Short-term Survivors Research Articles

Integration of incomplete multi-omics data using Knowledge Distillation and Supervised Variational Autoencoders for disease progression prediction

Objective:The rapid advancement of high-throughput technologies in the biomedical field has resulted in the accumulation of diverse omics data types, such as mRNA expression, DNA methylation, and microRNA expression, for studying various diseases. Integrating these multi-omics datasets enables a comprehensive understanding of the molecular basis of cancer and facilitates accurate prediction of disease progression. Methods:However, conventional approaches face challenges due to the dimensionality curse problem. This paper introduces a novel framework called Knowledge Distillation and Supervised Variational AutoEncoders utilizing View Correlation Discovery Network (KD-SVAE-VCDN) to address the integration of high-dimensional multi-omics data with limited common samples. Through our experimental evaluation, we demonstrate that the proposed KD-SVAE-VCDN architecture accurately predicts the progression of breast and kidney carcinoma by effectively classifying patients as long- or short-term survivors. Furthermore, our approach outperforms other state-of-the-art multi-omics integration models. Results:Our findings highlight the efficacy of the KD-SVAE-VCDN architecture in predicting the disease progression of breast and kidney carcinoma. By enabling the classification of patients based on survival outcomes, our model contributes to personalized and targeted treatments. The favorable performance of our approach in comparison to several existing models suggests its potential to contribute to the advancement of cancer understanding and management. Conclusion:The development of a robust predictive model capable of accurately forecasting disease progression at the time of diagnosis holds immense promise for advancing personalized medicine. By leveraging multi-omics data integration, our proposed KD-SVAE-VCDN framework offers an effective solution to this challenge, paving the way for more precise and tailored treatment strategies for patients with different types of cancer.

Estimation of Conditional Neurocognitive Function Failure (NCFF) Incidence in Patients Receiving Whole Brain Radiation Therapy (WBRT) for Brain Metastases (BM): Secondary Analysis of NRG CC001

NRG CC001 was a trial that demonstrated a significantly lower risk of neurocognitive function failure (NCFF) with the use of hippocampal avoidant whole brain radiotherapy (HA-WBRT) as compared to conventional WBRT in patients with brain metastases (BM). Although a sizeable proportion of patients ultimately still did develop NCFF, the utility of this data from time of radiation treatment diminishes over time. Conditional survival analyses can provide better estimates especially for patients who demonstrate longer term neurocognitive protection. We sought to use clinical trial data to estimate the conditional risk of development of NCFF for short and longer-term survivors and to evaluate if factors prognostic of NCFF at diagnosis remained relevant over time. We performed a post hoc analysis of 518 patients enrolled in NRG CC001, a phase III trial in which patients with BM were randomly assigned to WBRT plus memantine or HA-WBRT plus memantine, using data obtained from the NCI NCTN Data Archive. In this secondary analysis, cumulative incidence function and Gray's test were used to estimate conditional NCFF incidence for the entire cohort and between arms at various time points of survivorship without neurocognitive dysfunction. Risk factors were analyzed using cause-specific multivariable Cox proportional hazards modeling analysis (MVA). Overall, the cumulative risk of development NCFF by 6 months was 64.5%. Following 2- (n = 259), 4- (n = 74), 6- (n = 43), and 8-month (n = 26) survivorship without NCFF, the conditional probability of developing neurocognitive impairment within the next 2 months were 70.1%, 27.7%, 12.7%, and 3.8%, and within the next 4 months were 78.1%, 35.4%, 15.6%, and 3.8%, respectively. For those who retained intact neurocognitive function at 2 months, only receipt of HA-WBRT (HR = 0.743, P = 0.033) and age ≤61 (HR = 0.620, P = 0.003) were predictive on MVA for decreased risk of NCFF. Prognostic factors predictive of NCFF at diagnosis were no longer associated with decreased risk of NCFF following 4 months of survivorship without cognitive impairment. Patients who achieved survivorship of ≥4 months had similar conditional risk of cognitive dysfunction between treatment arms (Gray's test, P = 0.219), and this trend persisted for patients free of NCFF at ≥6 and 8 months. Our data highlight that the greatest risk for development of NCFF after WBRT is in within the first 4 months after treatment. Conditional risk of NCFF for patients who have survived ≥4-, 6-, and 8- months without NCFF steadily decreases the longer survivorship is; this risk also appears to plateau. HA-WBRT confers reduced risk of NCFF at time of diagnosis and for short-term survivors without NCFF. Most importantly, these data can be used to counsel patients about their conditional risk of neurocognitive dysfunction over time, and suggest that those who are able to remain free of cognitive impairment may have lower risks of developing NCFF in the future.

OS04.4.A LONG- AND SHORT-TERM SURVIVORS AMONG ADULT PATIENTS WITH DIFFUSE WHO GRADE 2-3 GLIOMA: CLINICAL FEATURES, MOLECULAR RECLASSIFICATION AND DNA METHYLATION PATTERNS

Abstract BACKGROUND Diffuse gliomas show considerable heterogeneity in terms of survival. The WHO classifications of 2016 and 2021 improved prognostic stratification due to the definition of biologically and clinically homogeneous tumor entities. However, further prognostic models considering clinical and molecular factors are needed to balance survival benefit with adverse treatment-related long-term effects in therapeutic decisions. MATERIALS AND METHODS Patients with diffuse gliomas of WHO grades 2 and 3 diagnosed in 2000 - 2019 have been included. Long term survivors (LTS) were defined as patients with an overall survival (OS) of >10 years after radiological diagnosis, whereas short-term survivors (STS) had an OS of <1 year. Histological diagnosis was performed by a board-certified neuropathologist. DNA methylation analysis of formalin-fixed, paraffin-embedded tumor tissue was conducted using the Illumina EPIC 850k platform. The Heidelberg Methylation Classifier was applied to obtain methylation-based diagnoses. RESULTS Of 697 patients with WHO grade 2 and 3 glioma, 182 (26.1%) were LTS, and 42 (6.0%) were STS. LTS were younger than STS (median age: 36 vs. 59.5; p<0.001) and had a higher Karnofsky Performance Score at diagnosis (median: 90% vs. 80%; p<0.001). LTS more frequently presented with epileptic seizures (p<0.001), while more STS had motoric (p<0.001), sensory (p=0.021), and visual deficits (p=0.027) as well as aphasia (p<0.001) and behavioral changes (p=0.009). Histological diagnoses (including pre-2016) showed astrocytic histology in 117 (70.9% LTS, 29.1% STS), oligodendroglial in 61 (93.4% LTS, 6.6% STS), oligo-astroglial in 43 (97.7% LTS, 2.3% STS) and not otherwise specified in 3 (all STS; p<0.001). Molecular reclassification of pre-2016 diagnoses (n = 143) yielded divergent entities in 46 (32.2%) cases. Overall, integrated molecular diagnoses included astrocytoma (isocitrate dehydrogenase [IDH]-mutant] in 65 patients (95.4% LTS and 4.6% STS), oligodendroglioma (IDH-mutant, 1p/19q-codeleted) in 64 patients (98.4% LTS and 1.6% STS), IDH-wildtype gliomas in 24 patients (100% STS), anaplastic pilocytic astrocytoma in 2 STS, diffuse midline glioma (H3K27-altered) in 1 STS, and dysembryoplastic neuroepithelial tumor in 1 LTS, while not otherwise specified diagnoses were found in 4 patients (75% LTS, 25% STS; p<0.001). Unsupervised clustering based on DNA methylation profiling revealed two major clusters consisting of IDH-wildtype STS (cluster A) and IDH-mutant patients (cluster B; 94.6% LTS, 5.4% STS). In cluster B, one subcluster (n = 8) contained 3/4 IDH-mt STS. Further analyses of these cases including validation with publicly available DNA methylation data are ongoing. CONCLUSION LTS and STS show distinct clinical and molecular features. Further profiling of cases with divergent survival could provide more refined prognostic stratification.

P02.11.A INTEGRATED GENOMIC PROfiLING OF LONG-TERM GLIOBLASTOMA SURVIVORS

Abstract BACKGROUND Glioblastoma (GBM) is a fatal brain tumor, and few patients survive beyond 5 years. Therefore, a study of genomic alterations in GBM long-term survivors (LTS) is essential for insights into tumor biology and biomarker identification. MATERIAL AND METHODS In our study, we reviewed medical records from Sun Yat-sen University Cancer Center for GBM patients received initial surgery between the years 2000 and 2018. Thirty patients with GBM had an overall survival of more than 5 years. In addition to established prognostic factors such as radiochemotherapy and total surgical excision, we sought to identify genomic alterations associated with LTS by collecting surgically resected tumor tissues and normal blood controls from 13 GBM LTS (overall survival > 60 months) and 19 short-term survivors (STS, overall survival < 24 months). We performed whole exome sequencing and transcriptome sequencing on these samples. RESULTS Our findings revealed no significant differences in the composition of driver genes between the two groups. However, mutation signature analysis indicated that the proportion of mutation signature 19 was higher in the LTS than in the STS (P=0.059). Analysis of copy number variants showed that the longer survivors group had higher copy number variants at the chromosomal level (P=0.049). At the chromosome arm level, the proportion of 19p amplification and 19q amplification in the longer survivors group was significantly higher than in the short survival group (P=0.001/0.002). And in the TCGA GBM dataset, GBM patients with 19p amplification also had a better prognosis (log-rank P=0.04). CONCLUSION In conclusion, our study identified the proportion of mutation signature 19 and amplification of 19p as potential genomic alterations that could be used as prognostic biomarkers for GBM. This study could pave the way for new therapeutic approaches to this challenging disease.

Breast cancer survival prognosis using the graph convolutional network with Choquet fuzzy integral

Breast cancer is the most prevalent kind of cancer among women and there is a need for a reliable algorithm to predict its prognosis. Previous studies focused on using gene expression data to build predictive models. However, recent advancements have made multi-omics cancer data sets (gene expression, copy number alteration, etc.) accessible. This has acted as the motivation for the creation of a novel model that utilizes a graph convolutional network (GCN) and Choquet fuzzy ensemble, incorporating multi-omics and clinical data retrieved from the publicly available METABRIC Database. In this study, graphs have been used to extract structural information, and a Choquet Fuzzy Ensemble with Logistic Regression, Random Forest, and Support Vector Machine as base classifiers has been employed to classify breast cancer patients as short-term or long-term survivors. The model has been run using all possible combinations of gene expression, copy number alteration, and clinical modality, and the results have been reported. Furthermore, a comparison has been made between the obtained results and different baseline models and state-of-the-art to demonstrate the efficacy of the proposed model in terms of different metrics. The results of this model based on Accuracy, Matthews correlation coefficient, Precision, Sensitivity, Specificity, Balanced Accuracy, and F1-Measure are 0.820, 0.528, 0.630, 0.666, 0.871, 0.769, and 0.647, respectively.

Vascular Aging Is Accelerated in Hematological Cancer Survivors Who Undergo Allogeneic Stem Cell Transplant.

Survivors of allogeneic stem cell transplant (SCT) receive intensive cancer treatments that are associated with cardiovascular dysfunction. Markers of vascular age can indicate early signs of adverse (cardio)vascular changes; however, the impact of SCT on these makers is unknown. We aimed to determine the short (3 months) and longer-term (≥2 years) effect of SCT on markers of vascular age in hematologic cancer survivors compared with an age-matched noncancer control group. The short-term effects of SCT, markers of vascular age (aortic compliance, arterial elastance, and ventricular-vascular coupling) were assessed via cardiac magnetic resonance imaging (cardiac and aortic volumes) before and ≈3 months post-SCT in 13 short-term survivors and compared with 11 controls. The longer-term impact was assessed by comparing 14 long-term survivors (6.5 [2-20] years post-SCT) to the short-term survivors (post-SCT) and controls (n=16). The groups were similar for age and body mass index. In the short-term survivors, no significant group-by-time interactions were observed for any markers of vascular aging from pretransplant to posttransplant (net difference for change in compliance between groups -0.07 [95% CI, -1.49 to 1.35]). For the time-course analysis, aortic compliance was significantly lower in both SCT groups (overall P=0.007) compared with controls, whereas ventricular-vascular coupling was higher in both survivor groups as was arterial elastance in long-term SCT survivors (ie, worse; P<0.01 for all). This study provides evidence of an accelerated vascular aging phenotype in allogeneic SCT survivors and provides insight into the increased burden of cardiovascular disease among hematologic cancer survivors.

MGMT methylation pattern of long-term and short-term survivors of glioblastoma reveals CpGs of the enhancer region to be of high prognostic value

Treatment with the alkylating agent temozolomide is known to be prognostically beneficial in a subset of glioblastoma patients. Response to such chemotherapeutic treatment and the prognostic benefit have been linked to the methylation status of O6-methylguanine-DNA methyltransferase (MGMT). To date, it has not been entirely resolved which methylation pattern of MGMT is most relevant to predict response to temozolomide treatment and outcome. In this retrospective study, we compared the methylation patterns, analyzed by Sanger sequencing, of 27 isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients that survived more than 3 years (long-term survivors) with those of 24 patients who survived less than a year after initial surgery (short-term survivors). Random Forest-, Correlation-, and ROC-curve analyses were performed. The data showed that MGMT is typically methylated in long-term survivors, whereas no prominent methylation is observed in short-term survivors. The methylation status of CpGs, especially in the promoter and exon1/enhancer region correlated highly with outcome. In addition, age and temozolomide treatment were strongly associated with overall survival. Some CpGs in the enhancer region, in particular CpG 86 (bp + 154), demonstrated high values associated with overall survival in the Random Forest analysis. Our data confirm previously published prognostic factors in IDH-wildtype glioblastoma patients, including age and temozolomide treatment as well as the global MGMT methylation status. The area frequently used for decision making to administer temozolomide at the end of exon1 of MGMT, was associated with outcome. However, our data also suggest that the enhancer region, especially CpG 86 (bp + 154) is of strong prognostic value. Therefore, we propose further investigation of the enhancer region in a large prospective study in order to confirm our findings, which might result in an optimized prediction of survival in glioblastoma patients, likely linked to response to temozolomide treatment.

SYST-03 PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD) FROM EPITHELIAL CARCINOMAS: FINAL RESULTS AND MOLECULAR ANALYSES WITH SINGLE CELL RNA SEQUENCING

Abstract BACKGROUND LMD has a dismal prognosis with median overall survival (mOS) of 3-4 months (mo). Preclinical studies showed PD-1 axis blocking therapy promotes antigen presentation within the CSF compartment, and increases BBB permeability and ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab with WBRT in LMD (NCT0371768). METHODS Patients received Avelumab 800mg IV q2 weeks, up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy, 10 daily fractions. Primary endpoints were safety/DLTs and 3-mo OS. Secondary endpoints i.e., CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6mo were excluded. RESULTS 15 patients were enrolled i.e., breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). 87% female, median age 59 range 32-82. 1 patient did not complete WBRT. 2 out of 15 patients had gr. 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related &amp;lt;gr. 3 AEs, i.e., hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). Median follow-up was 3.7mo (range, 0.9-36.8mo; 95% CI 1.3-14.7mo). Median follow-up time for survival analyses was 19.8mo. 10 out of 15 patients (66.7%) were alive at 3mo. mOS was 10.5 (95% CI 1.2 - 19.8mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3mo (95% CI, 0.9-15.2mo). 2 patients remain alive and well. ScRNAseq analyses are underway; signatures correlated with outcomes in short vs. long term survivors. CONCLUSIONS Combination of Avelumab and WBRT is safe, well tolerated, and shows encouraging activity in LMD with an OS longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short vs. long term survivors should be further explored.

NUCLEAR DEFECTIVE IL-33 DRIVES AN ANTI-TUMORIGENIC MICROENVIRONMENT IN GLIOBLASTOMA

Abstract Despite a sophisticated treatment regimen, including surgery, chemotherapy, and radiotherapy, survival outcomes for glioblastoma remain at a dismal 14.6 months. Multi-omics profiling have established that myeloid phagocytes drive glioma progression and contribute to therapeutic resistance. However, effective targeting of this axis remains an unmet clinical opportunity. Previously, we found that the dual-function (secreted and nuclear) cytokine IL-33 is a key regulator of the inflammatory microenvironment that aids glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization signal (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically suppressed resulting in extended long-term survival. Using spatial transcriptomics and multiplex immunohistochemistry with temporal resolution at different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of xenografts generated from patient brain tumor initiating cells found an enrichment of GIMs in xenografts with long-term survival (&amp;gt;300 days) compared to short-term survivors (&amp;lt;100 days). The ability of GIMs to inhibit glioma progression was further highlighted when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly prolonged survival through the polarization and activation of GIMs. Additional characterization of this phenotype and development of clinical strategies to deliver ΔNLS IL-33 to brain tumors is warranted to determine if recruitment and activation of GIMs is a translatable therapeutic strategy for glioma patients.

A Novel HOXA10-Associated 5-Gene-Based Prognostic Signature for Stratification of Short-term Survivors of Pancreatic Ductal Adenocarcinoma.

Despite the significant association of molecular subtypes with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC), few efforts have been made to identify the underlying pathway(s) responsible for this prognosis. Identifying a clinically relevant prognosis-based gene signature may be the key to improving patient outcomes. We analyzed the transcriptomic profiles of treatment-naïve surgically resected short-term survivor (STS) and long-term survivor (LTS) tumors (GSE62452) for expression and survival, followed by validation in several datasets. These results were corroborated by IHC analysis of PDAC-resected STS and LTS tumors. The mechanism of this differential survival was investigated using CIBERSORT and pathway analyses. We identified a short-surviving prognostic subtype of PDAC with a high degree of significance (P = 0.018). One hundred thirty genes in this novel subtype were found to be regulated by a master regulator, homeobox gene HOXA10, and a 5-gene signature derived from these genes, including BANF1, EIF4G1, MRPS10, PDIA4, and TYMS, exhibited differential expression in STSs and a strong association with poor survival. This signature was further associated with the proportion of T cells and macrophages found in STSs and LTSs, demonstrating a potential role in PDAC immunosuppression. Pathway analyses corroborated these findings, revealing that this HOXA10-driven prognostic signature is associated with immune suppression and enhanced tumorigenesis. Overall, these findings reveal the presence of a HOXA10-associated prognostic subtype that can be used to differentiate between STS and LTS patients of PDAC and inform on the molecular interactions that play a role in this poor prognosis.

Metabolomic analysis of gut metabolites in patients with colorectal cancer: Association with disease development and outcome.

Colorectal cancer (CRC) is one of the leading global malignancies with low 5-year survival and high mortality rates. Despite extensive research, the precise role of gut metabolites in CRC development and clinical outcomes remains unclear, while its elucidation may aid the development of improved clinical diagnosis and treatment options. In the present study, targeted metabolomic analysis was conducted on fecal samples from 35 patients with CRC, 37 patients with colorectal adenoma and 30 healthy controls (HC) to identify metabolite biomarkers. Using orthogonal partial least squares discriminant analysis, metabolomic features distinguishing the three groups were identified. Receiver operating characteristic (ROC) curve analysis was used to assess diagnostic utility for distinguishing CRC from HC. The association of gut metabolites with survival in patients with CRC was also analyzed by comparing short-term survivors (STS) and long-term survivors (LTS), and the prognostic ability of metabolites was predicted using Cox regression and Kaplan-Meier analysis. The results of the current study showed that the enriched pathways in CRC included 'caffeine metabolism', 'thiamine metabolism', 'phenylalanine, tyrosine and tryptophan biosynthesis' and 'phenylalanine metabolism'. ROC analysis found that 9,10-dihydroxy-12-octadecenoic acid, cholesterol ester (18:2) and lipoxinA4 distinguished CRC from HC. Joint quantification of these three metabolites resulted in an area under the ROC curve of 0.969 in the diagnosis of CRC. The analysis of the current study also showed that the expression of metabolites involved in 'sphingolipid metabolism' was mainly dysregulated in LTS and STS, while N-acetylmannosamine and 2,5-dihydroxybenzaldehyde were associated with better overall survival. In conclusion, the present study provided preliminary insight into the metabolic changes associated with CRC and may have important implications for the development of future diagnostic and treatment strategies.

Genetic characterization of primary and metastatic high-grade serous ovarian cancer tumors reveals distinct features associated with survival

High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and the majority of cases present with metastasis and late-stage disease. Over the last few decades, the overall survival for patients has not significantly improved, and there are limited targeted treatment options. We aimed to better characterize the distinctions between primary and metastatic tumors based on short- or long-term survival. We characterized 39 matched primary and metastatic tumors by whole exome and RNA sequencing. Of these, 23 were short-term (ST) survivors (overall survival (OS) < 3.5 years) and 16 were long-term (LT) survivors (OS > 5 years). We compared somatic mutations, copy number alterations, mutational burden, differential gene expression, immune cell infiltration, and gene fusion predictions between the primary and metastatic tumors and between ST and LT survivor cohorts. There were few differences in RNA expression between paired primary and metastatic tumors, but significant differences between the transcriptomes of LT and ST survivors in both their primary and metastatic tumors. These findings will improve the understanding of the genetic variation in HGSC that exist between patients with different prognoses and better inform treatments by identifying new targets for drug development.

Social vulnerability among cancer patients and changes in vulnerability during their trajectories – A longitudinal population-based study

BackgroundIdentification of socially vulnerable cancer patients in the health care system is difficult. Only little is known concerning changes in the patients’ social circumstances during the trajectory. Such knowledge is valuable regarding the identification of socially vulnerable patients in the health care system. The objective of this study was to use administrative data to identify population-based characteristics of socially vulnerable cancer patients and investigate how social vulnerability changed during the cancer trajectory. MethodologyA registry-based social vulnerability index (rSVI) was applied to each cancer patient prior to their diagnosis, and used to assess changes in social vulnerability after the diagnosis. ResultsA total of 32,497 cancer patients were included. Short-term survivors (n = 13,994) died from cancer from one to three years after the diagnosis, and long-term survivors (n = 18,555) survived at least three years after the diagnosis. 2452 (18 %) short-term survivors and 2563 (14 %) long-term survivors were categorized as socially vulnerable at diagnosis, of these 22 % and 33 % changed category to not socially vulnerable during the first two years after the diagnosis, respectively. For patients changing status of social vulnerability, several social and health-related indicators changed, which is in line with the complexity of the multifactorial social vulnerability. Less than 6 % of the patients categorized as not vulnerable at diagnosis, changed to become vulnerable during the following two years. ConclusionDuring the cancer trajectory, social vulnerability may change in both directions. Surprisingly, more patients, who were categorized as socially vulnerable when their cancer was diagnosed, changed status to not socially vulnerable during follow-up. Future research should attempt to increase knowledge on identifying cancer patients, who experience deterioration after the diagnosis.

Mental health at different stages of cancer survival: a natural language processing study of Reddit posts.

The purpose of this study was to use text-based social media content analysis from cancer-specific subreddits to evaluate depression and anxiety-loaded content. Natural language processing, automatic, and lexicon-based methods were employed to perform sentiment analysis and identify depression and anxiety-loaded content. Data was collected from 187 Reddit users who had received a cancer diagnosis, were currently undergoing treatment, or had completed treatment. Participants were split according to survivorship status into short-term, transition, and long-term cancer survivors. A total of 72524 posts were analyzed across the three cancer survivor groups. The results showed that short-term cancer survivors had significantly more depression-loaded posts and more anxiety-loaded words than long-term survivors, with no significant differences relative to the transition period. The topic analysis showed that long-term survivors, more than other stages of survivorship, have resources to share their experiences with suicidal ideation and mental health issues while providing support to their survivor community. The results indicate that Reddit texts seem to be an indicator of when the stressor is active and mental health issues are triggered. This sets the stage for Reddit to become a platform for screening and first-hand intervention delivery. Special attention should be dedicated to short-term survivors.

Comparative Analyses of the Clinicopathologic Features of Short-Term and Long-Term Survivors of Patients with Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Therapy and Pancreatoduodenectomy.

Neoadjuvant therapy (NAT) is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often show heterogenous responses to NAT with variable clinical outcomes, and the clinicopathologic parameters associated with these variable outcomes remain unclear. In this study, we systematically examined the clinicopathologic characteristics of 60 short-term survivors (overall survival < 15 months) and 149 long-term survivors (overall survival > 60 months) and compared them to 352 intermediate-term survivors (overall survival: 15-60 months) of PDAC who received NAT and pancreatoduodenectomy. We found that the short-term survivor group was associated with male gender (p = 0.03), tumor resectability prior to NAT (p = 0.04), poorly differentiated tumor histology (p = 0.006), more positive lymph nodes (p = 0.04), higher ypN stage (p = 0.002), and higher positive lymph node ratio (p = 0.03). The long-term survivor group had smaller tumor size (p = 0.001), lower ypT stage (p = 0.001), fewer positive lymph nodes (p < 0.001), lower ypN stage (p < 0.001), lower positive lymph node ratio (p < 0.001), lower rate of lymphovascular invasion (p = 0.001) and perineural invasion (p < 0.001), better tumor response grading (p < 0.001), and less frequent recurrence/metastasis (p < 0.001). The ypN stage is an independent predictor of both short-term and long-term survivors by multivariate logistic regression analyses. In addition, tumor differentiation was also an independent predictor for short-term survivors, and tumor response grading and perineural invasion were independent predictors for long-term survivors. Our results may help to plan and select post-operative adjuvant therapy for patients with PDAC who received NAT and pancreatoduodenectomy based on the pathologic data.

Diffuse intrinsic pontine gliomas: First registry effort in Mexico.

Brainstem tumors comprise 10.9% of all brain tumors, and pediatric diffuse intrinsic pontine gliomas (DIPG) have a fatal prognosis. Some countries have developed national and international register databases to characterize their populations to aid clinical and public policy decisions. This study provides information regarding the clinical characteristics of a retrospective cohort of children with DIPG in México from 2001 to 2021, and assesses the proposed prognostic factors previously described for survival outcome. Health institutions from Mexico were invited to contribute to a retrospective electronic registry of patients with DIPG based on the International DIPG Registry. Fisher's exact test was used to compare long- and short-term survivors. Overall survival was estimated using the Kaplan-Meier method. Differences between survival curves were evaluated using the log-rank test and Cox proportional hazard regression analysis. Total 110 patients were included. The median age of the patients at diagnosis was 7years. Sixty patients (54.5%) presented with symptoms in less than 6months; the most frequent symptom was ataxia (56.4%). Ninety patients received treatment (81.8%), the overall survival at 4years was 11.4%, and 16 patients (14.5%) were admitted for palliative end-of-life care. We found no significant survival differences for any of the prognostic factors. This study highlights the need to develop strategies to standardize healthcare processes and enhance the quality of care to improve clinical diagnosis in Mexico. We also observed a barrier to the acceptance of palliative end-of-life care in the family and medical teams.

Clinical predictors of survival in advanced epithelial ovarian cancer: Can we foresee the long-term survivors and develop a personalized treatment approach?

e17605 Background: While women with recurrent disease have a poor prognosis, a subset of women are long term survivors (LTS). We aimed to characterize the demographic and clinical characteristics associated with long and short-term survival of patients with advanced epithelial OC (EOC). Methods: We conducted a retrospective descriptive analysis of 822 patients diagnosed with advanced EOC (FIGO stage III/IV) and treated at a single institution, between 2002-2020. Characteristics of short-term survivors (STS), women who survived less than 2 years, were compared to LTS, patients who lived beyond 7 and 10 years from diagnosis. Descriptive statistics of the clinical, oncologic, and treatment parameters were performed using t-test, chi-square. We assessed the contribution of age and stage, BRCA carrier status, interval or primary debulking, optimal debulking, platinum sensitivity, and treatment scheduling upon oncological outcomes. Results: Among 822 patients with advanced EOC, 112 women (13.6%) died withing 24 months from diagnosis, while 139 (16.9%), and 64 (7.8%) survived beyond 7 and 10 years, respectively. Histology, CA125 level at diagnosis, and interval or primary debulking approach, were not significant among the STS and LTS. LTS were younger at diagnosis, (median age of 57, and 56.5 among women who lived &gt; 7 and 10 years, respectively vs. 70 in STS, p &lt; 0.0001). The majority of LTS were diagnosed with stage III disease, (95%, and 97%, &gt; 7 and &gt; 10 years, respectively vs. 67% of STS), in contrast to a greater proportion of STS diagnosed with stage IV (33.0% of STS vs. 5.0%, 3.1% of LTS &gt; 7 and &gt; 10 years, respectively, p &lt; 0.0001). BRCA mutation status was the strongest prognostic factor for LTS ( &gt; 7 and 10 years, OR = 17.8, 21.2 respectively, p &lt; 0.001). Almost half of LTS who were carriers of a deleterious BRCA mutation, (47.3%, 46.2% of LTS &gt; 7 and 10 years, respectively, p &lt; 0.0001), whereas most STS were not carriers of BRCA mutations (89.8%). LTS were predominantly platinum sensitive (99.3%, 98.4% &gt; 7 and &gt; 10 year, vs. 21.6% of STS, P &lt; 0.0001). Optimal cytoreductive surgery was performed in a smaller number of STS compared to the LTS (41.9% of STS vs. 83.5% and 88.7% of LTS &gt; 7 and 10 years, respectively, p &lt; 0.0001). A greater proportion of LTS received weekly treatment scheduling of paclitaxel and carboplatin compared to STS (50.8% and 49.2% of LTS &gt; 7 and 10 years, respectively vs. 31.6% of STS, p &lt; 0.01). Conclusions: The long and short-term survivors of advanced EOC may be identified early in the clinical assessment, based on distinct patient characteristics associated with survivorship, which are critical in developing a personalized treatment approach. Our work demonstrated that LTS are a distinct group of women diagnosed at a younger age, lower stage, optimally debulked, platinum sensitive disease, and BRCA mutation carriers.

Clinical features of long-term survivors with advanced high-grade serous ovarian cancer.

e17575 Background: Most patients diagnosed with high-grade serous ovarian cancer (HGSOC) at advanced stages (FIGO III&amp;IV) have limited survival. However, approximately 30% of patients survive more than 5 years, some of them without relapse. A better understanding of these patients may uncover novel factors contributing to their long survival beyond those known to be related to HGSOC prognosis (age, stage and residual disease after surgery). This descriptive study aims to analyze the clinical characteristics of these exceptional survivors and describe them in contrast to patients with worse survival in a cohort of patients diagnosed before the introduction of PARP inhibitors as first-line maintenance therapy. Methods: A descriptive analysis of patients newly diagnosed with advanced HGSOC at our University Hospital between 2009 and 2018 was conducted. We report clinical characteristics of long-term survivors (LTS), defined as patients alive after 5 years(y) from the date of diagnosis and characteristics of patients who survived less than two years from the date of diagnosis, classified as short- term survivors (STS). Results: Among 195 patients with advanced HGSOC 42 (21,5%) survived less than 2y and 48 (24,6%) more than 5y, 18 of them (37,5%) without relapse. The Median age was 61.1y for LTS and 64.8 for STS. In the LTS group, 77.1% of patients were stage III, and 22.9% were stage IV. In the STS group, the distribution of patients with stage III and IV was 42.9% and 57.1%, respectively. A higher proportion of LTS underwent surgery n=44 (91,7%), most of them as interval debulking surgery (59.1%). Almost half of STS did not undergo surgery (45,2%), being interval debulking surgery the most frequent systematic approach when surgery was performed (73.9%). Only 9,1% of LTS who underwent surgery had residual disease compared to 27,3% of STS. Harboring mutations in the BRCA1/2 genes is a favorable prognostic factor also associated with chemotherapy sensitivity, in our serires 23% of LTS were BRCA1&amp;2 mutation carriers (11 patients (23%) patients with germline BRCA mutations being 7patients(15%) BRCA1mut and 4patients(8%) BRCA2mut with 4patients(8%) of patients not analyzed). Conclusions: In our cohort, stage III and cytoreduction surgery were more frequent among LTS. Classical clinical characteristics are not enough to identify advanced HGSOC LTS. More investigation on their molecular profile might help to to identify exceptional LTS in order to elucidate better management approaches and new treatments for patients with worse prognosis.

Comparative analysis of deeply phenotyped GBM cohorts of ‘short-term’ and ‘long-term’ survivors

BackgroundGlioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS).MethodsPatients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed.ResultsTranscriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS.ConclusionOverall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM.Graphical abstract

Mortality risk according to smoking trajectories after cancer diagnosis among Korean male cancer survivors: A population-based cohort study.

Previous research on post-diagnosis smoking among cancer survivors mainly relied on smoking status, which may not fully reflect the impact of changes in smoking levels. This study aimed to evaluate mortality risk according to smoking trajectories among Korean male cancer survivors, using a trajectory approach to comprehensively capture smoking patterns. The study included 110555 men diagnosed with cancer between 2002 and 2018 from the Korean National Health Information Database. Group-based trajectory modelling was used to identify post-diagnosis smoking trajectories among pre-diagnosis current smokers (n=45331). Cox hazards models were fitted to evaluate mortality risk according to smoking trajectories for pooled cancers, pooled smoking-related cancers, smoking-unrelated cancers, and gastric, colorectal, liver, and lung cancers. Smoking trajectories included light-smoking quitters, heavy-smoking quitters, consistent moderate smokers, and decreasing heavy smokers. Smoking significantly increased all-cause and cancer mortality risks in cancer patients for pooled cancers, pooled smoking-related cancers, and pooled smoking-unrelated cancers. Compared to non-smokers, all-cause mortality risk for pooled cancers significantly increased according to smoking trajectories:(AHR=1.33; 95% CI: 1.27-1.40), (AHR=1.39; 95% CI: 1.34-1.44), (AHR=1.44; 95% CI: 1.34-1.54), and (AHR=1.47; 95% CI: 1.36-1.60), respectively. Smoking increased all-cause and cancer mortality risks in gastric and colorectal cancer patients and cancer-specific mortality in lung cancer patients. The significant associations of smoking trajectories with all-cause and cancer mortality risks were primarily observed in 5-year survivors but not in short-term survivors. Among heavy smokers, smoking cessation significantly reduced all-cause mortality risk in the long-term. The post-diagnosis smoking trajectory independently predicts cancer prognosis among male cancer patients. Proactive cessation support should be strengthened, particularly for those who smoke heavily.