Significant Difference In Survival Research Articles

Radiotherapy in patients with brain metastases with and without concomitant immunotherapy: comparison of patient outcome and neurotoxicity.

Recently, immune checkpoint inhibitors (ICI) have been added to the treatment of brain metastases. While combining radiotherapy and ICI can enhance therapeutic effects, it might also increase the risk of severe autoimmune adverse events. This retrospective study aims to compare treatment responses and neurotoxicity in patients treated with radiotherapy alone versus those receiving a combination of radiotherapy and ICI. All patients with brain metastases who received radiotherapy at Hannover Medical School from 2017 to 2019 were included. The medical reports of all study participants were evaluated. Patients who received radiotherapy alone and those who received a combination of radiation and ICI were compared. A total of 248 patients were analyzed, with the most common tumor types being non-small cell lung cancer (NSCLC) and malignant melanoma. Half of the patients received whole-brain radiotherapy (WBRT) and the other half stereotactic radiotherapy (SRT). Of these, 29 patients received concurrent immunotherapy and radiotherapy, 30 completed immunotherapy before radiotherapy, and 29 started ICI after completing radiotherapy. Two cases lacked information on the duration of immunotherapy. Overall survival post-initial tumor diagnosis within the total cohort was 52months, with significantly worse survival for patients with multiple brain metastases (p = 0.020). No significant differences in survival or incidence of neurological adverse events were observed between patients with or without ICI. Combining radiotherapy and ICI did not significantly increase neurotoxicity or improve survival in this cohort, though the heterogeneity of the subgroups limits the generalizability of these findings.

Subtyping colorectal cancer based on septic shock-associated genes: prognosis and immune characteristics

BackgroundSepsis and colorectal cancer (CRC) are leading causes of death. Given their mutual dependence for susceptibility, we used bioinformatics to explore potential connections between septic shock (SS) and CRC.MethodsWe identified 452 co-expressed genes between SS-related differential expression genes (SS-DEGs) and CRC patient-expressed genes (TCGA-CRC genes). CRC samples were categorized into two cluster subgroups through hierarchical clustering. We then compared the prognosis and immune landscapes of the two cluster subgroups through survival analysis, immune microenvironment analysis, and immune therapy response evaluation.ResultsClustering analysis of the 452 CRC patient-expressed SS-DEGs identified two subtypes: SS-like CRC (SL-CRC) and non-SS-like CRC (NSL-CRC). There were no significant differences in overall survival between the CRC subtypes. However, the subtypes displayed significant differences in immune score, stromal score, and ESTIMATE score. Based on immune therapy databases, there were also significant differences in responses to anti-CTLA-4 and anti-PD-1 immune checkpoint inhibitors between the subtypes.ConclusionOur study reveals significant differences in the immune microenvironment and immune therapy responses between SL-CRC and NSL-CRC subtypes. These findings provide a foundation for identifying new therapeutic targets and developing personalized treatment strategies for specific CRC subtypes.

No Socioeconomic Inequalities in Mortality among Catholic Monks: A Quasi-Experiment Providing Evidence for the Fundamental Cause Theory.

We propose a novel approach to test the fundamental cause theory (FCT) by analyzing the association between socioeconomic status (SES), as measured by the order titles "brothers" and "padres," and mortality in 2,421 German Catholic monks born between 1840 and 1959. This quasi-experiment allows us to study the effect of SES on mortality in a population with largely standardized living conditions. Mortality analyses based on Kaplan-Meier product limit estimation show that there were no statistically significant survival differences between the high and lower SES monks. This holds for all birth cohorts, indicating that monastic life offers health protection for monks with a lower SES regardless the disease patterns, causes of death, or main risk factors in a given period. These findings support the FCT: Whereas SES-related differences in mortality are a widely confirmed finding in the general population, a context with largely standardized conditions eliminates the importance of SES-related resources.

Diagnosis of TP53-mutated myeloid disease by the ICC and WHO 5th Edition Classifications.

The International Consensus (ICC) and World Health Organization 5th edition (WHO5) classifications introduced new but differing categories of myeloid disease defined by TP53 mutations. We reviewed a cohort of 188 cases of TP53-mutated myeloid disease to determine how diagnoses and outcomes differ between the two classifications. Overall, 120 (64%) cases were classified differently by the ICC and WHO5, including 24/80 (30%) cases with <20% blasts. These cases were discrepantly categorized primarily due to inclusion of complex karyotype (CK) as a surrogate for biallelic TP53 inactivation only in the ICC. However, there were no significant differences in clinicopathologic characteristics or overall survival between cases categorized as TP53-mutated disease by both classifications and those with a single TP53 mutation and CK, suggesting that CK reliably identifies TP53-mutated cases with biallelic TP53 inactivation. The majority of cases of AML (96/102; 94%) were discrepantly diagnosed between the ICC and WHO5 due to the introduction of AML with mutated TP53 as a distinct category only in the ICC. Nearly all of these were instead diagnosed as AML, myelodysplasia-related (AML, MR) by WHO5. However, when compared to a separate cohort of patients with AML, MR without TP53 mutations, patients with TP53-mutated AML showed a distinct genetic profile and significantly worse overall survival, supporting the inclusion of AML with mutated TP53 as a distinct disease category. Overall, our results show that a significant percentage of TP53-mutated myeloid disease is classified differently by the ICC and WHO5 and highlight areas to address in future classification systems.

HPB SO47 - Adjuvant chemotherapy for early pancreatic cancer: Meta-analysis of survival benefit and the need for a national study of UK practice

Abstract Background Stage I pancreatic cancer is defined as disease localised to the pancreas (T1-T2, N0, M0). Whilst landmark trials have demonstrated adjuvant chemotherapy (AC) improves survival in resectable disease, early stages comprise only 3-8% of cases. The benefit of AC in stage 1 pancreatic cancer is yet to be defined and there currently exists no data outlining the use of AC for early disease in the United Kingdom (UK). We aimed to perform a meta-analysis evaluating comparative outcomes of pancreatic cancer resection with or without AC in patients with stage I pancreatic cancer and outline plans for a national collaborative study. Method A systematic search of MEDLINE, CENTRAL and Web of Science and bibliographic reference lists were conducted. All comparative studies reporting outcomes of pancreatic cancer resection for stage I cancer with or without AC were included and their risk of bias were assessed using ROBINS-I tool. Survival outcomes were analysed using hazard ratio (HR) and odds ratio (OR) for the time-to-event and dichotomous outcomes, respectively. Results We included six studies reporting 6,874 patients with resected stage 1 pancreatic cancer of whom 3,951 patients had no AC and the remaining 2,923 patients received AC. The use of AC was associated with significantly higher overall survival (HR 0.71, P&amp;lt;0.00001) and 2-year survival (65.1% versus 57.4%, OR 1.99, P=0.04) compared to no use of AC. There was no statistically significant difference in 1-year (86.8% versus 78.4%, OR 1.60, P =0.25), 3-year (46.0% versus 44.0%, OR 1.07; P =0.43), or 5-year survival (24.8% versus 23.3%, OR 1.03; P =0.81) between the two groups. Conclusion Meta-analysis of best available evidence (level 2a with low to moderate certainty) demonstrates that AC may confer survival benefits for stage I pancreatic cancer when compared to the use of surgery alone. National evaluation of the use of AC within the UK is currently lacking but is necessary. Randomized control trials are required to escalate the level of evidence and confirm these findings with consideration of contemporary chemotherapy agents and regimens.

Abstract 4121812: Longitudinal Trajectory-Based Classification of Heart Failure with preserved Ejection Fraction: A Machine Learning Approach

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heterogeneous pathophysiology and dynamic changes in cardiac structure and function. Current research predominantly focuses on left ventricular ejection fraction (LVEF) or left ventricular structures with predefined categories. This study hypothesized that applying unsupervised methodologies to longitudinal echocardiography will reveal distinct trajectory patterns in cardiac structure and function related to clinical outcomes in HFpEF patients. Methods: This retrospective cohort study, conducted at UC Davis Medical Center (2014 to 2022), consisted of adult patients with HFpEF. The inclusion criteria included ICD HF codes, a left ventricular ejection fraction (LVEF) ≥50%, and a Brain natriuretic peptide (BNP) ≥100 pg/ml or N-terminal-pro BNP (NT-proBNP) ≥225 pg/ml. Longitudinal data were analyzed using unsupervised machine learning, including UMAP for dimensionality reduction and Gaussian Mixture Models for clustering. Primary and secondary outcomes included all-cause mortality and changes in BNP levels, respectively. Results: The study included 1,626 patients. The cohort had a median age of 69 years, was 57.5% female, and 51.8% white. Three distinct echocardiographic trajectory patterns emerged (p&lt;.05) among the HFpEF cohort. Trajectory #1 (n=568) exhibited a high-stable pattern with the highest mortality rates, Trajectory #2 (n=512) showed a high-decreasing pattern with high mortality rates, and Trajectory #3 (n=546) had a low-increasing pattern with the lowest mortality rates. Trajectories varied significantly in baseline characteristics and longitudinal echocardiographic changes, with Trajectory #3 having a lower baseline left ventricular mass index (p&lt;.001) and a higher mean arterial pressure ( p =.001) compared to the other trajectories. Kaplan-Meier survival analysis indicated significant differences in survival among the trajectories ( p =.004). Conclusion: The study utilized unsupervised analysis of longitudinal echocardiographic data to identify three distinct HFpEF trajectories, each associated with unique clinical features and outcomes. These findings underscore the heterogeneity of HFpEF and highlight the potential trajectory-based patient stratification to improve targeted intervention strategies. Future validation in larger, multicenter cohorts is warranted to enhance HFpEF management and patient prognosis.

Abstract 4138483: Outcomes of Hypoplastic Left Heart Syndrome by Subtype and Presence of Ventriculocoronary Connections: A Fetal Heart Society Multi-Center Retrospective study

Background: Hypoplastic left heart syndrome (HLHS) is classified by subtype: mitral atresia and aortic atresia (MA-AA), mitral stenosis and aortic atresia (MS-AA), and mitral stenosis and aortic stenosis (MS-AS). It is controversial whether specific HLHS subtypes and presence of ventriculocoronary connections (VCC) are associated with transplant-free survival. We aimed to determine whether there is an increased risk of mortality associated with specific HLHS subtypes, whether this risk is stratified by the presence of VCC, and if a specific type of stage I palliation in patients with VCC improves survival. We also aimed to determine practice variation in the evaluation of HLHS patients with VCC. Methods: We performed a multicenter retrospective cohort study of fetuses and infants &lt; 2 months of age with HLHS admitted between 1/2012-12/2016 to participating Fetal Heart Society institutions. Patients with HLHS variants were excluded. We collected patient specific data and surveyed participating centers for practice variation. Kaplan-Meier curves with log-rank test were used to assess transplant-free survival and cox proportional hazard analysis was performed with adjustment for center as a random intercept. Results: 341 patients from nine centers were included. MA-AA was the most common subtype (177, 52%), followed by MS-AA (102, 30%), and MS-AS (62, 18%). VCC were diagnosed or suspected in 65 patients (19%). A total of 287 patients were live born with intention to treat. HLHS subtype was not associated with transplant-free survival (Figure 1A). Presence of VCC was associated with a lower transplant-free survival (p=0.026, Figure 1B). In the subset of patients diagnosed with VCC, there was not a significant difference in survival based on type of stage I palliation (Figure 1C). Cox proportional hazard modeling adjusted for center demonstrates that presence of VCC has a hazard ratio of 1.74 (CI 1.02-2.98), p =0.04. Survey data regarding practice variation for patients with VCC (Figure 2) demonstrates 33% of centers modify the type of stage I palliation based on presence of VCC. Conclusions: In a multicenter cohort of HLHS patients, patients with VCC had lower transplant-free survival compared to those without VCC, while subtype and type of stage I palliation did not have a statistical difference. There is considerable practice variation in the management of HLHS patients with VCC that may warrant further investigation.

Abstract Su701: The Influence of Public Assistance Among Patients Who Received Extracorporeal Cardiopulmonary Resuscitation after Cardiac Arrest in Japan

Background: This study aimed to evaluate the influence of public assistance on patients with out-of-hospital cardiac arrest (OHCA) who received extracorporeal cardiopulmonary resuscitation (ECPR) in Japan. Methods: We conducted a secondary analysis of data from the SAVE-J II study, a retrospective, multicenter registry study involving 36 participating institutions in Japan. Patients with cardiac arrest who received ECPR were divided into two groups depending on whether or not they had received public assistance. The primary outcome was 30-day survival. Secondary outcomes were as follows: 30-day favorable neurological outcomes (cerebral performance category scores 1-2); survival at discharge; favorable neurological outcome at discharge; number of intensive care unit, hospital, ventilator, and extracorporeal membrane oxygenation days; medical expenses; proportion of percutaneous coronary intervention; target temperature management; mechanical circulatory support (MCS) device use; and withdrawal of life-sustaining therapy. Results: Of 2,157 patients registered in the SAVE-J II study, 1,885 patients were enrolled in this study; 99 patients (5.3%) received public assistance and 1,786 patients (94.7%) did not. Multivariable logistic regression analysis did not show a significant difference in 30-day survival (OR 1.22, 95% CI 0.77-1.95, p=0.40). The log-rank test for the Kaplan-Meiercurve on 30-day survival did not demonstrate a significant difference (p=0.46). Except for the use of MCS devices, there were no significant differences in secondary outcomes. Conclusions: The use of public assistance did not influence the prognoses of OHCA patients receiving ECPR. Treatment option during hospitalization may be affected by the use of public assistance.

Satisfactory outcomes following a second autologous hematopoietic cell transplantation for multiple myeloma in poor stem cell mobilizers: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Autologous hematopoietic cell transplants (auto-HCTs) remain the standard of care for transplant-eligible MM patients. The general practice has been to undergo upfront apheresis following induction to collect sufficient number of CD34+ cells to facilitate two auto-HCTs. However, 5-30% of MM patients do not initially mobilise a sufficient number of hematopoietic stem cells and are classified as poor mobilizers (PM). We compared the baseline characteristics and outcomes of 61 PMs and 816 non-PM patients who underwent a second auto-HCT and who were enrolled in the non-interventional CALM study (NCT01362972). Only patients who collected CD34+ prior to auto-HCT1 were included. Auto-HCT2 comprised both tandem and salvage transplants. PMs were re-mobilized with plerixafor (n = 24, 39.3%) or non-plerixafor-based regimens (n = 37, 60.7%). There were no significant differences in engraftment, progression-free survival (PFS) or overall survival (OS) after the second auto-HCT between PM and non-PM patients. There was a trend to shorter PFS in PM patients undergoing salvage auto-HCT (median 9.6 vs. 12.9 months; p = 0.08) but no significant difference in OS. The median OS was 41.1 months for PM and 41.2 months for non-PM patients (p = 0.86). These data suggest that salvage mobilization is effective and does not affect overall outcomes after a second auto-HCT.

Abstract 4127071: Pulmonary Artery Catheter Utilization in Cardiogenic Shock: Clinical Characteristics and Outcomes

Background: The pulmonary artery catheter (PAC) is used for hemodynamic monitoring, but its impact on patient outcomes, especially in cardiogenic shock (CS), is controversial. Several studies have shown no significant benefits and noted complications, leading to a decline in PAC use. However, PAC use appears to have increased recently in guiding management decisions in CS. Our study aims to assess the clinical characteristics and outcomes of CS patients receiving PACs versus not. Methods: We included patients with CS admitted to a tertiary academic medical center between May 2015 and December 2023. Variables were compared using Kruskal-Wallis, chi-squared, and Fisher's exact tests. Hemodynamic parameters were collected from either right heart catheterization or from a PAC. Endpoints included native heart survival to discharge, durable left ventricular assist device (LVAD) implantation, heart transplant (HTx), and 30-day and 1-year survival from discharge. Results: The study group consisted of 742 patients with CS. Of these, 385 (52%) received a PAC and 357 (48%) did not. The baseline characteristics of the two groups are shown in Table 1A . PAC patients had more severe shock, worse hemodynamics, and higher rates of temporary mechanical circulatory support (MCS) use. Hemodynamic measurements at shock onset differed, with PAC patients having higher right atrial pressures and lower cardiac index by Fick. Clinical outcomes and MCS related complications are shown in Table 1B. There was no significant difference in native heart survival at discharge, but HTx and durable LVAD implantation was higher in the PAC group. PAC placement was associated with longer hospital stays and more MCS related complications, including bleeding and hemolysis. The 30-day survival rate was similar between groups, and 1-year survival was marginally higher in the PAC group. Conclusion: PAC patients exhibited more severe clinical characteristics, longer hospital stays, higher rates of temporary MCS use and complications, durable LVAD implantation, and HTx. Short-term survival rates were similar, but 1-year survival was slightly better for PAC patients. Further studies are needed to provide clearer insights into PAC use in CS.

ArtiSentialⓇ versus conventional laparoscopic colorectal cancer surgery: a multicenter retrospective matched cohort study

Background: This study aims to compare outcomes of colorectal cancer surgeries performed using the newly developed articulating laparoscopic instrument, ArtiSential®, with those using conventional non-articulating or rigid laparoscopic instruments. Methods: This multicenter, retrospective, matched cohort study enrolled patients with colorectal cancer undergoing laparoscopic surgery in seven tertiary referral hospitals from January 2021 to October 2022. A 1:1 propensity score matching was performed between the articulating (Arti-LAP) and conventional (Rigid-LAP) laparoscopic groups. The primary outcome was the overall incidence of short-term complications. Results: The study initially comprised 694 and 2008 patients in the Arti-LAP and Rigid-LAP groups, respectively. After matching, each group consisted of 694 patients, with no significant differences in baseline clinical characteristics. Mean operation time was 161 ± 32 min in Arti-LAP and 152 ± 25 min in Rigid-LAP groups (P=0.105). Open conversion rates were 0% (0/694) in Arti-LAP and 1.0% (7/694) in Rigid-LAP groups (P=0.024). Overall morbidity rates were 9.5% (66/694) in Arti-LAP and 12.8% (89/694) in Rigid-LAP (P=0.061), with similar rates of severe morbidities. Specimen quality was acceptable in both groups. Multivariable regression analysis showed that the choice of instrument type (articulating or rigid) was not associated with perioperative morbidity. Despite a short median follow-up period of 19.5 months, no significant difference in disease-free survival was observed between the groups. Conclusion: Laparoscopic surgery using ArtiSential® was performed safely and effectively for patients with colorectal cancer. Articulating laparoscopic instruments may offer an advantage in reducing open conversion rates.

Abstract 4118641: Trend, Survival, and Disparity Analysis of Heart Transplantation in a Single Large Transplant Center

Background: In the landscape of organ transplantation, heart transplantation stands as a life-saving procedure for patients with end-stage heart failure. Comprehensive analyses of transplant programs are imperative to optimize outcomes and understand the complexities. Hypothesis: This study hypothesizes that an increasing trend of heart transplant service and short-term mechanical circulatory support (STMCS) is the bridge to transplant; the UNOS (United Network for Organ Sharing) guideline positively impacts STMCS utilization. Even with the standard of care, there might be a disparity in receiving care in terms of gender and race. Goal/ Aims: By examining this center's collective experience, this research provides valuable insights into the evolving landscape of heart transplantation, ultimately contributing to advancements in patient care and transplant policy. Methods: This retrospective cohort study includes heart transplant patients in a single large transplant center. For statistical analysis, Cox regression, Mann-Whitney test, Kruskal Wallis, and Chi-Square test were used in IBM SPSS 25. Result: Trends: This retrospective study covering 2010 to 2022 comprehensively analyzed 1513 heart transplant patients. The cohort consisted of 1071 (70.78%) males and 442 (29.21%) females, 31.9% were bridged through STMCS. 76.7% of Caucasian and 16.1% were African American.The mean utilization of STMCS was 20.08% before the UNOS policy change, increasing to 53.81% after that (p &lt; 0.001). Disparity Analysis: There was a statistically significant difference in STMCS utilization between white and black patients (p= 0.008) but no difference in between obese and non-obese cohorts (P=0.362).Wait time was similar among the genders (p=0.161) and different races (p=0.302). Survival Analysis: There is a significant survival discrepancy between patients bridged through MCS and those without STMCS(p&lt; 0.001). However, yearly trend analysis showed an evolving survival trajectory favoring STMCS users. There are statistically significant survival differences among whites and blacks (P =0.008) but similar among the genders (p=0.589). Summary: The study reveals significant changes in the trend of transplants regarding STMCS utilization since the UNOS guideline. There are substantial differences in survival between STMCS vs. non-STMCS groups and among the races.There was a significant difference in STMCS utilization among the races.

EPCO-31. THE GERMLINE POLYMORPHISM RS55705857 IS ASSOCIATED WITH A POOR SURVIVAL IN ASTROCYTOMA, IDH-MUTANT, GRADE 2

Abstract Histologic features, presence of CDKN2A/B homozygous deletion and methylation subtype are strong determinants of outcome and of therapy in IDH-mutant gliomas. We were interested in learning if there are additional markers of outcome in these tumors. To address this question, we assembled a cohort of 963 IDH-mutant gliomas with overall survival data (median follow-up alive 2.7 years, median follow-up deceased 3.9 years). Array-based copy number data, targeted NGS, germline genotyping data and Illumina EPIC array methylation data were available on 872, 226, 542, and 401 patients, respectively. Morphologic type (oligodendroglioma versus astrocytoma, grade (2/3 vs 4) and methylation subtype (A_IDH_LG vs A_IDH_HG) were all significantly associated with survival (p &amp;lt;0.001). There was no significant difference in survival between grade 2 vs 3 IDH-mutant astrocytomas (p=0.53 adjusting for age and sex). However, subjects with the risk allele (G) for rs55705857 had a better overall survival than subjects with the non-risk allele (A) in IDH-mutant oligodendroglioma (AG/GG vs AA, median overall survival 21.6 vs 15.7 years, p=0.048 after adjusting for grade, age, and sex). Conversely, rs55705857 was associated with a markedly worse survival in grade 2 IDH-mutant astrocytomas (AG/GG vs AA, median overall survival 8.6 vs 19.6 years, p=0.007 after adjusting for age and sex). Despite similar sample sizes and number of deaths, there was no significant difference in overall survival by rs55705857 genotype in grade 3 or 4 IDH-mutant astrocytomas. Upon further functional analyses, TLX1 and GALNT17 were found to be differentially methylated in IDH1-mutant astrocytomas and oligodendrogliomas, respectively, when stratified by rs55705857 risk allele. This is the first observation of a germline characteristic (e.g. rs55705857) predicting survival in low-grade IDH-mutant astrocytoma. While this observation requires validation, it suggests that germline genotype may be practice changing and inform results of trials such as CATNON and CODEL.

DDDR-25. IBUDILAST AND ANTI-PD-L1 COMBINATION TREATMENT SIGNIFICANTLY IMPROVES SURVIVAL IN A SEX-DEPENDENT MANNER IN A MURINE MODEL OF GLIOBLASTOMA

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor, and there remains a significant need for new treatments. Previous trials studying immune checkpoint inhibitors (ICI) as single agents have been negative. Ibudilast is a brain penetrant inhibitor of the macrophage migration inhibitory factor (MIF)-CD74 interaction that sensitizes GBM to temozolomide in vitro and alters myeloid-derived suppressor cells in vitro and in vivo. The purpose of this study was to investigate whether ibudilast increases ICI efficacy in a murine model of GBM. METHODS 6-week-old male and female C57BL/6 mice were implanted with SB28 cells intracranially. One week after implantation, each group was randomized to receive intraperitoneal treatment with either: ibudilast (50 mg/kg), anti-PD-L1 (1mg/kg), combination, or vehicle control. Mice were euthanized at neurological endpoint. Survival was modeled with Cox proportional hazards regression. RESULTS Among females, there was a significant difference in survival among treatment groups (p=0.0002). Specifically, combination treatment led to significantly longer survival compared to ibudilast (p=0.004) and control (p=0.03), but not anti-PD-L1 (p=0.12). Among males, there was no significant difference in survival among groups (p=0.40). Males had significantly shorter median survival compared to females (overall: 18 versus 22 days, combination treatment: 20 days versus 32 days, anti-PD-L1: 14 versus 22 days, ibudilast: 17 versus 17 days, control: 18 versus 22 days, p=0.02). CONCLUSIONS Ibudilast with anti-PD-L1 is a promising combination treatment against GBM. Future research is needed to identify the mechanisms underlying this treatment regimen and its sex-dependent effect. These results may inform the development of a combination new clinical trial, as ibudilast is currently being evaluated in the newly-diagnosed and recurrent GBM setting with temozolomide.

TMIC-01. TARGETABLE GENE EXPRESSION CHANGES MEDIATE EXTRAVASATION OF BREAST CANCER CELLS FROM THE CIRCULATION AND LOCAL PROLIFERATION IN THE BRAIN

Abstract As breast cancer migrates into the brain, it acquires distinct genomic, immunologic and phenotypic changes through interactions with the local microenvironment. We sought to determine how targetable gene expression changes mediate breast cancer extravasation into and proliferation within the brain. We created a brain metastatic cell line (“brain-seeking”) via serial intracardiac injection of mCherry+ 4T1 breast cancer cells in Balb/c mice and flow cytometry isolation of micrometastases. We conducted in vitro and in-vivo studies to uncover immunological and genetic differences between primary breast cancer and brain metastases. In culture, we observed significant upregulation in adhesion (p=0.01) and invasion (p=0.0004) along with upregulation of adhesion-promoting genes such as Sdc3, Serpine2 or ECM1 in brain-seeking cells. We observed significant differences in survival of Balb/c mice injected intracranially with brain-seeking cells vs. breast cancer cells (p=0.04). In the mammary fat pad (MFP), parental 4T1 cells caused increased mortality vs. brain-seeking cells (p=0.003). This rejection of brain-seeking 4T1 cells in the MFP could be due to prior adaptation to the brain microenvironment, while rejection of parental 4T1 cells in the brain could be due to lacking said adaptations. Consistent with this finding, of 20,382 analyzed genes in both cell lines, 108 related to immune regulation were significantly upregulated in brain-seeking cells including Cxcl1, Dusp1, C3. Flow cytometry showed increased cytotoxic and helper T cells in intracranially injected parental vs. brain-seeking cells (p &amp;lt;0.001). In the MFP, however, 4T1 parental cells displayed CD3+ T cell depletion and an increased number of neutrophils (p &amp;lt;0.05) while the “brain-seeking cells” showed increased numbers of CD3+ and CD4+ cells (p &amp;lt;0.01) and macrophages (p&amp;lt;0.05). This suggests that brain metastases evolve from their primary tumor through adhesive and invasive adaptations promoting extravasation, along with unique immunological adaptations that allow their proliferation free of immune surveillance in the brain microenvironment.

XRCC1 is linked to poor prognosis in adenocarcinoma of the esophagogastric junction after radiotherapy: transcriptome and alternative splicing events analysis.

This study aimed to (i) investigate the relationship between X-ray repair cross-complementing protein 1 gene (XRCC1) and prognosis in patients with adenocarcinoma of the esophagogastric junction (AEG), and (ii) analyze the roles of XRCC1 in human gastric adenocarcinoma (AGS) cells following X-ray radiation. A total of 46 AEG patients were enrolled and examined for XRCC1 protein by immunohistochemistry. XRCC1 was knocked down in AGS cells by transfection, and AGS cells were subsequently exposed to 6Gy of X-ray radiation. XRCC1 mRNA and protein expression was examined via quantitative real-time PCR (qRT-PCR) and Western blot analysis. The apoptosis of AGS cells was examined by flow cytometer. RNA-sequencing technology was used to identified differentially expressed genes and alternative splicing events following XRCC1 knockdown and radiation exposure. XRCC1 positivity was strongly associated with distant metastasis, pathological tumor-node-metastasis (pTNM) classification, and radiotherapy resistance in AEG patients. A significant difference in progression-free survival was observed between AEG patients with low and high XRCC1 protein expression. The knockdown of XRCC1 notably exacerbated the effects of X-ray radiation on apoptosis in AGS cells. Additionally, X-ray radiation modified the expression of genes related to apoptosis and immune response in XRCC1-knockdown AGS cells. Furthermore, the generation of splice variants was influenced by XRCC1 knockdown in AGS cells. XRCC1 may serve as a key oncogene that elucidates the role of alternative splicing events in the progression of AEG following X-ray treatment.

BIOM-09. CLINICAL EFFECT OF CD25 ON THE MTX-BASED CHEMOSENSITIVITY OF PRIMARY CENTRAL NERVUS SYSTEM LYMPHOMA

Abstract INTRODUCTION Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is treated with chemotherapy, mainly with high-dose methotrexate (HD-MTX), but some cases are resistant to treatment and relapse in a short period. However, a biomarker that predicts the chemosensitivity and recurrence has not yet been identified. In this study, we used surface marker analysis of tumor tissue using flow cytometry to search for biomarkers related to chemosensitivity and early recurrence. METHODS From 2017 to 2023, 25 patients were diagnosed with PCNSL by biopsy in Kobe University Hospital, and flow cytometry of the biopsy tissues were performed. Cerebrospinal fluid (CSF) examination including sIL2R, β2MG, and IL-10 was performed in all cases before surgery, and treatment based on methotrexate was administered postoperatively. We retrospectively analyzed patient characteristics, flow cytometry data, treatment details, response rate, time to recurrence, and overall survival. RESULTS The mean age of the patients was 71 (range, 37-80) years. In univariate analysis, high expression level of CD25 (interleukin-2 receptor, IL-2R) in the tissue was associated with a lower response rate to MTX-based chemotherapy (Fisher’s exact test, p=0.0072) and had a tendency of shorter time to recurrence. However, there were no significant differences in progression-free survival and overall survival. There was no correlation between expression level of CD25 in tissue and sIL-2R in CSF. Expression level of sIL-2R in CSF was independent of CD25 expression in tissue. CONCLUSION There are some reports that CD25 can be a prognostic factor in follicular lymphoma, but no reports in PCNSL. Here, we suggested that high expression level of CD25 in PCNSL tissue was associated to chemoresistance and early recurrence. In cases of PCNSL with high CD25 expression level, additional whole-brain irradiation and transition to tirabrutinib be considered because there are possibilities of chemoresistance and early recurrence.

Pretransplant immunotherapy increases acute rejection yet improves survival outcome of HCC patients with MVI post-liver transplantation.

Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as the most promising strategy for hepatocellular carcinoma (HCC) downstaging prior to liver transplantation (LT). However, further evidence is required to assess the feasibility and safety of pretransplant ICI exposure. We retrospective analyzed 159 HCC patients who underwent LT at our institution from June 2019 to December 2023, and 39 recipients (39/159, 24.5%) received pretransplant ICI therapy. The perioperative acute rejection rate and rejection-related mortality rate in the ICI group were 23.1% (9/39) and 12.8% (5/39), respectively, which were significantly higher than those in the non-ICI group, at 5% (6/120, P = 0.002) and 0% (0/120, P = 0.001). There was no significant difference in the 90-day post-transplant overall survival (OS) (P = 0.447) and recurrence-free survival (RFS) (P = 0.723) between these two groups. We found 37.1% (59/159) recipients were found to have microvascular invasion (MVI), no matter whether the HCC tumor is within Milan criteria or not. Notably, though MVI was identified as a risk factor for the LT recipients, pretransplant ICI exposure appeared to be a protective factor for HCC patients with MVI which benefits its overall survival. Besides, the RFS and OS in the ICI exposure recipients with MVI were comparable to the non-ICI exposure recipients without MVI. However, no synergistic anti-tumor effects were observed with pretransplant ICI immunotherapy when combined with locoregional of TACE, HAIC, RFA and systematic of lenvatinib or sorafenib downstaging treatments, nor with post-transplant adjuvant of systematic or FOLFOX chemotherapy. Further comprehensive studies are needed to balance the dual natural effects of immunotherapy by optimizing downstaging protocols and patient selection to reduce acute rejection and improve long-term survival.

Beyond the egg: sperm source does not impact cumulative live birth rates in autologous oocyte cryopreservation patients when adjusted for oocyte age.

To assess the impact of sperm source on cumulative live birth rate (CLBR) after oocyte thaw in autologous oocyte cryopreservation (AOC) patients. A retrospective cohort study of autologous oocyte thaw patients at an urban academic fertility center from 2006 to 2021. Patients were stratified by sperm source [partner sperm (PS) vs. donor sperm (DS)]. The primary outcome was CLBR per patient. Secondary outcomes were the oocyte survival rate and usable embryo rate. Statistics included Mann-Whitney U, Kruskal-Wallis, Fisher's exact, chi-square, two-sample t-tests, and multiple logistic regression (p < 0.05). A total of 653 patients were included; 455 (69.7%) used PS and 198 (30.3%) used DS. Time from the first AOC to the first thaw did not differ among DS and PS users (56.8 vs. 54.0months, p = 0.20). PS users were younger at AOC (37.9 vs. 38.5years, p < 0.001) and thaw (42.3 vs. 43.1years, p < 0.001). There were equivalent overall CLBRs (39.9% PS vs. 40.6% DS, p = 0.85) and CLBRs in patients < 35years at AOC (51.2% PS vs. 100% DS, p = 0.18), 35-37years at AOC (45.9% PS vs. 60.4% DS, p = 0.10), 38-40years at AOC (35.4% PS vs. 35.2% DS, p = 0.93), 41-42years at AOC (28.9% PS vs 14.3% DS, p = 0.21), and > 43years at AOC (12.5% PS vs 16.7% DS, p = 0.83) among PS and DS users. There were no significant differences in the oocyte survival (79% PS vs 80.5% DS, p = 0.08) or the proportion of patients with usable embryos (27.3% vs 27.8%, p = 0.70) between PS and DS groups. In AOC patients, CLBR, oocyte survival rate, and usable embryo rate did not differ based on sperm source.

Survival After Shunt Therapy in Normal-Pressure Hydrocephalus: A Meta-Analysis of 1614 Patients

Background: Ventriculoperitoneal (VP) shunt therapy is a crucial intervention for normal-pressure hydrocephalus (NPH). This meta-analysis delves into survival time and the impact of baseline symptom burden on survival after VP shunt therapy for NPH, employing reconstructed pooled survival curves and a one-stage meta-analysis. Methods: IPD regarding overall survival (OS) were acquired from published Kaplan–Meier charts, utilizing the R package IPDfromKM in R (Version 4.3.1, the R Foundation for Statistical Computing). Reconstructed Kaplan–Meier charts were then generated from the pooled IPD data. Both one-stage and two-stage meta-analyses were executed, with hazard ratios (HRs) employed as metrics to evaluate effectiveness. Results: From the initial screening of 216 records, five articles encompassing 1614 patients met the eligibility criteria for inclusion. In two of the five included studies, overall survival was stratified by gait score (1–4 vs. ≥4) in 1043 patients, continence score (1–3 vs. ≥4) in 1022 patients, and mRS (0–2 vs. ≥3) in 956 patients. Patients with good gait demonstrated a mean survival of 8.24 years, while those with poor gait had a mean survival of 6.19 years (log-rank test: p &lt; 0.001). The HR for gait was 2.25 (95% CI: 1.81–2.81, p &lt; 0.001). Continence score stratification revealed a significant difference in survival time (log-rank test: p &lt; 0.001), with an HR of 1.66 (95% CI: 1.33–2.06, p &lt; 0.001). Similarly, mRS stratification demonstrated a significant survival difference (log-rank test: p &lt; 0.001), with an HR of 2.21 (95% CI: 1. 74–2.80, p &lt; 0.001). The reconstructed survival curves for all NPH patients treated with VP shunt therapy, pooling data from five studies, revealed a median survival time of 8.82 years (95% CI: 8.23–9.40). Survival rates at 1, 3, 5, 7, 9, 11, and 13 years were 95.7%, 83.8%, 70.5%, 59.5%, 48.7%, 35.8%, and 25.4%, respectively. Comparison with a general control population showed an HR of 1.79 (95% CI: 1.62–1.98, p &lt; 0.001). Conclusions: This comprehensive meta-analysis underscores the influence of baseline symptom burden on survival after VP shunt therapy in NPH. Therapy in the early stages for those without significant comorbidities may enhance survival.