, BUS and MAM in series screening and biennial TCT and HPV in series screening are the most efficient combination strategy with sufficient budget.

Early Escalation to CentriMag for Acute Myocardial Infarction-Induced Out-of-Hospital Cardiac Arrest With Refractory to Extracorporeal Membrane Oxygen Support.

The mortality rate of acute myocardial infarction (AMI)-related refractory cardiogenic shock (rCS) remains high, particularly in patients experiencing cardiac arrest with extracorporeal cardiopulmonary resuscitation (ECPR). This study aimed to evaluate the outcomes of early escalation to CentriMag for AMI-induced out-of-hospital cardiac arrest (OHCA) with ECPR. Patients with AMI-induced OHCA with refractory to ECMO support after ECPR were enrolled. Clinical data were analyzed to identify predictive factors for mortality and survival benefits. Eighty-nine patients were enrolled, of whom 26 underwent CentriMag implantation. The 1-year survival rate for those with the implantation was 34.6%. In contrast, those without implantation showed a survival rate of 7.9%. The average time from the initiation of ECPR to CentriMag implantation was 22.5 ± 14.6 h. The surgical mortality group exhibited a larger body surface area, longer intervals from CPR to ECPR, shorter duration of CentriMag support, and higher preoperative serum creatinine and postoperative day 1 serum aspartate aminotransferase levels. A prolonged interval from CPR to ECPR was identified as an independent risk factor for mortality. Extended duration of CentriMag support was associated with improved survival outcomes. Early CentriMag implantation rescues patients experiencing AMI-related OHCA with rCS and refractory to ECMO support after ECPR. This intervention provides a critical time window, serving as a safe bridge to decision.

Cyclin-dependent kinase 4/6 inhibitor resistance mechanisms and strategies for subsequent treatment in breast cancer: A comprehensive review

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed the therapeutic landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, demonstrating significant efficacy in both early and advanced stages of the disease. Combined with endocrine therapy, these inhibitors have dramatically improved survival outcomes. However, resistance to CDK4/6 inhibitors inevitably develops, posing a significant challenge in clinical management. Resistance to CDK4/6 inhibitors can develop through inherent and acquired fashions, and their mechanisms are explored in this comprehensive review. Inherent resistance arises from pre-existing genetic or signaling pathway alterations that diminish cancer cell sensitivity to CDK4/6 inhibitors. Acquired resistance, on the other hand, develops over time through mechanisms, such as the activation of alternative signaling pathways or changes in the tumor microenvironment. The review also examines potential biomarkers for predicting resistance, especially circulating tumor DNA markers, and discusses strategies to overcome resistance. These include combination therapies targeting multiple pathways simultaneously, sequential approaches to delay the onset of resistance, and the development of next-generation CDK4/6 inhibitors with improved efficacy and reduced resistance potential. Understanding resistance mechanisms and developing effective countermeasures are crucial for optimizing patient outcomes and extending the clinical benefits of CDK4/6 inhibitors in cancer therapy. Leveraging these insights will enable clinicians to personalize treatment strategies, ultimately enhancing the long-term effectiveness of CDK4/6 inhibitors in managing breast cancer.

Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study.

Frontline daratumumab-based triplet and quadruplet standard-of-care regimens have demonstrated improved survival outcomes in newly diagnosed multiple myeloma (NDMM). For patients with transplant-ineligible NDMM, triplet therapy with either daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, lenalidomide and dexamethasone (VRd) is the current standard of care. This phase 3 trial evaluated subcutaneous daratumumab plus VRd (D-VRd) in patients with transplant-ineligible NDMM or for whom transplant was not planned as the initial therapy (transplant deferred). Some 395 patients with transplant-ineligible or transplant-deferred NDMM were randomly assigned to eight cycles of D-VRd or VRd followed by D-Rd or Rd until progression. The primary endpoint was overall minimal residual disease (MRD)-negativity rate at 10-5 by next-generation sequencing. Major secondary endpoints included complete response (CR) or better (≥CR) rate, progression-free survival and sustained MRD-negativity rate at 10-5. At a median follow-up of 58.7 months, the MRD-negativity rate was 60.9% with D-VRd versus 39.4% with VRd (odds ratio, 2.37; 95% confidence interval (CI), 1.58-3.55; P < 0.0001). Rates of ≥CR (81.2% versus 61.6%; P < 0.0001) and sustained MRD negativity (≥12 months; 48.7% versus 26.3%; P < 0.0001) were significantly higher with D-VRd versus VRd. Risk of progression or death was 43% lower for D-VRd versus VRd (hazard ratio, 0.57; 95% CI, 0.41-0.79; P = 0.0005). Adverse events were consistent with the known safety profiles for daratumumab and VRd. Combining daratumumab with VRd produced deeper and more durable MRD responses versus VRd alone. The present study supports D-VRd quadruplet therapy as a new standard of care for transplant-ineligible or transplant-deferred NDMM. ClinicalTrials.gov registration: NCT03652064 .

Trends in the Incidence and Survival Outcomes in Patients With Small Cell Lung Cancer in the United States: An Analysis of the SEER Database.

There has been a lack of updated epidemiological data on the incidence and survival outcomes for patients with small cell lung cancer (SCLC) in the United States over the last two decades. A retrospective, population-based study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program to identify patients with SCLC from 2000 to 2020. Trends in cancer incidence, incidence-based mortality rates, 1-year relative survival rates and 1-year observed survival were evaluated utilizing the SEER database. The database identified a total of 188,426 SCLC patients during the study period from 2000 through 2020. The age-adjusted incidence rate slowly declined, on average, by 3% (95% CI: -3.2% to -2.8%) each year from 9 per 100,000 in 2000 to 4.6 per 100,000 in 2020. The decline is evident for all age groups, sexes, and races. Incidence-based mortality also declined slowly from 6.6 in 2005 to 3.5 in 2020. However, survival outcomes, including 1-year relative survival and 1-year observed survivals, have not improved significantly over the last two decades. This study found that the incidence of SCLC has decreased from 2000 to 2020, likely due to a reduction in smoking rates, underscoring the importance of smoking abstinence. An improvement in incidence-based mortality is likely related to an enhanced medical care and a decrease in the incidence of SCLC, but the lack of improvement in survival outcomes reflects the need for more effective systemic therapy.

Impact of long-term chemotherapy (CTx) on outcomes in pancreatic ductal adenocarcinoma (PDAC): A real-world UK multi-centre study.

687 Background: PDAC is associated with poor outcomes with limited treatment options. Here, we present a multi-institutional review evaluating outcomes following short and long-term CTx with or without treatment breaks in PDAC patients (pts). Methods: All consecutive PDAC pts receiving &gt; 3 CTx cycles between 2019 – 2023 at University College London Hospitals and Oxford University Hospitals were included. Treatment response, survival outcomes and predictors of clinical benefit were evaluated. Wilcoxon test, Kaplan-Meier and multivariate Cox regression models were performed. Results: Of the 213 screened pts, 127 eligible subjects met the study criteria. 1 st , 2 nd and 3 rd line CTx were received by 127, 40 and 2 pts, respectively. 21 pts had resectable disease (9 remained relapse-free after adjuvant CTx and 8 pts alive at post 2 years follow-up surveillance). 106 pts had unresectable or metastatic disease and were selected for final analyses (12% borderline resectable (BR), 19% locally advanced (LA), 9% localised disease who developed metastases and 60% de novo metastatic pts). 7 pts (7%) pts underwent genetic profiling on pt request or previous clinical trial screening; KRAS aberrations (N = 4), actionable PLAB2 / BRCA2 mutations (N = 2). BR and LA pts (N = 33) achieved a median PFS1 (Progression Free Survival while on 1 st line CTx) of 8.28 (95% Confidence Interval (CI), 5.49 – 15.11) and Overall Survival (OS) of 15.15 (95% CI, 9.46 – 26.41) months (mos). De novo metastatic pts (N = 64) attained a PFS1 of 6.64 (95% CI, 5.98 – 8.18) and OS of 9.30 (95% CI, 8.05 – 12.81) mos. Patient-specific factors in both cohorts comprising of age, gender, performance status, smoking history, co-morbidities were not associated with PFS1 and OS. Improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = &lt; 0.001), median duration of 1 st CTx of ≥ 3.58 mos (P = &lt; 0.001) and best response to 1 st CTx (P = 0.007). A favourable OS was associated with &gt; 1 line of CTx (P = &lt; 0.001), ≥ 6 cycles of 1 st line CTx (P = 0.009), median duration of 1 st CTx of ≥ 3.58 mos (P = &lt; 0.001) and best response to 1 st CTx (P = 0.002). Subjects receiving ≥ 6 cycles of 1 st CTx were younger than pts tolerating fewer cycles (median age 62.41 vs 72.25 years) (P = 0.04). In the localised disease group, improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = 0.003), median duration of 1 st CTx of ≥ 2.99 mos (P = 0.008) and local treatment after commencing 1 st line CTx (P = &lt; 0.001). These three factors were also associated with OS; P = 0.02, P = 0.02 and P = &lt; 0.001, respectively. Median number and duration of 1 st line CTx interruptions were not associated with PFS1 or OS in both cohorts. Conclusions: Despite challenges associated with long-term CTx, survival outcomes may be better in pts receiving CTx for longer periods and multiple treatment lines. Genetic profiling currently offers limited value but in carefully selected pts, localised treatment options may be associated with improved survival outcomes.

Analysis of lipogenic and metabolic subtypes and survival outcome in patients with pancreatic adenocarcinoma.

775 Background: Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for Pancreatic Ductal Adenocarcinoma (PDAC). In previous studies, molecular profiling in tumor tissue has identified Cholesterogenic, Classical, or Exocrine-Like pathological subtypes associated with improved prognosis. Herein, in a clinical trial called Project Survival, we molecularly and clinically characterized a prospective PDAC biomarker cohort. This multicenter (n=6) clinical trial (NCT 02781012) of PDAC combined with high-fidelity longitudinal phenotypic characterization and multi-omic profiling was utilized to identify biomarkers with diagnostic and therapeutic utility. The study included assessment of plasma, serum, buffy coat, urine, saliva, and tumor tissue samples and followed 269 PDAC subjects for up to 7 years (Median survival was 700 days, with IQR of 822 days). Methods: We assessed plasma samples to identify circulating biomarkers using proteomics, metabolomics, and lipidomics profiling. Multi-omic comparison of patients with Overall Survival (OS) above the 75th percentile (improved survival) against those with OS below the 25th percentile (poor survival) was performed. Results: We identified distinct panels of proteins, metabolites, and lipids that were associated with patient survival outcomes. Protein biomarkers that were increased in improved survival outcomes were associated with cholesterol metabolism (7/14, p-value = 0.00085) and glycolysis/gluconeogenesis (5/12, p-value = 0.00089), however, protein markers associated with immune surveillance and inflammation were associated with poorer survival. For metabolite biomarkers, 19 metabolites were increased in poorer survivors of which 13/19 were carnitine metabolites, and 42 metabolites were increased in patients with improved survival. Interestingly, only two lipid molecular species of the diacylglyceride family were increased in patients with poorer survival. Conclusions: Project Survival, a prospective biomarker-driven clinical trial identified distinct metabolic and molecular subtypes of patients which characterize survival outcome in PDAC. These subtypes go beyond tumor genomic characterization and align with distinct cholesterogenic and glucogenic phenotypes associated with survival outcomes, which can potentially be leveraged for therapeutic intervention strategies.

Retrospective comparative survival analysis of ablation plus systemic therapy versus systemic therapy alone for breast cancer liver metastases, stratified by extrahepatic metastases status.

Current decision-making for the treatment of breast cancer liver metastases (BCLM) using ablation lacks strong evidence, especially for patients combined with extrahepatic metastases. To assess whether ablation plus systemic therapy (AS) improves survival outcomes in patients with BCLM compared to systemic therapy alone. This retrospective study analyzed patients with BCLM who received either AS or systemic therapy alone. Propensity score matching (PSM) and survival analysis were performed, taking into account factors like the characteristics of primary breast cancer, liver metastases and systemic therapies received. The study included 1021 female patients, with a median follow-up of 39.6 months. Of these patients, 132 underwent AS and 836 received systemic therapy alone. After PSM, among patients with BCLM (≤3 tumors, each ≤3cm), the median overall survival (OS) for those treated with AS or systemic therapy alone was 65.5 and 40.4 months, respectively (HR=0.48, p=.003); in the subset of patients with extrahepatic metastases, the median OS for those treated with AS and systemic therapy alone was 46.4 and 40.8 months, respectively (HR=0.58, p=.047). Among patients with >3cm or >3 lesions, the median OS for those treated with AS or systemic therapy alone was 45.2 and 29 months, respectively (HR=0.67, p=.084). Among patients with BCLM (≤3 tumors, each ≤3cm), AS provide longer survival compared to systemic therapy alone, even with extrahepatic metastases. For patients with larger or more numerous metastases (>3cm or >3 lesions), AS may provide survival benefit, but further validation is needed.

Organ-specific responses to nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma: A multicenter, retrospective study.

543 Background: The Check-Mate 9DW trial demonstrated that combining ipilimumab with nivolumab (Ipi/Nivo) improved survival outcomes compared with sorafenib or lenvatinib in advanced hepatocellular carcinoma (aHCC). Accumulated evidence suggests that immune checkpoint inhibitor (ICI) monotherapy elicits limited intrahepatic responses in patients with aHCC. Here, we aimed to examine the organ-specific objective response rate (OSORR) of Ipi/Nivo compared with that of nivolumab monotherapy (Nivo) and to evaluate the OSORR of Ipi/Nivo based on the prior use of ICI treatment. Methods: We conducted a retrospective assessment of 69 Ipi/Nivo-treated patients and 164 nivolumab-treated patients for aHCC at five referral hospitals in Korea. Only patients classified as Child-Pugh Class A were included. Organ-specific response criteria were adopted from RECIST 1.1, according to the indicated primary sites, including the liver, lungs, lymph nodes and other sites of metastasis. Results: Baseline characteristics of the Ipi/Nivo and Nivo groups were comparable. However, 65.2% of patients in the Ipi/Nivo group had prior ICI exposure, compared with only 4.3% in the Nivo group. The objective response rate (ORR) of Ipi/Nivo was 29.0%. The Ipi/Nivo combination therapy elicited OSORRs for 204 individual lesions: 18.0% in the liver, 17.7% in the lungs, 30.0% in the lymph nodes, and 12.5% in other sites. Within the Ipi/Nivo group, the ORR was 45.8% for patients without prior ICI exposure and 20.0% for those with prior ICI exposure. Patients without prior ICI exposure demonstrated OSORRs for 72 individual lesions: 29.0% in the liver, 31.3% in the lungs, 33.3% in the lymph nodes, and 23.1% at other sites. Conversely, patients with prior ICI exposure exhibited OSORRs for 132 individual lesions: 11.5% in the liver, 11.4% in the lungs, 27.8% in the lymph nodes, and 7.4% at other sites. Patients who exhibited a response in one organ were more likely to demonstrate responses in other organs irrespective of the organ type, with only two patients exhibiting variable responses across different organs. Furthermore, these responders had improved survival outcomes, including longer progression-free survival and overall survival, compared with non-responders. In terms of nivolumab monotherapy, the ORR was 21.3%. Nivo yielded OSORRs for 305 individual lesions: 13.5% in the liver, 25.3% in the lungs, 39.3% in the lymph nodes, and 18.4% at other sites. Conclusions: In contrast to lesions of patients who received Nivo, intrahepatic lesions of Ipi/Nivo-treated patients without prior ICI exposure exhibited favorable responses, comparable with treatment responses of extrahepatic lesions. Conversely, Ipi/Nivo-treated patients with prior ICI exposure had reduced organ-specific responses across all organs when compared with those without prior ICI exposure.

Real-world clinical outcomes of locally advanced unresectable and de-novo metastatic pancreatic ductal adenocarcinoma: A multicenter retrospective study from Saudi Arabia.

691 Background: Pancreatic ductal adenocarcinoma (PDAC) has dismal clinical outcomes, even with existing treatment regimens. This study evaluates the clinical characteristics and outcomes of patients with locally advanced unresectable or de-novo metastatic PDAC in Saudi Arabia to provide real-world data that can be compared to international benchmarks. Methods: This is a retrospective, multicenter study. Patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023 were included. Data were collected from 10 oncology centers across Saudi Arabia. Patient characteristics, treatment regimens, and clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using univariate and multivariate analyses. Results: A total of 350 patients were identified, with a median age of 60 years at time of diagnosis, 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, type of first-line regimen, and neutrophil-lymphocyte ratio (NLR). Conclusions: This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with trend of FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.

Survival analysis between different treatment strategies of mixed adenoneuroendocrine carcinoma (MANEC): a population‑based study.

Mixed adenoneuroendocrine carcinoma (MANEC) is rare and heterogeneous. Currently, there is no concise treatment standard for MANEC. This study aimed to explore the prognostic impact of different treatment methods in MANEC. The Surveillance, Epidemiology, and End Results (SEER) database was utilized to evaluate the outcomes of MANEC using propensity score matching (PSM) analysis, stratified and site-specific survival analysis. A total of 935 patients diagnosed with MANEC were enrolled in this study. Across most analyses, surgery performance (compared with no surgery) was associated with improved survival outcomes for MANEC patients, except for the site-specific analysis of small intestine, in which no significant association between surgery and patients' survival was found. Radiotherapy exhibited no significant association with patients' survival in most cases, and associated with poor prognosis of MANEC in certain specific analyses. Inconsistent effects of chemotherapy on MANEC were observed. Positive impact of chemotherapy on MANEC was indicated in PSM for chemotherapy or radiotherapy. Contradictory effects of chemotherapy were suggested based on the stage of MANEC, with unfavorable outcomes in early-stage and favorable outcomes in advanced-stage. The impact of chemotherapy on survival was influenced by the administration of surgery or radiotherapy. Site-specific analyses indicated chemotherapy was beneficial to MANEC of the hepatic-biliary-pancreatic system. The results of this study demonstrate the variable impact of different treatment strategies for MANEC. Surgery was generally associated with improved survival outcomes, while radiotherapy did not show a beneficial effect on MANEC. The effects of chemotherapy on MANEC were inconsistent in specific analyses.

Optimal preoperative treatment strategy for conversion surgery in unresectable locally advanced pancreatic cancer: A project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

718 Background: Conversion surgery (CS) for unresectable locally advanced pancreatic cancer (UR-LAPC) has been widely accepted when feasible. However, optimal preoperative treatment strategies remain unclear. To determine the most effective preoperative approach for UR-LAPC in the current treatment landscape, we conducted a project study in the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Methods: We analyzed 465 UR-LAPC patients who underwent CS following chemotherapy with FOLFIRINOX (FFX), gemcitabine plus nab-paclitaxel (GnP), or modified regimens between 2015 and 2020 across 84 Japanese board-certified training institutions. Overall survival (OS) was the primary endpoint. We used the Kaplan-Meier method for estimating survival analyses, the Cox proportional hazards model for multivariate analyses, and Maximally Selected Rank Statistics to determine the optimal preoperative treatment duration. Results: Median OS was 43.8 months, with a 5-year survival rate of 37.2%. The optimal preoperative treatment duration was 6.1 months. Patients receiving &gt;6 months of preoperative treatment (n=350) showed significantly better median OS and recurrence-free survival (RFS) compared to ≤6 months (n=115) (50.4 vs 29.7 months and 15.6 vs 9.1 months, respectively; both P&lt;0.001 ). FFX-based regimens (n=116) showed better OS and RFS than GnP-based regimens (n=349) (65.0 vs 36.5 months and 19.3 vs 12.4 months, respectively; both P&lt;0.01 ). Multivariate analysis identified preoperative treatment &gt;6 months (HR 0.53, 95% CI 0.407-0.697, P&lt;0.001 ) and initial FFX-based regimens (HR 0.63, 95% CI 0.464-0.843, P=0.002 ) as independent prognostic factors. Additional favorable factors included normal CA19-9 and CEA levels, PNI&gt;45 before CS, adjuvant chemotherapy, R0 resection, and Evans grade III/IV. Conclusions: This large-scale retrospective study has demonstrated that preoperative treatment duration &gt;6 months and the use of FFX-based regimens as initial treatment were associated with improved survival outcomes in UR-LAPC patients undergoing CS. These findings provide critical information for considering CS in UR-LAPC patients, especially in current clinical practice.

Investigating the clinical and molecular characteristics of class II and III BRAF mutations and their response to anti-EGFR therapy in MSS CRC: A comprehensive analysis.

274 Background: BRAF mutations (mts) are a heterogeneous group of molecular alterations seen in colorectal cancer (CRC). Class I BRAF mts (V600) are known to be associated with aggressive biology to CRC, but the knowledge of clinical characteristics of class II and III BRAF mts is limited. In this large cohort analysis, we evaluated the clinical and molecular features of class II and III BRAF mts and performed comparative analyses for their impact on survival outcomes. Methods: A total of 24402 MSS CRC samples were profiled by NGS (592-gene, NextSeq; WES, WTS NovaSeq) (Caris Life Sciences, Phoenix, AZ). BRAF mts were detected by NGS and classified using published literature (1). MAPK pathway activity score (MPAS) was calculated using RNA expression data. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact, while post-treatment survival from first treatment to last contact. KM estimates were calculated for defined patient cohorts. Significance was determined as P&lt;0.05. Results: A total of 1270, 134, and 327 patients with class I, II, and III BRAF mts were identified. BRAF mts overall and class I BRAF mts were significantly less common among younger pts (age&lt;50) compared to patients ≥ 50 (4.7% vs. 7.4 %; P&lt; 0.001 and 3.2% vs. 5.7%, respectively, P&lt;0.001). Class I BRAF mts were enriched with consensus molecular subtype 1 (CMS1) (class I, II, and III: 46% vs. 14% vs. 18% respectively) while class II and III mts had more CMS2 subtype compared to class I (2%, 30% and 29%, p&lt;0.05). Higher MPAS scores were noted among patients with class I BRAF mts than those with class II and III mts (1.73 versus 0.38 vs 0.79). Class I BRAF mts and KRAS mts were nearly mutually exclusive (0.5%), while KRAS mts were relatively common among class II and III mts (12.8% and 27.4%, respectively). Median OS for patients with wild-type BRAF , class I, II, and III BRAF mts were significantly different (29.8, 17.3, 21.8, and 24.6 months, respectively, p&lt;0.01). Similar OS was seen among patients who did not receive anti-EGFR therapy (28.3, 15.2, 20.7- and 21.9 months P&lt;0.001). Patients with class III mts had significantly better OS compared to patients with class I mts (HR=1.28 CI: 1.09-1.48 p=0.002), and while no significant difference was noted for patients with class II vs class I mts, numerically more favorable outcomes were noted (mOS 21.8 vs 17.3 months P=0.133). Among treated with anti-EGFR, patients with class II and III BRAF mts had numerically better post-anti-EGFR survival compared to class I mts; however, this was not statistically significant (21.2 vs 14.2 vs. 10.4 respectively P=0.3). Conclusions: Class II and III BRAF mts represent a distinct biological subgroup of MSS CRC with distinct prognoses. Class II and III BRAF mts are associated with improved survival outcomes compared to patients with class I mts. 1. Sahin et al. JCO OP 2021.

The effect of renin-angiotensin system inhibitors on patients with pancreatic cancer receiving systemic treatment: A retrospective cohort study from TriNetX US collaborative networks.

734 Background: This study aimed to assess the impact of renin-angiotensin system inhibitors, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), on patients with pancreatic cancer undergoing systemic chemotherapy. Methods: We conducted a global, retrospective collaborative network analysis using TriNetX data from January 1, 2014, to December 31, 2023, to explore this question. The study captured data on pancreatic cancer diagnoses, comorbidities, medications, and survival outcomes. Propensity score matching (PSM) was used to create 1:1 matched groups. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated to assess survival outcomes, while the Kaplan–Meier method was employed to evaluate survival probabilities. Subgroup analyses were performed based on sex, age, surgery, race, and comorbidities. Results: The study included 1,861 patients who were on ARBs/ACEIs and 4,875 patients who were not on these medications at baseline. After 1:1 propensity score matching, both groups were well-balanced with 1,627 patients each. Compared to the non-ARBs/ACEIs group, patients receiving ARBs/ACEIs demonstrated significantly better overall survival (HR: 0.846, 95% CI: 0.753–0.949). Subgroup analyses revealed significantly improved survival outcomes in patients on ARBs/ACEIs, including those without surgery (HR: 0.846, 95% CI: 0.749–0.956), males (HR: 0.762, 95% CI: 0.640–0.908), patients aged 65 years and older (HR: 0.801, 95% CI: 0.709–0.906), and White patients (HR: 0.806, 95% CI: 0.704–0.924). Notably, similar survival benefits were observed in patients with comorbidities such as diabetes, ischemic heart disease, dyslipidemia, and hypertension. Conclusions: In the largest TriNetX matched cohort study on pancreatic cancer, the use of ARBs/ACEIs was associated with a reduced risk of overall mortality. However, prospective studies are needed to further evaluate the effects of concomitant ARB/ACEI use in patients with pancreatic cancer undergoing systemic treatment.

LAPIS: Randomized phase 3 trial of chemotherapy (CTX) with and without pamrevlumab (PAM) for locally advanced pancreatic cancer (LAPC).

675 Background: PAM improved response, surgical eligibility, and resection rates when combined with CTX in phase 1/2 LAPC trials (NCT01181245; NCT02210559). LAPIS (NCT03941093) evaluated efficacy and safety of PAM + CTX in unresectable LAPC. Methods: LAPIS was a global, double-blind, placebo-controlled phase 3 trial of adults with treatment-naïve, -confirmed unresectable LAPC. Patients received (randomized 1:1) PAM (35 mg/kg Q2W) or placebo (PBO) plus CTX (gemcitabine + nab-paclitaxel [GnP] or FOLFIRINOX [FFX] per standard protocol) for up to six 28-day cycles. based on changes in -9, on FDG-PET, resectability, with final surgical decision made by surgeon. Primary endpoint: overall survival (OS); secondary endpoints: event-free survival (EFS), progression-free survival (PFS), and objective response rate (ORR. Safety (including treatment-emergent adverse events [TEAEs]) was evaluated in patients who received treatment. Results: 143 and 141 patients (median [range] age, 65.0 [31–90] yrs; 53.2% male) were randomized to PAM and PBO arms. 142 and 141 received treatment: GnP, 114 (79.7%) and 112 (79.4%); FFX, 28 (19.6%) and 29 (20.6%). PAM (64.8%) and 96 PBO (68.1%) patients completed 6 treatment cycles. . Survival similar for PAM and PBO arms (Table) and did not differ by. For PAM + FFX vs PBO + FFX, respiratory, thoracic and mediastinal disorders (39.3% vs 27.6%) and skin and subcutaneous tissue disorders (53.6% vs 37.9%) occurred &gt;10% more with PAM; TEAE frequencies were similar with PAM + GnP and PBO + GnP. One treatment-related death occurred in PAM arm. Conclusions: LAPIS contained important LAPC trial innovations: pre/post-CTX FDG-PET imaging, objective criteria for surgical intervention, external surgical review panel, and composite EFS measurement. Addition of PAM to CTX was not associated with additional toxicity but did not improve survival outcomes for unresectable LAPC. Clinical trial information: NCT03941093 . LAPIS endpoints. PAM arm (n=143) PBO arm (n=141) OS, months, median (95% CI) events=118 (82.5%)17.25 (15.47, 18.89) events=112 (79.4%)17.94 (14.59, 20.34) HR (95% CI)1.08 (0.83, 1.41)p=0.55 EFS, a months, median (95% CI) events=99 (69.2%)5.72 (5.59, 6.01) events=102 (72.3%)5.78 (5.62, 6.37) HR (95% CI)1.05 (0.78, 1.39) PFS, months, median (95% CI) events=48 (33.6%)9.36 (7.75, 11.79) events=44 (31.2%)9.40 (7.69, 10.84) HR (95% CI)1.01 (0.65, 1.56) ORR, n (%) 43 (30.1) 64 (45.4) OR (95% CI)0.50 (0.31, 0.82) Complete response 0 0 Partial response 43 (30.1) 64 (45.4) CI, confidence interval; HR, hazard ratio; OR, odds ratio. a Earliest of 1) failure to achieve local disease-free status at end of treatment and/or after surgery; 2) local or distant recurrence/progression; or 3) death.

Comprehensive analysis of Native Hawaiians and other Pacific Islanders with early-onset colorectal cancer.

31 Background: Rates of early-onset colorectal cancers (EOCRC) are increasing in Hawaii across all racial groups. Although previous studies have shown that Native Hawaiians have a higher mortality rate compared to other racial groups, the adjustment for sociodemographic factors have been limited. Our objective is to perform a comprehensive analysis of outcomes among patients with EOCRC in a racially diverse population accounting for tumor factors and patient sociodemographics. Methods: Patients diagnosed with EOCRC between 2000 and 2022 in Hawaii. Overall survival of Asians, Whites, and Native Hawaiian or Other Pacific Islanders (NHOPI) were calculated using the Kaplan-Meier method. Cox proportional hazard regression models assessed survival predictors adjusting for clinical and sociodemographic factors. Results: We included 379 patients in the final analysis. NHOPI had higher prevalence of underinsured status and higher histopathology grade compared to Whites and Asians. In unadjusted Cox regression, NHOPI race, underinsured status, grade, and stage were prognostic for survival. After adjusting for confounders, underinsured status, grade, and stage remained prognostic, but race was not significantly associated with survival. Conclusions: This study concludes that while NHOPI patients with EOCRC demonstrated poorer survival outcomes compared to other racial groups, this disparity was largely explained by the large percentage of underinsured NHOPI patients. Addressing treatment disparities in underinsured or uninsured is essential to improve survival outcomes. Univariate and multivariate analysis of survival. Univariate Multivariate HR (95% CI) p-value HR (95% CI) p-value Insurance Private Insurance - - - - Underinsured &amp; Uninsured 1.865 (1.331-2.612) &lt;0.001 1.843 (1.285-2.643) &lt;0.001 Race White - - - - Asian 1.179 (0.746-1.865) 0.48 0.936 (0.585-1.496) 0.781 NHOPI 2.005 (1.231-3.265) 0.005 1.051 (0.714-1.547) 0.8 Age at diagnosis 0.996 (0.967-1.025) 0.771 1.002 (0.971-1.034) 0.901 Histopathology grade Grade 1&amp;2 - - - - Grade 3&amp;4 2.785 (1.958-3.963) &lt;0.001 2.278 (1.571-3.303) &lt;0.001 Stage Stage 1 - - - - Stage 2 1.104 (0.49-2.487) 0.81 1.028 (0.451-2.342) 0.948 Stage 3 3.255 (1.666-6.359) &lt;0.001 2.873 (1.447-5.706) 0.003 Stage 4 14.851 (7.499-29.41) &lt;0.001 12.778 (6.283-25.987) &lt;0.001 Unknown 3.738 (1.506-9.275) 0.004 3.008 (1.189-7.608) 0.02 Sex Male - - - - Female 0.812 (0.587-1.123) 0.22 0.852 (0.609-1.194) 0.352 Microsatellite status Stable - - Unstable 0.481 (0.148-1.562) 0.204 Not done/Unknown 1.08 (0.737-1.582) 0.739 Time to Treatment Less than 1 month - - - - More than 1 month 1.221 (0.863-1.727) 0.26 1.123 (0.784-1.609) 0.527 Location of Tumors Right - - - - Left 1.239 (0.76-2.02) 0.391 1.466 (0.886-2.425) 0.137 Rectal 1.391 (0.86-2.249) 0.178 1.211 (0.738-1.986) 0.449 NHOPI: Native Hawaiians and Other Pacific Islanders; HR: Hazard Ratio; CI: Confidence Interval.

Chemoimmunotherapy plus radiotherapy in advanced esophageal squamous-cell carcinoma.

437 Background: Chemotherapy plus Immune checkpoint inhibitors (ICIs) have improved survival outcomes of patients with advanced or metastatic esophageal squamous-cell carcinoma in both first- and second-line settings. However, the benefit of additional radiotherapy for the residual esophageal lesion after chemo-immunotherapy remains unclear. Methods: We conducted a one-arm, three-center, open label study involving patients who were treatment naïve, radiological and histological confirmed advanced or metastatic squamous-cell esophageal carcinoma. Enrolled patients were expected the survival time was three months or longer; and ECOG performance status score was 0 or 1. In induction phase, patients received four cycles of TP regimen chemotherapy (docetaxel, 75/mg 2 , iv on day 1 and cisplatin, 75mg/m 2 , iv on day 1) combined with PD-1 inhibitor (sintilimab, 200mg intravenous infusion on day 1) every 21 days. Patients who finished four cycles of chemo-immunotherapy with stable disease (SD) or partial response (PR) were initiated 50Gy/25f irradiation for residual tumors. 3-4weeks after radiotherapy, maintenance sintilimab therapy was administered every 21 days for another 31 cycles or until disease progression or intolerable toxicity. Results: Total of 39 patients were enrolled in this study, 30 of them could be evaluated in efficiency and toxicities. All of them were male and were squamous-cell carcinoma in histology. 12/30 (40.0%) patients were in stage III, and 18/30 (60.0%) were in stage IV. 29/30 (96.7%) patients completed four cycles chemo-immunotherapy, the complete response (CR) rate was 6.7% (2/30), the partial response (PR) rate was 53.3% (16/30) and disease control rate (DCR) was 86.7% (26/30). The median depth of response (DpR) was 34.5% for chemoimmunotherapy and was 64.0% after radiotherapy. The progression-free survival (PFS) was 16.4 months and the overall survival (OS) was not reached. The most common grade 3 or worse adverse event was neutropenia and occurred in 3 (10.0%) patients. Conclusions: Four cycles sintilimab plus cisplatin and docetaxel followed by radiotherapy for residual tumors and maintained sintilimab had high response rate, prolonged PFS and tolerable toxicities as first line treatment in patients with advanced or metastatic esophageal squamous-cell carcinoma. Longer OS is promising and more patients enrolled in this study is needed in future. Clinical trial information: NCT06138028 . Clinicopathological features and patient factors. Factors No. of patients (n=30) (%) Gender Male 30 (100.0) Female 0 (0) Age (year) &lt; 65 27 (43.3) ≥ 65 17 (56.7) PD-L1 (CPS) &lt; 5 9 (30.0) ≥ 5 21 (70.0) Clinical Stage III 12 (40.0) IV 18 (60.0) Metastatic Pattern Regional lymph node 12 (40.0) Cervical &amp; Supraclavicular 4 (13.3) Abdomen 5 (16.7) Lung 6 (20.0)

Comparative outcomes of neuroendocrine tumors in the historically underserved population of Bronx, NY: Montefiore Einstein Comprehensive Cancer Center.

671 Background: Neuroendocrine tumors (NETs) pose different clinical implications based upon age at diagnosis, with regards to early-onset (EO&lt;50yrs) versus late-onset (LO&gt;=50yrs) disease. While primary-tumor resection is crucial for localized NETs, its benefit in metastatic cases without metastasectomy remains uncertain. This study examines variables associated with survival in EO versus LO cases, including primary tumor resection. Methods: A retrospective cohort of 91 patients with gastrointestinal(GI)-NETs were identified as part of an IRB-approved project. Disease-stage (local vs. metastatic), tumor grade (G1-3), 5-year-survival, primary-tumor removal, and race/ethnicity were included in this analysis. Results: Among all patients, 31.9% identified as Hispanic, 33% as non-Hispanic Black, 22% as non-Hispanic White, and 13.1% as other. Among all patients, 79 were classified as G1/G2. Among LO patients, 87.5% (n=63) were G1/G2, among which 46% (n=29) were metastatic. Among EO patients, 84% (n=16) were G1/G2, among which 68.8% (n=11) were metastatic. In the LO group with G1/G2 tumors, 5-year survival rate was 48.3% for metastatic disease and 58.8% for localized disease. For EO with G1/G2 tumors, the 5-year survival rate was 72.7% for metastatic disease and 80% for localized disease. In the EO G1/G2 group, 5 of the 11 patients with metastatic disease had primary tumor removal without metastasectomy with 100% 5-year survival rate. In the LO G1/G2 group, 7 of 29 metastatic patients had primary tumor removal without metastasectomy, with 86% 5-year survival rate. Resection of primary tumor (without metastasectomy) in patients with metastatic G1/G2 NETs was associated with improved 5-year survival, independent of age at diagnosis ( p-value =0.008), as shown in the table. Conclusions: This study helps to emphasize the importance of primary tumor removal in improving survival outcomes for patients with metastatic low-grade GI-NETs, regardless of age. Further investigation is warranted to study the role of certain imperative variables such as site of metastases, number of metastases, and patient co-morbidities. Survival outcomes based on primary tumor removal in metastatic low-grade GI-NETs. No 5-year survival 5-year survival Primary tumor removal without metastasectomy 1 11 No surgery 12 8

A Dual-Pipeline Lactate Removal Strategy to Reverse Vascular Hyperpermeability for the Management of Lipopolysaccharide-Induced Sepsis.

Sepsis is an underappreciated yet severe threat to human life, marked by organ dysfunction and high mortality resulting from disordered inflammatory responses to blood infection. Unfortunately, no specific drugs are available for effective sepsis treatment. As a pivotal biomarker for sepsis, lactate levels are closely related to vascular permeability and sepsis-associated mortality. Herein, a dual-pipeline lactate removal strategy is reported from circulating blood to ameliorate vascular permeability and lipopolysaccharide (LPS)-induced sepsis. This is achieved by formulating lactate oxidase (LOX)-encapsulated hollow manganese dioxide (HMnO2) nanohybrids (LOX@HMnO2-P[5]A) bearing pillar[5]arene (P[5]A) macrocycle with excellent host-guest properties. The highly biocompatible nanohybrids enable direct lactate consumption through LOX catalytic degradation and block lactate production by P[5]A-mediated LPS trapping, allowing for dual-pipeline lactate removal to maximize the reversal of lactate-mediated vascular hyperpermeability. Besides, HMnO2 cores decompose hydrogen peroxide produced from lactate oxidation into oxygen, further contributing to lactate consumption and mitigating the hypoxic inflammatory environment. In vivo investigations demonstrate that intravenous administration of LOX@HMnO2-P[5]A nanohybrids with extended blood circulation can effectively ameliorate endothelial barrier dysfunction, inflammatory responses, and multiple organ injury, ultimately improving survival outcomes in LPS-induced sepsis. Taken together, this dual-pipeline lactate removal strategy offers a promising approach for efficient sepsis treatment.

Impact of coronary revascularisation guided by cardiovascular magnetic resonance to predict death

Abstract Background After the REVIVED trial, the utility of cardiovascular magnetic resonance (CMR) assessing the myocardial viability to guide coronary revascularisation remains controversial. Objective To assess the prognostic impact of coronary revascularisation guided by CMR-based myocardial viability to predict death in patients with ischaemic cardiomyopathy (ICM) and reduced left ventricular ejection fraction (LVEF) &amp;lt;50%. Methods From 2008 to 2022, we included all consecutive ICM patients referred for CMR-based myocardial viability assessment in a multicentric study. Eligible patients had ≥70% stenosis in ≥1 epicardial coronary vessel on angiography, a history of myocardial infarction, or prior coronary revascularisation, and LVEF&amp;lt;50%. We collected data on revascularisation within 90 days of the index CMR. The primary endpoint was all-cause mortality. To define myocardial viability, ischaemic-late gadolinium enhancement (LGE) transmurality was assessed for maximal scar depth, considering myocardium with LGE transmurality &amp;lt;50% as viable and ≥50% as non-viable. Results Among 6,082 patients (mean age 65±12 years; 73% male), 3,591 (59%) exhibited ischaemic-LGE. Revascularisation was performed in 2,773 (46%) patients within 90 days of CMR. Revascularisation was more frequent in patients with viable myocardium (88%) than in those with non-viable myocardium (67%, Figure 1). Over a median follow-up of 9 years (interquartile range 7-12 years), 652 patients (11%) died. Using a Cox regression analysis, revascularisation was associated with a reduced risk of mortality (HR: 0.73 95% CI: 0.58-0.91, p&amp;lt;0.001, Figure 2A). Patients with LGE and myocardial viability who underwent revascularization had a similar prognosis to those without LGE (p=0.48). Interestingly, patients who underwent revascularisation with myocardial viability had better outcomes than those who underwent revascularisation without myocardial viability (p&amp;lt;0.001, Figure 2B). Conclusion In a large cohort of ICM patients, coronary revascularisation was beneficial and was associated with improved survival outcomes. The impact of this revascularisation was stronger in patients with myocardial viability assessed by CMR than patients without myocardial viability. Revascularisation in the ICM population Survival curves