Worse Survival In Patients Research Articles

393 Long-term prognostic value of haemodynamic determinants of right ventricular pulsatile afterload in patients with advanced heart failure

Abstract Aims Right ventricular (RV) dysfunction demonstrated a strong impact on survival of patients with advanced heart failure with reduced ejection fraction (HFrEF). Increased RV afterload is associated with poor prognosis in patients with HF. To examine the prognostic relevance of RV pulsatile afterload parameters, in particular pulmonary artery compliance (PAC), elastance (PAE), and pulsatile index (PAPi) in a large cohort of patients with advanced HFrEF evaluated for heart transplantation (HT). Methods and results 149 patients with HFrEF enlisted for HT were evaluated with right heart catheterization (RHT) and echocardiography and were followed until death or any censoring events including HT, left ventricular assist device (LVAD), and hospitalization for acute heart failure (HHF). Cox regression and ROC-curve analysis were used to test the prognostic value of RV pulsatile afterload determinants. During a mean observation time of 500 ± 424 days, the primary endpoint occurred in 29 (19.5%) patients. The mean age was 56.6 ± 10.1 years and 85.2% were male. The most frequent etiology of HF was ischaemic cardiomyopathy (52.3%). Mean LV ejection fraction was 25.7 ± 10.2%. Patients who met the primary endpoint were significantly older and with worse haemodynamic profile than event-free survivors. In particular, the primary endpoint occurred in patients with lower PAC (1.8 ± 0.8 vs. 2.7 ± 2.0, P = 0.01), higher mean pulmonary arterial pressure (mPAP) (33.5 ± 11.3 vs. 29.3 ± 11.0, P = 0.05), PVR (3.0 ± 1.6 vs. 2.6 ± 2.0, P = 0.09), and PEA (1.12 ± 0.5 vs. 0.98 ± 0.6, P = 0.04). A significant increased risk of adverse outcome was observed in patients with PAC <1.9 ml/mmHg (HR: 3, 95% CI: 1.3–6, P = 0.007), PEA > 0.9 mmHg/ml (HR: 2.5, 95% CI: 1.1–5.2, P = 0.02) and mPAP ≥25 mmHg (HR: 3.0, 95% CI: 1.0–7.5, P = 0.03). The predictive value of PAC was superior compared with PVR (AUC comparison, P = 0.019) and PAPi (P = 0.03). Conversely, PAC presented similar prognostic accuracy compared with mPAP (P = 0.51) and PEA (P = 0.19). Moreover, PAC demonstrated incremental prognostic value compared with the cardiac index (P = 0.02), whereas mPAP and PAE did not. Conclusions Impaired haemodynamic RV parameters are associated with worse survival in patients with advanced HFrEF. Pulsatile RV afterload indices should be considered in the evaluation of patients enlisted for HT. PAC demonstrated an independent prognostic value in this highly selected cohort of patients awaiting HT.

Itaconate and leptin affecting PPARγ in M2 macrophages: A potential link to early-onset colorectal cancer

BackgroundAlong with the rising incidence of obesity, there has been an increase in patients diagnosed with early-onset colorectal cancer (<50 years old). In colorectal cancer, worse patient survival is associated with certain cytokine expression and downregulation of peroxisome proliferator activated receptor gamma expression. The effects of the obesity hormone leptin and macrophage-specific metabolite itaconate on these mechanisms are poorly understood. We investigated their impact on peroxisome proliferator activated receptor gamma and macrophage cytokine expression in vitro. MethodsM2-like macrophages were treated with either leptin, 4-octyl itaconate, or dimethyl itaconate in a dose- and time-dependent manner. Gene expression after treatment with 4 doses (D1-4) of each compound was analyzed at 4 time points (3, 6, 18, and 24 hours). ResultsPeroxisome proliferator activated receptor gamma was downregulated after 4-octyl itaconate treatment at 18 hours (FC -32.67, P ≤ .001). Interleukin-8 was upregulated after leptin and dimethyl itaconate treatment at 6 hours (FC 26.35 at D4, P ≤ .001, and FC 23.26 at D3, P = .006). Dimethyl itaconate upregulated IL-1β at 24 hours (FC 18.00 at D4, P ≤ .001). Tumor necrosis factor-α showed maximum downregulation after 4-octyl itaconate at 18 hours (FC -103.25 at D4, P ≤ .001). ConclusionsItaconate downregulates peroxisome proliferator activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Itaconate provides a link between obesity and colorectal cancer and may be a key regulator in early-onset colorectal cancer.

High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy

PurposeTumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer.Materials and methodsTMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel.ResultsThe study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0–35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy.ConclusionThese data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy.Secondary abstractThis retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

Native glycan fragments detected by MALDI mass spectrometry imaging are independent prognostic factors in pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies to date. The impressively developed stroma that surrounds and modulates the behavior of cancer cells is one of the main factors regulating the PDAC growth, metastasis and therapy resistance. Here, we postulate that stromal and cancer cell compartments differentiate in protein/lipid glycosylation patterns and analyze differences in glycan fragments in those compartments with clinicopathologic correlates.ResultsWe analyzed native glycan fragments in 109 human FFPE PDAC samples using high mass resolution matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometric imaging (MALDI-FT-ICR-MSI). Our method allows detection of native glycan fragments without previous digestion with PNGase or any other biochemical reaction. With this method, 8 and 18 native glycans were identified as uniquely expressed in only stromal or only cancer cell compartment, respectively. Kaplan–Meier survival model identified glycan fragments that are expressed in cancer cell or stromal compartment and significantly associated with patient outcome. Among cancer cell region-specific glycans, 10 predicted better and 6 worse patient survival. In the stroma, 1 glycan predicted good and 4 poor patient survival. Using factor analysis as a dimension reduction method, we were able to group the identified glycans in 2 factors. Multivariate analysis revealed that these factors can be used as independent survival prognostic elements with regard to the established Union for International Cancer Control (UICC) classification both in tumor and stroma regions.ConclusionOur method allows in situ detection of naturally occurring glycans in FFPE samples of human PDAC tissue and highlights the differences among glycans found in stromal and cancer cell compartment offering a basis for further exploration on the role of specific glycans in cancer–stroma communication.

Sarcopenia diagnosis using different criteria as a predictor of early mortality in patients undergoing hemodialysis

ObjectivesChronic kidney disease (CKD) is a public health problem, causing secondary sarcopenia. The aim of this study was to evaluate sarcopenia using the definitions proposed by European Working Group on Sarcopenia in Older People in 2010 (EWGSOP2010) and 2019 (EWGSOP2019) as an independent prognostic factor for worse survival in patients with CKD undergoing hemodialysis. MethodsMuscle mass, muscle strength, and physical performance were assessed in a cohort of patients with CKD on hemodialysis. The sample consisted of 127 patients (40% >60 y of age) and 36 patients (28.3%) died after a median follow-up length of 23.5 mo (interquartile range= 14.9 – 29). The EWGSOP2010 and EWGSOP2019 definitions were used for diagnosing sarcopenia. Sarcopenia association with mortality by both definitions was investigated using Kaplan–Meier curves and Cox proportional hazard models. The area under the curve, sensitivity, specificity, positive, and negative predictive values for both definitions were also compared. ResultsPatients diagnosed with sarcopenia by both criteria had almost three times higher risk for mortality (95% confidence interval,1.45–6.06 and 1.44–6.13, respectively). Patients classified with severe sarcopenia by both definitions had a significantly lower survival, even after the adjusted analysis. The areas under the curve for EWGSOP2010 and EWGSOP2019 did not significantly differ. The sensitivity/specificity analysis was considered similar for both criteria, and around 70% of the patients was correctly classified. ConclusionSarcopenia, notably severe sarcopenia, diagnosed by EWGSOP2010 or EWGSOP2019 criteria, is an independent prognostic factor for worse survival in this population. Early detection with effective interventions may decrease the higher mortality risk among patients with sarcopenia and CKD.

Circular RNA circHERC4 as a novel oncogenic driver to promote tumor metastasis via the miR-556-5p/CTBP2/E-cadherin axis in colorectal cancer

BackgroundThe main cause of death in colorectal cancer patients is metastasis. Accumulating evidences suggest that circRNA plays pivotal roles in cancer initiation and development. However, the underlying molecular mechanisms of circRNAs that orchestrate cancer metastasis remain vague and need further clarification.MethodsTwo paired CRC and adjacent normal tissues were used to screen the upregulated circRNAs by circRNA-seq; then, cell invasion assay was applied to confirm the functional invasion-related circRNAs. According to the above methods, circHERC4 (hsa_circ_0007113) was selected for further research. Next, we investigated the clinical significance of circHERC4 in a large cohort of patients with CRC. The oncogenic activity of circHERC4 was investigated in both CRC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying circHERC4 as a malignant driver.ResultsWe demonstrated that circHERC4 was aberrantly elevated in CRC tissues (P < 0.001), and was positively associated with lymph node metastasis and advanced tumor grade (P < 0.01). Notably, the expression of circHERC4 was associated with worse survival in patients with CRC. Silencing of circHERC4 significantly inhibited the proliferation and migration of two highly aggressive CRC cell lines and reduced liver and lung metastasis in vivo. Mechanistically, we revealed that circHERC4 inactivated the tumor suppressor, miR-556-5p, leading to the activation of CTBP2/E-cadherin pathway which promotes tumor metastasis in CRC.ConclusionsCircHERC4 exerts critical roles in promoting tumor aggressiveness through miR-556-5p/CTBP2/E-cadherin pathway and is a prognostic biomarker of the disease, suggesting that circHERC4 may serve as an exploitable therapeutic target for patients with CRC.

DDRE-22. DISRUPTING REDOX BALANCE VIA THE TETRAHYDROBIOPTERIN PATHWAY IN GLIOBLASTOMA

Abstract Aberrant redox statuses are observed in glioblastoma (GBM), and we previously identified GTP cyclohydrolase I (GCH1) to be a redox regulator upregulated in brain tumor initiating cells (BTICs). GCH1 is a rate-limiting enzyme in the de novo synthesis of tetrahydrobiopterin (BH4), a cofactor that produces catecholamine precursors and nitric oxide (NO) and, once used, becomes 7,8-dihydrobiopterin (BH2). Regeneration of BH2 into BH4 by dihydrofolate reductase (DHFR) helps to maintain proper BH4/BH2 ratios for redox balance. Although the BH4 pathway has traditionally been studied in the vasculature system for its regulation of NO, our previous work and that of others suggests the GCH1/BH4 pathway plays a critical redox role including in neoplastic cells. In silico analysis of primary and recurrent gliomas indicate high expression of BH4 related enzymes that correlated with worse patient survival in both primary and recurrent gliomas. The observed elevation of the BH4 pathway not only emphasizes its importance, but a therapeutic opportunity for improving survival in glioma patients. By repurposing FDA approved drugs known to cross the blood brain barrier and previously suggested as anti-glioma therapies, combining inhibitors for the de novo synthesis (sulfasalazine) and regeneration (pyrimethamine) of BH4 could prove to be an effective strategy for targeting the GCH1/BH4 through redox disruption. Preliminary data BTICs isolated from patient derived xenografts (PDXs) indicated reduced viability when treated with sulfasalazine (SASP) and pyrimethamine (PYR). Furthermore, we observed lower/depleted levels of BH4 relative to BH2 when BTICs were treated with SASP and PYR. Lastly, there is an increase in mitochondrial ROS upon SASP and PYR treatment, suggesting dysregulated redox states. Importantly, temozolomide resistant GBM cells remained sensitive to SASP and PYR. Taken together, our preliminary data suggests the plausibility of targeting the GCH1/BH4 pathway with SASP and PYR to disrupt redox balance in glioma through the depletion of BH4.

Rearrangement-mediated cis-regulatory alterations in advanced patient tumors reveal interactions with therapy.

SUMMARYThe global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.

The Scavenger Receptor MARCO Expressed by Tumor-Associated Macrophages Are Highly Associated With Poor Pancreatic Cancer Prognosis.

Macrophage-targeting therapies have become attractive strategies for immunotherapy. Deficiency of MARCO significantly inhibits tumor progression and metastasis in murine models of pancreatic cancer. However, the role of MARCO in patients with pancreatic cancer remains unclear. In the present study, we analyzed tumor-associated macrophage (TAM)-related changes using the Cancer Genome Atlas database. We observed a significant enrichment of M2 macrophages in pancreatic cancer tissues. We found that several pro-tumor markers are increased in cancer tissues, including CD163, CD206, SIRPα, LILRB1, SIGLEC10, AXL, MERTK, and MARCO. Crucially, MARCO is highly or exclusively expressed in pancreatic cancer across many types of solid tumors, suggesting its significant role in pancreatic cancer. Next, we investigated the expression of MARCO in relation to the macrophage marker CD163 in a treatment-naïve pancreatic cancer cohort after surgery (n = 65). MARCO and CD163 were analyzed using immunohistochemistry. We observed increased expression of CD163 and MARCO in pancreatic cancer tissues compared with paracancerous tissues. Furthermore, we observed a large variation in CD163 and MARCO expression in pancreatic cancer tissues among cases, suggesting the heterogeneous expression of these two markers among patients. Correlation to clinical data indicated a strong trend toward worse survival for patients with high CD163 and MARCO macrophage infiltration. Moreover, high CD163 and MARCO expression negatively affected the disease-free survival and overall survival rates of patients with pancreatic cancer. Univariate and multivariate analysis revealed that CD163 and MARCO expression was an independent indicator of pancreatic cancer prognosis. In conclusion, high CD163 and MARCO expression in cancer tissues is a negative prognostic marker for pancreatic cancer after surgery. Furthermore, anti-MARCO may be a novel therapy that is worth studying in depth.

Follow-up Failure Is Associated with Worse Survival in Patients Undergoing Carotid Revascularization

Follow-up Failure Is Associated with Worse Survival in Patients Undergoing Carotid Revascularization

Influence of donor and recipient hepatitis B virus infection on long‐term outcomes after kidney transplantation

The demand for transplantable kidneys continues to outstrip supply, and the risk of donor-derived infection limits utilization. The effect of donor or recipient HBV status, defined by surface antigen (HBsAg) positivity, on long-term survival outcomes of kidney transplant (KT) is unknown. We conducted a retrospective cohort study based on Organ Procurement and Transplantation Network (OPTN) data from 2000 to 2019. We identified three cohorts based on donor (D) or recipient (R) HBsAg status: D-R, D-R+, and D+R-. Pairwise comparisons of patient survival (PS) and all-cause graft survival (GS) after propensity score matching were performed to assess the effect of HBV infection in KT recipients. Our findings showed that there were no statistically significant differences in PS and GS among D-R, D-R+, and D+R-groups, nor was the patient or GS different between donor and recipient HBsAg+ status. Finally, in 2019 kidney discard rates were 15% higher for HBsAg+ deceased donors compared to HBsAg- donors. HBsAg+ status was not associated with worse PS or GS after KT. Prior to broadly advocating utilization of HbsAg+ kidneys, further studies assessing KT recipient morbidity and safety are necessary.

Prognostic value of heart rate reserve during dipyridamole stress echocardiography in patients with abnormal chronotropic response to exercise

Abstract Aim To assess the prognostic meaning of HRR during dipyridamole stress echocardiography (DSE) in patients with abnormal chronotropic response to exercise. Methods From 2004 to 2019, we prospectively acquired and retrospectively analyzed 379 patients (age 62±11 years; ejection fraction 60±5%) with suspected (n=243) or known (n=136) chronic coronary syndromes, referred to DSE for chronotropic incompetence during upright bicycle exercise-electrocardiography test defined as HRR used [(peak HR − rest HR) / (220 − age) − rest HR] &amp;lt;80% in patients off and &amp;lt;62% in patients on beta-blockers. All patients were in sinus rhythm and underwent DSE (0.84 mg/kg) within 3 months of exercise testing. During DSE, age-independent HRR (peak/rest HR) &amp;lt;1.22 was considered abnormal. All patients were followed-up. All-cause death was the only outcome measure. Results HRR during DSE was normal in 275 (73%) and abnormal in 104 patients (27%). During a follow-up of 9.0±4.2 years, 67 patients (18%) died. The 15-year mortality rate was 23% in patients with normal and 61% in patients with abnormal HRR (p&amp;lt;0.0001) (Figure). At multivariable analysis a blunted HRR during DSE was an independent predictor of outcome (hazard ratio 2.01, 95% confidence intervals 1.23–3.29; p=0.005) with age and diabetes, while neither inducible ischemia nor ongoing beta-blocker therapy were significant predictors. Conclusion A blunted HRR during DSE predicts a worse survival in patients with chronotropic incompetence during exercise test. HRR during DSE is an appealingly simple biomarker of cardiac autonomic dysfunction independent of imaging, exercise and beta-blocker therapy. Funding Acknowledgement Type of funding sources: None.

Recurrent heart failure hospitalizations in patients with preserved ejection fraction: predictors and outcome

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is the most common form of HF and its prevalence is approaching epidemic proportions. Current treatment strategies aim to improve clinical status and reduce mortality rates. Episodes of acute HF are one of the main reasons for hospitalization in people over 65 years; however, they have not been well studied in HFpEF patients yet. Objectives The aim of this study was to investigate the impact of recurrent HF hospitalizations on long-term outcomes and to find predictors for subsequent events. Methods Between December 2010 and December 2019, 422 patients with confirmed HFpEF were enrolled in this study and prospectively followed. Results During follow-up, 190 HFpEF patients (45%) experienced HF hospitalizations with a median frequency of 2 (IQR: 1–4). Those presenting with acute HF had higher body mass indices (p=0.018), worse performance in 6-minute walking tests (p&amp;lt;0.001), higher levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP, p&amp;lt;0.001) and, compared to stable patients, a larger proportion suffered from New York Heart Association functional class ≥ III (p&amp;lt;0.001). Furthermore, baseline left ventricular diastolic dysfunction (early mitral inflow velocity/early diastolic mitral annular velocity; p=0.002) as well as right ventricular afterload (pulmonary artery wedge pressure; p&amp;lt;0.001) were more pronounced in patients with acute deteriorations. Over the observation period 107 patients (25%) died. Kaplan-Meier curves revealed increasingly worse survival in patients with recurrent HF events (5-years survival: 1 HF event 66% vs ≥3 HF events 53%, p&amp;lt;0.001; Figure). Time to last hospitalization was a strong predictor of survival with an adjusted HR of 2.5 (95% CI 1.63–3.98; p&amp;lt;0.001) in multivariate Cox regression analysis. Predictors of recurrent HF hospitalization were 6-minute walking distance (OR: 0.07, CI 0.02–0.22; p=0.001), systolic pulmonary artery pressure (OR: 1.05, CI 1.03–1.07, p=0.001) and NT-pro BNP (OR: 4.92, CI: 2.68–9.04, p=0.001) Conclusions HFpEF patients experiencing recurrent HF hospitalizations have worse long-term outcome. Intensive efforts should be made to maintain HFpEF patients compensated over time. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis

DEPTOR inhibits lung tumorigenesis by inactivating the EGFR-mTOR signals.

DEPTOR plays vital roles in the regulation of cell proliferation and survival by directly modulating the activity of mTORC1/2. However, the physiological role of DEPTOR in lung tumorigenesis, as well as its clinical significance, remains elusive. In this study, we revealed that decreased DEPTOR expression correlated with increased tumor size, poor differentiation, and worse survival in patients with lung cancer. DEPTOR depletion promoted cell proliferation, survival, migration, and invasion in human lung cancer cells. Mechanistically, DEPTOR bound to the kinase domain of EGFR via its PDZ domain to inactivate EGFR signal. Thus, DEPTOR depletion not only directly activated mTORC1/2, but also relieved the inhibition of EGFR to subsequently activate mTOR signals, leading to the induction of cell proliferation and survival. Additionally, activated EGFR-mTOR signals upregulated the expression of ZEB1 and SLUG to induce epithelial-mesenchymal transition, resulting in enhanced migration and invasion. Importantly, Deptor deletion accelerated KrasG12D;p53fl/fl-induced lung tumorigenesis and shortened mouse life span via the activation of EGFR-mTOR signals. Collectively, our study demonstrated that DEPTOR acts as a tumor suppressor in lung tumorigenesis, and its reduction may advance the progression of human lung cancer.

S1191 Trajectory of Cancer-Associated Weight Loss in Patients With Hepatocellular Carcinoma Is Associated With Prognosis

Introduction: Cancer cachexia, a clinical syndrome of wasting defined by specific weight loss criteria, is associated with functional decline and poorer outcomes in various cancers, including hepatocellular carcinoma (HCC). There are few data on weight loss trajectory and its impact on survival in patients with HCC. Methods: We performed a retrospective cohort study of consecutive patients diagnosed with HCC at two U.S. health systems between 2008-2018. Cachexia (CCX) was defined as >5% weight loss (or >2% weight loss if BMI < 20 kg/m2), according to international consensus definitions. Patients were classified into four groups based on weight loss trajectory, assessed by percent weight loss 6 months prior to HCC diagnosis and weight loss 6 months after HCC diagnosis: Group 1: CCX - /CCX -; Group 2: CCX + / CCX -; Group 3: CCX - /CCX +; Group 4: CCX + / CCX +. We used multivariable Cox proportional hazard models to identify factors associated with overall survival and log-rank tests to compare survival between groups. Results: We identified 507 patients meeting inclusion criteria; 52.1%, 27.4%, 16.2% and 4.3% in Groups 1, 2, 3, and 4, respectively. Most patients were Child Pugh class A (60.8%) or B (32.5%). Groups 1 and 2 had a higher proportion of tumors diagnosed at an early stage (BCLC 0/A) compared to groups 3 and 4 (72.6% and 66.7% vs 54.0% and 36.7%; p< 0.001). Similarly, a higher proportion of patients in groups 1 received surgical treatment compared to those in groups 2, 3 and 4 (33.6% vs 26.3%, 30.2% and 27.3%; p < 0.001). Among the subset of patients who underwent locoregional therapy (n = 256), there was no significant difference in objective response rates between the 4 groups (p = 0.50). Overall survival was best in group 1 patients (34.3 months), intermediate in groups 2 and 3 (20.3 and 17.3 months respectively) and worst in group 4 patients (11.4 months) (p < 0.001). In multivariable analysis, patients in group 4 had worse overall survival compared to group 1 after adjusting for age, sex, race, Child Pugh class, tumor stage, and HCC treatment modality (aHR 1.71, 95%CI 1.01 – 2.88), whereas survival differences for groups 2 (aHR 1.17, 95%CI 0.85 – 1.62) and 3 (aHR 1.11, 95%CI 0.84 - 1.45) were no longer statistically significant. Conclusion: Trajectory of cancer-associated weight loss is associated with lower rates of curative treatment receipt and worse survival in patients with HCC.Figure 1.: Kaplan-Meier curve demonstrating overall survival among Group 1: CCX - /CCX -; Group 2: CCX + / CCX -; Group 3: CCX - /CCX +; Group 4: CCX + / CCX +.

A systematic analysis of ATPase Cation transporting 13A2 (ATP13A2) transcriptional expression and prognostic value in human brain cancer

P-type transport ATPase’s are active transporters that dispense the majority of the cellular functions. ATP13A2 have a role in neurodegeneration which is commonly associated with lysosomal dysfunction. Lysosome plays a significant role in the metabolism, secretion, signaling, plasma membrane repair, and autophagy which have fundamental implications in different carcinomas. ATP13A2 is placed in the lysosome and the late endosome and the drastic dysfunction in the lysosome is caused from its mutation. However, this systematic study was done to evaluate ATP13A2 as the possible prognostic marker for the glioblastoma multiform (GBM) is the utmost frequent primary cancer of the central nervous system. Within this cumulative study, we have inspected the pattern of expression of ATP13A2 and their corresponding outcome in GBM patients using different available databases. We examined a comparative study of ATP13A2 expression between the normal tissues and their cancers using the UALCAN, Oncomine, GEPIA2, and GENT2 databases. Both analyses showed significantly high ATP13A2 mRNA and protein expression in GBM than those of normal tissues. We investigate clinicopathological expression and methylation characteristics of GBM using UALCAN database, which analysis showed clinicopathological expression of ATP13A2 was down regulated and methylation was over-expressed in GBM compared to normal tissues. We also investigate mutations and the alterations of copy number of ATP13A2 using a database called cBioPortal, which showing about 5 (0.2%) alteration and 0.6% mutation frequency and co-expression profile through the Oncomine. We used the Enricher tool to predict the signaling pathways in GBM through gene ontology and pathway analysis of co-expressed genes. The PrognoScan analysis revealed that the increased ATP13A2 expression correlates with worse patient survival. Finally, our derived data apprises that, ATP13A2 may serve as a potential biomarker of GBM/brain cancer patients.

Construction of circRNA‐based ceRNA network and its prognosis‐associated subnet of clear cell renal cell carcinoma

Circular RNAs (circRNAs) are novel biomarkers of various cancers. CircRNAs can sponge miRNAs and regulate target mRNAs, which was called competing endogenous RNAs (ceRNA). This study was designed to identify circRNAs related to patients with clear cell renal cell carcinoma (ccRCC) and the first to select three independent Gene Expression Omnibus microarrays covering circRNAs, miRNAs, and mRNAs for multiple analyses. The data of clinical cases applied in our study were obtained from The Cancer Genome Atlas. We successfully conducted a circRNA/miRNA/mRNA ceRNA network related to ccRCC patients via R software and Cytoscape including 8 circRNAs, 6 miRNAs, and 49 mRNAs. The prognosis‐associated subnet covered 8 circRNAs, 6 miRNAs, and 22 mRNAs. Quantitative real‐time PCR was applied to measure our prediction in three renal cell lines and 23 pairs of tissues. Small interfering RNA targeting the back‐splice region of hsa_circ_0001167 was further implied to confirm the regulation. Ultimately, hsa_circ_0001167/hsa‐miR‐595/CCDC8 regulatory axis was identified in this study, which may serve as prognostic indicators. Lower levels of hsa_circ_0001167 and CCDC8 were potentially correlated with worse patient survival.

Insulin and the insulin receptor collaborate to promote human gastric cancer

BackgroundGastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells.MethodsTumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence.ResultsINSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death.ConclusionsThe insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.

Microscopic Portal Vein Invasion in Relation to Tumor Focality and Dimension in Patients with Hepatocellular Carcinoma

BackgroundMicroscopic portal vein invasion (microPVI) and tumor multifocality are hepatocellular carcinoma (HCC) prognosis factors. To investigate whether microPVI and multifocality are directly related to each other. MethodsWe retrospectively analyzed the relationships between microPVI, multifocality, and maximum tumor diameter (MTD) in prospectively collected transplanted HCC patients. ResultsHCCs with 1, 2, or ≥ 3 foci had more microPVI in larger than in smaller HCCs, with microPVI being present in 52.24% of single large foci. Conversely, microPVI patients had similar percentages of single and multifocal lesions. A linear regression model of MTD, showed microPVI best associated with MTD, with 2.49 as coefficient, whereas multifocality had a 0.83 coefficient. A logistic regression model of microPVI showed significant association with tumor multifocality, especially for small HCCs. Trends for microPVI and multifocality in relation to MTD revealed that both increased with MTD but more significantly for microPVI. Survival was similar in patients with small HCCs, with or without microPVI, but was significantly worse in microPVI patients with larger HCCs. No patient survival differences were found in relation to focality. ConclusionsMTD had stronger associations with microPVI than with multifocality. microPVI was associated with worse survival in patients with large HCCs, but survival was not impacted by number of tumor foci. microPVI and multifocality appear weakly related, having different behavior in relation to MTD and survival.

Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness.

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non-steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency-induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding-disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL-induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC. SIGNIFICANCE: This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.