Multivariate Survival Analysis Research Articles

Clinical Relevance of Resection Margins in Patients with Total Laryngectomy or Laryngopharyngectomy

Background: Laryngeal and hypopharyngeal cancer is complex and resection margins are therefore constrained. The aim of this study was to investigate the clinical relevance of resection margins in laryngeal and hypopharyngeal surgery. Methods: A retrospective cohort study was performed for patients treated with a total laryngectomy (TL) or laryngopharyngectomy (TLP) for laryngeal or hypopharyngeal squamous cell carcinoma (LSCC and HSCC, respectively). Within the groups primary LSCC, recurrent LSCC, primary HSCC, and recurrent HSCC the relationship between the status of the resection margin according to the Royal Collage of Pathology and the recurrence and survival rates were investigated. Results: Positive resection margins were found in 54% for primary LSCC, 29% for recurrent LSCC, 62% for primary HSCC, and 44% for recurrent HSCC. For primary and recurrent LSCC, there was a linear association between total recurrence and narrowing margins (p = 0.007 resp. p = 0.008). Multivariate survival analysis for primary and recurrent LSCC showed a significantly worse disease free and disease-specific survival in case of positive margins compared to clear margins. Conclusion: Similar survival rates were recorded for close and clear margins for primary and recurrent LSCC. This may suggest that a margin > 5 mm is not clinically relevant in terms of survival. Therefore, a margin of 1–5 mm should be accepted in certain subsites. Margins < 1 mm are related to significantly worse outcomes and should be avoided.

#586 Effects of nursing facility residency on mortality in incident HD patients

Abstract Background and Aims As the elderly population increases and nuclear families are formed, the number of elderly people who are managed in nursing facility is increasing. We investigated whether dialysis performed while residing in a nursing facility before dialysis affects the mortality rate of dialysis patients. Method We enrolled 2,597 patients who visited the hemodialysis clinics of 17 teaching hospitals and surveyed the characteristics of underlying diseases, laboratory findings, and medication between patients who started dialysis while admitted to a nursing facility and those who did not. Then, multivariate survival analysis was performed to see if starting dialysis after entering a nursing facility increased mortality. Results 9.1% (n=237) of the subjects underwent dialysis while admitted to a nursing facility. This group was predominantly female and older. Also the prevalence of diabetes, dementia, heart failure and atrial fibrillation was higher. There were many users of anti-platelet agents, warfarin, dementia drugs, and antidepressants. Additionally this group showed lower weight, lymphocyte, iPTH, albumin, phosphorus, and total cholesterol and higher duration of diabetes, and alkaline phosphatase. In multivariate analysis controlling for age, sex, access type, dementia, malignancy, ischemic heart disease, cerebrovascular accident, heart failure, atrial fibrillation, liver cirrhosis, fracture, coronary artery disease, ejection fraction, lymphocyte, platelet, BUN, Cr, albumin, phosphorus, total cholesterol, RAS blockade, B-blocker, calcium channel blocker, warfarin, hyperlipidemia drugs, Calcium-based phosphate binder, sevelamer, anti-depressant, and dementia medication, the HR of group receiving dialysis after being admitted to a nursing facility was 1.658 [1.309, 2.100]. Conclusion In summary, the current study suggests a correlation between starting dialysis in a nursing facility and a higher mortality rate among dialysis patients.

#2822 Can KDPI estimate long-term graft survival in a cohort of Portuguese patients?

Abstract Background and Aims The Kidney Donor Profile Index (KDPI) was introduced in the United States in 2014 to support clinicians' decision-making regarding the acceptance or decline of potential donors. In Portugal, there is no valid stratification score to assist physicians in accepting or declining an organ offer. Our study aims to characterize a cohort of Portuguese kidney transplant recipients and donors and evaluate the correlation between KDPI and long-term graft survival. The results are interpreted considering the nuances of the Portuguese allocation system, which favors an age-matched donor-recipient allocation. Method We conducted an observational single-center retrospective cohort study, which included patients who received a deceased donor kidney transplant at our unit between January 2013 and December 2015. We excluded patients for whom the donor KDPI index was unavailable for retrieval. Besides the KDPI index, we collected data regarding the receptor's demographic, clinical, and immunological characteristics, as well as graft and recipient survival. The primary outcome was death-censored survival, and follow-up ended on the 31st of December 2023. The secondary outcome was survival with a functioning graft. Survival estimates were obtained using Kaplan-Meier curves. We performed univariate and multivariate survival analysis with log-rank tests and Cox proportional-hazards regression models. Results We selected 364 deceased-donor kidney recipients and 212 kidney donors. The mean KDPI was 60% and 53.3% of donors were classified as expanded criteria. The kidney recipients were predominantly male (68.4%), with a mean age of 50.16 years and an average of 4 HLA mismatches. Median follow-up was 102 months. Considering recipient characteristics according to pre-defined KDPI strata (≤ 20%, 21-85%, > 85%), recipients from higher KDPI were significantly older, with a mean age of 40.6, 48.8, and 61.1 years, respectively (p < 0.001), and had a higher average body mass index (p = 0.041). There were no significant differences regarding the number of HLA mismatches (p = 0.624) or the proportion of hypersensitized patients (p = 0.253) between classes. During follow-up, 16.8% patients presented graft failure and 9.9% died with a functioning graft. Cumulative death-censored graft survival at 5, 8, and 10 years was 87.7%, 87.1%, and 84.4% respectively. The cumulative percentage of patients living with a functioning graft at 5, 8, and 10 years was 83.6%, 76.7%, and 68.6%. Death-censored graft survival was lower in recipients of donors with higher KDPI (Fig. 1), although it did not reach statistical significance (p-value = 0.166). The number of HLA mismatches (p = 0.592) or the recipient's age (p = 0.513) did not significantly impact death-censored graft survival, whereas delayed graft function (DGF) was the variable with the strongest association in univariate analysis (p < 0.001). In a multivariate Cox regression model, KDPI (HR 1.02, p = 0.005) and DGF (HR 3.2, p < 0.001) correlated with graft loss, while older recipients (HR 0.971, p = 0.019) seemed to have a protective effect over death-censored survival. Patient survival with a functioning graft was significantly associated with KDPI strata (p = 0.008; Fig. 2), the recipient's age (p = 0.006), and DGF (p < 0.001) in univariate analysis. Considering KDPI kidneys ≥ 90%, 10-year cumulative death-censored survival was 67.9%. Conclusion In our sample, despite not reaching statistical significance, there was a trend for improved death-censored graft survival in patients with lower KDPI, which further emulates the results of other European cohorts. Nevertheless, the 10-year cumulative death-censored survival of higher KDPI kidneys (≥ 90%) was remarkable, showing that long-term acceptable outcomes can be achieved. The impact of KDPI on patient survival with a functioning graft is probably overestimated, given the bias introduced by the Portuguese matching system, which rewards an “old-for-old” donor-recipient allocation.

Risk factors of recurrence after incisional hernia preperitoneal repair: a long-term retrospective single-center cohort study.

To explore the risk factors for incisional hernia (IH) recurrence following open prepertioneal repair. Patients diagnosed with primary IH who underwent open preperitoneal repair at our hospital were enrolled. Patients were assessed, and perioperative factors were collected. Recurrence surveys were performed at regular intervals throughout the long-term postoperative follow-up. The risk factors for IH recurrence were identified using univariate and multivariate analyses. This study included 145 patients. Significant differences were found between recurrence and non-recurrence patients regarding pulmonary ventilation function (PVT), age, body mass index (BMI), mesh materials, type of surgery (clean, clean-contaminated, or contaminated), surgical site infections (SSIs), maximum width of the hernia defect (MWHD), and site of incisional hernia (P < 0.01). The univariate survival analysis revealed that PVT abnormalities, age > 70 years, BMI > 27kg/m2, porcine small intestine submucosal (PSIS) mesh, non-clean surgery, SSIs, MWHD > 10cm, and location in the lateral zones were significant factors for IH recurrence after open preperitoneal repair. The multivariate survival analysis showed that PVT abnormalities, age > 70 years, BMI > 27kg/m2, and PSIS mesh were independent risk factors for IH recurrence after open preperitoneal repair. We identified PVT abnormalities, age > 70 years, BMI > 27kg/m2, and PSIS mesh as novel risk factors for IH recurrence after open preperitoneal repair.

Flow cytometry-based peripheral blood analysis as an easily friendly tool for prognostic monitoring of acute ischemic stroke: a multicenter study

Background and objectiveAcute ischemic stroke (AIS) is a leading cause of mortality, severe neurological and long-term disability world-wide. Blood-based indicators may provide valuable information on identified prognostic factors. However, currently, there is still a lack of peripheral blood indicators for the prognosis of AIS. We aimed to identify the most promising prognostic indicators and establish prognostic models for AIS.Methods484 subjects enrolled from four centers were analyzed immunophenotypic indicators of peripheral blood by flow cytometry. Least absolute shrinkage and selection operator (LASSO) regression was applied to minimize the potential collinearity and over-fitting of variables measured from the same subject and over-fitting of variables. Univariate and multivariable Cox survival analysis of differences between and within cohorts was performed by log-rank test. The areas under the receiving operating characteristic (ROC) curves were used to evaluate the selection accuracy of immunophenotypic indicators in identifying AIS subjects with survival risk. The prognostic model was constructed using a multivariate Cox model, consisting of 402 subjects as a training cohort and 82 subjects as a testing cohort.ResultsIn the prospective study, 7 immunophenotypic indicators of distinct significance were screened out of 72 peripheral blood immunophenotypic indicators by LASSO. In multivariate cox regression, CTL (%) [HR: 1.18, 95% CI: 1.03–1.33], monocytes/μl [HR: 1.13, 95% CI: 1.05–1.21], non-classical monocytes/μl [HR: 1.09, 95% CI: 1.02–1.16] and CD56high NK cells/μl [HR: 1.13, 95% CI: 1.05–1.21] were detected to decrease the survival probability of AIS, while Tregs/μl [HR:0.97, 95% CI: 0.95–0.99, p=0.004], BM/μl [HR:0.90, 95% CI: 0.85–0.95, p=0.023] and CD16+NK cells/μl [HR:0.93, 95% CI: 0.88–0.98, p=0.034] may have the protective effect. As for indicators’ discriminative ability, the AUC for CD56highNK cells/μl attained the highest of 0.912. In stratification analysis, the survival probability for AIS subjects with a higher level of Tregs/μl, BM/μl, CD16+NK cells/μl, or lower levels of CD56highNK cells/μl, CTL (%), non-classical monocytes/μl, Monocytes/μl were more likely to survive after AIS. The multivariate Cox model showed an area under the curve (AUC) of 0.805, 0.781 and 0.819 and 0.961, 0.924 and 0.982 in the training and testing cohort, respectively.ConclusionOur study identified 7 immunophenotypic indicators in peripheral blood may have great clinical significance in monitoring the prognosis of AIS and provide a convenient and valuable predictive model for AIS.

Comparison of different treatment strategies for T3N1-3 stage gastric cancer based on the SEER database

Treatment options for T3N1 stage gastric cancer exhibit regional variation, with optimal approach remaining unclear. We derived our data from the SEER database, using Cox proportional risk regression models for univariate and multivariate analyses of 5-years overall survival (5yOS) and 5-years cancer-specific survival (5yCSS). The results showed that younger age, female, non-white race, highly differentiated histologic grade, non-Signet ring cell adenocarcinoma, low N stage, lesser curvature of the stomach, OP followed by adjuvant C/T with or without RT, partial gastrectomy, C/T and others, Radiation therapy, and Chemotherapy were significantly associated with better 5yOS and 5yCSS. For patients with stage T3N1-3 gastric cancer, multimodal treatment regimens demonstrate superior survival outcomes compared to surgery or radiotherapy alone. Among them, OP followed by adjuvant C/T with or without RT emerges as particularly efficacious, potentially offering enhanced benefits for non-Asian populations.

Liver Resection vs Nonsurgical Treatments for Patients With Early Multinodular Hepatocellular Carcinoma

The 2022 Barcelona Clinic Liver Cancer algorithm currently discourages liver resection (LR) for patients with multinodular hepatocellular carcinoma (HCC) presenting with 2 or 3 nodules that are each 3 cm or smaller. To compare the efficacy of liver resection (LR), percutaneous radiofrequency ablation (PRFA), and transarterial chemoembolization (TACE) in patients with multinodular HCC. This cohort study is a retrospective analysis conducted using data from the HE.RC.O.LE.S register (n = 5331) for LR patients and the ITA.LI.CA database (n = 7056) for PRFA and TACE patients. A matching-adjusted indirect comparison (MAIC) method was applied to balance data and potential confounding factors between the 3 groups. Included were patients from multiple centers from 2008 to 2020; data were analyzed from January to December 2023. LR, PRFA, or TACE. Survival rates at 1, 3, and 5 years were calculated. Cox MAIC-weighted multivariable analysis and competing risk analysis were used to assess outcomes. A total of 720 patients with early multinodular HCC were included, 543 males (75.4%), 177 females (24.6%), and 350 individuals older than 70 years (48.6%). There were 296 patients in the LR group, 240 who underwent PRFA, and 184 who underwent TACE. After MAIC, LR exhibited 1-, 3-, and 5-year survival rates of 89.11%, 70.98%, and 56.44%, respectively. PRFA showed rates of 94.01%, 65.20%, and 39.93%, while TACE displayed rates of 90.88%, 48.95%, and 29.24%. Multivariable Cox survival analysis in the weighted population showed a survival benefit over alternative treatments (PRFA vs LR: hazard ratio [HR], 1.41; 95% CI, 1.07-1.86; P = .01; TACE vs LR: HR, 1.86; 95% CI, 1.29-2.68; P = .001). Competing risk analysis confirmed a lower risk of cancer-related death in LR compared with PRFA and TACE. For patients with early multinodular HCC who are ineligible for transplant, LR should be prioritized as the primary therapeutic option, followed by PRFA and TACE when LR is not feasible. These findings provide valuable insights for clinical decision-making in this patient population.

Hierarchical learning of gastric cancer molecular subtypes by integrating multi‐modal DNA‐level omics data and clinical stratification

Hierarchical learning of gastric cancer molecular subtypes by integrating multi‐modal DNA‐level omics data and clinical stratification

The Role of Emphysema on Postoperative Prognosis in Early-Stage Nonsmall Cell Lung Cancer.

Emphysema is generally considered a poor prognostic factor for patients with nonsmall cell lung cancer; however, whether the poor prognosis is due to highly malignant tumors or emphysema itself remains unclear. This study was designed to determine the prognostic value of emphysema in patients with early-stage nonsmall cell lung cancer. A total of 721 patients with clinical stage IA nonsmall cell lung cancer who underwent complete resection between April 2007 and December 2018 were retrospectively analyzed regarding clinicopathological findings and prognosis related to emphysema. The emphysematous and normal lung groups comprised 197 and 524 patients, respectively. Compared with the normal lung group, lymphatic invasion (23.9% vs. 14.1%, P = 0.003), vascular invasion (37.6% vs. 17.2%, P < 0.001), and pleural invasion (18.8% vs. 10.9%, P = 0.006) were observed more frequently in the emphysema group. Additionally, the 5-year overall survival rate was lower (77.1% vs. 91.4%, P < 0.001), and the cumulative incidence of other causes of death was higher in the emphysema group (14.0% vs. 3.50%, P < 0.001). Multivariable Cox regression analysis of overall survival revealed that emphysema (vs. normal lung, hazard ratio 2.02, P = 0.0052), age >70 years (vs. <70 years, hazard ratio 4.03, P < 0.001), and SUVmax >1.8 (vs. ≤1.8, hazard ratio 2.20, P = 0.0043) were independent prognostic factors. Early-stage nonsmall cell lung cancer with emphysema has a tendency for the development of highly malignant tumors. Additionally, emphysema itself may have an impact on poor prognosis.

RISK FACTORS FOR MENISCAL REPAIR FAILURE FOLLOWING CONCURRENT PRIMARY ACL RECONSTRUCTION: RESULTS FROM THE NEW ZEALAND ACL REGISTRY

BackgroundAnterior cruciate ligament (ACL) reconstruction with concomitant meniscal injury occurs frequently. Meniscal repair is associated with improved long-term outcomes compared to resection but is also associated with a higher reoperation rate. Knowledge of the risk factors for repair failure may be important in optimizing patient outcomes.PurposeThis study aimed to identify the patient and surgical risk factors for meniscal repair failure, defined as a subsequent meniscectomy, following concurrent primary ACL reconstruction.MethodsData recorded by the New Zealand ACL Registry and the Accident Compensation Corporation, the New Zealand Government's sole funder of ACL reconstructions and any subsequent surgery, was reviewed. Meniscal repairs performed with concurrent primary ACL reconstruction was included. Root repairs were excluded. Univariate and multivariate survival analysis was performed to identify the patient and surgical risk factors for meniscal repair failure.ResultsBetween 2014 and 2020, a total of 3,024 meniscal repairs were performed during concurrent primary ACL reconstruction (medial repair = 1,814 and lateral repair = 1,210). The overall failure rate was 6.6% (n = 201) at a mean follow-up of 2.9 years, with a failure occurring in 7.8% of medial meniscal repairs (142 out of 1,814) and 4.9% of lateral meniscal repairs (59 out of 1,210). The risk of medial failure was higher in patients with a hamstring tendon autograft (adjusted HR = 2.20, p = 0.001), patients aged 21–30 years (adjusted HR = 1.60, p = 0.037) and in those with cartilage injury in the medial compartment (adjusted HR = 1.75, p = 0.002). The risk of lateral failure was higher in patients aged ≤ 20 years (adjusted HR = 2.79, p = 0.021) and when the procedure was performed by a surgeon with an annual ACL reconstruction case volume of less than 30 (adjusted HR = 1.84, p = 0.026).ConclusionWhen performing meniscal repair during a primary ACL reconstruction, the use of a hamstring tendon autograft, younger age and the presence of concomitant cartilage injury in the medial compartment increases the risk of medial meniscal repair failure, whereas younger age and low surgeon volume increases the risk of lateral meniscal repair failure.

Incremental Prognostic Value of Left Atrial Strain in Patients With Suspected Myocarditis and Preserved Left Ventricular Ejection Fraction.

Analysis of left atrial (LA) strain and left atrioventricular coupling index (LACI) have prognostic value in cardiovascular diseases. However, the prognostic value of LA strain and LACI in patients with suspected myocarditis and preserved left ventricular ejection fraction (LVEF) is unclear. To investigate the prognostic value of LA strain and LACI in patients with suspected myocarditis and preserved LVEF in comparison with conventional MRI outcome predictors. Retrospective. One hundred sixty-five patients with clinically suspected myocarditis and preserved LVEF with available follow-up data. Steady-state free precession cine and phase-sensitive inversion recovery segmented gradient echo late gadolinium enhancement sequences at 3.0 T. Left ventricular (LV) and LA strain were evaluated using feature tracking. LACI was calculated as the ratio of LA and LV volumes at LV end-diastole. Patients were followed-up with the primary endpoint being major adverse cardiovascular events (MACE). Independent-samples t-test and Mann-Whitney U test to compare patients with and without MACE, receiver operating characteristic (ROC) curve analysis to define high/low risk groups, Kaplan-Meier survival analysis and Cox proportional hazards regression to assess prognosis. A P value of <0.05 was considered statistically significant. The associations of LV strain parameters (including global radial, circumferential, and longitudinal strain) and LACI with MACE were not significant (P = 0.511, 0.108, 0.148, and 0.847, respectively). An optimal LA conduit strain (Ԑe) cutoff value of 10.4% was identified to best classify patients into low- and high-risk groups. Only Ԑe was significantly associated with MACE in both univariable (hazards ratio [HR] 0.936, 95% confidence interval [CI] 0.884-0.991) and multivariable Cox survival analyses (HR 0.937, 95% CI 0.884-0.994). LA conduit strain has prognostic value in patients with suspected myocarditis and preserved LVEF, incremental to conventional MRI outcome predictors, whereas LACI was not associated with MACE occurrence. 3 TECHNICAL EFFICACY: Stage 2.

Correlation of gasdermin B staining patterns with prognosis, progression, and immune response in colorectal cancer

BackgroundPyroptosis is a type of programmed cell death mediated by the gasdermin family. Gasdermin B (GSDMB), as a member of gasdermin family, can promote the occurrence of cell pyroptosis. However, the correlations of the GSDMB expression in colorectal cancer with clinicopathological predictors, immune microenvironment, and prognosis are unclear.MethodsSpecimens from 267 colorectal cancer cases were analyzed by immunohistochemistry to determine GSDMB expression, CD3+, CD4+, and CD8+ T lymphocytes, CD20+ B lymphocytes, CD68+ macrophages, and S100A8+ immune cells. GSDMB expression in cancer cells was scored in the membrane, cytoplasm, and nucleus respectively. GSDMB+ immune cell density was calculated. Univariate and multivariate survival analyses were performed. The association of GSDMB expression with other clinicopathological variables and immune cells were also analyzed. Double immunofluorescence was used to identify the nature of GSDMB+ immune cells. Cytotoxicity assays and sensitivity assays were performed to detect the sensitivity of cells to 5-fluorouracil.ResultsMultivariate survival analysis showed that cytoplasmic GSDMB expression was an independent favorable prognostic indicator. Patients with positive cytoplasmic or nuclear GSDMB expression would benefit from 5-fluorouracil based chemotherapy. The assays in vitro showed that high GSDMB expression enhanced the sensitivity of colorectal cancer cells to 5-fluorouracil. Patients with positive membranous or nuclear GSDMB expression had more abundant S100A8+ immune cells in the tumor invasive front. Positive nuclear GSDMB expression indicated more CD68+ macrophages in the tumor microenvironment. Moreover, GSDMB+ immune cell density in the stroma was associated with a higher neutrophil percentage but a lower lymphocyte counts and monocyte percentage in peripheral blood. Furthermore, the results of double immunofluorescence showed that GSDMB co-expressed with CD68 or S100A8 in stroma cells.ConclusionThe GSDMB staining patterns are linked to its role in cancer progression, the immune microenvironment, systemic inflammatory response, chemotherapeutic efficacy, and prognosis. Colorectal cancer cells with high GSDMB expression are more sensitive to 5-fluorouracil. However, GSDMB expression in immune cells has different effects on cancer progression from that in cancer cells.

Abstract PS03-08: Spatial biomechanics determines fate in breast cancer

Abstract Background: With the recent advancements of spatial omics, it has become increasingly recognized that spatial analysis the of tumor architecture is key to decipher the heterogenous intratumoral relationships between different tumor components and provide better understanding of cancer therapy resistance, as well as help to identify potential targets for personalized therapy. The challenge of the discovery and implementation of such biomarkers still lays in the technological and methodological difficulties, and their translation into clinical practice. In parallel a major advancement in cancer research has been the recognition of the importance of cancer biomechanical properties in cancer progression, metastasis, and therapy response. Methods: We developed a new computational platform to identify biomechanical drivers of cancer outcome from spatial omics data. We used it to identify recurring spatial patterns of these markers within the tumor microenvironment, and define the spatial scale of heterogeneity of such patterns. Our dataset consists in 700 primary breast cancer baseline samples analyzed with two 30-marker imaging mass cytometry panels to identify cancer, immune, and stromal cells and structures and their biomechanical states. Our patient cohort includes 20+ years of follow up, with up to 6 samples per patient from 64 patients alive 12 years post diagnosis, and 49 patients lost to breast cancer deaths. Patients were treated with surgery, radiation, chemotherapy, endocrine therapy, or combinations of these post-surgery. Based on this approach, we derived a new three-parameter quantitative metric of preferential spatial co-localization between different cells or structures, and we use this metric to stratify patients into responders and non-responders with the aid of single and multivariate survival analysis. Finally, we include a correlation with Atomic Force Microscopy to identify the mechanical signature of these driving patterns in breast cancer. Results: Our work enabled the identification of tumor-immune-stromal spatial patterns that drive breast cancer outcome and their spatial scale. Among our results, we were able to further define spatial regions of hypoxia-driven EMT. We found these regions to be usually on the scale of 50 mm radius, and enriched in presence of unspecified immune cells. They are also more frequent in ER+ areas, with high NaKATPase activity. Our analysis also shed light on the controversy on the role of fibroblasts. We have found that the presence of a strong, spatially structured stroma, in fibroblast-rich regions is a strong predictor of positive outcome. Similarly, in our analysis collagen cross-linking emerges as a positive control factor in Vimentin-rich microenvironments, offering new interpretation to the role of the ECM structure. Importantly, our first principle approach allows for the identification of driving structures beyond heterogeneity, and thus enables easy extension to additional datasets. Finally, when correlating these patterns with Atomic force microscopy measurements, we can clearly see that patterns predictive of poor survival present a clear heterogeneous stiffness signature, as opposed to a very homogenous good survival pattern signature. Conclusion: These results confirm the importance of spatial distribution of biomechanical drivers in cancer, offering new avenues of physics-based therapeutic targets. Our results also offer a solid base to inform machine learning algorithms on how to significantly parametrize spatial patterns in breast cancer for clinical significance. Furthermore, we demonstrate for the first time the use of Atomic Force Microscopy as a single biomarker for these patterns in breast cancer with a direct correlation based on pathology matching. Citation Format: Sara Nizzero, Maria Pelaez Soni, Gregory Zaugg, Mariam Gachechiladze, Yitian Xu, Licheng Zhang, Junjun Zheng, Brian Menegaz, Lee B Jordan, Colin A Purdie, Philip R Quinlan, Chandandeep Nagi, Karla A Sepulveda, Philipp Oertle, Tobias A Appenzeller, Marko Loparic, Zhihui Wang, Shu-Hsia Chen, Vittorio Cristini, Marija Plodinec, Alastair Thompson. Spatial biomechanics determines fate in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS03-08.

Prioritizing Disease Diagnosis in Neonatal Cohorts through Multivariate Survival Analysis: A Nonparametric Bayesian Approach.

Understanding the intricate relationships between diseases is critical for both prevention and recovery. However, there is a lack of suitable methodologies for exploring the precedence relationships within multiple censored time-to-event data, resulting in decreased analytical accuracy. This study introduces the Censored Event Precedence Analysis (CEPA), which is a nonparametric Bayesian approach suitable for understanding the precedence relationships in censored multivariate events. CEPA aims to analyze the precedence relationships between events to predict subsequent occurrences effectively. We applied CEPA to neonatal data from the National Health Insurance Service, identifying the precedence relationships among the seven most commonly diagnosed diseases categorized by the International Classification of Diseases. This analysis revealed a typical diagnostic sequence, starting with respiratory diseases, followed by skin, infectious, digestive, ear, eye, and injury-related diseases. Furthermore, simulation studies were conducted to demonstrate CEPA suitability for censored multivariate datasets compared to traditional models. The performance accuracy reached 76% for uniform distribution and 65% for exponential distribution, showing superior performance in all four tested environments. Therefore, the statistical approach based on CEPA enhances our understanding of disease interrelationships beyond competitive methodologies. By identifying disease precedence with CEPA, we can preempt subsequent disease occurrences and propose a healthcare system based on these relationships.

Abstract PO2-15-03: Platelet-to-lymphocyte ratio in patients with metastatic breast cancer treated with eribulin

Abstract Eribulin is widely used to treat metastatic breast cancer (BC). Higher neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) are associated with higher mortality in several cancer types. However, the association between BC prognosis and peripheral immune status remains controversial. We quantified the relative effects of NLR and PLR on survival in patients with recurrent/stage IV BC and evaluated their clinical prognostic value. This retrospective study included 156 patients with recurrent/stage IV BC who received eribulin monotherapy at Saitama Medical University International Medical Center. We examined clinicopathological features (peripheral blood findings and biochemical liver and kidney function test results) and conducted univariate and multivariate analyses of the overall survival (OS). The 156 eribulin-treated patients had a median follow-up duration of 18.3 months. Before eribulin treatment, patients with absolute lymphocyte counts (ALC) &amp;gt;1500/uL, NLRs &amp;lt; 3.0, and PLRs &amp;lt; 150 had significantly longer OS than those with lower ALCs, and higher NLR and PLRs (median OS, 25.5 vs. 15.5 months; p&amp;lt; 0.01; 20.3 vs. 13.6 months, P&amp;lt; 0.01; and 29.2 vs. 14.8 months; P&amp;lt; 0.001, respectively). Patients with anemia (hemoglobin &amp;lt; 10 g/dL) or liver dysfunction (albumin-bilirubin grade 2/3) had significantly shorter OS than those without (P&amp;lt; 0.001, respectively). Multivariate analysis revealed low albumin-bilirubin grade (P&amp;lt; 0.001), high hemoglobin (P&amp;lt; 0.01), and low PLR (P&amp;lt; 0.05) as independent factors of longer OS after eribulin administration. Low PLR, anemia, and liver dysfunction might be factors associated with prolonged OS in patients with recurrent/stage IV BC on eribulin therapy, which could be clinically useful, as their evaluation requires neither new equipment nor invasive testing. Citation Format: Hiroko Shimada, Kazuo Matsuura, Shunsuke Kohyama, Aya Asano, Masahiro Ohara, Hiroshi Ishiguro, Akihiko Osaki, Toshiaki Saeki. Platelet-to-lymphocyte ratio in patients with metastatic breast cancer treated with eribulin [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-03.

Abstract PS11-06: Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival

Abstract Background: Previous studies have shown that breast cancer receptor subtype switching between matched primary and metastatic brain metastases (BrM) is common. HER2 expression at low levels, termed “HER2 Low”, has emerged as a new therapeutic biomarker for highly active antibody drug conjugates with potential intracranial activity. Trastuzumab deruxtecan is FDA approved for the treatment of HER2 Low and HER2 positive breast cancer with emerging evidence of CNS responses and clinical benefit in patients with BrM. This study aimed to investigate the relationship between HER2 expression including HER2-Low between matched breast cancer primary tumors and brain metastases. We also sought to evaluate the impact of low HER2 expression on overall survival in breast cancer brain metastases. Methods: We identified pts with MBC seen at least once at a single, NCI-designated center and had a diagnosis of BrM between 2003 and 2023. Of 1252 MBC pts with a diagnosis of BrM, 265 pts underwent resection/biopsy for BrM with available ER/PR/HER2 status. Only pts with available matched primary and BrM tissue were analyzed. HER2 expression was defined as: HER2+ (3+ or 2+/ISH amplified), HER2-Low (1+, 2+/ISH neg) or HER2-0 [by ASCO-CAP guidelines]. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate overall survival (OS) analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between HER2+, HER2-Low and HER2-0 patients controlling for ER and age. Results: 197 matched breast cancer primary and BrMs with available ER, PR, and HER2 testing were evaluated. Median age at BrM resection was 51 yrs. ER was positive in 48% (N=95) of BrMs. Of 265 resected BrMs, HER2 expression was found in 72%: 49.8% HER2+ (N=132), 22.2% HER2-Low (N=59), and 27.9% HER2-0 (N=74). HER2 expression by 197 primary tumors was: 57% HER2+ (N=112), 24% HER2-Low (N=48), 19% HER2 0 (N=37). Amongst 112 HER2+ primary tumors, 97% (N=109) had concordant HER2+ BrMs, 3 (2.6%) switched to HER2-Low, with 100% retaining some HER2 expression. Of 37 HER2-0 primaries, 35% (13/37) gained HER2-Low expression and 5.4% (2/37) gained HER2+ expression in the BrM. Amongst 48 HER2-Low primary tumors, half (52%) changed expression to either HER2+ (21%) or HER2-0 (31.2%) in the brain. 66 tumors had extracranial tissue biopsied prior to BrM resection available for HER2 analysis. Of 15 HER2-0 extracranial tumors, 47% gained HER2-Low and 13% gained HER2+ at time of BrMs. After adjusting for age and ER status at the time of BrMs, patients with HER2+ BrM had a statistically significant lower risk of death at time of follow up than those with HER2-Low BrM (HR=0.41, P=0.0006). The risk of death between patients with HER2-0 BrM did not differ from HER2-Low BrM after adjustment for ER and age (HR=0.96, p =0.9). Median survival from BrM resection was 12.4m, 16.1m, 47.6m for HER2-Low, HER2-0 and HER2+ respectively (p = .0004). Conclusions: HER2 expression amongst primary, extracranial and brain metastases is dynamic with frequent change. Over 40% of HER2-0 primary or extracranial tumors gain HER2 expression in the brain. These changes have therapeutic implications given HER2 targeting antibody drug conjugates with improved OS and emerging evidence of CNS activity, highlighting the need for better diagnostics, including those that do not require invasive tissue sampling, to determine HER2 status in the brain. Patients with HER2-Low and HER2-0 BrMs have inferior survival and are a clinical unmet need. Citation Format: Alyssa Pereslete, Melissa Hughes, Alyssa Patterson, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric Winer, Tianyu Li, Sara Tolaney, Nancy Lin, Sarah Sammons. Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-06.

Abstract PO1-16-01: Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort

Abstract Background: Estrogen receptor (ER) expression is currently the most consequential biomarker for prognostic and therapeutic decision making in clinical management of early breast cancer. Endocrine therapy (ET) is an important part of standard of care in most cases with ER-positive disease, and an effective therapy for patients with endocrine-responsive tumors, decreasing the risk of recurrence and improving the rate of survival. Unfortunately, ET comes with frequently bothersome side-effects and tend to decrease quality of life. The threshold to define ER positivity as a marker of endocrine responsiveness is non-uniform between international and local guidelines. Among ER low positive tumors (ERlow ,1-10% expression) endocrine responsiveness is uncertain. Swedish national guidelines recommend a cut-off of ≥10% for ER positivity and ET prescriptions, thus patients with ERlow tumors are often exempted from adjuvant ET. This study explores the clinicopathological characteristics, global transcriptional complexity and clinical outcome of ERlow tumors to better understand their biology and response to therapy. Methods: 9138 patients diagnosed with early breast cancer between 2010 – 2021 in Sweden with available clinicopathological data and RNA sequencing data were included. Patients were classified according to ER expression: ERneg (&amp;lt; 1%; n=897), ERlow (1-10%, n=158) and ERhigh ( &amp;gt;10%, n=8083). Adjuvant ET was provided to 3.6%, 16.8% and 91.5% of patients with ERneg, ERlow, and ERhigh tumors, respectively. Clinicopathological characteristics, overall survival (OS) and global transcriptional profiles of ERlow tumors were compared with ERneg and ERhigh tumors, respectively. Results: Generally, ERlow and ERneg tumor pathological characteristics were more similar to each other but were significantly distinct compared to ERhigh tumors. However, among patients with HER2-negative disease only, significant differences related to tumor biology persisted between ERlow compared with ERneg tumors; ERlow was enriched with tumors displaying a lobular histology, NHG grades 1&amp;2, PgRlow/high expression, low proliferation and Luminal &amp; HER2-enriched molecular subtypes (p&amp;lt; 0.05 for all comparisons). Moreover, multivariable survival analyses revealed that the risk of dying was significantly lower for patients with ERlow tumors compared to patients with ERneg (p=0.005) or ERhigh tumors (p=0.011) in this cohort. The distribution of clinicopathological characteristics and overall survival between ERlow compared with ERneg or ERhigh tumors were similar among patients with HER2-positive tumors only. Global transcriptional comparisons identified only 42 genes to be differentially expressed between ERlow vs ERneg tumors (FDR&amp;lt; 0.05); but gene set enrichment analyses failed to identify any significantly enriched cancer-related processes/pathways within the queried databases. Conclusions: Identification of optimal therapies for all subsets of breast cancer is necessary in the pursuit of personalized medicine. These results confirm that ERneg and ERlow tumors are pathologically and transcriptionally distinct from ERhigh tumors. Although subtle differences exists in the underlying biology of ERlow compared to ERneg tumors, similar therapeutic management excluding ET for patients with ERlow and ERneg disease is recommended in the Swedish context. Omission of adjuvant ET did not seem to compromise overall survival for ERlow relative to ERneg or ERhigh tumors, urging the need for prospective studies investigating the true benefit of ET for ERlow tumors. Our results also raise reasonable clinical thoughts on the benefits of new treatment strategies such as cyclin-dependent kinase 4/6 inhibitors, immunotherapy and antibody-drug conjugates for patients with ERlow expressing tumors. Citation Format: Siker Kimbung, Srinivas Veerla, Anna Ehinger, Johan Vallon-Christersson, Martin Malmberg, Niklas Loman. Clinicopathological and global transcriptional complexity of estrogen receptor low positive breast cancers in a contemporary Swedish prospective population-based cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-16-01.

Age-related clusters and favorable immune phenotypes in breast cancer of the young

Breast cancer (BC) patients aged below 40 years at diagnosis experience aggressive disease and poorer survival compared to women diagnosed at 40-49 years, but the age-related biology is described to little extent. Here, we explored transcriptional alterations in BC to gain better understanding of age-related tumor biology. We studied a subset of the Bergen in-house cohort (n=127, age range 26-49) and used the NanoString Breast Cancer 360 expression panel on formalin-fixed paraffin-embedded breast cancer tissue, and publicly available global breast cancer mRNA expression data (n=204, age range 22-49), to explore differentially expressed genes between the young (age <40) and older (age 40-49) patients. Unsupervised hierarchical clustering was applied to identify gene expression-based patient clusters. We applied established computational approaches to define the PAM50 subtypes, Risk of recurrence scores (ROR), and Risk groups, and to infer the proportions of 22 immune cell types from bulk gene expression profiles of patients aged <50 at breast cancer diagnosis. Differentially expressed genes and gene sets were investigated using OncoEnrichR and g:Profiler to describe functional profiles and pathway enrichment. We identified four age-related patient clusters presenting distinct characteristics of PAM50 subtypes and ROR profiles, which demonstrated independent prognostic value when adjusted for traditional clinico-pathologic variables and the known molecular subtypes. Our findings showed better survival than expected in the basal-enriched cluster 2, and in triple negative and basal-like BC. Deconvolution analyses of immunophenotypes indicated higher levels of M0 and M1 macrophages than M2 macrophages in subsets of young BC. Our approach identifies age-based patient clusters with distinct clinico-pathologic profiles, to a large extent overlapping with the PAM50 subtypes, although with independent prognostic value in multivariate survival analyses. The patient clusters provided new insight in the immune cell distribution across tumor subtypes, potentially contributing to survival differences between the clusters and the molecular subtypes and indicating age-related mechanisms improving outcome. Our study confirms the applicability of ROR as a valid prognosticator also in a young breast cancer cohort.

AI-Derived Body Composition Parameters as Prognostic Factors in Patients with HCC Undergoing TACE: Results from a Multicenter Study

Background & AimsBody composition assessment (BCA) parameters have recently been identified as relevant prognostic factors for patients with hepatocellular carcinoma (HCC). Here we aimed to investigate the role of BCA parameters for prognosis prediction in patients with HCC undergoing transarterial chemoembolization (TACE). MethodsThis retrospective multicenter study included a total of 754 treatment-naïve patients with HCC who underwent TACE at six tertiary care centers between 2010–2020. Fully automated artificial intelligence-based quantitative 3D volumetry of abdominal cavity tissue composition was performed to assess skeletal muscle volume (SM), total adipose tissue (TAT), intra- and intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) on pre-intervention computed tomography scans. BCA parameters were normalized to the slice number of the abdominal cavity. We assessed the influence of BCA parameters on median overall survival (OS) and performed multivariate analysis including established estimates of survival. ResultsUnivariate survival analysis revealed that impaired median OS was predicted by low SM volume (p < 0.001), high TAT volume (p = 0.013), and high SAT volume (p = 0.006). In multivariate survival analysis, SM remained an independent prognostic factor (p = 0.039), while TAT and SAT volumes no longer showed predictive ability. ConclusionsSkeletal muscle volume is an independent prognostic factor for survival prediction. Thus, the integration of SM into novel scoring systems could potentially improve survival prediction and clinical decision-making. Fully automated approaches are needed to foster the implementation of this imaging biomarker into daily routine. Impact and implicationsBody composition assessment parameters, especially skeletal muscle mass, have been identified as relevant prognostic factors for many diseases and treatments. In this study skeletal muscle volume has been identified as an independent prognostic factor for patients with HCC undergoing TACE. Therefore, skeletal muscle mass as a metaparameter could play a role as an opportunistic biomarker in holistic patient assessment and be integrated into decision support systems. Workflow integration with AI evaluation is essential for automated body composition assessment quantification output enabling broad availability in multidisciplinary case discussions.

Assessment by a multidisciplinary team conference affects treatment strategy and overall survival in patients with synchronous colorectal liver metastases

BackgroundThe aim of this retrospective observational study was to investigate the geographical or sex differences in patients with synchronous colorectal liver metastases (sCRLM) in terms of assessment by a multidisciplinary team conference (MDT), curative treatment, and overall survival. MethodAll sCRLM patients in the South-East Health Care Region of Sweden from 2009-2015 were included (n=615). Data were derived from the Swedish Colorectal Cancer Registry, Swedish Registry of Liver and Bile Surgery and medical records. ResultsPatients who had a hepatobiliary unit (HBU) at the nearest hospital were more likely to undergo liver surgery (HBU+, 37% (n=106), compared to HBU-, 22% (n=60); p=0.001) and had a better median survival (p<0.001). No sex differences were observed. In multivariate Cox regression analyses of overall survival, assessment by an MDT that included a liver surgeon was independently linked to better survival (HR 0.574, 0.433-0.760). ConclusionThere were no sex differences in access to liver surgery or overall survival, however, there were geographical inequalities, where residency near a hospital with HBU was associated with increased overall survival and the possibility to receive liver surgery. Assessment at MDT with liver surgeon present was associated with greater survival, indicating its important role for treatment.