Univariate Survival Analysis Research Articles

Interplay between strain pattern-based classification of dyssynchrony and myocardial scar in CRT patients

Abstract Introduction Echocardiography-derived septal strain patterns are valuable for predicting volumetric reverse remodelling and survival in patients undergoing cardiac resynchronization therapy (CRT). Nevertheless, presence of myocardial scarring in the left ventricle (LV) is known to attenuate CRT treatment response. Purpose This study aims to investigate the interplay between septal strain patterns and myocardial scarring in CRT candidates, and how they link to outcome after CRT. Methods In this prospective multicentre study, CRT candidates from five European institutions underwent pre-implantation assessments using speckle-tracking strain analysis on echocardiography and cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). Dyssynchrony was graded through analysis of septal strain curves, categorizing patients into five distinct patterns, denoted as strain Stage-0 through strain Stage-4 (Fig. A). LGE of the LV wall was quantitatively assessed using CMR (as a percentage). The study endpoints were volumetric reverse remodelling (volume responder = more than 15% decrease LV end-systolic volume) after one year, and all-time all-cause mortality. Results A total of 267 patients, with a mean age of 66±11 years (69% males, 90% left bundle branch block [LBBB]) presented with an average LV ejection fraction (EF) of 30±7%. With each stepwise increase in strain stage, global LV scarring decreased (p<0.01; Fig. B) and the proportion of volume responders increased (all p<0.0001; Fig. C). ROC curves demonstrated that the predictive power of strain stages for CRT volumetric response was not significantly improved when scarring percentage was added (AUC 0.78 [95% CI: 0.69-0.83] vs. 0.81 [95% CI: 0.71-0.90]; p>0.05; Fig. D). In a multivariate cox regression model – including clinical characteristics that were significantly related to survival in univariate analysis – a patients’ strain stage was the only significant predictor of survival, also outperforming scar burden as determinant of outcome (HR 0.68; p=0.041; Fig. E). Conclusions Septal strain patterns show a strong association with the extent of reverse remodelling and outcome in CRT-treated patients. An inverse relationship is observed between pre-implant strain stages and the extent of myocardial scarring. However, scar burden did not provide incremental predictive value over the strain stages. Strain-pattern-based dyssynchrony assessment is a meaningful predictive marker which integrates information on myocardial dysfunction due to dyssynchrony as well as scar burden.

Long-term survival after coronary artery bypass grafting comparing bilateral versus single internal mammary artery in a women cohort

Abstract Introduction Although neutral results from the ART randomized controlled trial, observational studies have been supporting better survival after bilateral internal mammary artery (BIMA) vs single internal mammary artery (SIMA) coronary artery bypass grafting (CABG). However, for some specific subgroups, like women patients, more doubts remain about BIMA benefits. Aim To compare long-term survival and early results in women after SIMA vs BIMA. Methods Longitudinal, retrospective, single-center study including consecutive women with at least 2 left-coronary system (LCS) vessel disease who underwent primary isolated CABG with at least 1 internal mammary artery (IMA) conduit and a minimum of 2 conduits targeting the LCS, between 2004-2014. Emergent or salvage surgeries, on-pump beating-heart, BIMA in which 1 IMA targeted the right coronary artery territory were excluded. The primary outcome was all-causes mortality (checked on February 2023). Time-to-event outcomes were studied using Kaplan-Meier Curves, Log-Rank test and multivariable Cox Regression. Median follow-up was 11 years, maximum of 19 years. Results From 539 women selected for this study, BIMA CABG was performed in 30%. SIMA patient’s were older (mean age 68.95±8.39 vs 62.75±9.82 years, p<0.001), but the prevalence of cardiovascular risk factors were similar between groups (arterial hypertension, p=0.693; dyslipidemia, p=0.111; diabetes mellitus, p=0.462 and obesity, p=0.109). Peripheral artery disease (p=0.707), left ventricular dysfunction (p=0.727), cerebrovascular disease (p=0.730), active smoking habits (p=0.05) and chronic obstrutive pulmonary disease (p=0.537) were also similar. Severe chronic kidney disease (27% vs 14%, p<0.001) and Canadian Coronary Society - grade IV (74% vs 63%, p=0.011) were more frequent in SIMA group. In the univariable survival analysis, SIMA had worse survival results than BIMA (Log Rank test p<0.01). At 5-, 10- and 15- years of follow-up, cumulative survival for SIMA vs BIMA were 88% vs 90%, 68% vs 75%, 42% vs 58%, respectively. However, the multivariable Cox regression showed that BIMA was not associated with long-term survival (HR [95%CI]: 1.09 [0.75-1.59], p=0.6). Most of post-operative outcomes were similar between groups, with the exception of atrial fibrilation (25% vs 16%, p=0.031) and time to discharge (median days [min-max]: 7 [4-128] vs 7 [4-59]) that were higher in SIMA. No differences were found in immediate reexploration of thorax (sternal infection – 0.3% SIMA vs 1.2% BIMA, p=0.219; bleeding- 1.6% SIMA vs 0.6% BIMA, p=0.681). Redo CABG occurred in 1 SIMA and 1 BIMA women, at 41 and 84 months of follow-up, respectively. Conclusion In this study, revascularization with BIMA seems to be safe in women and provides similar results than SIMA. More studies in women are needed to establish the better approach for this specific subgroup.

Impact of coronary revascularization on clinical outcomes of post-acute myocardial infarction patients with left ventricular thrombus

Abstract Background Left ventricular thrombus (LVT) is an uncommon, but dangerous complication seen in post-acute myocardial infarction (AMI). With advances in percutaneous coronary intervention (PCI) techniques, the incidence of post-AMI LVT has declined in the contemporary era. However, a minority of patients do not undergo coronary revascularisation due to medical contraindications or patient preference. This study aimed to evaluate the clinical characteristics and outcomes of post-AMI LVT patients treated with and without coronary revascularisation. Methods This was a retrospective study of 263 consecutive post-AMI patients diagnosed with LVT from November 2012 to January 2021, retrieved from a echocardiography database. Patients were stratified by the presence or absence of revascularisation treatment. Baseline clinical characteristics, treatment and outcomes data were collected and analysed. Results The median follow-up duration was 2.9 years (IQR: 0.9 – 4.7). A majority of post-AMI LVT patients underwent revascularisation via PCI (71.5%, n = 188), CABG (4.2%, n = 11) or thrombolysis (0.4%, n = 1). Unrevascularised patients (24.0%, n = 63) were older (p <0.001), more likely to be female (p <0.001), and had more co-morbidities such as previous stroke (p <0.001), heart failure (p = 0.001), chronic kidney disease (p = 0.020), and malignancy (p = 0.021). More unrevascularised patient had NSTEMI (p < 0.001), and significantly fewer were treated with triple therapy (p < 0.001). Incidence of LVT resolution was lower (p < 0.001) while all-cause mortality was higher (p < 0.001) for unrevascularised patients on univariate survival analyses. On multivariable Cox regression, revascularisation status was not an independent predictor of LVT resolution, bleeding, stroke, or all-cause mortality outcomes. Conclusion While unrevascularised post-AMI LVT patients had poorer outcomes compared to revascularised patients overall, revascularisation status itself was not independently associated with poorer clinical outcomes. Optimising medical therapy such as triple therapy remains a key treatment goal for post-AMI LVT patients.

Cardiac chamber three-dimensional volumes and deformation predict clinical outcomes in chronic mitral regurgitation

Abstract Background In patients with mitral regurgitation (MR), cardiac remodeling assessed by two-dimensional (2D) echocardiographic linear indexes is highly variable and not suitable for individualized risk assessment. Purpose To evaluate whether measurements of myocardial strain and left atrial (LA), left ventricular (LV) and right ventricular (RV) three-dimensional (3D) volumes improve risk assessment in MR. Methods In the prospective 3D Echocardiography and Cardiovascular Prognosis in Mitral Regurgitation study (3D-PRIME), 176 patients with significant (moderate or greater) MR were investigated with 2D/3D echocardiography. Referral criteria for mitral intervention followed current guidelines. LA remodeling was assessed by the maximum and minimum 3D LA volume (3D-LAV), peak reservoir strain (LASr), and stiffness (i.e. the ratio: mitral peak E-wave divided by the annular e’ velocity (E/e´) / LASr). LV and RV were considered dilated in case of increased 3D end-diastolic (LV>=86/74 and RV>=87/74ml/m2 in men/women) and end-systolic volumes indexed for body surface area (LV>=41/33 and RV>=44/36ml/m2 in men/women). Peak global longitudinal strain was measured in the LV (LV-GLS) and the RV free wall (RV-FWS). The primary outcome was a composite of mitral valve surgery, percutaneous mitral edge-to-edge repair and death. Results During a 14 [8-24] months follow-up, the patients (70±13 years, 39% women) experienced 73 events including 14 deaths. In univariate survival analyses, LV and RV dilatation, but not LV-GLS and RV-FWS, were associated with the primary outcome (Figure) and had superior predictive value to 2D volumes and diameters (p<0.05). On contrary, both atrial size and function predicted outcome, with 3D-LAV (HR 1.01, 95% CI 1.00-1.01), LASr (HR 1.03, 95% CI 1.01-1.06) and increased LA stiffness (Figure) all significant predictors of events (p<0.05). In multivariate Cox analysis with adjustment for age, sex, body mass index and MR etiology, dilated LV (HR 2.6, 95% CI 1.5-4.4), dilated RV (HR 2.0, 95% CI 1.1-3.6) and increased LA stiffness ((HR 2.4, 95% CI 1.3-4.6) were independently associated with higher rate of events (p<0.05). Conclusion In patients with moderate or greater MR, increased cardiac chamber 3D volumes and LA stiffness, as well as impaired LA reservoir strain are associated with higher risk of disease progression towards mitral valve intervention and death. Our findings indicate that assessment of both cardiac chamber 3D size and LA deformation can contribute to increased diagnostic and prognostic precision in patients with MR.

Fat necrosis after accelerated partial breast irradiation or hypofractionated whole breast irradiation: A case-control study.

This study aimed to compare the incidence of fat necrosis after accelerated partial breast irradiation (APBI) vs hypofractionated whole breast irradiation (WBI) in patients with early-stage breast cancer. Data from early-stage breast cancer patients who underwent breast-conserving surgery and adjuvant radiotherapy between 2009 and 2022 were retrospectively collected. Radiation therapy consisted of APBI of 30 Gy in 5 daily fractions (Fx) (delivered in one week, consecutively) to the tumour bed or WBI (42.4 Gy in 16 Fx). Reports on fat necrosis were extracted from yearly mammograms and breast ultrasound imaging. The primary endpoint was the incidence of radiologically detected fat necrosis. A total of 536 patients were included among the APBI and WBI cohorts, with 268 and 268 patients respectively. The three-year Kaplan-Meier actuarial rate of fat necrosis was 32.8% (95% CI: 30.0% - 35.6%) for APBI and 22.3% (95% CI: 19.7% - 24.9%) for WBI patients. Univariate Kaplan-Meier survival analysis revealed a Hazard Ratio of 1.6 [95% CI: 1.1 - 2.2; p = 0.0055] for the fat necrosis rate within the APBI group compared to WBI. Multivariate Cox proportional hazard regression confirmed significant associations between fat necrosis and APBI (HR = 2.2 95% CI: 1.2 - 4.0; p = 0.01). The occurrence of radiologically diagnosed fat necrosis was higher in the APBI group compared to the WBI. Further investigations aiming to identify a lower-dose schedule with comparable efficacy to 30 Gy in 5 Fx but fewer toxicities, particularly for high-risk patients, are warranted.

Former jean sandblasters die younger.

Silicosis remains a critical public and occupational health issue, exacerbated by its expansion into non-traditional industries and resulting in significant global morbidity and mortality. This study aims to investigate the death rates associated with silicosis from jean sandblasting by comparing the results of diagnosed individuals to those of the general population. Conducted from 2008 to 2023 in Taşlıçay and Toklular villages, Bingöl City, Turkey, this retrospective cohort study analysed mortality among 220 diagnosed males versus 2851 undiagnosed residents. Data were derived from the Cohort database and validated with the Bingöl Provincial Health Directorate and the Turkish Statistical Institute. Statistical analysis involved univariate comparisons and survival analysis, utilizing the Mann-Whitney U-test, Kruskal-Wallis test and Cox proportional hazards model, with significance set at P < 0.05. The analysis revealed a silicosis mortality rate of 10% in diagnosed individuals over 15 years, notably higher than the 4% in the general population. Higher radiological profusions and younger ages at diagnosis were significant mortality factors. A radiological profusion above five notably increased the mortality risk by 1.37 times, with age and radiological density proving critical in survival rates. This research highlights the increased mortality risk in silicosis patients, particularly among former jean sandblasters, underscoring the significant effects of radiological density and early age exposure on mortality, thereby addressing a crucial gap in understanding the impact of silicosis on life expectancy and community health.

The vasculogenic mimicry, CD146+ and CD105+ microvessel density in the prognosis of endometrioid endometrial adenocarcinoma: a single-centre immunohistochemical study

The microvessel compartment is crucial in the tumour microenvironment of endometrioid adenocarcinoma (EA). This study investigated the role of vasculogenic mimicry (VM), CD146, and CD105 microvessel density in the clinical prognosis of EA. A total of 188 EA cases were analyzed, with VM channels and microvessels detected using PAS/CD31, CD146, and CD105 staining. Mann-Whitney and Fisher exact tests were used to compare the study groups according to the evaluated criteria. ROC analysis included determination of the confidence interval (CI) and area under the ROC curve. The Mantel-Cox test was used to analyze progression-free survival. Multivariate Cox proportional hazard analysis was performed using stepwise regression. Results showed that VM channels and CD146 and CD105 microvessels were significantly higher (p < 0.0001) in cases with unfavourable prognosis. Univariate survival analysis highlighted the significant role of these factors in progression-free survival, while multivariate Cox analysis identified VM and CD146+ vessels as predictive factors. This study demonstrates, for the first time, that VM, CD146, and CD105-positive vessels are involved in EA prognosis, suggesting their potential as independent prognostic indicators and targets for antiangiogenic therapy. However, these findings require further validation through large-scale studies.

Outcome of donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation in relapsed myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (HSCT) improves outcomes for myelodysplastic syndrome (MDS) patients, but relapse rates remain high, and post-relapse treatment options are limited. Therefore, this study aimed to identify the factors contributing to the response to donor lymphocyte infusion (DLI) in relapsed MDS patients post-HSCT. This study included 107 patients with relapsed and DLI-treated MDS who underwent their first HSCT between 2002 and 2022 and were registered in the Transplant Registry Unified Program. Univariate and multivariate survival analyses were conducted using log-rank tests and Cox proportional hazards models. Overall survival (OS) and response rates to DLI were also analyzed. The 1-year OS was 30.0% and univariate analysis identified poor prognostic factors: age ≥58 years (P = 0.003), complex karyotype (P = 0.026), hematologic relapse (P = 0.026), and early relapse (P = 0.004). Azacitidine plus DLI also improved prognosis (P < 0.001). Multivariate analysis confirmed age ≥58 years, hematologic relapse, and early relapse as poor prognostic factors. The adjusted OS for patients aged ≥ 58 years who relapsed <110 days post-transplant showed that the 1-year OS in patients with cytogenetic/molecular relapse was 43.6%, compared to 9.4% for those with hematologic relapse. Acute GVHD occurred in 62.3% of patients, and chronic GVHD in 30.8%, with manageable outcomes. DLI may improve OS in younger patients, those with cytogenetic/molecular relapse, and those with late relapse. Despite the risk of GVHD, its impact on prognosis is minimal. Given the limited treatment options, DLI should be considered for relapsed MDS patients post-HSCT.

Potential of quantitative T1 mapping to serve as a novel prognostic predictor of clear cell renal cell carcinoma after nephrectomy.

Accurate preoperative risk stratification methods are important for clear cell renal cell carcinoma (ccRCC) patients to enable personalized treatment. However, there are still no accurate and quantitative prognostic factors. This study aimed to investigate the effectiveness of T1 mapping in predicting the progression-free survival (PFS) of ccRCC after nephrectomy. A retrospective cohort study was performed in a China tertiary care hospital. This study reviewed the clinical and magnetic resonance imaging (MRI) data of consecutive inpatients with pathologically confirmed ccRCCs between September 2014 and September 2021. PFS was evaluated by following patients until the first adverse event. Radiological features including T1 relaxation time of tumors were assessed by 2 radiologists. Cox regression and visual nomogram, Kaplan-Meier survival, and log-rank test were utilized for survival analysis. A total of 195 patients with pathologically confirmed ccRCCs (mean age ± standard deviation, 56.0±12.0 years; 133 men) with eligible data were included in the study. The median follow-up was 27.6 months (range, 1-88 months), and 22 (11.3%) patients experienced metastasis or recurrence. Univariate and multivariate survival analysis showed the higher post-contrasted T1 relaxation time [P=0.001; hazard ratio (HR), 2.077; 95% confidence interval (CI): 1.350-3.196] and the incomplete tumor capsule (P<0.001; HR, 7.849; CI: 2.614-23.570) were independently associated with a shorter PFS of patients. Patients with ≥222.73 ms post-contrasted T1 relaxation time ccRCCs had worse PFS than the lower post-contrasted T1 relaxation time group. The T1 mapping quantitative parameters may be a new potential biomarker for predicting PFS in patients with ccRCCs.

Tertiary lymphoid structures' pattern and prognostic value in primary adenocarcinoma of jejunum and ileum.

To date, there have been no reports on tertiary lymphoid structures (TLS) in primary adenocarcinoma of jejunum and ileum. In this study, we employed digital pathology image analysis software to classify and quantify TLS, and evaluated the maturity of TLS using immunohistochemistry. Molecular genetics and immunotherapy biomarker detection were performed using next-generation sequencing technology, such as tumor mutational burden (TMB) and microsatellite instability (MSI). The aim of this study was to investigate the presence, location, maturity, association with immunotherapy biomarkers, and prognostic value of TLS in primary adenocarcinoma of jejunum and ileum. Compared to secondary follicle-like TLS (SFL-TLS), intra-tumoral TLS (IT-TLS) were more likely to manifest as early TLS (E-TLS) (P = 0.007). Compared to IT-TLS, SFL-TLS had a higher propensity to occur at the invasive margin(IM) (P = 0.032) and showed a trend towards being more prevalent at the tumor periphery (P = 0.057). In terms of immunotherapy biomarkers, there was a higher trend of IM-TLS density in PD-L1(22C3) score CPS < 1 group compared to PD-L1(22C3) score CPS ≥ 1 group (P = 0.071). TMB-H was significantly associated with MSI-H (P = 0.040). Univariate survival analysis demonstrated a correlation between high SFL-TLS group and prolonged disease free survival (DFS) (P = 0.047). There was also a trend towards prolonged DFS in the E-TLS-high group compared to the E-TLS-low group (P = 0.069). The peri-tumoral TLS (PT-TLS)-high group showed a trend of prolonged overall survival (OS) compared to the PT-TLS-low group (P = 0.090). In conclusion, the majority of TLS were located at the invasive margin and tumor periphery, predominantly consisting of mature TLS, while IT-TLS were mainly immature. Notably, TMB was closely associated with MSI and PD-L1, indicating potential predictive value for immunotherapy in primary adenocarcinoma of jejunum and ileum.

The Impact of Positive Peritoneal Cytology on the Survival of Endometrial Cancer Patients

Background: Since the revision of the FIGO staging of endometrial cancer in 2009, patients with positive peritoneal cytology are no longer upstaged to stage IIIA. However, several studies demonstrated poorer outcomes in patients with positive washings. We conducted a survival analysis with the aim of evaluating the impact of positive peritoneal cytology on the survival of EC patients. Methods: We performed a retrospective analysis of prospectively collected data on patients with endometrial cancer operated in our institution between 2008 and 2014. We analysed the impact of positive peritoneal cytology and other established prognostic factors on survival. Results: A total of 227 patients with a median follow-up of 6.9 years were included in the study. A total of 12.8% had positive peritoneal cytology. Positive peritoneal cytology was significantly associated with worse overall survival (HR 1.82; 95% CI 1.02–3.26; p 0.043) but not with worse recurrence-free survival (HR 1.64; 95% CI 0.92–2.93; p 0.091) in univariate analyses. In addition, tumour stage, histologic subtype, lymphovascular space invasion, grade, and the depth of myometrial invasion were all significant prognostic factors for overall survival in univariate analyses. In multivariate survival analysis, only the histologic subtype, tumour stage, and myometrial invasion remained in the model at the last step. Conclusions: Positive peritoneal cytology was associated with worse overall survival in our series of endometrial cancer patients. However, other traditional prognostic factors had a more important prognostic role for survival in a multivariate model.

Abstract C166: Overall survival and mutational landscape comparison between Appalachian and non-Appalachian patients with ovarian cancer - An Oncology Research Information Network (ORIEN) analysis

Abstract Objectives: Few studies have examined the mutational landscape in ovarian cancers, and none have focused on the Appalachian region which has a higher incidence of ovarian cancer, higher rates of poverty, and limited access to care compared to non-Appalachian region. Women with ovarian cancer enrolled in the Total Cancer Care prospective cohort study were evaluated to compare overall survival, mutational landscape, and immune cell composition between subjects in Appalachian and Non-Appalachian regions. Methods: Clinical and genomic data are available for 627 ovarian cancer patients with varying histology, including 66 from Appalachian Kentucky. MutSigCV was used to identify significantly mutated genes. CIBERSORTx was used to estimate the immune cell composition based on RNA sequencing data. Fisher’s exact test was used to compare clinical and genomic characteristics, Cox regression analysis was used to compare survival, and Wilcoxon rank-sum was used to compare immune cell composition. Results: Appalachian women with ovarian cancer were more likely to be older at time of diagnosis (64 years vs 58 years, p= 0.003), have a higher BMI (28.8 vs 26.9 kg/m2, p= 0.045), and be diagnosed at the highest pathologic grade (Grade III, 90.3% vs 84.8%, p=0.023) than non-Appalachian residents. A higher proportion of Appalachian residents were diagnosed at advanced stage III/IV (85.9% vs 75.4%, p= 0.128). In univariate survival analysis, those residing in Appalachian areas had poorer survival than the non-Appalachian residents (HR1.92, 95% CI 1.25-2.94, p=0.0022). Appalachian status remained significantly associated with worse survival after adjusting for age, BMI and stage at diagnosis (HR 1.72, 95% CI 1.04-2.86, p=0.036). There was no significant difference between cohorts on histology of ovarian carcinomas. Multiple genes were significantly different between the two populations. The Appalachian cohort had more frequent PRF1 (8.3% vs 1.9%, p=0.013), MECOM (6.7% vs 1.3%, p=0.018), and ITGAV mutations (6.7% vs 1.5%, p=0.026). RECQL4, EZR, SRGAP3, USP6 were also significantly more frequent in Appalachian residents. LRP1B was the only gene significantly associated with non-Appalachian status (9.4% vs 1.7%, p= 0.047). When analyzing immune cell composition by Appalachian status, Appalachian residency was significantly associated with higher levels of activated dendritic cells. Non-Appalachian residents had non-significantly higher levels of M2 macrophages. Conclusion: Women with ovarian cancer residing in Appalachia are older at time of diagnosis, have a higher BMI, and are diagnosed at higher pathologic grade compared to non- Appalachian residents. Even after controlling for age, stage and BMI, Appalachian residence remained significantly associated with worse survival. Multiple mutations associated with oncogenesis were significantly over-represented in the Appalachian cohort, which may contribute to excess mortality in the region. Citation Format: Allison L. Swiecki-Sikora, Jinge Liu, Michelle Churchman, Jinpeng Liu, Dava Piecoro, Taylor A. Rives, Julia Nagle, Eugenia Girda, Aliza Leiser, Sheri Holmen, Jennifer Doherty, Jing-Yi Chern, Robert Wenham, Bodour Salhia, Marilyn Huang, Stephen Edge, Laura L. Holman, Abdul Rafeh Naqash, Bradley Corr, Bryan Schneider, Chi Wang, Charles S. Dietrich, Jill M. Kolesar. Overall survival and mutational landscape comparison between Appalachian and non-Appalachian patients with ovarian cancer - An Oncology Research Information Network (ORIEN) analysis [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C166.

Neuroblastoma with high ASPM reveals pronounced heterogeneity and poor prognosis

ObjectiveWe explored the preliminary value of abnormal spindle-like microcephaly- associated (ASPM) protein in aiding precise risk sub-stratification, prediction of metabolic heterogeneity, and prognosis of neuroblastoma (NB).MethodsThis retrospective study enrolled newly diagnosed patients with NB who underwent positron emission tomography/computed tomography (PET/CT) before therapy, and tumor tissue was collected after surgery. Regression analysis was used to evaluate ASPM expression and risk stratification in patients with NB. The expression levels of ASPM, clinical information, and PET/CT text features were analyzed using univariate and multivariate survival analyses. Finally, a correlation analysis was used to explore the relationship between ASPM and tumor metabolic heterogeneity.ResultsThere were 48 patients with NB in this study (35 boys and 13 girls); 22 patients progressed and 16 died. We found that the level of ASPM was highly associated with risk stratification (OR = 5.295, 95%IC: 1.348–41.722, p = 0.021). Patients with NB and high-risk stratification with high ASPM level had a lower 3-year progression-free survival (PFS) rate (14.28%) and 1-year PFS rate (57.14%) than those with low ASPM level (57.14% and 93.75%, respectively). Using univariate and multivariate survival analyses, this study revealed that ASPM and LDH were independent risk factors for both PFS and overall survival (OS), whales GLZLM_ZLNU was only a risk factor for PFS.ConclusionASPM holds promise as a novel biomarker for refining current risk stratification and predicting prognosis in neuroblastoma. Elevated levels of ASPM, LDH, and GLZLM_ZLNU may be associated with poorer survival outcomes in neuroblastoma patients.

Hypoalbuminemia and hypercalcemia are independently associated with poor treatment outcomes of anti-PD-1 immune checkpoint inhibitors in patients with recurrent or metastatic head and neck squamous cell carcinoma

BackgroundRecent randomized phase III trials have demonstrated the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in treating patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC). However, a large proportion of such patients still have poor response. This study aimed to identify biomarkers for predicting anti-PD-1 ICI treatment outcomes .MethodsWe retrospectively analyzed 144 patients with RMHNSCC who received anti-PD-1 ICIs after progression to platinum-based chemotherapy between January 2017 and December 2022 at Kaohsiung Chang Gung Memorial Hospital. Data on clinicopathological parameters, albumin levels, calcium levels, and other pretreatment peripheral blood biomarkers, including total lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI) were collected and correlated with the treatment outcome of anti-PD-1 ICIs.ResultsLow tumor proportion score (TPS), low combined positive score (CPS), NLR ≥ 5, PLR ≥ 300, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly correlated with poor response of ICIs. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL, respectively (P = 0.007). The overall response rates were 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL, respectively (P < 0.001). Univariate survival analysis showed that low TPS, low CPS, NLR ≥ 5,, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly associated with worse progression-free survival (PFS) and inferior overall survival (OS). Multivariate analysis revealed that calcium ≥ 10 mg/dL and albumin < 4 g/dL were independent poor prognosticators for worse PFS and inferior OS. The two-year OS rates were 26% and 9% in patients with calcium < 10 mg/dL and ≥ 10 mg/dL, respectively (P < 0.001). The two-year OS rates were 10% and 33% in patients with albumin < 4 g/dL and ≥ 4 g/dL, respectively (P < 0.001).ConclusionsHypercalcemia and hypoalbuminemia can potentially predict poor treatment outcomes of anti-PD-1 ICIs in patients with RMHNSCC. Blood calcium and albumin levels may be helpful in individualizing treatment strategies for patients with RMHNSCC.

A time-dependent explainable radiomic analysis from the multi-omic cohort of CPTAC-Pancreatic Ductal Adenocarcinoma

Background and ObjectiveIn Pancreatic Ductal Adenocarcinoma (PDA), multi-omic models are emerging to answer unmet clinical needs to derive novel quantitative prognostic factors. We realized a pipeline that relies on survival machine-learning (SML) classifiers and explainability based on patients’ follow-up (FU) to stratify prognosis from the public-available multi-omic datasets of the CPTAC-PDA project. Materials and MethodsAnalyzed datasets included tumor-annotated radiologic images, clinical, and mutational data. A feature selection was based on univariate (UV) and multivariate (MV) survival analyses according to Overall Survival (OS) and recurrence (REC). In this study, we considered seven multi-omic datasets and compared four SML classifiers: Cox, survival random forest, generalized boosted, and support vector machines (SVM). For each classifier, we assessed the concordance (C) index on the validation set. The best classifiers for the validation set on both OS and REC underwent explainability analyses using SurvSHAP(t), which extends SHapley Additive exPlanations (SHAP). ResultsAccording to OS, after UV and MV analyses we selected 18/37 and 10/37 multi-omic features, respectively. According to REC, based on UV and MV analyses we selected 10/35 and 5/35 determinants, respectively. Generally, SML classifiers including radiomics outperformed those modelled on clinical or mutational predictors. For OS, the Cox model encompassing radiomic, clinical, and mutational features reached 75 % of C index, outperforming other classifiers. On the other hand, for REC, the SVM model including only radiomics emerged as the best-performing, with 68 % of C index. For OS, SurvSHAP(t) identified the first order Median Gray Level (GL) intensities, the gender, the tumor grade, the Joint Energy GL Co-occurrence Matrix (GLCM), and the GLCM Informational Measures of Correlations of type 1 as the most important features. For REC, the first order Median GL intensities, the GL size zone matrix Small Area Low GL Emphasis, and first order variance of GL intensities emerged as the most discriminative. ConclusionsIn this work, radiomics showed the potential for improving patients’ risk stratification in PDA. Furthermore, a deeper understanding of how radiomics can contribute to prognosis in PDA was achieved with a time-dependent explainability of the top multi-omic predictors.

BioFusionNet: Deep Learning-Based Survival Risk Stratification in ER+ Breast Cancer Through Multifeature and Multimodal Data Fusion.

Breast cancer is a significant health concern affecting millions of women worldwide. Accurate survival risk stratification plays a crucial role in guiding personalised treatment decisions and improving patient outcomes. Here we present BioFusionNet, a deep learning framework that fuses image-derived features with genetic and clinical data to obtain a holistic profile and achieve survival risk stratification of ER+ breast cancer patients. We employ multiple self-supervised feature extractors (DINO and MoCoV3) pretrained on histopathological patches to capture detailed image features. These features are then fused by a variational autoencoder and fed to a self-attention network generating patient-level features. A co-dual-cross-attention mechanism combines the histopathological features with genetic data, enabling the model to capture the interplay between them. Additionally, clinical data is incorporated using a feed-forward network, further enhancing predictive performance and achieving comprehensive multimodal feature integration. Furthermore, we introduce a weighted Cox loss function, specifically designed to handle imbalanced survival data, which is a common challenge. Our model achieves a mean concordance index of 0.77 and a time-dependent area under the curve of 0.84, outperforming state-of-the-art methods. It predicts risk (high versus low) with prognostic significance for overall survival in univariate analysis (HR=2.99, 95% CI: 1.88-4.78, p 0.005), and maintains independent significance in multivariate analysis incorporating standard clinicopathological variables (HR=2.91, 95% CI: 1.80-4.68, p 0.005).

The role of autophagy dysregulation in low and high-grade nonmuscle invasive bladder cancer: A survival analysis and clinicopathological association

IntroductionBladder cancer disproportionately affects men and often presents as nonmuscle-invasive bladder cancer (NMIBC). Despite initial treatments, the recurrence and progression of NMIBC are linked to autophagy. This study investigates the expression of autophagy genes (mTOR, ULK1, Beclin1, and LC3) in low and high-grade NMIBC, providing insights into potential prognostic markers and therapeutic targets. Material and methodsA total of 115 tissue samples (n = 85 NMIBC (pTa, pT1, and CIS) and n = 30 control from BPH patients) were collected. The expression level of autophagy genes (mTOR, ULK1, Beclin1, and LC3) and their proteins were assessed in low and high-grade NMIBC, along with control tissue samples using quantitative real-time polymerase chain reaction and western blotting. Association with clinicopathological characteristics and autophagy gene expression was analyzed by multivariate and univariate survival analysis using SPSS. ResultIn high-grade NMIBC, ULK1, P = 0.0150, Beclin1, P = 0.0041, and LC3, P = 0.0014, were substantially downregulated, whereas mTOR, P = 0.0006, was significantly upregulated. The KM plots show significant survival outcomes with autophagy genes. The clinicopathological characters, high grade (P = 0.019), tumor stage (CIS P = 0.039, pT1 P = 0.018, P = 0.045), male (P = 0.010), lymphovascular invasion (P = 0.028) and autophagy genes (ULK1 P = 0.002, beclin1 (P = 0.010, P = 0.022) were associated as risk factors for survival outcome in NMIBC patients. ConclusionThe upregulated mTOR, downregulated ULK1, and beclin1 expression is linked to a high-grade, CIS and pT1 stage, resulting in poor recurrence-free survival and progression-free survival and highlights the prognostic significance of autophagy gene in nonmuscle-invasive bladder cancer.

382. NUMBER OF LYMPH NODES RESECTED IS ASSOCIATED WITH OVERALL SURVIVAL IN PATHOLOGICALLY NODE-NEGATIVE ESOPHAGEAL CANCER

Abstract Background Lymphadenectomy is a key part of curative resection of esophageal cancer, with multiple quality assurance systems suggesting a minimum of 15 lymph nodes should be resected and subjected to pathological examination. Nevertheless, whether the absolute number of nodes resected is a surrogate marker for quality in surgery and staging, or has therapeutic benefit is debated. The aim of this study was to determine the impact of lymphadenectomy on survival in patients with resected pathologically node-negative disease (both treated and untreated with neoadjuvant therapy). Methods A review of our institutional prospectively maintained database was conducted from 2010-2020 inclusive. Inclusion criteria were patients undergoing esophagectomy for esophageal cancer aged 18+ who consented to data inclusion. Exclusion criteria were patients undergoing resection for benign disease, patients with Siewert III tumours undergoing gastrectomy or extended total gastrectomy, patients undergoing re-operative surgery, or patients where final pathology was not available. Univariable and multivariable analyses were performed as appropriate. Results 195 patients (49%) had pathologically node negative disease, with median lymph node count of 25. 47% of patients were clinically node positive, but pathologically node negative following neoadjuvant therapy. On univariable survival analysis, number of nodes resected was a significant predictor of overall survival (HR 0.96, 0.93-0.98, p=0.001). On multivariable analysis, R status (HR 4.9, 1.2-21.1, p=0.03), number of nodes resected (HR 0.97, 0.94-0.99, p=0.02) and prior cN+ status (HR 2.28, 1.16-4.49, p=0.02) were predictors of overall survival. Patients with cN0, (y)pN0 disease had improved overall survival compared with cN+, (y)pN0 (median not reached vs 43.4 months, p=0.04). Conclusion Lymphadenectomy is a key part of resection of esophageal cancer. In pathologically node negative patients, the extent of lymphadenectomy remains a key predictor of overall survival. Conversion from clinically node positive to pathologically node negative disease is associated with worse outcomes compared to clinically and pathologically node negative disease. Even in early stage cancer, a thorough, multi-field lymphadenectomy should be encouraged.

The Association of Statin Use With Survival Outcomes in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Androgen Receptor Targeted Therapies (ART)

BackgroundStatins may provide a compounded effect on ART by decreasing cholesterol levels thus decreasing de novo androgen synthesis and tumor cell viability. We investigated the clinical efficacy of concurrent statin use on outcomes of patients with mCRPC taking ART. MethodsA single-institution retrospective analysis of patients with mCRPC receiving ART from 2010 to 2021 was performed. Our primary outcome was PSA progression free survival (PFS), and our secondary outcomes were overall survival (OS). Patient characteristics were collected in addition to ART treatment course, statin treatment, and survival outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HR) for OS and PSA PFS and multivariable logistic regression to determine risk factors. Results153 patients with mCRPC treated with ART were included. A total of 67 patients (43.8%) received concurrent statins. Median PSA PFS was 20.4 months for patients that received statins versus 15.3 months for patients who did not receive statins. Median OS was 45.1 months for patients who received concurrent statins versus 29.7 months for patients who did not. On univariate and multivariate survival analyses, there was no statistically significant difference between groups for PSA PFS (HR 0.7; CI 0.44-1.1; P = .123) and OS (HR 0.67; CI 0.42-1.06; P = .089). ConclusionsOur analysis suggests that statins do not significantly improve clinical outcomes in patients with mCRPC. Ultimately, current understanding remains limited, and prospective studies are needed, but here we provide a cost-effective, timely, and selective preliminary analysis.

Proof of concept that melanoma nuclear count compares favourably with the benchmark histological prognostic feature, Breslow thickness.

Breslow thickness (BT) is the most important histological prognostic feature for melanoma prognosis, but it only captures tumour size in one dimension. Adding a further measurement in a different axis has been shown to improve prognostic value. It seems reasonable that further prognostic value could be obtained by estimating the number of invasive melanoma cells using nuclear count. The aim of this study was to show proof of concept that nuclear count has prognostic value independent of BT. Melanoma cell nuclei were labelled with SRY-related HMG-box 10 (SOX10) protein, the sections scanned and StarDist machine-learning algorithm used to count nuclei in 102 cases of primary cutaneous melanoma. Prognostic value was assessed using survival analyses. Nuclear count correlated strongly with T category, BT and calculated tumour area (each P < 0.001), suggesting that it was a valid marker of melanoma burden. Nuclear count was a predictor for overall survival in univariable analysis [hazard ratio (HR) = 2.25, confidence interval (CI) = 1.66-3.06, P < 0.001] and multivariable analysis (HR = 2.60, CI = 1.59-4.24, P < 0.001). BT and ulceration were significant in univariable analyses, but not in multivariable models with nuclear count. Models containing nuclear count showed the best fit. Similar results were seen for melanoma-specific and metastasis-free survival. Nuclear count was able to stratify melanomas within a given T stage. This study demonstrated proof of concept that counting melanoma nuclei may be an improved measure of invasive tumour burden compared to BT. Future studies will need to refine methods of nuclear detection and also to confirm its prognostic value.