Univariate Cox Proportional Hazards Analyses Research Articles

The combination of the low immunohistochemical expression of peroxiredoxin 4 and perilipin 2 predicts longer survival in pancreatic ductal adenocarcinoma with peroxiredoxin 4 possibly playing a main role.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Therefore, indicators that can be used for the early prediction of the prognosis of PDAC are needed. Peroxiredoxin (PRDX) 4 is a secretion-type antioxidant enzyme located in the cytoplasmic endoplasmic reticulum. Recent studies have reported that it is closely related to the development and prognosis of many types of cancer. Perilipin (PLIN) 2 is a lipid droplet coating protein. The high expression of PLIN2 is known to be an indicator of some types of cancer and oxidative stress management. It is highly suggestive of the interplay between PRDX4 and PLIN2 to some degree. In this study, we collected 101 patients' clinical data and paraffin-embedded specimens with PDAC and analyzed them with immunohistochemical staining of PRDX4 and PLIN2. We found that the low expression of PRDX4 predicts longer survival and a better clinical condition in PDAC patients. Moreover, when the low expression of PRDX4 is combined with the low expression of PLIN2, the 3-year survival is significantly improved. Univariate and multivariate Cox proportional hazard analyses showed that the PRDX4 expression in PDAC was an independent prognostic factor for survival. Taken together, between PRDX4 and PLIN2, PRDX4 plays a main role in prognosis and has the potential to become a clinical prognostic indicator of PDAC.

The Proliferative History Index, Epicmit, Derived from Genome-Wide Epigenomic Profiling, Is a Key Driver of Clinical Survival in Splenic Marginal Zone Lymphoma

The epiCMIT (epigenetically-determined Cumulative MIToses) mitotic clock (Durran-Ferrer, 2020) tracks DNA hypo- and hyper-methylation changes in heterochromatin and H3K27me3-containing chromatin, respectively, providing a comprehensive record of B cell mitotic history (pre- and post-malignant transformation). Higher epiCMIT levels correlate with poor survival in CLL and MCL, suggesting that a greater mitotic history predicts future proliferative capacity. However, no studies have investigated epiCMIT in splenic marginal zone lymphoma (SMZL). We studied 142 SMZL cases, a rare lymphoid malignancy with specific genetic characteristics [del(7q), KLF2and NOTCH2 mutations, biased use of IGHV1-2*04]. After calculating epiCMIT scores from 450/850K Illumina arrays we compared these data with gene mutations from targeted resequencing and WGS, copy number variations, telomere length, RNA-Seq, miRNA-Seq data, and clinical outcome data. By defining epiCMIT-hyper [mean: 0.6, range: 0.29-0.91] and -hypo [mean: 0.71, range: 0.39-0.90] values in our cohort, we demonstrate a strong positive correlation between hyper- and hypo- scores, as previously observed in MCL and CLL (Durran-Ferrer, 2020). The highest score obtained for epiCMIT-hyper or -hypo per sample was then selected as the epiCMIT score per patient [mean: 0.72, range: 0.39-0.91]. We identified significant correlations between epiCMIT and key clinico-biological characteristics, including a significant negative correlation between epiCMIT and telomere length (R 2=0.67 p<0.001) supporting cell proliferation and concomitant telomere attrition. High epiCMIT scores were associated with female gender (p=0.02), IGHV1-2*04 alleles (p<0.001) with intermediate levels of IGHV somatic hypermutation (SHM) load (97-99.9%, p=0.04), driver somatic gene mutations, including those in KLF2 (p<0.001), NOTCH2 (p<0.01), TP53 (p=0.01) and KMT2D (p<0.001) and deletion of 7q (p=0.01) ( Fig1). Using previously defined classification systems (Arribas, 2015 and Bonfiglio, 2022), we show enrichment of high-risk subgroups [Arribas- high global methylation subgroup (High-M, p<0.001) and Bonfiglio- NFKB, NOTCH and KLF2 genetic subgroup (NNK, p=0.01)] in cases with high epiCMIT. In a sub-cohort of 42 SMZL cases, with a spectrum of epiCMIT values and WGS/ (mi)RNA-Seq data available, we demonstrated 1) a significantly higher genome-wide somatic mutational burden in patients with high epiCMIT-total scores (25 v 17mut/Mb, p=0.001), and 2), correlations between epiCMIT and specific gene/miRNA expression associated with cellular survival and proliferation ( CARD11 [R 2=0.6, p<0.01], MAP2K1 [R 2=0.61, p<0.01], miRNA-155 [R 2=0.58, p=0.018]), apoptosis ( BCOR [R 2=0.61, p<0.01]), and epigenetic regulation ( EZH2 [R 2=0.58, p<0.01]). We then conducted univariate Cox Proportional Hazards analysis to investigate the prognostic significance of clinical and molecular features on time to first treatment (TTFT; most prevalent treatments: splenectomy, n=51; rituximab, n=20) and overall survival (OS). The epiCMIT score and epiCMIT-hyper values showed the highest hazard ratios (HR) for TTFT (HR=26.6, p=0.001) and OS (HR=9.45, p=0.043) respectively ( Fig2). Other factors associated with shorter TTFT included TP53 mutation, 3q gain, IGHV1-2*04 usage, High-M, short telomeres and female gender. Shorter OS was significantly (p<0.05) linked to mutations in key genes (including TP53 and NOTCH2), genomic complexity and del(7q). To avoid redundancy and collinearity, only the most significant epiCMIT metric was included in a multivariate Cox Proportional Hazards model (backwards selection, 94 patients/63 events), and epiCMIT-total emerged as an independent marker for shorter TTFT (HR=44.4, p=0.004), together with gain of chromosome 3q (HR=2.6, p=0.002). Kaplan-Meier analysis further confirmed the importance of epiCMIT-total, with higher scores (>median: 0.73) associated with significantly shorter TTFT (median 23 vs 3.5 months) and higher mortality (p=0.004). To conclude, we demonstrate the potential clinical utility of epiCMIT score in SMZL patients, identifying that SMZL patients with high epiCMIT harbour specific genetic characteristics, and exhibit reduced treatment-free survival. EpiCMIT could be valuable in clinical practice, helping to identify those patients destined to progress and require closer monitoring.

Outcome prediction for symptomatic patients with fibroids who underwent uterine artery embolization

PurposeTo predict the clinical outcome of symptomatic patients with uterine leiomyomas who underwent uterine artery embolization (UAE), based on clinical and radiological features. MethodsPatients with symptomatic uterine leiomyomas who underwent UAE from March 2010 to September 2019 were consecutively included in this retrospective study. Patients with persistent or recurrent symptoms and those who needed repeated UAE, myomectomy, or hysterectomy following the initial treatment were considered to have a poor outcome after UAE. The total and enhancing volume of the dominant leiomyoma in each location and uterine volume were obtained before and after UAE. Univariate and multivariate Cox proportional hazard analyses were used to evaluate the parameters that could predict poor outcome. ResultsA total of 116 patients (mean age, 45 ± 5 years) were included. Forty-six patients (46/116, 39.7%) showed poor outcome. Cox regression analysis showed higher hazard of poor outcome for younger patients vs. older patients (HR: 0.92, p-value: 0.01), patients with adenomyosis vs. patients without adenomyosis (HR: 2.47, p-value < 0.01), patients with adenomyosis thickness > 2.5 cm before UAE vs. patients without adenomyosis (HR: 4.2, p-value < 0.01) and for patients with intramural fibroid enhancement volume > 440 cm3 compared to patients with no intramural fibroids (p-value: 0.06). Multivariate Cox regression analysis including age, the thickness of adenomyosis, and intramural leiomyoma volume of enhancement before UAE was chosen as the best model to predict the outcome. ConclusionsPretreatment clinical and MRI features could identify patients with a higher risk for poor outcome after UAE.

Prognostic impact of improvement in quality of life after discharge in patients with ADHF with preserved ejection fraction regardless of the course of HF -PURSUIT-HFpEF registry

Abstract Background Lower quality of life (QOL) is associated with poor clinical outcome in patients with heart failure (HF). However, there is not fully clarified whether the changes in QOL could have prognostic value in patients with HF with preserved ejection fraction (HFpEF). Purpose The purpose of this study is to investigate the prognostic impact of changes in QOL in patients with HFpEF in relation to the changes in condition of heart failure. Methods We prospectively studied 435 patients with acute decompensated heart failure with preserved ejection fraction (ADHF-HFpEF) without the poor outcome within 1 year after the discharge. The patients’ QOL was evaluated at discharge and 1 year after the discharge using EuroQol 5 dimensions 5-level (EQ-5D-5L) and the difference in the EQ-5D-5L index at these two time points was used to assess the change in QOL. The primary outcome was all-cause death. Results The median EQ-5D-5L index were 0.753 (0.562-0.875) at discharge and 0.784 (0.646-0.895) at 1 year after the discharge. During a mean follow-up period of 1.6±1.2 years, primary outcome occurred in 92 patients. Patients with improved QOL (defined as equal to or greater than the EQ-5D-5L index at discharge) were significantly younger, had lower volume load on echocardiography and higher level of hemoglobin and serum sodium than those without improved QOL. Both the improved QOL and the improvement of HF (defined as more than -0.035 in the difference in Log NTproBNP value within 1 year after discharge by ROC analysis: AUC 0.570 [0.506-0.635]) were associated with primary outcome at univariate Cox proportional hazard analysis and the improved QOL was significantly independently associated with primary outcome after multivariable adjustment. Kaplan-Meier analysis revealed that patients with improved QOL had significantly lower risk for primary outcome than those without improved QOL not only in the whole study patients (14% vs 27%, p=0.0007) but also both in the group with improving HF (11% vs 22% p=0.0129) and in those with worsening HF (17% vs 31% p=0.0468). Conclusion(s) The improvement in QOL had the prognostic impact in patients with ADHF-HFpEF regardless of the course of heart failure.

Identification and validation of a ferroptosis-related signature for prediction of the prognosis and tumor microenvironment in patients with chromophobe renal cell carcinoma

BackgroundFerroptosis is a novel form of regulated cell death that is different from other forms, which has an important role in tumor growth inhibition. The purpose of this study was to construct and validate a prognostic signature related to ferroptosis in chromophobe renal cell carcinoma (ChRCC) and to explore its role in immune cell infiltration and systemic therapy.MethodsThe gene expression profiles of ChRCC patients obtained from The Cancer Genome Atlas (TCGA) database were used to identify differentially expressed prognostic ferroptosis-related genes (FRGs) by univariate Cox proportional hazards analyses. Ferroptosis molecular subtypes were obtained by consensus clustering analysis. The FRG-based signature in the training set was established by least absolute shrinkage and selection operator analysis and verified in the testing set. The association between molecular subtypes and the prognostic signature and immune microenvironment was explored to predict responses to immunotherapy. Immunohistochemistry was used to verify expression of the FRG-based signature externally.ResultsChRCC patients were divided into two FRG subtypes. Two FRGs (TFRC and SLC7A11) were identified to construct the prognostic signature. The high-risk group and cluster 2 had worse overall survival than the low-risk group and cluster 1, respectively. The low-risk group and cluster 1 had higher levels of immune cell infiltration and expression of MHC and immune checkpoint molecules than the high-risk group and cluster 2. The risk score was a predictor of overall survival and had a good predictive ability, which was verified in the testing set and evaluated by ROC and calibration curves. The high-risk group had a higher tumor mutation burden. The different sensitivities of targeted drugs in patients with different risks were evaluated. External immunohistochemical analysis showed that TFRC and SLC7A11 were highly expressed in tumor tissues compared with para-cancer normal tissues, and the expression level was significantly associated with a more advanced stage and worse cancer-specific survival.ConclusionsAn FRG signature was identified and validated to predict the clinicopathological features and prognosis of ChRCC. A significant association between the signature and immune cell infiltration, immune checkpoint expression, and drug response is helpful to guide comprehensive treatment of ChRCC.

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.

Unraveling the role of disulfidptosis-related LncRNAs in colon cancer: a prognostic indicator for immunotherapy response, chemotherapy sensitivity, and insights into cell death mechanisms.

Background: Colon cancer, a prevalent and deadly malignancy worldwide, ranks as the third leading cause of cancer-related mortality. Disulfidptosis stress triggers a unique form of programmed cell death known as disulfidoptosis, characterized by excessive intracellular cystine accumulation. This study aimed to establish reliable bioindicators based on long non-coding RNAs (LncRNAs) associated with disulfidptosis-induced cell death, providing novel insights into immunotherapeutic response and prognostic assessment in patients with colon adenocarcinoma (COAD). Methods: Univariate Cox proportional hazard analysis and Lasso regression analysis were performed to identify differentially expressed genes strongly associated with prognosis. Subsequently, a multifactorial model for prognostic risk assessment was developed using multiple Cox proportional hazard regression. Furthermore, we conducted comprehensive evaluations of the characteristics of disulfidptosis response-related LncRNAs, considering clinicopathological features, tumor microenvironment, and chemotherapy sensitivity. The expression levels of prognosis-related genes in COAD patients were validated using quantitative real-time fluorescence PCR (qRT-PCR). Additionally, the role of ZEB1-SA1 in colon cancer was investigated through CCK8 assays, wound healing experiment and transwell experiments. Results: disulfidptosis response-related LncRNAs were identified as robust predictors of COAD prognosis. Multifactorial analysis revealed that the risk score derived from these LncRNAs served as an independent prognostic factor for COAD. Patients in the low-risk group exhibited superior overall survival (OS) compared to those in the high-risk group. Accordingly, our developed Nomogram prediction model, integrating clinical characteristics and risk scores, demonstrated excellent prognostic efficacy. In vitro experiments demonstrated that ZEB1-SA1 promoted the proliferation and migration of COAD cells. Conclusion: Leveraging medical big data and artificial intelligence, we constructed a prediction model for disulfidptosis response-related LncRNAs based on the TCGA-COAD cohort, enabling accurate prognostic prediction in colon cancer patients. The implementation of this model in clinical practice can facilitate precise classification of COAD patients, identification of specific subgroups more likely to respond favorably to immunotherapy and chemotherapy, and inform the development of personalized treatment strategies for COAD patients based on scientific evidence.

Influence factors of the survival in colorectal cancer patients with second primary malignancy after surgery: A SEER database analysis.

The survival rate is significantly reduced in patients with colorectal cancer (CRC) who developing a second primary malignancy (SPM), and however, little has known about the factors that contribute to the mortality of SPMs among CRC survivors. This study aims to explore the influence factors in both the all-cause and cancer-specific mortality of patients with SPMs after CRC surgery. Data of adult CRC patients with SPMs were extracted from the Surveillance, Epidemiology, and End Results (SEER) database in this retrospective cohort study. The associations between potential influence factors and all-cause mortality and cancer-specific mortality were explored using univariate and multivariate Cox proportional hazards analyses. The evaluation indexes were hazard ratios (HRs), and 95% confidence intervals (CIs). We also drew pie charts to respectively reflect the distributions of SPMs sites and time interval in study population. A total of 1202 (56.14%) patients died for all-cause, and 464 (21.67%) died due to CRC. The results showed that after adjusting for covariates, age, sex, marital status, T stage of CRC, second primary cancer site, stage of SPMs, grade of SPMs, TNM stage of SPMs, and time interval were associated with all-cause mortality, while marital status, stage of CRC, T stage of CRC, chemotherapy, second primary cancer site, stage of SPMs, grade of SPMs, TNM stage of SPMs, and time interval were associated with cancer-specific mortality in patients with CRC. In addition, colon (23.5%) was the most common site of SPMs, followed by digestive system (19.0%), and the time interval between CRC and SPMs in most patients was over 5 years (28.4%). Our findings may assist clinicians to identify high-risk patients for SPMs after CRC surgery. Also, the postoperative long-term follow-up and close attention on the key systems where the SPMs may occur are of great necessary in patients with CRC.

Phase II Trial of Definitive Therapy for Osseous Oligometastases in Breast Cancer

Phase II data for consolidative local therapy for oligometastatic disease demonstrated improved outcomes for various malignancies. However, a randomized phase II study of oligometastatic breast cancer patients testing predominantly ablative dose radiotherapy (RT) did not demonstrate progression-free survival (PFS) benefit. We conducted a single-arm phase II trial evaluating local therapy as part of the multidisciplinary management of breast cancer patients with limited bone metastases. Patients with synchronous (n = 15) and metachronous (n = 15) oligometastatic breast cancer involving ≤3 osseous sites were enrolled from July 2009 to April 2016 and treated to a total of 44 bone metastases. The trial closed early due to slow accrual. Following ≤9 months of systemic therapy, local therapy entailed surgery (n = 3) or RT delivered via conventional fractionation (≥60 Gy, n = 36) or stereotactic technique (27 Gy/3 fractions for spine mets, n = 6). When indicated, RT to the primary was delivered concurrently (n = 15). The primary endpoint was to determine PFS. Secondary endpoints were overall survival (OS), local control (LC) and toxicity. Outcomes were evaluated with Kaplan-Meier and univariate Cox proportional hazards analyses. Of the 30 patients included in the trial, 23 (77%) had ER+ or PR+/HER2- disease, 4 (13%) had Her2+ disease, and 3 (10%) were triple negative. Median age was 53, and 20 patients (67%) presented with 1 distant metastasis. A total of 21 patients (70%) experienced disease progression at a median 20.5 months (IQR: 8.2-41.2), including 5 local failures among 44 treated bone metastases (11%). At a median follow-up of 76.7 mon (IQR: 45.4-108.8), the median PFS was 37.8 mon, with 2- and 5-year rates (95% CI) of 60% (45-80%) and 32% (19-55%), respectively. The 2- and 5-year OS rates were 93% (85-100%) and 64% (48-85%), respectively, and the 2- and 5-year LC rates were 91% (80-100%) and 71% (51-98%). For patients who achieved LC, median PFS was 47.7 months (IQR 12.2-73.0). Twenty-one patients (70%) received cytotoxic chemotherapy with or without endocrine therapy for newly diagnosed oligometastatic disease. Nine patients (30%) were still alive with no evidence of disease (NED) at a median 96.9 mon (range: 47.7-158.6). PFS was worse among triple negative patients (p = 0.03), with no difference based on synchronous vs non-synchronous presentation (p = 0.10), receipt of cytotoxic chemotherapy prior to definitive therapy (p = 0.08) or Her2+ status (p = 0.21). There were no Grade ≥3 adverse events. Definitive, predominantly conventionally fractionated local therapy was associated with long-term NED status for 30% of patients with oligometastatic breast cancer involving osseous sites, with minimal treatment-associated toxicity. Developing randomized trials for breast cancer subsets may warrant consideration of standard fractionation regimen data and the need for strategies to identify patients who may benefit from definitive local therapy.

Prognostic Significance of Serum Lipids in Patients with Non-Small Cell Lung Cancer Treated with Radiotherapy: A Multicenter Prospective Study

Although lipids have been assessed for their possible roles in cancer survival prediction, studies on the association between serum lipids levels and the prognosis of non-small cell lung cancer (NSCLC) patients are limited. This study aimed to evaluate whether serum lipids are associated with outcomes in patients with NSCLC treated with radiotherapy. We conducted a multicenter prospective study on patients diagnosed with NSCLC between January 2018 and February 2021. Participants received thoracic radiotherapy of 60ཞ80 Gy to the primary lung tumor and positive lymph node metastases. We measured patients' serum lipids levels (serum triglyceride, TGs; total cholesterol, TC, high density lipoprotein cholesterol, HDL-C; low density lipoprotein cholesterol, LDL-C) before radiotherapy. The association between serum lipids levels and overall survival (OS) was evaluated using hazard ratios. We sought to determine a threshold point using optimal stratification. Survival analysis was performed using Kaplan-Meier curves. Of the 300 participants diagnosed with NSCLC treated with radiotherapy, 165 (55.0%) were men. Median follow-up time was 24.4 months (range 1.0- 101.9 months). Using univariate and multivariate Cox proportional hazard analysis, among those serum lipids, only serum TG was shown to be independent prognostic factors for OS (hazard ratio: 1.203, 95% confidence interval: 1.038 - 1.393, p = 0.014). The cut-off for TG associated with OS was 2.04 mmol/L. Based on the TG cut-off value, 55 NSCLC patients were categorized into the high TG group (>2.04 mmol/L) and 245 in the low TG group (<2.04 mmol/L). The NSCLC patients in the low TG group exhibited higher OS than the high group (median OS, not reach vs 41.4 months, p = 0.025). TG levels were found to be a significant negative prognostic biomarker for OS in NSCLC patients treated with radiotherapy.

Platelets as a prognostic factor for patients with adenocarcinoma of the gastroesophageal junction

ObjectiveThe aim of this study was to investigate the prognostic role of plasma platelet count (PLT), mean platelet volume (MPV), and the combined COP-MPV score in patients with resectable adenocarcinomas of the gastroesophageal junction.BackgroundPlatelet activation, quantified by PLT and elevated MPV, plays an essential part in the biological process of carcinogenesis and metastasis. An increased preoperative COP-MPV is associated with poor survival in various tumor entities.MethodsData of 265 patients undergoing surgical resection for adenocarcinoma of the gastroesophageal junction were abstracted. COP-MPV score was defined for each patient. Utilizing univariate and multivariate Cox proportional hazard analyses, survival was determined.ResultsIn univariate analysis, elevated PLT (HR 3.58, 95% CI 2.61–4.80, p<0.001) and increased COP-MPV (HR 0.27, 95% CI 0.17–0.42, p<0.001 and HR 0.42, 95% CI 0.29–0.60, p<0.001) significantly correlated with shorter patients’ overall and disease-free survival, for all 256 patients, as well as in the subgroups of neoadjuvantly treated (p<0.001) and primarily resected patients (p<0.001). COP-MPV remained a significant prognostic factor in multivariate analysis for OS. However, PLT alone showed significant diminished OS and DFS in all subgroups (p<0.001) in univariate and multivariate analysis.ConclusionPLT is a potent independent prognostic biomarker for survival in a large prospective cohort of patients with resectable adenocarcinoma of the gastroesophageal junction. Additionally, we confirm that the COP-MPV score is significantly associated with worse outcome in these patients, but has no benefit in comparison to PLT.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas

BackgroundWith advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC.Methods and materialsPatients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration.ResultsOne hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0–1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups.ConclusionsHigher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Clinical features and outcomes analysis of Gallbladder neuroendocrine carcinoma.

Gallbladder neuroendocrine carcinoma (GB-NEC) is an uncommon and highly malignant tumor. This research aimed to investigate the clinical characteristics and prognostic factors of GB-NEC. Our survey of case reports from January 2000 to May 2022 screened a total of 84 patients with complete data who received surgical resection for gallbladder NEC. Log-rank generated survival curves using the Kaplan-Meier method for univariate survival analysis. To identify GB-NEC independent prognostic indicators for overall survival (OS), univariate and multivariate Cox proportional hazard analyses were conducted. These patients consisted of 25 men and 59 women, with an average age of 60 (range 29-85). Patients under 60 years old made up 44% of the population, while patients over 60 made up 56%. Fifty-three tumors were advanced pathologic TNM stage III and IV. After surgery, 44 patients underwent chemotherapy or radiotherapy. The median OS of 84 patients with GB-NEC was 16.8 months. In univariate and multivariate analysis, tumor size (diameter ≥5 cm), TNM tumor stage, and the receipt of postoperative adjuvant chemotherapy are independent factors influencing the prognosis of patients with GB-NEC. Tumor size (diameter ≥5 cm) and TNM tumor stage were independently related to a shorter OS. An enhanced OS was independently linked to receiving postoperative adjuvant chemotherapy.

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.

Outcomes and Treatment Algorithm in Glioblastoma Patients 80 Years and Older

The current standard of care for patients with glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy with concurrent temozolomide chemotherapy. Previous studies that identified this treatment regimen focused on younger patients with GBM. The proportion of patients with GBM over the age of 80 years is increasing. We investigate whether elderly patients benefit from the current standard of care with additional maximal safe resection. Clinical, operative, radiographic, demographic, genetic, and outcomes data were retrospectively collected for patients treated for histologically confirmed World Health Organization grade 4 GBM at University of Pittsburgh Medical Center from 2009 to 2020. Only patients 80 years and older were included (n= 123). Statistically significant values were set at P < 0.05. A univariate Cox proportional hazards analysis of GBM patients aged >80 years identified the use of temozolomide, radiation, Karnofsky Performance Status (KPS) > 70, and methylguanine DNA methyltransferase methylation with increased overall survival (OS). Further multivariate Cox proportional hazards model analysis showed that the variables identified in the univariate analysis passed multicollinearity testing, and that use of temozolomide, KPS >70, and gross total resection were shown to significantly impact survival. Survival analysis showed that patients with biopsy alone had a shorter median OS compared with patients who received resection, temozolomide, and radiation (P < 0.0001, median OS 1.6 vs. 7.5 months). Additionally, patients who underwent biopsy and then received temozolomide and radiation had a shorter median OS when compared with patients who received resection, temozolomide, and radiation (P= 0.0047, median OS 3.6 vs. 7.5 months). For elderly patients with KPS >70, GTR followed by radiation and temozolomide is associated with maximum OS.

The prognostic value of HALP score in predicting in-hospital mortality in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Despite major advances in reperfusion therapies, morbidity and mortality rates associated with cardiovascular disorders remain high, particularly in patients with ST-segment elevation myocardial infarction (STEMI). Therefore, identifying prognostic variables that can be used to predict morbidity and mortality in STEMI patients is critical for better disease management. The HALP (hemoglobin, albumin, lymphocyte, and platelet) score, a novel index indicating nutritional status and systemic inflammation, provides information about prognosis. In this context, this study was carried out to investigate the relationship between HALP score assessed at admission and in-hospital mortality in STEMI patients. The population of this retrospective study consisted of 1307 consecutive patients diagnosed with STEMI and who underwent primary percutaneous coronary intervention (pPCI). The 1090 patients included in the study sample were divided into two groups based on the median HALP score value of 3.59. In-hospital and all-cause mortality rates during the follow-up were obtained from the registry. In-hospital mortality rate was significantly higher in patients with a HALP score of less than 3.59 compared to those with a HALP score of more than 3.59 (7.5% and 0.7%, respectively; P < 0.001). Univariate and multivariate Cox proportional hazard analyses revealed that the HALP score is independently associated with in-hospital mortality. The optimal HALP score cutoff value of <3.72 predicted in-hospital mortality with 95.56% sensitivity and 49.19% specificity. This study's findings indicate that HALP score may be a significant independent predictor of in-hospital mortality in patients with STEMI treated with pPCI.

Survival Trends and Profiling of Gastric Mixed Adenoneuroendocrine Carcinoma (gMANEC) in the Current Era

Background: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a histopathologic diagnosis with at least 30% each of exocrine and endocrine components. Although prognosis is thought to be driven by the relative exocrine or endocrine dominance, gMANEC has been clinically treated as gastric adenocarcinoma (gAC). The overall survival of gMANEC as compared to gastric neuroendocrine carcinoma (gNEC) or gAC remains undefined. Methods: Using the National Cancer Database, patients with gastric tumors were queried from 2004 to 2016 for gMANEC, gNEC, and gAC histologies. Demographic and clinicopathologic features were recorded. Univariate and multivariate Cox proportional hazards analyses were performed to delineate factors associated with overall survival (OS). Results: Overall, 404 patients diagnosed with gMANEC were identified. Patients had a median age 68 years, were majority male, and predominantly Caucasian. Gastric MANEC was more frequently poorly differentiated (73%vs 52% (gAC) vs 20% (gNEC), P &lt; .001) with lymphovascular invasion (57%vs 38%vs 27%, P &lt; .001) and lymph node involvement (59%vs 49%vs 36%, P &lt; .001); these factors were associated with worse OS on univariable analysis. Finally, tumors &gt;5 cm and lymph node involvement were independent predictors of worse survival. The median OS of patients with gMANEC was 41.5 months. Conclusion: Gastric MANEC and gAC have a similarly dismal prognosis and thus should be continued to treat like gAC. Pathologic nodal metastasis, tumor size and grade are useful prognostic factors.

Association of lactate-to-albumin ratio with in-hospital and intensive care unit mortality in patients with intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with a high mortality rate; the lactate-to-albumin ratio (LAR) is a new biomarker for predicting clinical outcomes in patients with ICH. However, the relationship between LAR and mortality in patients with ICH treated in the intensive care unit (ICU) remains controversial. Therefore, in this study, we aimed to investigate the association between LAR and in-hospital and ICU mortality in patients with ICH. Patients with ICH were selected from the Medical Information Mart for Intensive Care III (MIMIC-III) database; their clinical information, including baseline characteristics, vital signs, comorbidities, laboratory test results, and scoring systems, was extracted. Univariate and multivariate Cox proportional hazards analyses were used to investigate the association of LAR with in-hospital and ICU mortality. The maximum selection statistical method and subgroup analysis were used to investigate these relationships further. Kaplan-Meier (KM) analysis was used to draw survival curves. This study enrolled 237 patients with ICH whose lactate and albumin levels, with median values of 1.975 and 3.6 mg/dl, respectively, were measured within the first 24 h after ICU admission. LAR had an association with increased risk of in-hospital mortality [unadjusted hazards ratio (HR), 1.79; 95% confidence interval (CI), 1.32-2.42; p < 0.001] and ICU mortality (unadjusted HR, 1.88; 95% CI, 1.38-2.55; p < 0.001). A cut-off value of 0.963 mg/dl was used to classify patients into high LAR (≥0.963) and low LAR (<0.963) groups, and survival curves suggested that those two groups had significant survival differences (p = 0.0058 and 0.0048, respectively). Furthermore, the high LAR group with ICH had a significantly increased risk of in-hospital and ICU mortality compared to the low LAR group. Our study suggests that a high LAR is associated with an increased risk of in-hospital and ICU mortality in patients with ICH. Thus, the LAR is a useful prognostic predictor of clinical outcomes in patients with ICH.

PEDS3: Risk Factors for Thromboembolic Events in Pediatric Patients with Ventricular Assist Devices

Background: Pediatric patients on ventricular assist device (VAD) support are at risk of thromboembolic (TE) complications which include pump thrombosis, ischemic stroke, and transient ischemic attack. Methods: We conducted a retrospective chart review of pediatric patients implanted with Paracorporeal Pulsatile (PP) or Paracorporeal Continuous (PC) VADs between 2005-2022, at the Stollery Children’s Hospital (Edmonton, AB). Patients that transitioned from PC to PP were classified in a combination group. Patient and device related factors, including initial anti-coagulation strategies were collected. Kaplan Meier (KM) survival analysis was performed to determine freedom from TE event based on initial anti-coagulation strategy and VAD type. Univariate and multivariate Cox proportional hazard analysis was conducted to look for factors associated with TE events. Results: Of the 95 patients included, median age was 0.92 years (IQR 0.27, 5.37), median weight at implant was 8.4 kg (IQR 4.4, 18.0). Almost two-thirds (63%) had non congenital disease, with 47% supported on PC devices, 25% on PP devices, and 28% with a combination of devices. Initial anti-coagulation was with either Heparin (61.5%) or Bivalirudin (38.5%). Unadjusted freedom from a TE event was significantly higher in those who received Bivalirudin as their initial anti-coagulation strategy (p=0.022, Figure 1). KM analysis based on device type found that PC VADs predicted shorter freedom from TE events (p=0.012). In multivariate analysis, initial anticoagulation strategy (HR 0.359, 95% CI 0.165–0.785, p=0.01) for Bivalirudin was protective against events, while device type (HR 10.9, 95% CI 2.68–44.2, p<0.001), specifically PC devices, was found to be a predictor of TE events. Conclusions: This study suggests that device type, particularly PC, and heparin as an initial anti-coagulation strategy are risk factors TE events. Further work is needed to understand the interaction between device type and initial anti-coagulation strategy.

One-year change in the health status predicts the subsequent hospitalization and mortality in patients waitlisted for lung transplantation in Japan

BackgroundPoor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation. MethodsIn a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization. ResultsAmong 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL. ConclusionsPatients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality.