Short-term Survivors Research Articles

P3.13D.05 Genomics and Immune Infiltration Biomarkers for Short-term and Long-Term ES-SCLC Survivors with First-Line Chemoimmunotherapy

P3.13D.05 Genomics and Immune Infiltration Biomarkers for Short-term and Long-Term ES-SCLC Survivors with First-Line Chemoimmunotherapy

Characteristics of long-term survivors with malignant pleural mesothelioma

Pleural mesothelioma (PM) is a cancer with usually a dismal prognosis. However, long-term survivors do exist. Herein, we analyzed long-term survivors (>5 years after surgery) from high-volume centres around the world. This is a multicenter retrospective descriptive analysis of long-term survivors (overall survival ≥ 5 years from surgery) treated within a multimodality therapy approach including macroscopic complete resection. Overall survival was calculated with Kaplan Meier analysis and cases were matched by center and surgery year and compared with a control group of short-term survivors (<2 years) in a conditional logistic regression analysis. There were 276 long-term survivors, most were male (n=166, 63%) with a median age of 59 (range 21-83) years at time of diagnosis. The histology for 246 was epithelioid and non-epithelioid for 30 patients. The disease was on the right side in 58% of the patients. As of this analysis, 148 patients were dead, 104 were alive and 10 were lost to follow-up. Pathological tumor stages were: pT1 (n=50), pT2 (n=63), pT3 (n=90) or pT4 (n=16), pN0 (n=150), pN1 (n=20) and pN2 (n=39). The matched control dataset included 333 patients, 95 cases and 238 controls. Comparing short- with long-term survivors, there was moderate evidence that a low white blood cell (WBC) count before surgery was more often observed in long-term survivors. The data show that long-term survival in PM is possible in a subgroup of surgically treated patients; histological subtype and WBC count seem to be prognosticators for longer survival.

SelK promotes glioblastoma cell proliferation by inhibiting β-TrCP1 mediated ubiquitin-dependent degradation of CDK4

BackgroundGlioblastoma (GB) is recognized as one of the most aggressive brain tumors, with a median survival of 14.6 months. However, there are still some patients whose survival time was greater than 3 years, and the biological reasons behind this clinical phenomenon arouse our research interests. By conducting proteomic analysis on tumor tissues obtained from GB patients who survived over 3 years compared to those who survived less than 1 year, we identified a significant upregulation of SelK in patients with shorter survival times. Therefore, we hypothesized that SelK may be an important indicator related to the occurrence and progression of GBM.MethodsProteomics and immunohistochemistry from GB patients were analyzed to investigate the correlation between SelK and clinical prognosis. Cellular phenotypes were evaluated by cell cycle analysis, cell viability assays, and xenograft models. Immunoblots and co-immunoprecipitation were conducted to verify SelK-mediated ubiquitin-dependent degradation of CDK4.ResultsSelK was found to be significantly upregulated in GB samples from short-term survivors (≤ 1 year) compared to those from long-term survivors (≥ 3 years), and its expression levels were negatively correlated with clinical prognosis. Knocking down of SelK expression reduced GB cell viability, induced G0/G1 phase arrest, and impaired the growth of transplanted glioma cells in nude mice. Down-regulation of SelK-induced ER stress leads to a reduction in the expression of SKP2 and an up-regulation of β-TrCP1 expression. Up-regulation of β-TrCP1, thereby accelerating the ubiquitin-dependent degradation of CDK4 and ultimately inhibiting the malignant proliferation of the GB cells.ConclusionThis study discovered a significant increase in SelK expression in GB patients with poor prognosis, revealing a negative correlation between SelK expression and patient outcomes. Further mechanistic investigations revealed that SelK enhances the proliferation of GB cells by targeting the endoplasmic reticulum stress/SKP2/β-TrCP1/CDK4 axis.

Comprehensive genomic and spatial immune infiltration analysis of survival outliers in extensive-stage small cell lung cancer receiving first-line chemoimmunotherapy

BackgroundA minority of patients with extensive-stage small cell lung cancer (ES-SCLC) exhibit prolonged survival following first-line chemoimmunotherapy, which warrants the use of reliable biomarkers. Here, we investigated the disparities in genomics and immune cell spatial distribution between long- and short-term survival of patients with ES-SCLC. MethodsWe retrospectively recruited 11 long-term (>2 years) and 13 short-term (<9 months) ES-SCLC survivors receiving first-line chemoimmunotherapy. The samples were processed using targeted next-generation sequencing (tNGS), programmed death ligand-1 staining, multiplex immunohistochemical staining for immune cells (mIHC), tumor mutation burden (TMB), and chromosomal instability score measurements. The expression of putative genes in SCLC at the bulk and single-cell RNA-sequencing levels, as well as the role of putative genes in pan-cancer immunotherapy cohorts, were analyzed. ResultsAt the genomic level, a greater proportion of the smoking signature and higher TMB (>3.1) were associated with favorable survival. At the single-gene and pathway levels, tNGS revealed that MCL1 and STMN1 amplification and alterations in the apoptosis pathway were more common in short-term survivors, whereas alterations in the DLL3, KMT2B, HGF, EPHA3, ADGRB3, lysine deprivation, and HGF-cMET pathways were observed more frequently in long-term survivors. mIHC analysis of immune cells with different spatial distributions revealed that long-term survivors presented increased numbers of M1-like macrophages in all locations and decreased numbers of CD8+ T cells in the tumor stroma. Bulk transcriptomic analysis demonstrated that high levels of STMN1 and DLL3 represented an immune-suppressive tumor immune microenvironment (TIME), whereas HGF indicated an immune-responsive TIME. The expression levels of our putative genes were comparative in both TP53/RB1 mutant-type and TP53/RB1 wild-type. At the single-cell level, STMN1, MCL1, and DLL3 were highly expressed among all molecular subtypes (SCLC-A, SCLC-N, and SCLC-P), with STMN1 being enriched in cell division and G2M checkpoint pathways. ConclusionsFor ES-SCLC patients receiving first-line chemoimmunotherapy, alterations in DLL3, KMT2B, HGF, EPHA3, and ADGRB3 and a greater proportion of M1-like macrophages infiltration in all locations were predictors of favorable survival, while MCL1 and STMN1 amplification, as well as a greater proportion of CD8+ T cells infiltrating the tumor stroma, predicted worse survival.

AB047. Searching for factors relating to long-term survivors of glioblastoma.

There remains controversy in the observed survival of gliomas worldwide, especially for glioblastoma (GBM). The 5-year survival rate ranged wildly, but comparable higher in several Asian countries, such as China showed almost 18% from CONCORD-3 data. Are there any special factors relating to long-term survivors (LTSs)? We reviewed our single center real-world data for the last 20 years, of 536 GBM [World Health Organization (WHO) grade 4] patients revealed 5-year overall survival (OS) of 19.1%. We analyzed our GBM patients and searched for possible factors relating to LTSs. We collected tumor samples of 13 LTSs (OS >60 months) and 19 short-term survivors (OS <24 months), and performed whole exome sequencing and transcriptome sequencing. From treatment setting, besides surgical resection, post-operational adjutant treatment (radiotherapy plus chemotherapy) are the most important factor contributing to long-term survival. Whole exome sequencing analysis revealed a higher proportion of mutation signature 19 was associated with LTSs. Analysis of copy number variation (CNV) showed that the LTSs had higher copy number variants at the chromosomal level (P=0.049). At the arm level, the proportion of 19p amplification in the LTS was significantly higher than in the short-term survivors (P=0.001). And in The Cancer Genome Atlas (TCGA) GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04). Based on RNA sequencing (RNAseq) and differential expression analysis, the differentially expressed genes were enriched in hypoxia-related processes, apoptosis, and immune-related processes. From our single-institution data, the factors relating to GBM LTSs should be both clinical management and genomic alternation which could be potential novel targets be applied to future clinical practice.

The tumor immune microenvironment in resected treatment-naive pancreatic cancer patients with long-term survival

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Presently, only a fraction of patients undergo successful surgical resection, the most effective treatment. Enhancing treatment strategies necessitates a deep comprehension of the factors underlying extended survival after surgical resection in patients. MethodsThis study aims to identify the important factors of PDAC patients’ long-term survival with metatranscriptomics and multiplex immunofluorescence (IF) staining analyses. Specifically, differences in tumor immune microenvironment (TIME) were investigated between treatment-naïve PDAC short-term survivors (STS, overall survival <6 months) and long-term survivors (LTS, overall survival >5 years). ResultsAs a result, we detected 589 over-expressed genes, including HOXB9, CDA, and HOXB8, and 507 under-expressed genes, including AMY2B, SCARA5, and SLC2A2 in LTS. Most of the Reactome overbiological pathways enriched in our data were over-expressed in LTS, such as RHO GTPase Effectors and Cell Cycle Checkpoints. Eleven microbiomes significantly differed between LTS and STS, including Sphingopyxis and Capnocytophaga. Importantly, we demonstrate that the TIME profile with an increased abundance of memory B cells and the reduction of M0 and pro-tumoral M2 macrophages are associated with a good prognosis in PDAC. ConclusionsIn this study, we delved into the TIME with metatranscriptomics and IF staining analyses to understand the prerequisite of prolonged survival in PDAC patients. In LTS, several biological pathways were overexpressed, and specific microbiomes were identified. Furthermore, apparent differences in driven immune factors were found that provide valuable insights into developing new treatment strategies.

Palliative Radiotherapy in Non-small Cell Lung Cancer: Patterns of Use and Predictors of 30-Day Mortality in End-of-Life Care.

Introduction Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) being the most common type. More than half of patients require radiotherapy throughout their treatment. Palliative radiotherapy (PRT) is an important tool for symptom control and quality of life improvement in advanced NSCLC patients. However, the benefits of PRT must be balanced against possible disadvantages, especially in end-of-life (EOL) care. This study aims to describe the profile of PRT-treated deceased NSCLC patients, quantify the proportion of PRT recipients in the last 30 days of life and identify short-term survival prognostic factors in this group. Materials and methods This retrospective analysis was performed at two radiotherapy facilities within the Kent Oncology Centre, UK, for two years, running from January 1, 2022, to January 1, 2024. Data were collected from 857 deceased NSCLC patients who received PRT. Demographics, cancer diagnosis, histology, tumour, node, metastasis (TNM) staging, radiotherapy details, recent treatments, performance status (PS) and comorbidities were analysed. Patients have been stratified as long-term survivors (more than 30 days after PRT initiation, LTS group) along with short-term survivors (STS) (died within 30 days, STS group). Descriptive statistics, chi-squared tests, t-tests and multivariable logistic regression have been used in the data analysis. Results Out of 857 patients, 148 (17.3%) died within 30 days of PRT initiation. PS was considerably worse (p = 0.027), Adult Comorbidity Evaluation 27 (ACE-27) scores were higher (p = 0.018), and metastatic disease was more prevalent (60.1% vs. 47.5%, p = 0.02) in STS group patients. Fewer patients in the STS group completed their treatment compared to the LTS group (63.5% vs. 82.8%, p < 0.001). The STS group also received lower mean radiation dose (17.7 Gy vs. 19.6 Gy, p = 0.022) and fewer fractions (4.4 vs. 5.2, p = 0.019). The most common RT regimen in both cohorts was 20 Gy in five fractions, used in 55.4% of STS and 49.8% of LTS patients, with no significant difference in single fraction RT use between groups (33.1% in STS vs. 36.8% in LTS, p = 0.401). Multivariate logistic regression identified significant predictors of 30-day mortality: poorer PS (adjusted OR: 1.981, 95% CI: 1.33-3.12, p = 0.001), metastatic disease (adjusted OR: 2.02, 95% CI: 1.246-3.571, p = 0.002), incomplete PRT (adjusted OR: 0.337, 95% CI: 0.21-0.514, p < 0.001) and no recent chemotherapy (adjusted OR: 0.542, 95% CI: 0.342-0.941, p = 0.044). Conclusion This study demonstrated that compared with previous reports, a higher proportion of NSCLC patients who received PRT died within 30 days of treatment initiation, and low treatment adherence rates highlight challenges in EOL settings. Identification of poor PS and metastatic disease as predictors of short-term mortality would help inform PRT decision-making. The underutilisation of single-fraction radiotherapy and the link between recent chemotherapy and lower 30-day mortality warrant further study. These results highlight the need for better prognostic tools and more selective use of PRT, including increased consideration of single-fraction radiotherapy, in NSCLC patients approaching end of life and emphasise the importance of balancing benefit against treatment burden in this vulnerable population.

Clinical features and prediction of long-term survival after surgery for perihilar cholangiocarcinoma.

The treatment of perihilar Cholangiocarcinoma (pCCA) poses specific challenges not only due to its high perioperative complication rates but also due its dismal long-term prognosis with only a few long-term survivors (LTS) among the patients. Therefore, in this analysis characteristics and predictors of LTS in pCCA patients are investigated. In this single center analysis, patients undergoing curative-intent liver resection for pCCA between 2010 and 2022 were categorized into long-term and short-term survivors (STS) excluding perioperative mortality. Binary logistic regression was used to determine key differences between the groups and to develop a prognostic composite variable. This composite variable was subsequently tested in the whole cohort of surgically treated pCCA patients using Cox Regression analysis for cancer-specific survival (CSS). Within a cohort of 209 individuals, 27 patients were identified as LTS (median CSS = 125 months) and 55 patients as STS (median CSS = 16 months). Multivariable analysis identified preoperative portal vein infiltration (OR = 5.85, p = 0.018) and intraoperative packed red blood cell (PRBC) transfusions (OR = 10.29, p = 0.002) as key differences between the groups. A prognostic composite variable based on these two features was created and transferred into a Cox regression model of the whole cohort. Here, the composite variable (HR = 0.35, p<0.001), lymph node metastases (HR = 2.15, p = 0.001) and postoperative complications (HR = 3.06, p<0.001) were identified as independent predictors of CSS. Long-term survival after surgery for pCCA is possible and is strongly negatively associated with preoperative portal vein infiltration and intraoperative PRBC transfusion. As these variables are part of preoperative staging or can be modulated by intraoperative technique, the proposed prognostic composite variable can easily be transferred into clinical management to predict the oncological outcome of patients undergoing surgery for pCCA.

Analyzing Vital Capacity in Short-Term COVID-19 Survivors between 20 to 40 years and over 40 years Population: Understanding Respiratory Health in New Normal situation

COVID-19 global coronavirus is a pandemic caused by coronavirus 2 (SARS-CoV-2). Coronavirus effect on multiple organ dysfunction but pulmonary function is most affected area of a patients. Pulmonary function or vital capacity have significance in the treatment of COVID affected patients. Vital capacity is defined as the maximal volume of air that can be exhaled from the lungs following maximal inspiration. Present study aim is to compare vital capacity between COVID-19 survivors and non-COVID populations. A total of eight hundred fifty-nine (859) subjects of different ages have been selected for the present study. The present study data were collected by the Multi-Functional Spirometer HI-801 for vital capacity, and the digital weighing scale was used for the measurement of body weight. The collected data was analyzed using descriptive statistics, the mean and the standard deviation (SD). An inferential statistically paired and independent t-test was applied to check the level of significance. The significance level was set at p&lt;0.05. The results of this study, male COVID survivors between the ages of 20 to 40 have better vital capacity recovery than male COVID survivors over the age of 40, while female COVID survivors between the ages of 20 to 40 outperform female COVID survivors over the age of 40. Female COVID-19 survivors generally regain essential capabilities far more quickly than male survivors. We conclude that female COVID survivors recover vital capacity much faster than male COVID survivors.

DIPG-91. CLINICAL, RADIOGRAPHIC, HISTOPATHOLOGIC, AND MOLECULAR CHARACTERISTICS OF LONG-TERM SURVIVORS OF DIFFUSE INTRINSIC PONTINE GLIOMA-AN UPDATE FROM THE INTERNATIONAL AND EUROPEAN SOCIETY FOR PEDIATRIC ONCOLOGY DIPG REGISTRIES (IDIPGR/SIOPE-DIPGR)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a childhood tumor with median survival of &amp;lt; 1 year. Survival-associated factors for this rare disease are poorly understood. METHODS Clinical, radiological, and histo-molecular data were abstracted from databases of the IDIPGR and SIOPE-DIPGR and analyzed using descriptive statistics. Survival was estimated by the Kaplan Meier method. Short term survivors (STS) were defined as overall survival (OS) &amp;lt; 2 years, and long term survivors (LTS) had OS &amp;gt;2 years. We present data from the IDIPGR with additional analyses forthcoming. RESULTS Analysis included 1123 patients with DIPG, with 476 undergoing central radiographic review. Median OS for the entire cohort was 11 months (IQR 7-15 months), with 2 yr OS 6.9% (5.6% to 8.6%). Median age at diagnosis was 6.6 years (5-9.7 years) for 1045 STS (93.1%) and 6.8 years (3.7-13 years) for 78 LTS (6.9%). Factors significantly associated with LTS included longer symptom duration (STS 73.7% vs LTS 42%; p&amp;lt;0.001), age &amp;lt; 3 and &amp;gt; 10 years (STS 4.5 and 22.8% vs LTS 17.9 and 35.9%; p&amp;lt;0.0001), and receipt of chemotherapy at any time during therapy (STS 54.7% vs LTS 67.9%; p=0.025). A similar percentage of STS and LTS received EGFR, MTOR, PI3K, HDAC, local delivery and immunotherapy, although more LTS used VEGF inhibition (20.5 % vs 8.6%; p = 0.002). Of 104 patients with molecular data, 69 harbored the H3.3 histone mutations (7 LTS, 62 STS), and 15 had H3.1(3 LTS, 12 STS). CONCLUSION Early analysis of factors associated with survival in patients with DIPG reveal similar findings as the prior IDIPGR/SIOPE-DIPGR study in 2018. These findings will be updated for the final presentation to include ~400 more cases and additional radiological and molecular data.

DIPG-54. PREDICTING EARLY DEATH IN DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG) is an invariably fatal diagnosis with a median survival of 9-11 months. While early death is uncommon, such cases do exist. Identification of children at risk of short-term survival can support clinicians to provide informed counselling to families regarding important treatment decisions. METHODS We identified patients with a radiological diagnosis of DMG at the Royal Children’s Hospital (Melbourne) and the Women’s and Children’s Hospital (Adelaide) between 2001-2023. Clinical, imaging, and histopathological data were abstracted and compared between short-term survivors (STSs) and longer survivors (LSs). RESULTS Among 89 patients included, 21 (24%) had an overall survival (OS) of &amp;lt; 6 months of which 7 (8%) had an OS &amp;lt; 3 months. 5 of these cases had dramatic early death with &amp;lt; 1 month since diagnosis. While neither the pattern nor presence of contrast enhancement were predictive of poor survival, STSs were found to have a larger volume of contrast enhancement on T1-weighted imaging compared to LSs (1.3 cm3 vs 0.2 cm3, p &amp;lt; 0.01). Evaluation of the presence and extent of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) demonstrated higher grades of ITSS (&amp;gt; 5 foci) were strongly associated with poor survival (p = 0.01, median OS = 5.5 months). Furthermore, 50% (6/12) of STSs had ≥ 11 dot-like or fine linear ITSSs in a maximum tumour cross section. From a treatment standpoint, as expected, patients who did not receive upfront radiotherapy experienced significantly worse OS (3.4 months vs 10.4 months, p &amp;lt; 0.01). Notably, a number of STSs did not receive palliative therapy in the context of their rapid and unforeseen disease progression. CONCLUSIONS The preliminary findings from this multi-centre study provide the foundation for future exploratory analysis alongside international collaborators at the DMG/DIPG registry to improve prognostication for patients with high-risk features of early death.

IMG-30. DIFFUSE MIDLINE GLIOMA MAP TO A COMMON FUNCTIONAL NETWORK ASSOCIATED WITH TUMOUR PROGRESSION AND OVERALL SURVIVAL

Abstract BACKGROUND Gliomas form bidirectional, functional synapses with otherwise healthy neurons: increasing neuronal excitability and driving tumour growth. The prognostic significance of this phenomenon does, however, remain unknown. METHODS This study used tumour location and tumour network mapping to identify brain networks associated with tumour progression and overall survival (OS) in 90 children with diffuse midline glioma, H3K27-altered (DMG). Tumours were segmented on volumetric magnetic resonance imaging and mapped to a standard template. Brain networks functionally connected to each tumour were computed using normative paediatric resting-state functional magnetic resonance imaging (n=525). RESULTS Median OS in the discovery cohort was 9.5 months (interquartile range 7.0-14.5 months). Comparison of tumour location in short-term (&amp;lt;18 months; n=75) and long-term (≥18 months; n=15) survivors of DMG identified an area of maximal anatomic overlap associated with short-term survival in the mid-pontine tegmentum and corticospinal tracts (89%; P&amp;lt;0.05). Tumour location was, however, not associated with OS (P=0.347). We, therefore, seeded tumour-to-brain resting-state functional connectivity maps from this a priori tegmental region-of-interest, identifying a specific brain network associated with short-term survival defined by functional connectivity to the medial prefrontal cortex, thalami, and cerebellum (P&amp;lt;0.0005). High and low tumour connectivity to this network was associated with short-term and long-term OS, respectively, using both univariate (P=0.013) and multivariate models controlling for treatment and tumour volume (P=0.016). Final, subset analysis of longitudinal neuroimaging in children within one month of death (n=21) showed tumour progression mapped to this same functional network and exhibited a dominant (left) hemispheric predominance (P&amp;lt;0.05), underpinned by increased tumour connectivity to the right (P=0.0270) rather than left (P=0.1802) corticospinal tract, and associated with OS (P=0.02). DISCUSSION We map DMG to a unified and prognostically important functional network, further establishing DMG as a circuit disorder. Interventions aiming to modulate this network may inform future treatment strategies for affected children.

Clinical and molecular features of patients with IDH1 wild-type primary glioblastoma presenting unexpected short-term survival after gross total resection.

This study investigated the factors influencing short-term survivors (STS) after gross total resection (GTR) in patients with IDH1 wild-type primary glioblastoma. We analyzed five independent cohorts who underwent GTR, including 83 patients from Kitasato University (K-cohort), and four validation cohorts of 148 patients from co-investigators (V-cohort), 66 patients from the Kansai Molecular Diagnosis Network for the Central Nervous System tumors, 109 patients from the Cancer Genome Atlas, and 40 patients from the Glioma Longitudinal AnalySiS. The study defined STS as those who had an overall survival ≤ 12months after GTR with subsequent radiation therapy, and concurrent and adjuvant temozolomide (TMZ). The study included 446 patients with glioblastoma. All cohorts experienced unexpected STS after GTR, with a range of 15.0-23.9% of the cases. Molecular profiling revealed no significant difference in major genetic alterations between the STS and non-STS groups, including MGMT, TERT, EGFR, PTEN, and CDKN2A. Clinically, the STS group had a higher incidence of non-local recurrence early in their treatment course, with 60.0% of non-local recurrence in the K-cohort and 43.5% in the V-cohort. The study revealed that unexpected STS after GTR in patients with glioblastoma is not uncommon and such tumors tend to present early non-local recurrence. Interestingly, we did not find any significant genetic alterations in the STS group, indicating that such major alterations are characteristics of GB rather than being reliable predictors for recurrence patterns or development of unexpected STS.

Molecular characterization of long-term and short-term survivors of metastatic uterine leiomyosarcoma.

Molecular characterization of long-term and short-term survivors of metastatic uterine leiomyosarcoma.

Spatial Heterogeneity of Immune Drivers Coordinates the Organisation of Antitumor Immunity in Pancreatic Cancer, Affecting Patient Outcome

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is considered low immunogenic with “cold” tumor microenvironment (TME) and is mostly unresponsive to immune checkpoint blockade therapies. Aims We aim to decipher the impact of intratumoral heterogeneity of immune determinants on antitumor response. Methods 130PDAC specimens were classified according to overall survival in long-term survivors (LTSs, n=29, OS≥60 months) and short-term survivors (STSs, n=101, OS&amp;lt;60 months). Spatial compartment masks were defined by immunofluorescence imaging (tumor cells: Pancytokeratin+CD45-, leukocytes: CD45+Pancytokeratin-, stroma cells: PanCK-CD45-). 4regions of interest from tumor center (TC) and the invasive front (IF) were examined by transcriptomic and proteomic analysis using the Nanostring platform for immune pathway targets. Results of NGS and morphological features were integrated. 20samples underwent immunophenotypic analysis by multiplex immunofluorescence. Results LTSs displayed mostly homogeneous morphology with extended glandular differentiation and immunogenic TME both at TC and IF, with increasing gradient towards the IF. There was higher presence of immune checkpoint-associated and immunogenic genes and proteins at the IF as compared to the TC, including CD40, CD3, CD8, CD4, GZMB and PD-L1. In contrast, STSs were characterized by morphologic heterogeneity, including areas with reduced glandular differentiation and high tumor budding, and a mostly immunosuppressive TME with negative gradient towards the IF. Moreover, there was reduced gene expression and protein abundance at the IF as compared to the TC, including CD3, CD8, CXCL10, GZMB, IFNG, HLA-DR and CD40. Conclusion LTSs display a highly immunogenic TME, underscoring their effective antitumor immunity, especially at the area of IF compared with STSs. A significant intratumoral heterogeneity between TC and IF exists with regards to immune determinants in both, LTSs and STSs, which might explain the different antitumor immune responses, affecting patient outcome. The differential expression of immune drivers may help selecting patients for combination therapies to improve antitumor immunity and harness the responsiveness to immune checkpoint inhibitors in PDAC.

Comprehensive molecular characterization of long-term glioblastoma survivors

Fewer than 5 % glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8 % of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM.

Comparing symptom clusters in cancer survivors by cancer diagnosis: A latent class profile analysis

PurposeResearch on symptom clusters in oncology is progressing, but knowledge gaps remain. One question is whether the number and types of symptom subgroups (i.e., latent classes) differ based on cancer diagnosis. The purpose of this study was to: (1) identify and compare latent class subgroups based on four highly prevalent symptoms (pain, fatigue, sleep disturbance, and depression), and (2) examine the differences in sociodemographic and clinical factors in the identified latent classes across the seven cancer types (i.e., prostate, non-small cell lung, non-Hodgkin’s lymphoma, breast, uterine, cervical, and colorectal cancer).MethodsThis study is a cross-sectional secondary analysis of data obtained from the My-Health study in partnership with four Surveillance, Epidemiology, and End Results (SEER) cancer registries located in California (two), Louisiana, and New Jersey. The sample included 4,762 cancer survivors 6-13 months following diagnosis of one of the seven cancer types mentioned. Latent class profile analysis was used.ResultsSubjects were primarily young (59% age 21-64 years), Caucasian (41%), married/cohabitating (58%) and unemployed (55%). The number and types of symptom subgroups varied across these seven cancer populations: four-subgroups were the common in prostate, lung, non-Hodgkin’s lymphoma, and breast cancer survivors. Unmarried, low education, and unemployment status were associated with high risk of symptom burden across the cancer types.ConclusionIdentifying symptom subgroups by cancer diagnosis has the potential to develop innovative and effective targeted interventions in cancer survivors. Further research is needed to establish extensive knowledge in symptom clustering between treatment regimens, and short-term and long-term cancer survivors.

Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8+ T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer.

Long-Term Survival and Immune Response Dynamics in Melanoma Patients Undergoing TAPCells-Based Vaccination Therapy.

Cancer vaccines present a promising avenue for treating immune checkpoint blockers (ICBs)-refractory patients, fostering immune responses to modulate the tumor microenvironment. We revisit a phase I/II trial using Tumor Antigen-Presenting Cells (TAPCells) (NCT06152367), an autologous antigen-presenting cell vaccine loaded with heat-shocked allogeneic melanoma cell lysates. Initial findings showcased TAPCells inducing lysate-specific delayed-type hypersensitivity (DTH) reactions, correlating with prolonged survival. Here, we extend our analysis over 15 years, categorizing patients into short-term (<36 months) and long-term (≥36 months) survivors, exploring novel associations between clinical outcomes and demographic, genetic, and immunologic parameters. Notably, DTHpos patients exhibit a 53.1% three-year survival compared to 16.1% in DTHneg patients. Extended remissions are observed in long-term survivors, particularly DTHpos/M1cneg patients. Younger age, stage III disease, and moderate immune events also benefit short-term survivors. Immunomarkers like increased C-type lectin domain family 2 member D on CD4+ T cells and elevated interleukin-17A were detected in long-term survivors. In contrast, toll-like receptor-4 D229G polymorphism and reduced CD32 on B cells are associated with reduced survival. TAPCells achieved stable long remissions in 35.2% of patients, especially M1cneg/DTHpos cases. Conclusions: Our study underscores the potential of vaccine-induced immune responses in melanoma, emphasizing the identification of emerging biological markers and clinical parameters for predicting long-term remission.

Abstract 3977: Neoadjuvant chemotherapy and radiation shape the local and regional adaptive antitumor immune response in lung squamous cell carcinomas

Abstract Chemotherapy (CT) and radiotherapy (RT) are known for their stimulating as well as inhibiting effects on the anti-tumor immune response. This study aimed to understand how CT and RT change the local immune microenvironment of the tumor and the regional immune response in draining lymph nodes. Evaluations were performed on lung squamous cell carcinomas (LUSC) with a special focus on tertiary lymphoid structures (TLS) and lymph follicles. A cohort of 21 untreated LUSC (naiveLUSC) and 21 matched neoadjuvantly treated LUSC (neoLUSC) was compiled. Digitized H&amp;E whole slide images of the tumor and of two representative probes of a proximal and distal lymph node were assessed. A pathologist blinded to the groups assigned tumors to one of three immunophenotypes (inflamed, excluded, desert) by visual analysis. Tertiary lymphoid structures (TLS) in the tumor area and lymph follicles in the regional lymph nodes were counted and characterized according to their maturation status (with/without germinal center). RNAseq analyses were performed for a subset of tumors. NeoLUSC tended to more frequently have a desert immune phenotype (6/21 versus 1/21, p=0.0931). The mean number of TLS was significantly reduced in neoLUSC compared to naiveLUSC (4 versus 9, p=0.0179). Additionally, neoLUSC had a significantly lower likelihood for the presence of mature TLS with germinal centers (3/21 versus 9/21, p=0.0327). While the mean number of lymph follicles in regional lymph nodes was comparable between neoLUSC and naiveLUSC, neoLUSC had a significantly reduced number of mature lymph follicles (20% versus 41% of lymph follicles, p=0.0376) in distant lymph nodes and showed a similar, but less pronounced trend in proximal lymph nodes. In general, the amount of TLS correlated with the amount of lymph follicles in naiveLUSC patients (p=0.0154), but not in neoLUSC patients. Across the complete cohort, long-term survivors (&amp;gt;2 years) tended to have higher numbers of lymph follicles in lymph nodes than short term survivors (1.6 versus 1.1 lymph follicles/mm2, p=0.0805). RNAseq analysis revealed a significant upregulation of inflammatory gene sets and downregulation of cell cycle associated gene sets in neoLUSC as compared to naiveLUSC. This study demonstrates that CT and RT are potent, but multimodal influencers of the local tumor immune microenvironment as well as the regional immune response of the draining lymph nodes. While gene expression results underline the inflammation promoting effect of CT and RT, histological evaluations suggest that CT and RT negatively affect the adaptive anti-tumor immune response by reducing the development and maturation of TLS and lymph follicles in the lymph nodes. Next steps include an artificial intelligence based cell characterization and spatial evaluation of the tumor immune microenvironment to further unveil functional changes induced by CT and RT. Citation Format: Rosemarie Krupar, Justin Nieder, Johannes Braegelmann, Mareike Haarmann, Torsten Goldmann, Sharon Ruane, Timo Milbich, Cornelius Boehm, Lukas Ruff, Julika Ribbat-Idel, Christian Watermann, Sven Perner, Christiane Kuempers. Neoadjuvant chemotherapy and radiation shape the local and regional adaptive antitumor immune response in lung squamous cell carcinomas [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 3977.