Determinant Of Long-term Survival Research Articles

Determinants of long-term survival in patients with IDH-mutant gliomas.

Survival times of patients with IDH-mutant gliomas are variable and can extend to decades. Many studies provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored characteristics of short- and long-term survivors within a cohort of patients with extended follow-up. This single-center, case-control study included 86 patients diagnosed between 1998 and 2023 who either died within 6 years after diagnosis or survived at least 15 years. Patient characteristics and prognostic factors were stratified by short- (< 6 years) versus long-term (≥ 15 years) survival. Forty-seven patients (55%) diagnosed with astrocytoma and 39 patients (45%) with oligodendroglioma were included retrospectively. Median follow-up of the survivors was 16.6 years (range 15-28.9). Thirty-four deaths (40%) had been reported at database closure. Long-term survival was associated with CNS WHO grade 2 (p < 0.01), smaller tumor volumes (p = 0.01), lack of contrast enhancement (p < 0.01), wait-and-scan strategies (p < 0.01) and female sex (p = 0.04). In multivariate analyses for oligodendroglioma, larger T2 tumor volumes were associated with shorter survival (HR 1.02; 95% CI 1.01-1.05; p = 0.04). In patients with astrocytoma, lack of contrast enhancement (HR 0.38; 95% CI 0.15-0.94; p = 0.04) and wait-and-scan strategies (HR 5.75; 95% CI 1.66-26.61; p = 0.01) were associated with longer survival. Large T2 tumor volume and contrast enhancement may be important risk factors for shorter survival, while age might be of lesser importance. Wait-and-scan strategies may yield excellent long-term survival in some patients with astrocytoma.

Long-Term Survival among Octogenarians Undergoing Aortic Valve Replacement with or without Simultaneous Coronary Artery Bypass Grafting: A 22-Year Tertiary Single-Center Experience.

The impact of concomitant coronary artery bypass grafting (CABG) on aortic valve replacement (AVR) in octogenarians is still debated. We analyzed the characteristics and long-term survival of octogenarians undergoing isolated AVR and AVR + CABG. All octogenarians who consecutively underwent AVR with or without concomitant CABG at our tertiary cardiac center between 2000 and 2022 were included. Patients with redo, emergent, or any other concomitant procedures were excluded. The primary endpoints were 30-day and long-term survival. The secondary endpoints were early postoperative outcomes and determinants of long-term survival. Univariable and multivariable logistic regression analyses were performed to identify independent predictors of 30-day mortality, and Cox regression analysis was performed for predictors of adverse long-term survival. A total of 1011 patients who underwent AVR (83.0 [81.0-85.0] years, 42.0% males) and 1055 with AVR + CABG (83.0 [81.2-85.4] years, 66.1% males) were included in our study. Survival at 30 days and at 1, 3, and 5 years in the AVR group was 97.9%, 91.5%, 80.5%, and 66.2%, respectively, while in the AVR + CABG group it was 96.2%, 89.6%, 77.7%, and 64.7%, respectively. There was no significant difference in median postoperative survival between the AVR and AVR + CABG groups (7.1 years [IQR: 6.7-7.5] vs. 6.6 years [IQR: 6.3-7.2], respectively, p = 0.21). Significant predictors of adverse long-term survival in the AVR group included age (hazard ratio (HR): 1.09; 95% CI: 1.06-1.12, p < 0.001), previous MI (HR: 2.08; 95% CI: 1.32-3.28, p = 0.002), and chronic kidney disease (HR 2.07; 95% CI: 1.33-3.23, p = 0.001), while in the AVR + CABG group they included age (HR: 1.06; 95% CI: 1.04-1.10, p < 0.001) and diabetes mellitus (HR: 1.48; 95% CI: 1.15-1.89, p = 0.002). Concomitant CABG was not an independent risk factor for adverse long-term survival (HR: 0.89; 95% CI: 0.77-1.02, p = 0.09). The long-term survival of octogenarians who underwent AVR or AVR + CABG was similar and was not affected by adding concomitant CABG. However, octogenarians who underwent concomitant CABG with AVR had significantly higher in-hospital mortality. Each decision should be discussed within the heart team.

Nonhome Discharge in Patients Undergoing Pelvic Reconstructive Surgery: A National Analysis.

Discharge to home after surgery has been recognized as a determinant of long-term survival and is a common concern in the elderly population. The aim of the study was to determine the incidence and risk factors for nonhome discharge in patients undergoing major surgery for pelvic organ prolapse. We performed a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program Database from 2010 to 2018. We included patients who underwent sacrocolpopexy, vaginal colpopexy, and colpocleisis. We compared perioperative characteristics in patients who were discharged home versus those who were discharged to a nonhome location. Stepwise backward multivariate logistic regression was then used to control for confounding variables and identify independent predictors of nonhome discharge. A total of 38,012 patients were included in this study, 209 of whom experienced nonhome discharge (0.5%). Independent predictors of nonhome discharge included preoperative weight loss (adjusted odds ratio [aOR], 5.9; 95% confidence interval [CI], 1.3-27.5), dependent health care status (aOR, 5.0; 95% CI, 2.6-9.5), abdominal hysterectomy (aOR, 2.3; 95% CI, 1.4-3.7), American Society of Anesthesiologists class 3 or greater (aOR, 2.0; 95% CI, 1.5-2.7), age (aOR, 1.1; 95% CI, 1.05-1.09), operative time (aOR, 1.005; 95% CI, 1.003-1.006), laparoscopic hysterectomy (aOR, 0.6; 95% CI, 0.4-1.0), and laparoscopic sacrocolpopexy (aOR, 0.5; 95% CI, 0.3-0.8). In patients undergoing surgery for pelvic organ prolapse, nonhome discharge is associated with various indicators of frailty, including age, health care dependence, and certain comorbidities. An open surgical approach increases the risk of nonhome discharge, while a laparoscopic approach is associated with lower risk.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma

To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. Retrospective cohort study with validation. We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P=.002), having no symptoms (OR 4.19; P=.005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P=.001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Determinants of long-term survival in late HIV presenters: The prospective PISCIS cohort study.

SummaryBackgroundLate HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined.MethodsFrom PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005–2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4<500 cells/µL). We used logistic regression and propensity score matching.FindingsWe included 2,719 participants (16593·1 person-years): 1441 (53%) late presenters (LP) and 1278 non-LP (1145 non-LP with two-year CD4 count >500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200–500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or <200 cells/µL (aMRR 4·59[2·25-9·37]).Conversely, no differences were observed in participants with two-year CD4 counts >500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]).InterpretationTwo-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens.FundingSouthern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Determinants of Long-Term Survival in Late HIV Diagnosed Individuals: A Prospective Cohort Study

Determinants of Long-Term Survival in Late HIV Diagnosed Individuals: A Prospective Cohort Study

Prediction of mortality following pediatric heart transplant using machine learning algorithms.

Optimizing transplant candidates' priority for donor organs depends on the accurate assessment of post-transplant outcomes. Due to the complexity of transplantation and the wide range of possible serious complications, recipient outcomes are difficult to predict accurately using conventional multivariable regression. Therefore, we evaluated the utility of 3 ML algorithms for predicting mortality after pediatric HTx. We identified patients <18years of age receiving HTx in 2006-2015 in the UNOS Registry database. Mortality within 1, 3, or 5years was predicted using classification and regression trees, RFs, and ANN. Each model was trained using cross-validation, then validated in a separate testing set. Model performance was primarily evaluated by the area under the receiver operating characteristic (AUC) curve. The training set included 2802 patients, whereas 700 were included in the testing set. RF achieved the best fit to the training data with AUCs of 0.74, 0.68, and 0.64 for 1-, 3-, and 5-year mortality, respectively, and performed best in the testing data, with AUCs of 0.72, 0.61, and 0.60, respectively. Nevertheless, sensitivity was poor across models (training: 0.22-0.58; testing: 0.07-0.49). ML algorithms demonstrated fair predictive utility in both training and testing data, but the sensitivity of these algorithms was generally poor. With the registry missing data on many determinants of long-term survival, the ability of ML methods to predict mortality after pediatric HTx may be fundamentally limited.

On the use of flexible excess hazard regression models for describing long-term breast cancer survival: a case-study using population-based cancer registry data

BackgroundBreast cancer prognosis has dramatically improved over 40 years. There is, however, no proof of population ‘cure’. This research aimed to examine the pattern of long-term excess mortality due to breast cancer and evaluate its determinants in the context of cancer registry data.MethodsWe used data from the Geneva Cancer Registry to identify women younger than 75 years diagnosed with invasive, localised and operated breast cancer between 1995 and 2002. Flexible modelling of excess mortality hazard, including time-dependent (TD) regression parameters, was used to estimate mortality related to breast cancer. We derived a single “final” model using a backward selection procedure and evaluated its stability through sensitivity analyses using a bootstrap technique.ResultsWe analysed data from 1574 breast cancer women including 351 deaths (22.3%). The model building strategy retained age at diagnosis (TD), tumour size and grade (TD), chemotherapy and hormonal treatment (TD) as prognostic factors, while the sensitivity analysis on bootstrap samples identified nodes involvement and hormone receptors (TD) as additional long-term prognostic factors but did not identify chemotherapy and hormonal treatment as important prognostic factors.ConclusionsTwo main issues were observed when describing the determinants of long-term survival. First, the modelling strategy presented a lack of robustness, probably due to the limited number of events observed in our study. The second was the misspecification of the model, probably due to confounding by indication. Our results highlight the need for more detailed data and the use of causal inference methods.

Determinants of Long-Term Outcome in Type 1/like Calreticulin-Mutated Myelofibrosis

Background:Type 1 calreticulin (CALR) variants comprise ~70% of all CALR mutations in primary myelofibrosis (PMF) and form a distinct phenotypic and prognostic disease subset (Leukemia. 2014;28:1568). Determinants of long-term outcome have not, however, been systematically appraised in this population. The current study documents the natural history, molecular correlates, and independent predictors of overall (OS), leukemia-free (LFS), and thrombosis-free (TFS) survival in CALR type 1/like-mutated myelofibrosis.Methods:Patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses were consistent with World Health Organization (PMF, fibrotic/leukemic transformations) (Blood. 2016;127:2391) and International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria (post-essential thrombocythemia (ET) MF) (Leukemia. 2008;22:437). Laboratory and clinical data were retrospectively abstracted corresponding to time of referral (PMF) or myelofibrotic transformation (post-ET MF). Conventional prognostic scoring was as previously outlined (Blood. 2010;115:1703; J Clin Oncol. 2018;36:1769). Recipients of allogeneic stem cell transplant were censored at the time of transplant. Standard statistical methods were used for all analyses using the JMP® Pro 13.0.0 software package (SAS Institute, Cary, NC, USA).Results:A total of 162 consecutive patients with CALR type 1/like-mutated myelofibrosis were identified: 139 (86%) with PMF and 23 (14%) with post-ET MF with median age 55 years (range 23-85), 62% male. The PMF and post-ET MF cohorts displayed similar phenotypic features with the exception of higher platelet counts (median 443 vs 340 x 109/l; P=0.02) in post-ET MF (Table 1). The most frequent co-existing mutations were ASXL1 (n=47; 37%) and SRSF2 (n=4; 3%), with ASXL1 seen more frequently in PMF (39% vs 11% post-ET MF; P=0.07). Over a median follow-up of 6 years (range 0-25 years), a total of 20 (12%) leukemic transformations and 66 (41%) deaths were recorded, with no significant differences between the PMF and post-ET MF cohorts (P=0.16 and 0.11, respectively). Kaplan-Meier survival estimates revealed comparably favorable median OS in both CALR type 1/like-mutated variants: not yet reached and 13 years in post-ET MF vs PMF, respectively (P=0.7) (Figure 1A).Multivariable analysis disclosed moderate to severe sex-adjusted anemia (P<0.001), ≥2% circulating blasts (P<0.001), very high risk (VHR) karyotype (P<0.001), age >70 years (P=0.006), and constitutional symptoms (P=0.008) to be independent predictors of inferior OS in CALR type 1/like-mutated PMF (Table 2). LFS was significantly shortened in the presence of IDH1 mutations (P=0.01) and platelets <100 x 109/l (P=0.02) while IDH2 mutations (P=0.02), leukocytosis ≥11 x 109/l (P=0.03) and history of arterial thrombosis (P=0.04) were independent predictors of shortened TFS. Importantly, myelofibrosis variant (primary vs post-ET) did not influence survival (P=0.7) or complication rates (P=0.8 for LFS, P=0.09 for TFS) (Table 2).The karyotype- and mutation-enhanced international prognostic scoring system (MIPSS70+ version 2.0), was effective in risk stratifying type 1/like CALR-mutated PMF (P-values 0.01 to <0.0001), with the exception of low vs intermediate (P=0.22) and intermediate vs high risk (P=0.49) (Figure 1C). The detrimental influences of unfavorable/VHR karyotype and ASXL1 mutations were confirmed (Figure 2A-B) while borderline adverse and prognostically neutral effects were seen on OS for U2AF1 (n=116; P=0.05) and SRSF2 (n=120; P=0.98) respectively (Figure 2C-D).Conclusions:The current study documents analogous disease patterns in primary and post-ET CALR type 1/like-mutated MF and provides information on determinants of long-term survival. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Angiographic Outcomes after Drug-eluting Stents and Bare-metal Stents in Patients with Cardiac Allograft Vasculopathy: A Metanalysis

Background Coronary Allograft Vasculopathy (CAV) is a major determinant of long term survival after cardiac transplantation and remains one of the leading causes of death after the first year of orthotopic heart transplantation (OHT). Percutaneous revascularization is an option for amenable lesions with either drug-eluting stents (DES) or bare-metal stents (BMS). Choice of stent is dependent on patient and angiographic characteristics. Previous studies comparing the two stent subtypes have shown inconsistent results and thus we decided to do a meta-analysis to evaluate the net clinical effect. Methods PubMed, Medline & EMBASE were queried for all English articles from 1993 to 2017. Inclusion criteria were patients with CAV undergoing percutaneous coronary intervention with either DES or BMS with follow up angiography at 1 year. Primary outcome was In-stent restenosis (ISR): defined as more than 50% stenosis of the stent diameter angiographically. Secondary outcome was mortality. Outcomes were analyzed in two groups: Patient-based analysis and Lesion-based analysis. Data were pooled with absolute event rate and metanalysis of the outcomes was performed using a weighted random effects model in RevMAN 5.0. Results Seven studies including a total of 526 angiographic lesions (BMS 267; 50.7%) and 268 patients were analyzed. On lesion-based analysis, mean incidence of ISR in the BMS group vs the DES group was 31% vs 10.2% (RR 0.36; 95% CI 0.19–0.69; p=0.002). No difference in mortality was observed between the two groups (RR 0.86; 95% CI 0.16–0.46; p=0.86). Forest-plots for the outcomes are shown below. Conclusion Our analysis suggests that when compared with BMS implantation, DES have a lower rate of in-stent restenosis but offer no reduction in mortality at 1 year.

The Associations of Internal Audit Quality with Job Burnout and Job Satisfaction Based on Theory of Reasoned Action

Among the important determinants of long term survival in public shareholding companies, is the quality of internal audit, which is considered among the primary factors affecting the financial information credibility. For this, it is necessary to identify the factors that influence the quality of internal audit, such as internal auditor behavior in the audit process. It is equally important to develop a framework for its determination and to address the factors. Accordingly, this paper developed a theoretical framework to identify individual factors - job burnout and job satisfaction - and their influence on dysfunctional audit behavior. The primary aim of this paper is to explain the motivation behind engaging in dysfunctional behaviors in the internal audit environment. Therefore, it provided theoretical evidences about the risk associated with the dysfunctional behaviors that are expected to lead to reduced internal audit quality. In addition, empirical evidence to address the concerns of the Jordanian regulatory authorities of audit quality in the public shareholding companies indicates additional directions for future studies.

Clinical and immunological correlates of long term survival in glioblastoma.

Glioblastoma (GBM) is the most common and most aggressive type of primary brain tumour in adults. It represents 54% of all gliomas and 16% of all brain tumours (Ostrom et al. 2016). Despite surgery and treatment with radiotherapy plus an oral alkylating agent, temozolomide (TMZ), tumours invariably recur, and the patient survival is an average of ~14–16 months. In this review we summarise the current understanding of multiple factors that may affect survival of patients with GBMs. In particular, we discuss recent advancements in surgery and detection of genomic-based markers with prognostic values, such as IDH1/2 mutations, MGMT gene promoter methylation, and TERT gene promoter alterations. We address the issue of tumour heterogeneity and evolution that may result in different parts of the same tumour exhibiting different GBM subtypes and in subtype switching, which may restrict the usefulness of the expression-based classification as a prognostic marker before relapse. The determinants of long-term survival in patients with IDH1/2wt GBM, beyond MGMT promoter methylation, remain to be identified, and even the absence of both IDH1/2 mutations and MGMT promoter methylation does not preclude long-term survival. These findings suggest that host-derived factors, such as immune system responsiveness may contribute to long-term survival in such patients. We report the results of high-throughput approaches, suggesting links between long-term survival and enhanced immune-related gene expression. The further search for new gene candidates, promoter methylation status, and specific features of host immunity should provide prognostic biomarkers for the evaluation of survival of IDH1 wild-type/non-G-CIMP GBMs.

FRI-074 - Determinants of long term survival and recurrence patterns after radiofrequency ablation for hepatocellular carcinoma developed on cirrhosis

FRI-074 - Determinants of long term survival and recurrence patterns after radiofrequency ablation for hepatocellular carcinoma developed on cirrhosis

Acute kidney injury and outcome following aortic valve replacement for aortic stenosis.

Most studies on acute kidney injury (AKI) following open-heart surgery have focused on short-term outcome following coronary artery bypass grafting. We reviewed the incidence, risk factors and outcome, including long-term survival, of AKI after aortic valve replacement (AVR) in a population-based cohort. A retrospective review of 365 patients who underwent AVR for aortic stenosis during 2002-2011 was made. AKI was defined according to the RIFLE criteria. All patients requiring dialysis were followed up in a centralized registry. Risk factors for AKI were analysed with univariable and multivariable analysis, and survival was graphically presented with the Kaplan-Meier method. The rate of AKI was 82/365 (22.5%); 40, 28 and 14 patients belonging to the Risk, Injury and Failure groups, respectively. Preoperatively, 37 (45.1%) AKI patients had reduced kidney function. Transfusion of red blood cells, obesity and prolonged cardiopulmonary bypass time were independent risk factors for AKI. Acute postoperative dialysis was required in 15 patients (4.1%), and 1 patient developed dialysis-dependent end-stage renal disease. Major postoperative complications were more common in the AKI group (65 vs 22%, P < 0.001). The 30-day mortality rate in the AKI group was 18%, as opposed to 2% in the non-AKI group (P < 0.001), with a 5-year survival rate of 66 vs 87%, respectively (P < 0.001). In multivariable analysis AKI was an independent predictor of operative mortality [odds ratio = 5.89, 95% confidence interval (CI) = 1.99-18.91] but not of long-term survival (hazard ratio = 1.44, 95% CI = 0.86-2.42). More than 1 in 5 patients (22.5%) who underwent AVR developed AKI postoperatively. AKI was associated with higher morbidity and was an independent predictor of operative mortality. However, AKI was not a determinant of long-term survival.

S97 Long Term Survival In Patients Who Undergo Oesophagectomy Is Lower In Patients Who Develop Post-operative Acute Respiratory Distress Syndrome

Oesophagectomy is a complicated procedure with high risk of complications in the immediate post-operative period. We have previously shown that patients undergoing oesophagectomy have ~ 25% risk of Acute Respiratory Distress Syndrome (ARDS) post op. Post-operative complications have been shown to decrease long term post-operative survival following major surgery. 1 We hypothesised that long term survival would be reduced in patients who develop ARDS post oesophagectomy. We analysed data from 55 patients recruited to the translational sub-study of the BALTI prevention trial. 26 of the 55 patients (47%) died within 2 years of their operation. Patients who died within two years of their oesophagectomy were more likely to have required ventilation for ARDS during their hospital admission. In addition, patients who survived less than two years were more likely to have developed a surgical complication (e.g. anastomotic leak, wound infection, chyle leak) post-op. There was no difference in age, lung function, BMI or cancer staging. Patients who did not survive more than 2 years post-op were more likely to be smoking at the time of the operation, but there was no difference in pack year smoking history between the two groups. Perioperative markers of alveolar epithelial damage (PICCO EVLWI and PVPI), and the severity of both local (BAL CRP) and systemic inflammation (IL-17, ICAM-1, and TNFR-1/2) were associated with outcome. In conclusion, complications during recovery from oesophagectomy have an adverse effect on the chances of long term survival. Development of strategies to reduce post-operative morbidity may improve long term outcomes. References Khuri et al . Determinants of Long-Term Survival After Major Surgery and the Adverse Effect of Postoperative Complications. Ann Surg . 2005 Sep;242(3):326–41

Abstract 440: The TRiC chaperonin in breast cancer cell growth, survival and response to taxane therapy

Abstract Large-scale efforts such as The Cancer Genome Atlas (TCGA) have identified the landscape of genetic, epigenetic and proteomic alterations in breast cancer through analysis of ∼1000 primary breast tumors. Importantly, all of the samples analyzed by TCGA also come with long-term clinical follow-up data that allows for examination of how identified alterations affect patient outcomes. Although powerful, the sheer number of alterations identified by TCGA and similar efforts makes it difficult to separate alterations that drive cancer from those that are merely passengers. We have been combining data from TCGA with data from genome-wide, RNAi-based, functional genetic screens that we have been performing on a panel of breast cancer cell lines that were developed in our lab. This combination of functional genetic data with data from the TCGA has resulted in the identification of genes that are responsible for driving breast cancer cell growth and survival that also affect patient outcomes. Using this approach, we have identified the TRiC chaperonin protein complex as playing a critical role in driving breast cancer and affecting patient outcomes. In the SUM-52 breast cancer cell line, a member of the TRiC complex known as TCP-1 was a hit in the genome wide, RNAi-based screen and examination of TCP1 in the TCGA database revealed that it is altered in ∼9% (85 of 929 cases) of breast cancers and patients with TCP1 alterations have significantly reduced long-term survival (pval&amp;lt;.0000001). Expression of this gene was found to be regulated by a known driver oncogene in this cell line, FGFR2, and we have identified the PI3K signaling pathway as the mediator of this regulation. Examination of additional cell lines in our panel showed that TCP-1 expression is regulated by driver oncogene activity in multiple breast cancer cell lines e.g. HER2 in SUM-225 cells. Knocking down TCP-1 resulted in a dramatic decrease in the colony forming ability of the SUM-52 cell line while a much weaker effect on colony forming is observed in MCF10A cells, suggesting differential dependency on TRiC activity between transformed and non-transformed cells. Interestingly, a second member of TRiC was also a hit in the genome-wide RNAi screen in SUM-52 cells. Although not regulated by FGFR2, this gene is amplified and overexpressed in this cell line, and examination of TCGA data showed that ∼12% (113/929) of all breast cancers overexpress CCT2 and, these patients display a survival disadvantage (pval&amp;lt;.005) the severity of which correlates with increased CCT2 expression levels. Similar to TCP-1, knocking down CCT2 significantly reduces the colony forming ability of the SUM-52 cell line. The identification of two genes that function as part of the same complex, both up-regulated by different mechanisms in breast cancer cells and both determinants of long term survival, points to a significant role for these genes and the TRiC complex in breast cancer. Citation Format: Stephen Guest, Jon Irish, Zachary Kratche, Elizabeth Garrett-Mayer, Robert Wilson, Stephen Ethier. The TRiC chaperonin in breast cancer cell growth, survival and response to taxane therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 440. doi:10.1158/1538-7445.AM2014-440

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival. We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques. The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment. IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival &gt; 36 months (LTS-36), including 33 patients surviving &gt; 60 months (LTS-60), with 259 patients surviving &lt; 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

Right Ventricular Function Is a Determinant of Long-Term Survival after Cardiac Resynchronization Therapy

Right ventricular (RV) dysfunction is a marker of poor prognosis in patients with heart failure. The aim of this study was to investigate the impact of RV function on the long-term outcomes of patients undergoing cardiac resynchronization therapy (CRT). A total of 120 consecutive patients treated with CRT according to guideline criteria were followed over 5 years. Comprehensive echocardiographic analyses of RV function and radial and longitudinal mechanical left ventricular dyssynchrony were performed at baseline and 6 months after implantation. RV function was evaluated by two-dimensional longitudinal strain of the free wall, fractional area change, tricuspid annular plane systolic excursion, and tricuspid annular systolic velocity. Long-term follow-up events were defined as all-cause mortality, heart transplantation, or assist device implantation. Long-term events occurred in 38 patients. Among the studied variables for RV function, RV strain < 18% had the highest sensitivity (79%) and specificity (84%) to predict a poor outcome after CRT (area under curve, 0.821; P < .0001). When adjusted for confounding baseline variables of ischemic etiology, mechanical dyssynchrony, left ventricular end-systolic volume, mitral regurgitation, and medical therapy, RV dysfunction remained independently associated with outcomes, indicating a 5.7-fold increased risk for hard events (P < .0001). Preserved RV function as assessed by speckle-tracking strain imaging appears to be an independent predictor of long-term event-free survival after CRT.

Determinants of Long-term Survival in Well Differentiated Extremity and Retroperitoneal Liposarcoma: A Population Based Outcomes Study of 1,358 Patients From the SEER Database (1973 - 2008)

Lipomatous neoplasms account for approximately 50% of soft tissue tumors with well differentiated liposarcoma (WDL) being the most common histological subtype. WDL are low-grade neoplasms with a low propensity for local recurrence and metastasis. Surgery is the primary treatment and the role of radiation therapy is highly debated for this sub-type. This study compares demographic and clinical characters, and the impact of radiation therapy on the long term survival of extremity (EX) and retroperitoneal (RP) WDL.