Survival Scoring Research Articles

Predicting Survival Among Colorectal Cancer Patients: Development and Validation of Polygenic Survival Score.

Colorectal cancer is the second leading cause of cancer-related death in the United States. A multi-omics approach has contributed in identifying various cancer-specific mutations, epigenetic alterations, and cells response to chemotherapy. This study aimed to determine the factors associated with colorectal cancer survival and develop and validate a polygenic survival scoring system (PSS) using a multi-omics approach. Data were obtained from the Cancer Genome Atlas (TCGA). Colon Adenocarcinoma (TCGA-COAD) data were used to develop a survival prediction model and PSS, whereas rectal adenocarcinoma (TCGA-READ) data were used to validate the PSS. Cox proportional hazards regression analysis was conducted to examine the association between the demographic characteristics, clinical variables, and mRNA gene expression. Overall accuracy of PSS was also evaluated. The median overall survival for TCGA-COAD patients was 7 years and for TCGA-READ patients was 5 years. The multivariate Cox proportional hazards model identified age, cancer stage, and expression of nine genes as predictors of colon cancer survival. Based on the median PSS of 0.38, 48% of TCGA-COAD patients had high mortality risk. Patients in the low risk group had significantly higher 5-year survival rates than those in the high group (p <0.0001). The PSS demonstrated a high overall accuracy in predicting colorectal cancer survival. This study integrated clinical and transcriptome data to identify survival predictors in patients with colorectal cancer. PSS is an accurate and valid measure for estimating colorectal cancer survival. Thus, it can serve as an important tool for future colorectal cancer research.

AB077. An evaluation of prognostic scoring systems for survival in a surgically treated cohort of 318 metastatic spine tumour surgery patients.

Survival prognostication plays a key role in the decision-making process for the surgical treatment of patients with spinal metastases. In the past traditional scoring systems such as the modified Tokuhashi and Tomita scoring systems have been used extensively, however in recent years their accuracy has been called into question. This has led to the development of machine learning algorithms to predict survival. In this study, we aim to compare the accuracy of prognostic scoring systems in a surgically treated cohort of patients. This is a retrospective review of 318 surgically treated spinal metastases patients between 2009 and 2021. The primary outcome measured was survival from the time of diagnosis. Predicted survival at 3 months, 6 months and 1 year based on the prognostic scoring system was compared to actual survival. Predictive values of each scoring system were measured via area under receiver operating characteristic curves (AUROC). The following scoring systems were compared, Modified Tokuhashi (MT), Tomita (T), Modified Bauer (MB), Van Den Linden (VDL), Oswestry (O), New England Spinal Metastases score (NESMS), Global Spine Study Tumor Group (GSTSG) and Skeletal Oncology Research Group (SORG) scoring systems. For predicting 3 months survival, the GSTSG 0.980 (0.949-1.0) and NESM 0.980 (0.949-1.0) had outstanding predictive value, while the SORG 0.837 (0.751-0.923) and O 0.837 (0.775-0.900) had excellent predictive value. While for 6 months survival, only the O 0.819 (0.758-0.880) had excellent predictive value and the GSTSG 0.791(0.725-0.857) had acceptable predictive value. For 1 year survival, the NESM 0.871 (0.822-0.919) had excellent predictive value and the O 0.722 (0.657-0.786) had acceptable predictive value. The MT, T and MB scores had an area under the curve (AUC) of <0.5 for 3-month, 6-month and 1-year survival. Increasingly, traditional scoring systems such as the MT, T and MB scoring systems have become less predictive. While newer scoring systems such as the GSTSG, NESM and SORG have outstanding to excellent predictive value, there is no one survival scoring system that is able to accurately prognosticate survival at all 3 time points. A multidisciplinary, personalised approach to survival prognostication is needed.

Can Survival Scoring Systems for Spinal Metastases be Used to Predict Postoperative Neurologic Recovery? A Retrospective Study on 204 Patients With Thoracolumbar Metastases Treated at a Tertiary Center.

Retrospective Cohort Study. Scoring systems for metastatic disease of the spine are used to select patients for surgical treatment based on survival estimation, but it is unknown whether they can be used to predict the outcome of surgery. This study aims to investigate the association between two widely used prognostic scores and the neurologic function after surgery. Retrospective analysis of 204 patients with thoracolumbar metastases treated with decompressive surgery at Karolinska University Hospital (2001-2020). Modified Bauer and Tokuhashi scores were categorized based on surgical indication, and post-operative neurological function was assessed using the Frankel scale at two different post-surgery intervals. Modified Bauer scores ≥2 yielded higher late follow-up Frankel scores (3.9 ± 1.1) than scores <2 (3.5 ± 1.1), P = .03. Modified Tokuhashi scores ≥9 correlated with higher Frankel scores (4.5 ± .9) than scores <9 (3.5 ± 1.1), P < .0001. Both scoring systems positively predicted neurological outcomes at late follow-up, with odds ratios of 1.6 (P = .03) for Bauer and 9.2 (P < .0001) for Tokuhashi. However, only Tokuhashi predicted ambulatory function at late follow-up (P < .0001), demonstrating its utility in prognosticating post-surgical mobility. Higher modified Bauer and Tokuhashi scores were associated with better neurologic function at last follow-up, as well as greater likelihood of being able to walk again. The Tokuhashi score was found to be more accurate than the modified Bauer score in predicting the neurological outcome after surgery.

Clinical impacts of severe thrombocytopenia in the first cycle of azacitidine monotherapy and cytogenetics in patients with myelodysplastic syndrome: The Kyoto Conditional Survival Scoring System.

Azacitidine (AZA) has been one of the standard treatments for transplantation-ineligible patients with myelodysplastic syndrome (MDS); however, hematological toxicities frequently cause treatment interruption in the early phase of the therapy. The present study conducted a multicenter retrospective study to investigate the prognostic impacts of various factors, including factors included in the Revised International Prognostic Scoring System (IPSS-R) and severe cytopenia in the early phase of AZA monotherapy in 212 patients with MDS. Severe cytopenia was evaluated after the initiation of therapy by absolute neutrophil counts on the 29th day after AZA (ANC29) initiation, and red cell concentrates (RCC) and platelet concentrate (PC) transfusion units required within 28 days from the start of AZA, designated in the present study as RCC28 and PC28, respectively. The survival period was determined from the 29th day of AZA treatment to death from any cause as the conditional survival period after the first cycle of AZA (CS-AZA1). Multivariate analysis demonstrated that severe thrombocytopenia defined by >30 units of PC28 and very poor risk cytogenetics according to IPSS-R were independent prognostic factors for CS-AZA1. The Kyoto Conditional Survival Scoring System was subsequently developed by incorporating severe thrombocytopenia defined by PC28 and very poor risk cytogenetics, which successfully stratified the risks of the patients in CS-AZA1. In conclusion, extreme PC transfusion dependency during the first cycle of AZA and very poor risk cytogenetics are important prognostic factors in AZA monotherapy for MDS.

Comparing the Accuracy of Seven Scoring Systems in Predicting Survival of Lung Cancer Patients With Spinal Metastases: An External Validation From Two Centers.

Retrospective case series. To investigate the accuracy of seven scoring systems for the prediction of survival in lung cancer patients with spinal metastases (SPM). Although survival scoring systems have been developed for surgical decision-making, the reliability and validity of these models are unclear for specific cancer types. As the prevalence of patients with lung cancer increases, it is imperative to determine the accuracy of these models for lung cancer patients with SPM. This is a retrospective study of a cohort of lung cancer patients with SPM who underwent spine surgery between 2019 and 2021 at two centers. The optimal area under the curve (AUC) was calculated to evaluate the accuracy of seven candidate scoring systems at 3, 6, and 12 months. Calibration and decision curve analysis was used for further validation. A total of 166 patients (mean age: 58.98±10.94; 105 males and 61 females) with SPM were included. The median postoperative survival was 12.87±0.93 months. The modified Bauer score, revised Tokuhashi score, Linden score, Tomita score, the Skeletal Oncology Research Group nomogram, and the New England Spinal Metastasis Score in prediction survival at 3, 6, and 12 months showed a slightly weaker AUC (range 0.464-0.659). The AUC of the Katagiri-New score in predicting 1-year survival for lung cancer patients was the highest (0.708; range 0.619-0.798). The decision curve analysis showed that the Katagiri-New score led to a greater net benefit than the strategies of changing management for all patients or none of the patients. This study suggests that the most commonly used models have limitations in predicting survival in patients undergoing spinal surgery for metastatic lung cancer and underestimate survival. In this sample of lung cancer patients, the Katagiri-New Scoring system score had the best performance in predicting 1-year survival. 4.

A Lower Frequency of Spliceosome Mutations Distinguishes Clonal Cytopenias of Undetermined Significance From Low-Risk Myelodysplastic Syndromes, Despite Inherent Similarities in Genomic, Laboratory, and Clinical Features

Clonal cytopenias of undetermined significance (CCUS) are associated with an increased risk of developing a myelodysplastic syndrome (MDS); however, the mechanism and factors associated with evolution remain unclear. We propose that next-generation sequencing (NGS) of cytopenic cases with equivocal morphologic dysplasia will improve patient clinical care and that serial sequencing of such equivocal cases could identify the factors that predict evolution to MDS. We performed targeted NGS of samples from 193 individuals with confirmed or suspected MDS or MDS/myeloproliferative neoplasm, including sequential investigation for 28 individuals at the time of diagnosis and during follow-up. NGS facilitated the diagnosis of all suspicious cases as myeloid neoplasm (21%), CCUS (34%), or idiopathic cytopenias of undetermined significance (45%) when no variants were detected. We found that there was no significant difference in most measured clinical features or clonal phenotypes, such as cell counts, number of variants, variant allele frequencies, and overall survival, between CCUS and International Prognostic Scoring System-Revised–defined low-risk MDS. However, there was a significant difference in the types of variants between CCUS and low-risk MDS, with a significantly lower number of splicing factor mutations in CCUS cases (P < .001). Moreover, we observed an increased probability of evolution to MDS of individuals with CCUS compared with that in those with idiopathic cytopenias of undetermined significance over the first 5 years (P = .045). Our analyses revealed no conclusive pattern associating clonal expansion or the number of variants with the evolution of CCUS to MDS, perhaps further supporting the similarity of these diseases and the clinical importance of recognizing and formally defining CCUS as a category of precursor myeloid disease state in the next revision of the World Health Organization guidelines.

Prognosis Score for Overall Survival with CAR-T Therapy in Aggressive Lymphoma

Background: Since 2017, six chimeric antigen receptor T cell (CAR-T) therapies have been approved by the FDA for hematologic malignancies. Despite the transformative potential of this therapy, more tools to assist with identifying patients with increased likelihood of benefitting from this therapy will be helpful, particularly given the logistical complexity and socio-economic demands for CAR-T relative to other therapies. Health care resource restriction during the COVID-19 pandemic highlights the need for these tools. We present a simple survival score that uses 3 readily available clinical labs: platelet (plt), absolute lymphocyte count (ALC), and Lactate dehydrogenase (LDH) to predict the risk of dying within 6 months of CAR-T therapy in patients with aggressive lymphoma. Methods: We conducted a retrospective chart review of patients with aggressive non-Hodgkin lymphoma (NHL) who received FDA-approved CAR-T between Jan 2018 to Jan 2022 at Mayo Clinic Rochester. Demographics and lab variables were selected based on univariate analysis for clinical and statistical significance and tested in a multivariate logistic regression model. Bootstrapping test was used to test the accuracy of the model to predict for death within 6 months of CAR-T infusion. Patients were scored based on the model, and Kaplan-Meier curve for overall survival (OS) based on the score was plotted. Results: Among a total of 110 pts who received CAR-T, 27 (25%) pts died within the first 6 months post CAR-T infusion (OS ≤ 6 mo). Disease progression was the main cause of death (18/25, 72%), followed by infection (4/25, 16%), CAR-T related (HLH/MAS, 2/25, 8%), second primary malignancy (1/25, 4%) and unknown (2/25, 8%).Baseline demographics were comparable between the OS>6mo and ≤6months groups (Table 1). Patients’ ECOG, Karnofsky performance status and 11 labs at the time of evaluation for CAR-T therapy (initial eligibility assessment, prior to leukapheresis) were compared between those who died from any cause within 6 months of CAR-T infusion and those who did not. Hemoglobin, plt, ALC, absolute monocyte count, C- Reactive Protein, ferritin, and LDH were selected as clinically and/or statistically significant variables for multivariate testing. Multivariate regression with boot-strap testing identified plt, ALC, and LDH as the most predictive variables with 80.9 ± 11.7% accuracy for predicting death within 6 months of CAR-T infusion. Patients were scored 0-3 using these 3 labs, with 1 point assigned for plt ≤ 100 X109/L, ALC ≤ 0.4 X109/L, or LDH > 222 U/L (upper limit of normal). OS by this survival score is shown in Figure 1. Discussion: Due to the curative potential of CAR-T, patients with broader characteristics than those treated on registration studies have been treated in standard of care practice. While an estimated 5%-10% risk of CAR-T associated deaths in the first 3 months is seen across all patients in clinical trials, predictors for early death after CAR-T in real-world patient populations can provide additional context for pts and providers when selecting treatment. This survival score is important proof of concept that a simple model using readily accessible clinical labs at the time of CAR-T evaluation could provide additional context to help with additional clinical decision-making. Multicenter prospective studies will help define and validate the definitive survival scoring system. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Towards survival prediction of cancer patients using medical images.

Survival prediction of a patient is a critical task in clinical medicine for physicians and patients to make an informed decision. Several survival and risk scoring methods have been developed to estimate the survival score of patients using clinical information. For instance, the Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores are developed for the survival prediction of heart patients. Recently, state-of-the-art medical imaging and analysis techniques have paved the way for survival prediction of cancer patients by understanding key features extracted from Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scanned images with the help of image processing and machine learning techniques. However, survival prediction is a challenging task due to the complexity in benchmarking of image features, feature selection methods, and machine learning models. In this article, we evaluate the performance of 156 visual features from radiomic and hand-crafted feature classes, six feature selection methods, and 10 machine learning models to benchmark their performance. In addition, MRI scanned Brain Tumor Segmentation (BraTS) and CT scanned non-small cell lung cancer (NSCLC) datasets are used to train classification and regression models. Our results highlight that logistic regression outperforms for the classification with 66 and 54% accuracy for BraTS and NSCLC datasets, respectively. Moreover, our analysis of best-performing features shows that age is a common and significant feature for survival prediction. Also, gray level and shape-based features play a vital role in regression. We believe that the study can be helpful for oncologists, radiologists, and medical imaging researchers to understand and automate the procedure of decision-making and prognosis of cancer patients.

A Protective Role of NOD2 on Oxazolone-induced Intestinal Inflammation Through IL-1β-mediated Signalling Pathway.

NOD2 has emerged as a critical player in the induction of both Th1 and Th2 responses for potentiation and polarisation of antigen-dependent immunity. Loss-of-function mutations in the NOD2-encoding gene and deregulation of its downstream signalling pathway have been linked to Crohn's disease. Although it is well documented that NOD2 is capable of sensing bacterial muramyl dipeptide, it remains counter-intuitive to link development of overt intestinal inflammation to a loss of bacterial-induced inflammatory response. We hypothesised that a T helper bias could also contribute to an autoimmune-like colitis different from inflammation that is fully fledged by Th1 type cells. An oedematous bowel wall with a mixed Th1/Th2 response was induced in mice by intrarectal instillation of the haptenating agent oxazolone. Survival and clinical scoring were evaluated. At several time points after instillation, colonic damage was assessed by macroscopic and microscopic observations. To evaluate the involvement of NOD2 in immunochemical phenomena, quantitative polymerase chain reaction [PCR] and flow cytometry analysis were performed. Bone marrow chimera experimentation allowed us to evaluate the role of haematopoietic/non-hematopoietic NOD2-expressing cells. Herein, we identified a key regulatory circuit whereby NOD2-mediated sensing of a muramyl dipeptide [MDP] by radio-resistant cells improves colitis with a mixed Th1/Th2 response that is induced by oxazolone. Genetic ablation of either Nod2 or Ripk2 precipitated oxazolone colitis that is predominantly linked to a lack of interferon-gamma. Bone marrow chimera experiments revealed that inactivation of Nod2 signalling in non-haematopoietic cells is causing a biased M1-M2 polarisation of macrophages and a decreased frequency of splenic regulatory T cells that correlates with an impaired activation of CD4 + T cells within mesenteric lymph nodes. Mechanistically, mice were protected from oxazolone-induced colitis upon administration of MDP in an interleukin-1- and interleukin-23-dependent manner. These findings indicate that Nod2 signalling may prevent pathological conversion of T helper cells for maintenance of tissue homeostasis.

Eligibility of extracorporeal cardiopulmonary resuscitation on in-hospital cardiac arrests in Sweden: a national registry study

Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest (CA) is used in selected cases. The incidence of ECPR-eligible patients is not known. The aim of this study was to identify the ECPR-eligible patients among in-hospital CAs (IHCA) in Sweden and to estimate the potential gain in survival and neurological outcome, if ECPR was to be used. Data between 1 January 2015 and 30 August 2019 were extracted from the Swedish Cardiac Arrest Register (SCAR). Two arbitrary groups were defined, based on restrictive or liberal inclusion criteria. In both groups, logistic regression was used to determine survival and cerebral performance category (CPC) for conventional cardiopulmonary resuscitation (cCPR). When ECPR was assumed to be possible, it was considered equivalent to return of spontaneous circulation, and the previous logistic regression model was applied to define outcome for comparison of conventional CPR and ECPR. The assumption in the model was a minimum of 15 min of refractory CA and 5 min of cannulation. A total of 9209 witnessed IHCA was extracted from SCAR. Depending on strictness of inclusion, an average of 32-64 patients/year remains in refractory after 20 min of cCPR, theoretically eligible for ECPR. If optimal conditions for ECPR are assumed and potential negative side effects disregarded of, the estimated potential benefit of survival of ECPR in Sweden would be 10-19 (0.09-0.19/100 000) patients/year, when a 30% success rate is expected. The benefit of ECPR on survival and CPC scoring was found to be detrimental over time and minimal at 60 min of cCPR. The number of ECPR-eligible patients among IHCA in Sweden is dependent on selection criteria and predicted to be low. There is an estimated potential benefit of ECPR, on survival and neurological outcome if initiated within 60 min of the IHCA.

Prognostic scores for survival as decisional support for surgery in spinal metastases: a performance assessment systematic review.

To review the evidence on the relative prognostic performance of the available prognostic scores for survival in spinal metastatic surgery in order to provide a recommendation for use in clinical practice. A systematic review of comparative external validation studies assessing the performance of prognostic scores for survival in independent cohorts was performedaccording to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Eligible studies were identified through Medline and Embase until May 2021. Studies were included when they compared at least four survival scoring systems in surgical or mixed cohorts across all primary tumor types. Predictive performance was assessed based on discrimination and calibration for 3-month, 1-year and overall survival, and generalizability was assessed based on the characteristics of the development cohort and external validation cohorts. Risk of bias and concern regarding applicability were assessed based on the 'Prediction model study Risk Of Bias Assessment Tool' (PROBAST). Twelve studies fulfilled the inclusion criteria and covered 17 scoring systems across 5.130 patients. Several scores suffer from suboptimal development and validation. The SORG Nomogram, developed in a large surgical cohort, showed good discrimination on 3-month and 1-year survival, good calibration and was superior in direct comparison with low risk of bias and low concern regarding applicability. Machine learning algorithms are promising as they perform equally well in direct comparison. Tokuhashi, Tomita and other traditional risk scores showed suboptimal performance. The SORG Nomogram and machine learning algorithms outline superior performance in survival prediction for surgery in spinal metastases. Further improvement by comparative validation in large multicenter, prospective cohorts can still be obtained. Given the heterogeneity of spinal metastases, superior methodology of development and validation is key in improving future machine learning systems.

Sepsis induced sequential organ failure assessment score as a prognostic marker in surgical sepsis: a study of 30 cases in 02 years

Background: For the last few decades critical care medicine has been reinventing and fine-tuning organ dysfunction grading to establish a survival scoring system to accurately predict survivality and organ salvageability of critically ill patient in intensive care unit (ICU). The sequential organ failure assessment (SOFA) score assesses the performance of several organ systems in the body and assigns a score, where higher the SOFA score, higher the likelihood of mortality and morbidity. Early prediction of outcome in surgical sepsis is very likely to aid suitable modification of management strategies 13. This may improve prognosis in such patients and prevent mortality to some extent. Methods: Observational and prospective study of 30 cases, aged&gt;18 years &amp; patients admitted to post-operative ward and surgical intensive care unit (SICU) with suspected surgical infection, and with two or more criteria of SIRS. Results: In this study out of total 30 patients 63.3% patients survived and 36.6% succumbed to their illness. Our study depicted significant increase in mortality rate when the SOFA score was above 12. Ventilated patient showed a higher mortality rate. Delta, mean, total SOFA Score were statistically significant in our study.Conclusions: SOFA score is useful in predicting mortality and morbidity in critically ill patients, because has a strong correlation between a rise in the score and mortality in all stages of admission. In our study, out of 09 patients whose T0 SOFA score was very high (above 12) out of which 03 patients only survived.

Obstructive sleep apnea intensifies stroke severity following middle cerebral artery occlusion

Study objectivesObstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion. MethodsWe used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring. ResultsWe found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals. ConclusionsOur findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke.

A method for studying the metabolic activity of individual tardigrades by measuring oxygen uptake using microrespirometry.

Studies of tardigrade biology have been severely limited by the sparsity of appropriate quantitative techniques, informative on a single-organism level. Therefore, many studies rely on motility-based survival scoring and quantifying reproductive success. Measurements of O2 respiration rates, as an integrating expression of the metabolic activity of single tardigrades, would provide a more comprehensive insight into how an individual tardigrade is responding to specific environmental factors or changes in life stages. Here, we present and validate a new method for determining the O2 respiration rate (nmolO2mg-1h-1) of single tardigrades under steady state, using O2 microsensors. As an example, we show that the O2 respiration rate determined in MilliQ water for individuals of Richtersius coronifer and of Macrobiotus macrocalix at 22°C was 10.8±1.84 and 13.1±2.19 nmol O2mg-1h-1, respectively.

Bromodomain and Extraterminal (BET) Domain Inhibition with PLX51107 and PLX2853 Improves Survival and Decreases Acute GVHD Severity in Murine Models

Introduction: Acute Graft-versus-Host Disease (aGVHD) affects 30-70% of all allogeneic stem cell transplant (alloSCT) recipients, contributing to high non-relapse mortality. aGVHD is due to donor T cell cytotoxic inflammatory effects stimulated by exposure to foreign host antigens. Epigenetic modulation by BET inhibition boasts anti-inflammatory effects. BET proteins are a class of epigenetic "reader molecules," functioning as key mediators of transcription. BET proteins regulate inflammatory gene expression and are targetable. BET inhibition decreases NF-kB dependent cytokine expression and Th1/Th17 differentiation without affecting regulatory T cell differentiation. BET inhibition disrupts BRD4 interaction with the acetylated component of NF-kB, RelA. Therefore, we hypothesize that BET inhibition is a feasible and effective strategy to mitigate T cell mediated aGVHD inflammation. In this study, we have used PLX51107 and PLX2853 - novel BET inhibitors developed by Plexxikon Inc that possess a unique binding mode and high bioavailability ideal for preclinical evaluation. PLX2853 (second generation) was designed to increase potency and improve tolerability. Materials and Methods: aGVHD allogeneic mouse model: Lethally irradiated (1200 cGy) B6D2F1 recipients received T cell depleted bone marrow cells (TCD-BM, 10x106) and CD45.1+ B6 splenocytes (15x106) intravenously via tail vein injection. Recipients were treated by oral gavage, 3x weekly with PLX51107 (10 mg/kg), PLX2853 (4 mg/kg) or vehicle. We evaluated two dosing schedules - starting at day +1 or day +7 after transplant in the PLX51107 studies and day +1 only after infusion of allogeneic CD45.1+ B6 splenocytes in the PLX2853 studies. Survival and clinical aGVHD scores were assessed. Xenogeneic mouse model: NSG mice were conditioned with 50 cGy X-ray irradiation and injected with 15-20x106 human PBMCs and treated with PLX2853 (4 mg/kg) or vehicle starting day +1. Survival was assessed. Graft-versus-Tumor model: In vivo: Lethally irradiated F1 mice were intravenously injected with firefly luciferase-transduced murine mastocytoma P815 cells on day 0 with B6 TCD-BM ± allogeneic B6 splenocytes (n=8 per cohort). Recipients were treated with PLX2853 (4 mg/kg) or vehicle (oral gavage, 3x weekly) starting at day +1 post-transplant. Survival was assessed. In vitro: Murine CD45.1 B6 CD8+ T cells were stimulated in vitro with PMA/Ionomycin ± PLX2853 (10nM) for 5 days and then degranulation was analyzed in response to P815 tumor challenge to evaluate CTL capacity via flow cytometry of intracellular CD107a expression. Study designs are illustrated in the Figure (Panel A). Results: PLX51107 demonstrates potent biological activity and improves survival in a murine model of aGVHD. Administration of PLX51107 dramatically improved survival of recipient mice (B) and reduced aGVHD clinical scores (C). PLX2853 significantly improves survival in multiple mouse models of aGVHD. Our in-vitro data show that PLX2853 (IC50 ~10nM) is more potent than PLX51107 (IC50 ~500nM). Therefore, we validated the biological activity and efficacy of PLX2853 in mouse models of aGVHD. PLX2853 significantly prolonged survival of allogeneic transplanted recipient mice (D) and resulted in reduced clinical scores (E). Recipient mice in the xenogeneic mouse model showed improved survival with PLX2853 treatment (F). PLX2853 maintains Graft Versus Tumor response in vivo and does not abrogate CD8+ cytotoxic T lymphocyte (CTL) responses in vitro. BET inhibition retained beneficial GVT effects as seen by improvement in survival comparable to vehicle group (G). PLX2853 treated CD8+ T cells showed comparable degranulation to control as measured by CD107a mobilization (H, I). These results suggest that BET inhibition does not abrogate CD8+ CTL capacity, correlating to retention of GVT effects observed in vivo. Conclusions: PLX51107 was well tolerated at both day +1 and +7 initiation, demonstrating the future feasibility of BET inhibition as a prophylactic or therapeutic strategy for aGVHD. PLX2853 given at lower doses demonstrated similar improvements in survival and GVHD scoring, consistent with increased potency. Preliminary in vivo and in vitro studies of PLX2853 on GVT and on CD8+ CTLs show that PLX2853 retains GVT effects. Additional mechanistic in vivo and in vitro studies are ongoing. Figure Disclosures Powell: Plexxikon Inc.: Employment. Bollag:Plexxikon Inc.: Employment.

Modified Unipolar Hemiarthroplasty for the Treatment of Metastatic Lesions of Proximal Femur with Pathological Fractures: Case Series of Six Patients.

Introduction: Proximal femur resection and endoprosthetic reconstruction is the preferred treatment for extensive bony destruction and pathological fractures. Due to the relatively high cost of endoprosthesis, we adopted the modified unipolar hemiarthroplasty (MUH) for reconstruction when the mode of treatment was for palliation.Materials and Methods: This is a retrospective case study of six patients, who had bone and multi-organs metastases with extensive proximal femur involvement with pathologic fractures who underwent resection and MUH reconstruction during the period 2013 to 2017. All patients were classified as Group B / C based on Scandinavian Sarcoma Group survival scoring, with estimated survival of maximum six months. The basic MUH construct consisted of Austin-Moore prosthesis which was secured to a Küntscher nail using cerclage wire and cemented into the femoral canal. Subsequently, the whole length of the prosthesis which remained outside the canal was coated with cement.Results: The mean age was 61.8 years. The mean survival was 3.9 months, post-operation. There was no implant failure during patients’ life span; however, a third of the patients developed infection. Wheel chair ambulation was started immediately post-operation for all patients, and two patients progressed to walking frame ambulation. The total cost of each construct was below US$490 in comparison to long-stem hemiarthroplasty (roughly US$ 1700).Conclusion: Our aim was to alleviate pain, facilitate rehabilitation, ease nursing care and improve quality of life for metastatic bone disease patients until end of life. MUH for the treatment of pathological fracture in proximal femoral metastases is a feasible palliative surgical modality in resource-limited settings.

New label-free automated survival assays reveal unexpected stress resistance patterns during C.elegans aging.

Caenorhabditis elegans is an excellent model for high‐throughput experimental approaches but lacks an automated means to pinpoint time of death during survival assays over a short time frame, that is, easy to implement, highly scalable, robust, and versatile. Here, we describe an automated, label‐free, high‐throughput method using death‐associated fluorescence to monitor nematode population survival (dubbed LFASS for label‐free automated survival scoring), which we apply to severe stress and infection resistance assays. We demonstrate its use to define correlations between age, longevity, and severe stress resistance, and its applicability to parasitic nematodes. The use of LFASS to assess the effects of aging on susceptibility to severe stress revealed an unexpected increase in stress resistance with advancing age, which was largely autophagy‐dependent. Correlation analysis further revealed that while severe thermal stress resistance positively correlates with lifespan, severe oxidative stress resistance does not. This supports the view that temperature‐sensitive protein‐handling processes more than redox homeostasis underpin aging in C. elegans. That the ages of peak resistance to infection, severe oxidative stress, heat shock, and milder stressors differ markedly suggests that stress resistance and health span do not show a simple correspondence in C. elegans.

PS1513 ESTIMATING LIFE‐YEAR LOSS OF PRIMARY MYELOFIBROSIS IN EUROPE

Background:Primary myelofibrosis (PMF) is a myeloid neoplasm impacting patient survival and quality of life. Although JAK2 inhibitors were recently approved for the treatment of patients with PMF, there is still a lack of strong evidence supporting a survival benefit in this patient population.1 Existing published survival data focus on describing duration of survival, however as there is no general population comparator for this outcome, interpretations are often subjective.Aims:This study aimed to quantify the real‐world mortality caused by PMF in comparison with the general population in Germany, France, Italy, Spain, and the UK (EU5).Methods:A simulation model was developed in Microsoft Excel, using parameters sourced from a large‐scale European‐based real‐world retrospective MF study by the International Working Group for Myeloproliferative Neoplasm Research and Treatment.2 Baseline demographics predictive of survival, including age, sex, and International Prognostic Scoring System (IPSS) risk level, were simulated using the patient characteristics statistics published by Cervantes et al. in 2012.2 The survival of patients with PMF was simulated using the exponential survival function. To examine the rate of mortality, the exponential distribution parameter (modeled as a function of age, sex, and IPSS risk level) was estimated using published median survival times and derived hazard ratios. Patient characteristics and survival statistics from the simulation sample were verified with the published data.2 Real‐world life‐year loss was calculated as the difference between simulated survival time and the population‐level life expectancy specific to the patient's age, sex, and country.Results:A total of 5,000 patients were simulated (Table), with 1,000 from each EU5 country. The simulated sample generated similar patient characteristics statistics and median survival years as found by Cervantes et al.2 The additional mean life‐year loss of PMF was estimated at 9.6 years (median 10.7 years; 5 and 95 percentile [−18.7, 33.4]), with a 45% relative survival loss, compared with the general population. Overall, 81% of patients with PMF were estimated to experience life‐year loss. More pronounced life‐year loss was found to be associated with being male (mean 11.3 years; 57% relative survival loss; 86% with life‐year loss), age &lt;65 years (mean 14.3 years; 48% relative survival loss; 84% with life‐year loss), and IPSS Intermediate‐2 to High risk classification (mean 15.4 years; 73% relative survival loss; 95% with life‐year loss). The results were consistent among the EU5 countries modeled.Summary/Conclusion:PMF patients experience significant real‐world life‐year loss when compared with the general population in Europe.image

A Survival Scoring System for Non-Small Cell Lung Cancer Patients with De Novo Bone Metastases.

In the pre-tyrosine kinase inhibitors (TKIs) era, non-small cell lung cancer (NSCLC) patients with de novo bone metastases had a worse prognosis than those without. However, whether epidermal growth factor receptor (EGFR)-TKIs affect the outcomes of EGFR mutant NSCLC patients with de novo bone metastases has not been well studied thus far. We retrospectively studied the effect of EGFR mutation status and first-line EGFR-TKIs on patient outcomes and created a survival scoring system for NSCLC patients with de novo bone metastases. This retrospective study evaluated 1510 NSCLC patients diagnosed between November 2010 and March 2014. Among these patients, 234 patients had de novo bone metastases. We found that 121 of these 234 patients (51.7%) had positive EGFR mutation tests, and a positive EGFR mutation test significantly affected overall survival (OS) (EGFR mutant: 15.2 months, EGFR wild type: 6.5 months; p < 0.001). Other prognostic factors significant in the multivariable analysis for NSCLC with de novo bone metastases included Eastern Cooperative Oncology Group performance status (PS) (OS; PS 0–2: 11.2 months, PS 3–4: 4.9 months; p = 0.002), presence of extraosseous metastases (OS; with extraosseous metastases: 8.8 months, without extraosseous metastases: 14.0 months; p = 0.008), blood lymphocyte-to-monocyte ratio (LMR) (OS; LMR > 3.1: 17.1months, LMR ≤ 3.1: 6.9months; p < 0.001). A positive EGFR mutation status reversed the poor outcomes of NSCLC patients with de novo bone metastases. A simple and useful survival scoring system including the above clinical parameters was thus created for NSCLC patients with de novo bone metastases.

Bag Score: An ICU Survival Scoring System in a Veteran Population

Bag Score: An ICU Survival Scoring System in a Veteran Population