Multivariate Survival Analysis Research Articles

1240 Assessing Survival Outcomes of PCV-Based and Temozolamide-Based Adjuvant Therapy in Oligodendroglioma Patients

INTRODUCTION: When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. METHODS: 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS: The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in the following variables: age, tumor genetic profiling, the extent of resection, and KPS score. However, more patients in the TMZ-based group received concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer in those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for previously mentioned variables, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99). CONCLUSIONS: PCV treatment confers longer progression-free survival than TMZ treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as the preferred therapeutic option for oligodendroglioma patients.

PCV Adjuvant Therapy as a Preferred Treatment Option for Oligodendroglioma Patients: A Comparative Study With Temozolomide and Concurrent Radiotherapy

INTRODUCTION: When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life. METHODS: 87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis. RESULTS: The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in terms of age, tumor genetic profiling, extent of resection, or KPS score, however, the TMZ-based group had more patients receiving concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS [HR = 0.46, p = 0.04] and OS [HR = 0.26, p = 0.04] were significantly longer for those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for factors mentioned above, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99). CONCLUSIONS: PCV confers improved progression-free survival than TMZ-based treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as a preferred therapeutic option for oligodendroglioma patients.

Prognostic impact of spread through air spaces in patients with ≤2 cm stage IA lung adenocarcinoma.

In 2015, the World Health Organization (WHO) included spread through air space (STAS) as a new invasive mode of lung cancer. As a new mode of lung cancer dissemination, STAS has a significant and negative impact on patient prognosis. The surgical approach as well as lymph node dissection (LND) for STAS-positive patients is currently unclear. The aim of this study was to investigate the impact of different surgical approaches to STAS and LND on the prognosis of patients with ≤2 cm stage IA lung adenocarcinoma (LUAD). This study also investigated the possible relationship between STAS and the micropapillary histological subtype and its impact on patient prognosis. A total of 212 patients with LUAD were included in this study from January 2016 to December 2017, and the overall survival (OS) of the patients was compared. The chi-square test and t-test were applied to compare the clinicopathological data of the patients, and the Cox model was used for the multivariate survival analysis. Of the 212 patients, 93 (43.9%) were STAS positive. The univariate analysis showed that the surgical approach, LND type, micropapillary pattern (MP), solid pattern, and STAS were risk factors for OS. The multivariate analysis showed that the surgical approach, MP, and STAS were risk factors for OS. The STAS-positive patients who underwent lobectomy had a better prognosis than those who underwent sublobar resection; however, there was no significant difference between the two surgical procedures in the STAS-negative group. Additionally, the STAS-positive patients who underwent systematic lymph node dissection (SLND) had a better prognosis than those who underwent limited lymph node dissection (LLND); however, there was no significant difference between the two LNDs in the STAS-negative group. STAS plays an important role in patient prognosis and is an independent risk factor for OS of patients with ≤2 cm stage IA LUAD. When STAS is positive, the choice of lobectomy with SLND may result in a better long-term prognosis for patients.

No healthcare coverage, big problem: lack of insurance for older population associated with worse emergency general surgery outcomes

IntroductionOlder populations, being a unique subset of patients, have poor outcomes for emergency general surgery (EGS). In regions lacking specialized medical coverage for older patients, disparities in healthcare provision lead...

Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88years vs. 6.80years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23years vs. 10.69years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

Tumor-infiltrating lymphocytes and breast cancer mortality in racially and ethnically diverse participants of the Northern California Breast Cancer Family Registry.

Stromal tumor-infiltrating lymphocyte (sTIL) enrichment in pretreatment breast tumors has been associated with superior response to neoadjuvant treatment and survival. In a population-based cohort, we studied sTIL-survival associations by race and ethnicity. We assessed associations of continuous sTIL scores and sTIL-enriched breast cancers (defined as percent lymphocytic infiltration of tumor stroma or cell nests at cutoffs of 30%, 50%, and 70%) with clinical and epidemiologic characteristics and conducted multivariable survival analyses. Although we identified no difference in sTIL score by race and ethnicity, higher continuous sTIL score was associated with lower breast cancer-specific mortality only among non-Hispanic White and Asian American but not African American and Hispanic women. This finding suggests that complex factors influence treatment response and survival, given that sTIL enrichment was not associated with a survival advantage among women from minoritized groups, who more often experience health disparities. Further study of patient selection for sTIL-guided treatment strategies is warranted.

Association of gut microbiome with immune microenvironment in surgically treated colorectal cancer patients

This study explored the relationship between faecal microbiota distribution and local or systemic immune response in patients with colorectal cancer (CRC). The study population included 114 surgically treated CRC patients. Faeces were analysed using 16S rRNA gene sequencing. The immune score in tumour microenvironment was evaluated using CD3 and CD8 immunohistochemistry. Genetic alterations, microsatellite instability status and five systemic inflammatory markers were also analysed. Thirty of 114 (26.3%) CRC patients were categorised as the 'immune type' with a high density of T-cells. The immune type CRC cases showed lower angiolymphatic invasion and longer overall survival. Of the 123 selected bacterial species, Bacteroides fragilis and Collinsella aerofaciens were prevalent in immune CRC cases, whereas Odoribacter splanchnicus and Phascolarctobacterium succinatutens were prevalent in non-immune CRC patients. Bacteroides fragilis was associated with shorter disease free survival in univariable and multivariable survival analyses. Regarding systemic immunity, a high prevalence of C.aerofaciens was associated with a high modified Glasgow prognostic score. This study revealed a potential relationship among the gut microbiome, immune microenvironment, and disease progression in patients with CRC. Our findings suggest that abundant B.fragilis in patients with CRC is associated with a 'cold immune' tumour microenvironment.

Substance use treatment completion and criminal justice system contact in Chile: A retrospective, linked data cohort study.

Substance use treatment (SUT) has shown to be effective in reducing self-reported offending; however, the association between SUT completion and criminal justice system (CJS) contact has been underexplored, especially in Latin America. This study aimed to estimate the association between SUT completion status and (1) any subsequent CJS contact and (2) CJS contact leading to imprisonment, at 1, 3 and 5years post-discharge, in Chile. Retrospective cohort study using multivariable survival analysis based on linked administrative data from 2010 to 2019. This study took place in Chile, where SUT is available at no cost through Chile's publicly funded health-care, and is provided in outpatient and inpatient modalities in public and private centres. A total of 70 854 individuals received their first SUT from 2010 to 2019. They were mainly males (76.3%), and their main substance used at admission was cocaine paste (39.2%). SUT completion status included completion, late dropout (≥3months) and early dropout (< 3months). Outcomes were (1) any CJS contact and (2) CJS contact leading to imprisonment after baseline treatment. We estimated the association between treatment completion and CJS contact through flexible parametric Royston-Parmar models while adjusting for several covariates. Those who completed SUT (27.2%) were less likely to have any CJS contact at 5years post-SUT compared with those who dropped out late [with a gap of -9.5%, 95% confidence interval (CI) = -8.7, -10.3] and early (-11.2%, 95% CI = -10.1, -12.3). Also, those who completed SUT were less likely to have CJS contact leading to imprisonment at 5years post-SUT compared with those who dropped out late (-2.6%, 95% CI = -2.2, -3.1) and early (-4.0%, 95% CI = -3.3, -4.6). These differences were also observed at 1 and 3years post-SUT for each outcome. In Chile, completion of substance use treatment appears to be associated with lower probabilities of both any criminal justice system contact and contact leading to imprisonment.

Extracellular Volume Fraction by Computed Tomography Predicts Prognosis After Transcatheter Aortic Valve Replacement.

Extracellular volume fraction (ECV) on magnetic resonance imaging can predict prognosis after aortic valve replacement in patients with aortic stenosis (AS). However, the usefulness of ECV on computed tomography (CT) for patients who have undergone transcatheter aortic valve replacement (TAVR) is unclear, so we investigated whether ECV analysis on CT is associated with clinical outcomes in TAVR candidates.Methods and Results: We analyzed 127 patients with severe AS who underwent preoperative CT for TAVR. We evaluated the utility of ECV analysis on single-energy CT for predicting patient prognosis after TAVR. The primary outcome was a composite of all-cause death and hospitalization due to heart failure (HF) after TAVR. 15 patients (12%) had composite outcomes: 4 deaths and 11 hospitalizations due to HF. In multivariate survival analysis using the Cox proportional hazard model, atrial fibrillation (AF) (hazard ratio (HR), 7.86; 95% confidence interval (CI), 2.57-24.03; P<0.001), history of congestive HF (HR, 4.91; 95% CI, 1.49-16.2; P=0.009) and ECV ≥32.6% on CT (HR, 6.96; 95% CI, 1.92-25.12; P=0.003) were independent predictors of composite outcomes. On Kaplan-Meier analysis, the higher ECV group (≥32.6%) had a significantly greater number of composite outcomes than the lower ECV group (P<0.001). ECV on CT is an independent predictor of prognosis after TAVR.

Extranodal extension in laryngeal squamous cell carcinoma.

Although large retrospective database studies have associated extranodal extension (ENE) with worse survival in several head and neck cancers, the prognostic significance of ENE in laryngeal squamous cell carcinoma (LSCC) remains unclear. Our study examines ENE and overall survival (OS) in LSCC. The 2006-2017 National Cancer Database was queried for patients with LSCC undergoing surgical resection and neck dissection, with or without adjuvant therapy. Kaplan-Meier and multivariable Cox regression survival analyses were implemented to identify the independent impacts of pathologic nodal (pN) classification and ENE on OS. Of 4208 patients satisfying inclusion criteria, 2343 (55.7%) were pN0/ENE-negative, 1059 (25.2%) were pN1-2/ENE-negative, and 806 (19.2%) were pN1-2/ENE-positive. The 5-year OS of pN0/ENE-negative, pN1-2/ENE-negative, and pN1-2/ENE-positive patients was 62.8%, 56.7%, and 32.9%, respectively (p < .001). Among pN1-2/ENE-positive patients undergoing no adjuvant therapy, adjuvant radiotherapy alone, and adjuvant chemoradiotherapy, 5-year OS was 24.1%, 30.7%, and 36.7%, respectively (p < .001). After adjusting for patient demographics, clinicopathologic features, and adjuvant therapy, ENE-positivity was associated with worse OS than ENE-negativity (adjusted hazard ratio [aHR] 1.76, 95% confidence interval [CI] 1.53-2.02, p < .001). pN1/ENE-positivity (aHR 1.82, 95% CI 1.31-2.54) and pN2/ENE-positivity (aHR 1.89, 95% CI 1.49-2.40) were associated with worse OS than pN1/ENE-negativity (p < .001). Microscopic (aHR 1.83, 95% CI 1.54-2.18) and macroscopic ENE-positivity (aHR 1.75, 95% 1.35-2.26) were associated with worse OS than ENE-negativity (p < .001). ENE-positivity has prognostic significance in LSCC and is associated with worse OS than ENE-negativity. pN classification did not have prognostic significance independent of ENE. ENE should be carefully considered when determining the prognosis of LSCC and selecting adjuvant therapy. 4.

Time considerations and outcomes in pediatric tracheostomy decannulation

ObjectiveThe study objective is to identify factors that impact the time to decannulation in pediatric patients ages 0 through 18 years who are tracheostomy-dependent. MethodsThis retrospective chart review from January 1, 2005 through December 31, 2020 identified pediatric tracheostomy patients at a single pediatric institution. Data extracted included demographic, socioeconomic factors, and clinical characteristics. Multivariate regression and survival analysis were used to identify factors associated with successful decannulation and decreased time with tracheostomy. ResultsOf the 479 tracheostomy-dependent patients identified, 162 (33.8%) were decannulated. Time to decannulation ranged from 0.5 months to 189.2 months with median of 24 months (IQR 12.91–45.71). In the multivariate analysis, patients with bronchopulmonary dysplasia (p = 0.021) and those with Passy-Muir® Valve at discharge (p = 0.015) were significantly associated with decannulation. In contrast, neurologic comorbidities (p = 0.06), presence of gastrostomy tube (p < 0.001), or discharged on a home ventilator (p < 0.001) were associated with indefinite tracheostomy. When adjusting for age, sex, race, ethnicity, and insurance status, for every one month delay in establishment of outpatient otolaryngology care, time to decannulation was delayed by 0.5 months (p = 0.010). For each additional outpatient otolaryngology follow-up visit, time to decannulation increased by 3.36 months (p < 0.001). ConclusionsDecannulation in pediatric tracheostomy patients is multifactorial. While timely establishment of outpatient care did correlate with quicker decannulation, factors related to medical complexity may have a greater impact on time to decannulation. Our results can help guide institutional decannulation protocols, as well as provide guidance when counseling families regarding tracheostomy expectations.

The Vitamin D Receptor as a Prognostic Marker in Breast Cancer-A Cohort Study.

Previous research has indicated an association between the presence of the vitamin D receptor (VDR) in breast cancer tissue and a favorable prognosis. This study aimed to further evaluate the prognostic potential of VDR located in the nuclear membrane or nucleus (liganded). The VDR protein levels were analyzed using immunohistochemistry in tumor samples from 878 breast cancer patients from Lund, Sweden, included in the Breast Cancer and Blood Study (BCBlood) from October 2002 to June 2012. The follow-up for breast cancer events and overall survival was recorded until 30 June 2019. Univariable and multivariable survival analyses were conducted, both with complete case data and with missing data imputed using multiple imputation by chained equations (MICE). Tumor-specific positive nuclear membrane VDR(num) staining was associated with favorable tumor characteristics and a longer breast cancer free interval (BCFI; HR: 0.64; 95% CI: 0.44-0.95) and overall survival (OS; HR: 0.52; 95% CI: 0.34-0.78). Further analyses indicated that VDRnum status also was predictive of overall survival when investigated in relation to ER status. There were significant interactions between VDR and invasive tumor size (Pinteraction = 0.047), as well as mode of detection (Pinteraction = 0.049). VDRnum was associated with a longer BCFI in patients with larger tumors (HR: 0.36; 95% CI: 0.14-0.93) or clinically detected tumors (HR: 0.28; 95% CI: 0.09-0.83), while no association was found for smaller tumors and screening-detected tumors. Further studies are suggested to confirm our results and to evaluate whether VDR should and could be used as a prognostic and targetable marker in breast cancer diagnostics.

Abstract 7399: Development of a reproducible AI-based spatial biomarker of the tumor immune infiltrate on H&amp;E slides

Abstract Background: The immune infiltrate in the tumor microenvironment (TME) has been shown to be associated with prognosis in several studies. However, a comprehensive assessment of the TME composition is not performed in routine practice due to the lack of standardized methods and tools for quantification. The aim of our study is to develop a reproducible, artificial intelligence (AI)-based, spatial biomarker of the tumor related immune response to predict patients outcome on routine Hematoxylin &amp; Eosin (H&amp;E) slides. To the best of our knowledge, this is the first study that implements a robust H&amp;E pipeline to assess, across multiple cohorts, the prognostic power and the added-value of a spatial marker in comparison to non-spatial measures such as the overall lymphocytes density on the slide. Methods: We trained AI models on both publicly available (NuCLS and Lizard) and proprietary datasets to automatically detect cells and tissue types on H&amp;E stained Whole Slide Images of cancers from different origins. We used these models on TCGA COAD and TCGA BRCA and computed spatial measures related to the lymphocyte densities in the tumor core versus the invasive margin as well as the immune infiltration in the tumor stroma (in between tumor islets) versus in the tumor islets themselves. Univariate and multivariate survival analysis is performed through repeated cross-validation. A log-rank test on the stratified groups is performed for each evaluated marker, using the median value as cutoff. Preliminary results on TCGA-COAD and TCGA-BRCA show that spatial markers of the tumor-related immune response are individually associated with overall survival, reinforcing findings from prior studies emphasizing the importance of the spatial relationship between tumor and immune cells. Multivariate analysis with both linear and non-linear models is currently ongoing across selected cohorts. Citation Format: Valentina Di Proietto, Jean El-Khoury, Benjamin Adjadj, Lucie Gillet, Ulysse Marteau, Kathryn Schutte, Katharina Von Loga. Development of a reproducible AI-based spatial biomarker of the tumor immune infiltrate on H&amp;E slides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7399.

Abstract 2487: KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma

Abstract PD-L1 protein expression is the most important predictive biomarker for immune checkpoint inhibition (ICI) in advanced non-small cell lung cancer (NSCLC), but has limited sensitivity and specificity. We analyzed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information. The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas of the Thoraxklinik Heidelberg who were negative for actionable EGFR and ALK/RET/ROS1 alterations. Two external cohorts of patients treated with immunotherapy (SU2C-ICI: n=247, MSK-ICI: n=135) and two external cohorts of surgical early stage patients were additionally analyzed (TCGA-LUAD: n=417, MSK-LUAD: n=394). Therapy benefit was assessed stratified by KRAS and TP53 mutations. RNA-Seq data of TCGA were analyzed to reveal the molecular characteristics of KRASmut/TP53mut tumors. Analyzing overall survival, an interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses (HR=0.56, p=0.0044 and HR=0.53, p=0.0021). KRASmut/TP53muts tumors performed better than tumors not harboring the dual mutation configuration (HR=0.71, CI 0.55-0.92). This observation could be confirmed in the external cohorts of immunotherapy patients (SU2C-ICI: HR=0.54, CI 0.28-1.03 and MSK-ICI: HR=0.35, CI 0.14-0.88), whereas KRASmut/TP53mut was not associated with prolonged survival in the surgical cohorts. Tumor mutational burden, proliferation (measured by TOP2A mRNA expression), and PD-L1 mRNA were significantly higher in TP53mut compared with TP53wt tumors, regardless of KRAS status. Genome-wide mRNA expression analysis revealed 64 genes including the chemokine CX3CL1 (fractalkine) as specific transcriptomic characteristic of KRASmut/TP53mut tumors. In summary, KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumor features. Further validation studies are warranted. Mutation testing of the two genes can be easily implemented using small gene panels or even single gene analyses. Citation Format: Jan Budczies, Eva Romanovsky, Martina Kirchner, Olaf Neumann, Miriam Blasi, Johannes Schnorbach, Rajiv Shah, Farastuk Bozorgmehr, Rajkumar Savai, Thorsten Stiewe, Solange Peters, Peter Schirmacher, Thomas Michael, Daniel Kazdal, Petros Christopoulos, Albrecht Stenzinger. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2487.

Intensive pre-operative information course (IPIC) and pre-operative weight loss results in long-term sustained weight loss following bariatric surgery: 11years results from a tertiary referral centre.

Outcomes of long-term (5-10-year) weight loss have not been investigated thoroughly and the role of pre-operative weight loss on long-term weight loss, among other factors, are unknown. Our regional bariatric service introduced a 12week intensive pre-operative information course (IPIC) to optimise pre-operative weight loss and provide education prior to bariatric surgery. The present study determines the effect of pre-operative weight loss and an intense pre-operative information course (IPIC), on long-term weight outcomes and sustained weight loss post-bariatric surgery. Data were collected prospectively from a bariatric center (2008-2022). Excess weight loss (EWL) ≥ 50% and ≥ 70% were considered outcome measures. Survival analysis and logistic regression identified variables associated with overall and sustained EWL ≥ 50% and ≥ 70%. Three hundred thirty-nine patients (median age, 49years; median follow-up, 7years [0.5-11years]; median EWL%, 49.6%.) were evaluated, including 158 gastric sleeve and 161 gastric bypass. During follow-up 273 patients (80.5%) and 196 patients (53.1%) achieved EWL ≥ 50% and ≥ 70%, respectively. In multivariate survival analyses, pre-operative weight loss through IPIC, both < 10.5% and > 10.5% EWL, were positively associated with EWL ≥ 50% (HR 2.23, p < 0.001) and EWL ≥ 70% (HR 3.24, p < 0.001), respectively. After a median of 6.5years after achieving EWL50% or EWL70%, 56.8% (154/271) had sustained EWL50% and 50.6% (85/168) sustained EWL70%. Higher pre-operative weight loss through IPIC increased the likelihood of sustained EWL ≥ 50% (OR, 2.36; p = 0.013) and EWL ≥ 70% (OR, 2.03; p = 0.011) at the end of follow-up. IPIC and higher pre-operative weight loss improve weight loss post-bariatric surgery and reduce the likelihood of weight regain during long-term follow-up.

Abstract 6826: Comparative analysis of a predictive transcriptomic model and functional gene expression signatures (FGES) for tertiary lymphoid structure (TLS) detection in lung adenocarcinoma (LUAD)

Abstract Background: TLS are recognized as significant biomarkers for patient prognosis and therapy selection. In current clinical practice, TLS are often detected by manual assessment of H&amp;E slides, which has been associated with reproducibility issues. Here, we developed a transcriptomic model using TLS density to stratify LUAD patients into TLS-high and -low groups and compared it with 5 published TLS FGES to assess the predictive value for patient outcomes. Design: A regression model to predict TLS density (units(u)/mm²) was created using RNA expression data and histological mapping of 415 TCGA-LUAD samples. Features were chosen based on differential gene expression analysis of sample groups with low (&amp;lt;Q1, 0.26 u/mm²) and high (&amp;gt;Q3, 2.04 u/mm²) TLS density. The model was trained on 269 samples and independently validated on 146 TCGA and 9 internal samples. The RNA model and five previously reported TLS FGES were compared by Wilcoxon paired test to Spearman’s ρ and F1-scores from bootstrapped validation set. The resulting predictions stratified immunotherapy-treated samples from SU2C-MARK (n=58) and GSE182328 (n=28) into TLS-high and TLS-low groups by Q2 threshold for TLS density (0.78 u/mm²) for further univariate (Kaplan-Meier) and multivariate (Cox model, adjusted for age and sex) analyses for overall survival (OS) with log-rank tests. P-values were adjusted with Bonferroni correction, and 95% confidence intervals (CIs) were provided. Results: Statistically significant upregulated genes in samples with high TLS density included FDCSP, MS4A1, and CXCL13 (logFC ≥ 0.95, FDR&amp;lt;0.01). The transcriptomic model showed confident superiority in correlation with TLS density compared to the best FGES in TCGA samples (ρ=0.53±0.03 vs 0.41±0.03, p&amp;lt;0.001). The TLS model also outperformed the highest performing FGES when stratifying TCGA samples into TLS-high and TLS-low groups (F1=0.73±0.02 vs 0.69±0.02, p&amp;lt;0.005). In the internal cohort, the model demonstrated robust performance (F1=0.76±0.05, ρ=0.81±0.04) and outperformed all FGES except one (FGES F1=0.78±0.05, ρ=0.86±0.05). The TLS-high group defined by the TLS RNA model had a significantly better prognosis on immunotherapy cohorts (p=0.01; 1 year OS 49% for TLS-low vs 70% for TLS-high), whereas no discernible difference in OS was identified for the 5 TLS FGES. The TLS model had a log hazard ratio (logHR) of -3.11 (CI:-5.31,-0.91; p&amp;lt;0.05, Harrell's C-index=0.64), indicative of a stronger association with OS than of the TLS FGES (logHR=-2.11; CI:-4.1,-0.08; p=ns; C-index=0.59). Conclusions: Comparative analysis of the proposed transcriptomic model for TLS detection in LUAD samples demonstrated improved performance metrics and prognostic value compared to previously reported TLS FGES, affirming its potential for guiding therapeutic decision-making. Citation Format: Nadezhda Lukashevich, Daniil Dymov, Aleksandr Sarachakov, Sofya Kust, Anna Love, Ivan Valiev, Dmitry Ivchenkov, Alexander Bagaev, Viktor Svekolkin, Nikita Kotlov, Vladimir Kushnarev. Comparative analysis of a predictive transcriptomic model and functional gene expression signatures (FGES) for tertiary lymphoid structure (TLS) detection in lung adenocarcinoma (LUAD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6826.

Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer

It is unclear whether breast cancer (BC) with low ERBB2 expression (ERBB2-low) is a distinct clinical, pathological, and epidemiological entity from BC classified as no ERBB2 expression (ERBB2-negative). To evaluate the clinical, pathological, and epidemiologic features of BC with ERBB2-low expression compared with ERBB2-negative BC in a large population study. This cohort study was conducted as part of the Pathways Study, a prospective, racially and ethnically diverse cohort study of women with BC enrolled between 2006 and 2013 in Kaiser Permanente Northern California (KPNC). The hematoxylin and eosin slides underwent centralized pathology review, including the percentage of tumor infiltrating lymphocytes (TILs). Breast biomarker results were extracted from pathology reports, and women were included if they had a documented ERBB2 value that was not classified ERBB2-positive. Data were analyzed from February 2023 through January 2024. Clinical and tumor characteristics associated with BC and ERBB2-low or ERBB2-negative status. ERBB2-low was defined as immunohistochemistry score of 1+ or 2+ (negative by in situ hybridization); ERBB2-negative was defined as immunohistochemistry score of 0+. Other data were collected by self-report or extraction from electronic health records, including BC risk factors, tumor characteristics, treatment modality, and survival outcomes, with recurrence-free survival (RFS) as the primary outcome and overall survival (OS) and BC-specific mortality (BCSM) as secondary outcomes. The clinical, pathological, and epidemiological variables were compared between ERBB2-low and ERBB2-negative BC. Of 2200 eligible patients (all female; with mean [SD] age, 60.4 [11.9] years), 1295 (57.2%) had tumors that were ERBB2-low. Hormone receptors were positive in 1956 patients (88.9%). The sample included 291 Asian patients (13.2%), 166 Black patients (7.5%), 253 Hispanic patients (11.5%), 1439 White patients (65.4%), and 51 patients (2.3%) who identified as other race or ethnicity (eg, American Indian or Alaska Native and Pacific Islander). Within the hormone receptor-negative group, patients whose tumors had ERBB2-low staining, compared with those with ERBB2-negative tumors, had better OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91; P = .02), RFS (HR, 0.53; 95% CI, 0.30-0.95; P = .03), and BCSM (HR, 0.43; 95% CI, 0.22-0.84; P = .01). In multivariable survival analysis stratified by hormone receptor status and adjusted for key covariates, patients with ERBB2-low and hormone receptor-negative tumors had lower overall mortality (HR, 0.48; 95% CI, 0.27-0.83; P = .009), RFS (HR, 0.45; 95% CI, 0.24-0.86; P = .02), and BCSM (subdistribution HR, 0.21; 95% CI, 0.10-0.46; P < .001) compared with patients with ERBB2-negative and hormone receptor-negative tumors. Within the hormone receptor-negative subtype, patients with ERBB2-low and high TILs tumors had better survival across all 3 outcomes compared with patients with ERBB2-negative and low TILs tumors. Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03). These findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

O80: Intensive pre-operative information course (IPIC) and pre-operative weight loss results in long-term sustained weight loss following bariatric surgery: 11year results from a Tertiary Referral Centre

Abstract Introduction Outcomes of long-term (5-10 year) weight loss have not been investigated thoroughly and the role of pre-operative weight loss on long-term weight loss, among other factors, are unknown. Our regional bariatric service introduced a 12-week intensive pre-operative information course (IPIC) to optimise pre-operative weight loss and provide education prior to bariatric surgery. The present study determines the effect of pre-operative weight loss and an intense pre-operative information course (IPIC), on long-term weight outcomes and sustained weight loss post-bariatric surgery. Methods Data were collected prospectively from a bariatric center (2008-2022). Excess weight loss (EWL) ≥50% and ≥70% were considered outcome measures. Survival analysis and logistic regression identified variables associated with overall and sustained EWL≥50% and ≥70%. Results 339 patients (median age, 49 years; median follow-up, 7 years [0.5-11years]; median EWL%, 49.6%.) were evaluated, including 158 gastric sleeve and 161 gastric bypass. During follow-up 273 patients (80.5%) and 196 patients (53.1%) achieved EWL≥50% and ≥70%, respectively. In multivariate survival analyses, pre-operative weight loss through IPIC, both &amp;lt;10.5% and &amp;gt;10.5%EWL, were positively associated with EWL≥50% (HR2.23,p&amp;lt;0.001) and EWL≥70% (HR 3.24,p&amp;lt;0.001), respectively. After a median of 6.5years after achieving EWL50% or EWL70%, 56.8% (154/271) had sustained EWL50% and 50.6% (85/168) sustained EWL70%. Higher pre-operative weight loss through IPIC increased the likelihood of sustained EWL≥50% (OR,2.36;p=0.013) and EWL≥70% (OR,2.03;p=0.011) at the end of follow up. Conclusions IPIC and higher pre-operative weight loss improve weight loss post-bariatric surgery and reduce the likelihood of weight regain during long-term follow-up.

Impact of Alcian blue and periodic acid Schiff expression on the prognosis of gastric signet ring cell carcinoma.

The Alcian blue (AB) and periodic acid Schiff (PAS) stains are representative mucus markers in gastric signet ring cell carcinoma (SRCC). They are low-cost special staining methods used to detect acidic mucus and neutral mucus, respectively. However, the clinical importance of the special combined AB and PAS stain is unclear. To investigate AB expression, PAS expression and the AB-to-PAS (A/P) ratio in gastric SRCC patients and to assess patient prognosis. Paraffin-embedded sections from 83 patients with gastric SRCC were stained with AB and PAS, and signet ring cell positivity was assessed quantitatively. Immunohistochemical staining for Ki67, protein 53 (P53) and human epidermal growth factor receptor 2 (HER2) was performed simultaneously. The cancer-specific survival (CSS) rate was estimated via Kaplan-Meier analysis. Cox proportional hazards models were used for univariate and multivariate survival analyses. Kaplan-Meier survival analysis revealed that the 3-year CSS rate was significantly greater in the high-PAS-expression subgroup than in the low-PAS-expression subgroup (P < 0.001). The 3-year CSS rate in the A/P ≤ 0.5 group was significantly greater than that in the A/P > 0.5 group (P = 0.042). Univariate Cox regression analysis revealed that the factors affecting prognosis included tumor diameter, lymph node metastasis, vessel carcinoma embolus, tumor stage, the A/P ratio and the expression of Ki67, P53 and the PAS. Cox multivariate regression analysis confirmed that low PAS expression [hazard ratio (HR) = 3.809, 95% confidence interval (CI): 1.563-9.283, P = 0.003] and large tumor diameter (HR = 2.761, 95%CI: 1.086-7.020, P = 0.033) were independent risk factors for poor prognosis. A/P > 0.5 is potentially a risk factor for prognosis, and low PAS expression is an independent risk factor in the prognosis of gastric SRCC. PAS expression and the A/P ratio could help in predicting the clinical prognosis of patients with SRCC.