Prognosis For Overall Survival Research Articles

Analysis of potential risk factors in the survival of patients with primary retroperitoneal liposarcoma

IntroductionThe present work is an observational study of a series of variables regarding overall survival and disease-free survival in patients diagnosed with primary liposarcoma. MethodsThe study is prospective with retrolective data collection that includes all patients with primary liposarcoma referred to Hospital Son Espases University Hospital, Palma de Mallorca, Spain from January 1990 to December 2019. ResultsThe study includes 50 patients and the compartment surgery was performed in 18 patients (36%) of cases. The mean overall survival of the sample was 15.57 years (95% CI: 12.02–19.12) and the mean disease-free survival was 6.70 years (95% CI: 4.50–8.86). ConclusionCompartment surgery has not shown benefits in terms of overall survival and disease-free survival. The ASA classification (≥3) predicts a poor prognosis in both overall survival and disease-free survival. Resection with free margins, described on the pathological results and defined in this work as R0, show better disease-free survival.

Prognostic Significance of a Scoring System Combining p16, Smoking, and Drinking Status in a Series of 131 Patients with Oropharyngeal Cancers.

Background Tobacco and alcohol are two main risk factors associated with head and neck squamous cell carcinoma (HNSCC). Studies showed that human papillomavirus (HPV) plays a role in the etiology of this cancer. HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients present in general a better response to conventional therapy and better overall survival (OS). However, OSCC is a heterogeneous disease regarding treatment. This study aimed to identify more effective prognostic factors associated with a poor clinical outcome for OSCC patients to improve treatment selection. Materials and Methods OSCC patients diagnosed between 2007 and 2017, in two Belgian hospitals, were included. Demographic and clinicopathologic data were extracted from medical records. HPV status was determined through p16 immunohistochemistry. Univariable and multivariable Cox proportional hazard regression analyses allowed to identify variables prognostic for OS and recurrence-free survival (RFS). Kaplan–Meier survival curves have been assessed for survival. Results The study included 131 patients. Statistics showed that monotherapies were significantly associated with a shorter OS; p16 overexpression was significantly associated with a weak consumption of tobacco or alcohol, and a high p16 expression was significantly associated with both longer RFS and OS. The study validated that tobacco and alcohol consumption were significantly correlated with poorer RFS and poorer OS. Only p16 expression trended to be significant for RFS when compared to smoking and drinking habits, while p16 upregulation and alcohol use were both vital for OS indicating that p16 is an independent and significant prognostic factor in OSCC patients. Finally, a scoring system combining p16, tobacco, and alcohol status was defined and was significantly associated with longer RFS and longer OS for nonsmoker and nondrinker p16-positive OSCC patients. Conclusions This study confirmed that the overexpression of the p16 protein could be viewed as a factor of good prognosis for RFS and OS of OSCC patients. The prognostic significance of a scoring system combining p16 expression, smoking, and drinking status was evaluated and concluded to be a more effective tool to determine therapeutic orientations based on the risk factors for better treatment relevance and survival.

Biomarker Screening and Prognostic Significance Analysis for Renal Cell Carcinoma.

BackgroundStudies report that conventional treatment of clear cell renal cell carcinoma (ccRCC) is effective, but several advanced patients present with poor prognosis. The current study explored potential new tumor markers and therapeutic targets in advanced ccRCC.MethodsBiomarker gene expression of ccRCC was retrieved from GEO database and the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database. Gene ontology (GO) analysis and protein–protein interaction (PPI) networks of biomarker genes were constructed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. Kaplan–Meier analysis and receiver operating characteristic curve (ROC) analysis were performed to explore the prognostic and diagnostic roles of these genes. Gene set enrichment analysis (GSEA) analysis was used to determine hallmark functions of the biomarker genes. qRT-PCR was used to verify the reliability of the analysis results in tumor tissues.ResultsA total of 21 upregulated genes were identified between advanced ccRCC and early ccRCC (grade III+IV vs grade I+II). Gene ontology analysis showed that the 21 upregulated genes were mainly implicated in biological processes including metabolic and lipid transport. The findings showed that 7 out of the 21 genes were significantly upregulated in 72-paired samples retrieved from the TCGA-KIRC. High expression of 5 genes indicated a poor prognosis of overall survival and disease-free survival in KIRC. Three genes effectively distinguished renal cancer tissue and adjacent renal tissues in a total of 533 ccRCC samples. GSEA showed that the 3 biomarkers were significantly enriched in epithelial–mesenchymal transition, G2M checkpoint, and angiogenesis. The results of qRT-PCR showed that STEAP3, IBSP, and AQP9 had a significant identification effect in ccRCC.ConclusionThe findings showed that 3 biomarkers were significantly upregulated in advanced ccRCC and could be used for diagnosis, prediction, and potential novel therapeutic targets for progression of ccRCC.

Development and Validation of Prognostic Nomogram for Young Patients with Kidney Cancer

BackgroundThe aim of this study was to establish a nomogram model to evaluate the prognosis of early-onset kidney cancer (EOKC) in terms of overall survival (OS) and cancer-specific survival (CSS).MethodsPatients with EOKC diagnosed between 2004 and 2015 were collected from Surveillance, Epidemiology and End Results (SEER) and randomly assigned to the training and validation set at a ratio of 2 to 1. Important variables for constructing nomograms were screened by univariate and multivariate Cox analysis. The nomogram model was evaluated using concordance index (C-index), decision curve analysis (DCA) curves, and receiver operating characteristic (ROC) curves.ResultsA total of 12,526 EOKC patients were included in the study. OS nomogram was constructed based on gender, age, race, grade, AJCC stage, TNM stage, histology, chemotherapy and radiotherapy. CSS nomogram was constructed based on listed above except gender. In the external validation, the C-index for the OS nomogram was 0.855 (95% CI 0.834–0.976), and the C-index for the CSS nomogram was 0.938 (0.925–0.951). High-quality calibration curves were noted in both OS and CSS nomogram models. ROC and DCA curves showed that nomograms had better predictive performance than TNM stage and SEER stage.ConclusionThe nomogram model provides an applicable tool for evaluating the OS and CSS prognosis of EOKC.

Eosinophilic features in clear cell renal cell carcinoma correlate with outcomes of immune checkpoint and angiogenesis blockade

BackgroundClear cell renal cell carcinoma (ccRCC) displays heterogeneity in appearance—a distinctive pale clear to eosinophilic cytoplasm; however, little is known about the underlying mechanisms and clinical implications. We investigated the...

Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer.

BackgroundEsophageal cancer often appears as postoperative metastasis or recurrence after radical surgery. Although we had previously reported that serum programmed cell death ligand 1 (PD-L1) level correlated with the prognosis of esophageal cancer, further novel biomarkers are required for more precise prediction of the prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with the cholesterol metabolism. But there was no report of relationship between serum PCSK9 antibody and cancer. Therefore, we investigated whether anti-PCSK9 antibodies could be a novel biomarker for solid cancer.MethodsSerum levels of anti-PCSK9 antibodies and antigens in patients with solid cancer were analyzed using amplified luminescence proximity homogeneous assay-linked immunosorbent assay (AlphaLISA). The reactivity of serum antibodies against recombinant PCSK9 protein was investigated by Western blotting, and the expression of PCSK9 antigens in esophageal cancer tissues was examined by immunohistochemical staining.ResultsAlphaLISA showed that serum anti-PCSK9 antibody (s-PCSK9-Ab) levels were significantly higher in patients with esophageal cancer, gastric cancer, colorectal cancer, lung cancer, and breast cancer than in healthy donors, and patients with esophageal cancer had the highest levels. The presence of serum antibody in patients was confirmed by Western blotting. There was no apparent correlation between s-PCSK9-Ab and PCSK9 antigen levels. Immunohistochemical staining demonstrated the expression of PCSK9 antigen in both the cytoplasm and nuclear compartments of esophageal squamous cell carcinoma tissue but not in normal tissue. Compared with patients with low s-PCSK9-Ab levels, those with high s-PCSK9-Ab levels had a favorable postoperative prognosis after radical surgery for esophageal cancer. In the multivariate analysis, tumor depth and s-PCSK9-Ab level were identified as independent prognostic factors. In the univariate analysis of clinicopathological features, high PCSK9 antibody levels were not associated with sex, age, location, tumor depth, lymph node status, squamous cell carcinoma antigen, or p53-Ab, whereas they correlated significantly with PD-L1 levels, which were associated with unfavorable prognosis. Correlation between s-PCSK9-Ab and PD-L1 levels was also confirmed in the logistic regression analysis; therefore, low s-PCSK9-Ab levels could discriminate another poor prognosis group other than high-PD-L1 group.ConclusionsPatients with solid cancer had higher s-PCSK9-Ab levels than healthy donors. High s-PCSK9-Ab levels indicated better prognosis for overall survival after surgery in patients with esophageal cancer.

Development of a prognostic prediction model based on microRNA-1269a in esophageal cancer.

BACKGROUNDEsophageal cancer (ESCA) is a heterogeneous cancer with variable outcomes that are challenging to predict. MicroRNA (miR)-1269a is a newly discovered non-coding RNA that shows promising prognostic prediction in other cancers, but its clinical value in ESCA remains unclear.AIMTo explore the relationship between miR-1269a and its clinical value and to develop a nomogram to succinctly display this relationship.METHODSWe analyzed the expression of miR-1269a in 125 ESCA tissue samples with complete clinical data and 52 normal tissue samples. We determined the prognostic value of miR-1269a for overall survival (OS) and cancer-specific survival (CSS) and evaluated the association between miR-1269a and clinical variables including tumor location, histologic grade, metastatic stage, and American Joint Committee on Cancer (AJCC) stage using multivariate Cox analysis. Additionally, we developed a nomogram for OS and CSS based on miR-1269a expression using age and AJCC stage and assessed its prognostic performance. Using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes analyses, we predicted the target genes of miR-1269a and analyzed their potential function in caner development.RESULTSThe expression of miR-1269a was significantly higher in ESCA patients than healthy controls. Patients with high expression of miR-1269a showed poor prognosis in OS and CSS, suffered increased rates of low differentiation and metastasis, and exhibited tumor stage T3 + T4, positive lymph stage, and AJCC stage III + IV. The area under the receiver operating characteristic curve of miR-1269a was 0.716 for OS and 0.764 for CSS. Multivariate Cox analysis revealed that AJCC stage and miR-1269a were independent factors for OS and CSS. Combing with age, we constructed a nomogram for prognostic prediction. Additionally, our nomogram showed excellent predictive performance for OS and CSS after 3 years and 5 years and was easy to use. Ultimately, the functional analysis suggested that miR-1269a was mostly involved in the PI3K-AKT signaling pathway.CONCLUSIONmiR-1269a can be used as a potential indicator for the prognosis of ESCA patients. We developed an easy-to-use nomogram with excellent ESCA prognostic prediction for clinical use.

Factors Prognostic for Brain Metastases from Colorectal Cancer: A Single-Center Experience in China.

PurposeThis study aimed to analyze clinicopathological, survival, prognostic factors, as well as the timing of brain metastases (BM) in colorectal cancer (CRC) using data from a Chinese center.Patients and MethodsData of 65 consecutive CRC patients with BM were collected from a single institution in China. The time from primary tumor surgery to the occurrence of BM was calculated. Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox’s proportional hazard regression models.ResultsThe median time interval from CRC surgery to the diagnosis of BM was 24 months. After diagnosis of BM, median OS values for patients were 11 months. Extracranial metastases occurred in 45 cases (69.2%) when BM was diagnosed, and 58.5% of these patients with lung metastases Time of BMs (P=0.018), presence of extracranial metastases (P=0.033), treatment (P=0.003), CA199 (P=0.034), CA125 (P<0.001), CA242 (P=0.018), and CA211 (P=0.012) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only treatment was an independent predictor for OS (conservative treatment; HR=1.861, 95% CI=1.077–3.441; P=0.048).ConclusionSurgical treatment of metastatic lesions may be an alternative choice for CRC patients with BM. Identifying the timing of brain metastases can help to detect this disease early, leading to a better survival outcome.

EEF2K as a novel metastatic and prognostic biomarker in gastric cancer patients

BackgroundAlthough eukaryotic elongation factor 2 kinase (eEF2K) has been reported to be a potential oncogenic factor in many human cancers, its usefulness as a clinical prognostic biomarker for gastric cancer has not been investigated. MethodsIn this study, data about 540 patients with stomach adenocarcinoma (STAD) were analyzed from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases to determine the expression of eEF2K. Immunohistochemistry (IHC), western blots, and real-time polymerase chain reaction (RT-PCR) were also performed to determine the clinical significance of eEF2K expression in 96 postoperative patients with gastric cancer. Among the 96 patients, 36 had low expression of eEF2K and 60 had high expression. ResultsAnalysis of the TCGA and GEO datasets revealed that eEF2K expression was significantly higher in the STAD tissue samples than in the non-tumorous gastric tissues. IHC, western blots, and RT-PCR confirmed these findings. The high expression level of eEF2K was found to be related to the presence of lymph node metastasis (p = 0.002). Moreover, multivariate analysis showed that eEF2K was an independent indicator of prognosis for overall survival (OS) (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.06–2.79; p = 0.03) and disease-free survival (DFS) (HR = 1.66, 95% CI = 0.997–2.765; p = 0.052) in patients with surgically resected STAD. ConclusionCollectively, our findings suggest that eEF2K is a clinical indicator of metastatic and prognostic significance for STAD survival and could serve as a potential therapeutic target.

Cytoplasmic EBP50 and elevated PARP1 are unfavorable prognostic factors in ovarian clear cell carcinoma.

Patients with ovarian clear cell carcinoma (OCCC) experience frequent recurrence, which is most likely due to chemoresistance. We used shotgun proteomics analysis and identified upregulation of ezrin-binding phosphoprotein 50 (EBP50) in recurrent OCCC samples. Cytoplasmic and/or nuclear (Cyt/N), but not membranous, EBP50 immunoreactivity was significantly higher in recurrent OCCC as compared with that of primary tumors. OCCC cells expressing cytoplasmic EBP50 were significantly less susceptible to cisplatin (CDDP)-induced apoptosis compared with cells expressing membranous EBP50. Abrogation of resistance following knockdown of cytoplasmic EBP50 was accompanied by decreased XIAP and BCL2, increased BAX and increased caspase-3 cleavage. We found that poly (ADP-ribose) polymerase1 (PARP1), which is involved in DNA damage detection and repair, binds to EBP50 through its PDZ1 domain. CDDP treatment of cells expressing cytoplasmic (but not membranous) EBP50 increased nuclear PARP1 expression, whereas knockdown of EBP50 cells decreased PARP1 expression and activity following CDDP treatment. Finally, OCCC patients with a combination of Cyt/N EBP50 and high PARP1 score had worst the prognosis for overall and progression-free survival. Together, our data suggest that cytoplasmic EBP50 inhibits apoptosis and promotes OCCC survival through stabilization of PARP1 activity and modulation of the XIAP/BCL2/BAX axis. This may increase the likelihood of tumor recurrence, and we therefore suggest a combined analysis for EBP50 and PARP1 may have great utility in OCCC prediction and prognosis.

Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer outcomes in patients without radical cystectomy.

Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) is a newly defined subtype that is unlikely to benefit from BCG rechallenge. Radical cystectomy is currently recommended for BCG-unresponsive NMIBC; however, a certain proportion of these patients can be managed with treatments other than that. Herein, we conducted a multicenter retrospective study to analyze the clinical outcomes of BCG-unresponsive NMIBC patients who did not receive radical cystectomy. Of the 141 BCG-unresponsive NMIBC patients, 94 (66.7%) received treatment except radical cystectomy. Survival outcomes were calculated from the date of diagnosis using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified using the multivariate Cox regression model. This group was further classified into three groups according to the number of risk factors, and survival outcomes were compared. Multivariate analyses identified low estimated glomerular filtration rate (< 45ml/min/1.73 m2) and large tumor size (≥ 30mm) before BCG induction as independent poor prognostic factors for progression-free survival and overall survival, while the latter was also an independent factor for cancer-specific survival. The presence of variant histology was an independent poor prognostic factor for overall survival. The high-risk non-cystectomy group showed a significantly poor prognosis for progression-free survival (hazard ratio: 7.61, 95% confidence interval: 2.11-27.5), cancer-specific survival (10.4, 0.54-70.02), and overall survival (8.28, 1.82-37.7). Our findings suggest that patients with renal impairment and large tumors should undergo radical cystectomy if the complications and intentions of the patients allow so.

Prognostic factors for ovarian metastases in colorectal cancer patients

PurposeThe aim of this study was to analyze prognostic factors for ovarian metastases (OM) in colorectal cancer (CRC) using data from a Chinese center. In addition, the study aimed at developing a new clinical scoring system for prognosis of OM of CRC patients after surgery.Patients and methodsData of CRC patients with OM were collected from a single Chinese institution (n = 67). Kaplan-Meier analysis was used to evaluate cumulative survival of patients. Factors associated with prognosis of overall survival (OS) were explored using Cox’s proportional hazard regression models. A scoring system to determine effectiveness of prognosis was developed.ResultsMedian OS values for patients with or without surgery were 22 and 7 months, respectively.Size of OM, number of OM, peritoneal metastasis (PM), Peritoneal cancer index (PCI), and completeness of cytoreduction (CC) were associated with OS of patients through univariate analysis. Multivariate analysis using a Cox regression model showed that only CC was an independent predictor for OS. Three variables (the size of OM >15cm, PCI ≥ 10, and carcinoembryonic antigen (CEA) >30 ng/mL) assigned one point each were used to develop a risk score. The resulting score was used for prognosis of OS.ConclusionSurgical treatment of metastatic sites is effective and safe for CRC patients with OM. CC-0 is recommended for improved prognosis. The scoring system developed in this study is effective for prediction of OS of patients after surgery.

Abstract 483: TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes

Abstract Background: Targeting the PD1:PD-L1 pathway revolutionized treatment options for patients with metastatic triple negative breast cancer (TNBC). Other immune checkpoint inhibitors are being investigated in clinical settings, such as anti-TIGIT antibodies. The goal of this analysis was to evaluate the expression of the TIGIT/PVR/NECTIN molecule family in breast cancer subtypes. Methods: We used the publicly available METABRIC dataset (Curtis C, Nature 2012; Pereira B, Nature Comm 2016) to evaluate microarray RNA expression levels for TIGIT, CD226, PVR, PVRIG, NECTIN2, NECTIN3, NECTIN4, PDCD1 and CD274 from primary breast tumors annotated with ER, PR and HER2 IHC status (Hormone receptor positive [HR+]: n=1369; HER2 amplified [HER2+]: n=236; TNBC: n=299). Biomarker association with overall survival (OS) was evaluated using Cox proportional hazard analysis adjusted for clinical covariates. Results: Expression of the TIGIT/PVR/NECTIN members revealed three expression patterns across breast cancer subtypes: 1) highest in TNBC, followed by HER2+ and then by HR+ BC (PVR); 2) similar levels in TNBC and HER2+, and higher than HR+ BC (TIGIT, CD226, PVRIG, NECTIN4); 3) highest in HR+, followed by HER2+ and then by TNBC (NECTIN2). NECTIN3 showed the lowest expression differences across subtypes. Correlation of these genes with each other varied: 1) Receptors TIGIT, CD226 and PVRIG were moderately correlated with each other and with PDCD1 (Pearson correlation index [r]: 0.45 - 0.78) and strongly correlated with the T cell markers CD3E, CD8A, and GZMB (r: 0.53 - 0.90); 2) PVR family ligands PVR, NECTIN2, NECTIN3 and NECTIN4 were not correlated with each other, nor to the receptors or biomarkers for T-cell, macrophage or stromal biology (r: -0.36 - 0.30). CD274, the PD1 ligand, was weakly associated with TIGIT, CD226, PVRIG, PDCD1 and with immune cell markers (0.25 - 0.38). This pattern was similar across breast cancer subtypes. No OS prognostic value was observed for the TIGIT/PVR family members in HR+ or HER2+ BC. Only CD226 was associated with an improved OS in TNBC (HR: 0.69 [0.48-0.99]). As expected, PDCD1, CD274, and T-cell biomarkers were linked to improved OS prognosis (HR: 0.61-0.69), observed only in TNBC. Conclusions: Overall, RNA expression levels of TIGIT/PVR/NECTIN family members are higher in HER2+ and TNBC compared to HR+ in the large breast cancer METABRIC dataset. While TIGIT, CD226 and PVRIG are clearly associated with T cells, the cell subsets expressing the PVR/NECTIN ligands remain to be defined in breast cancer. Our analysis suggests that TNBC and HER2+ are the breast cancer subtypes more likely to benefit from anti-TIGIT therapeutic targeting. Citation Format: Kelly J. DuPree, Luciana Molinero. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 483.

Identification of Flap Endonuclease 1 With Diagnostic and Prognostic Value in Breast Cancer.

ObjectiveThis study aims to identify the potential value of flap endonuclease 1 (FEN1) as a diagnostic and prognostic marker for breast cancer (BC).MethodsELISA was used to measure serum FEN1 levels and ECLIA for CA153 and CEA levels. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value. Oncomine and UALCAN databases were used to analyze the differences in FEN1 mRNA and protein expressions. Kaplan-Meier Plotter database was then used to assess the prognostic value.ResultsBioinformatics analysis showed that the FEN1 mRNA and protein levels were significantly higher in BC tissues than in normal tissues. FEN1 was detected in culture medium of BC cell lines and serum FEN1 concentrations were significantly increased in BC patients than in cancer-free individuals. Besides, FEN1 exhibited higher diagnostic accuracy (AUC values>0.800) than CA153 and CEA for distinguishing BC patients, especially early BC, from the healthy and benign groups, or individually. Additionally, serum FEN1 levels were significantly associated with the stage (P=0.001) and lymph invasion (P=0.016), and serum FEN1 levels were increased with the development of BC. Furthermore, serum FEN1 levels were significantly decreased in post-operative patients than in pre-operative patients (P=0.016). Based on the Kaplan-Meier Plotter database, the survival analysis indicated that FEN1 overexpression was associated with poor prognoses for overall survival (OS), relapse-free survival (RFS), and distant metastasis-free survival (DMFS) in BC patients.ConclusionFEN1 might be a novel diagnostic and prognostic marker for BC.

Low Peripheral Blood Eosinophil Counts in Patients with Acute Graft-Versus-Host-Disease Prior to Systemic Corticosteroid Therapy Is Associated with Poor Prognosis

Background: Acute graft-versus-host-disease (aGVHD) is one of the main complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), occurring in about half of patients. Patients with grade II-IV aGVHD require treatment with systemic corticosteroids. However, 30% of them show steroid resistance, leading to poor prognosis. Thus, pretreatment prediction of steroid refractoriness allows for early secondary treatment introduction, which may improve aGVHD outcomes. The possible association between elevated peripheral blood (PB) eosinophil counts and the development of aGVHD has been previously reported. In contrast, several studies showed an association with better outcomes after allo-HSCT. These reports imply that PB eosinophil counts may predict prognosis in patients with aGVHD. In this study, we investigated the predictive role of pretreatment PB eosinophil counts in patients with aGVHD treated with systemic corticosteroid therapy.Methods: Retrospective case analysis was performed on 121 patients with hematological malignancies who underwent allo-HSCT between October 2010 and January 2017 in our institutes and developed any grade of aGVHD. We excluded patients who did not require systemic corticosteroid therapy (n=53), and who developed aGVHD after premature discontinuation of calcineurin inhibitors (n=5) because of relapse or calcineurin toxicities. Finally, a total of 63 patients were enrolled. PB smears obtained within 2 days before the start of systemic corticosteroid therapy were microscopically examined. The cut-off value of eosinophil counts for predicting survival was determined using receiver operating characteristic (ROC) curve analysis. The primary endpoint was 1-year overall survival (OS), measured from the start of systemic corticosteroid therapy to death due to any cause or the last follow-up. The secondary endpoints were 1-year progression-free survival (PFS), 1-year cumulative incidence (CI) of non-relapse mortality (NRM), and CI of relapse. OS and PFS were compared using the log-rank test and CIs of NRM and relapse were compared using Gray's test. Predictors of OS were evaluated using univariate and multivariate analysis using Cox's proportional hazards model.Results: The median age was 48 years (range: 40-59 years), and 31 patients (60.8%) were male. Primary diagnoses were acute myeloid leukemia (n=21), acute lymphoblastic leukemia (n=18), myelodysplastic syndrome (n=9), malignant lymphoma (n=13), multiple myeloma (n=1), and chronic myelomonocytic leukemia (n=1). They received bone marrow (n=38), peripheral blood stem cells (n=5), and cord blood (n=20). The median PB eosinophil count was 96/mm3 (range: 0-2903/mm3). ROC analysis revealed the cut-off value for predicting 1-year OS as 133/mm3 (area under the curve: 0.783; 95% confidence interval, 0.662-0.904). Thus, we defined patients with eosinophil counts ≥133/mm3 as the “high eosinophil group” (n=30) and the others as the “low eosinophil group” (n=33). There was no difference in clinical characteristics between the two groups, with the exception of days from transplantation to systemic corticosteroid therapy (29 days in the low eosinophil group vs. 43 days in the high eosinophil group, p<0.001). Regarding the primary endpoint, the 1-year OS rates were 65.2% and 93.3% in the low and high eosinophil groups, respectively (p=0.008) (Figure A). In the univariate analysis, the hazard ratio (HR) for 1-year OS of the low eosinophil group was 6.0 (95% confidence interval: 1.3-27.2, p=0.020). In the multivariate analysis adjusted for eosinophil counts (low vs. high), recipient age (≥50 vs. <50 years), aGVHD grade (III-IV vs. I-II), and stem cell source, the low eosinophil group showed independent poor prognosis for 1-year OS (HR, 6.0; 95% confidence interval, 1.3-28.4; p=0.023). Especially in patients with grade III-IV aGVHD, the low eosinophil group showed substantially inferior 1-year OS rates than those in the high eosinophil group (35.0% vs. 88.9%, p=0.032) (Figure B). Regarding secondary endpoints, 1-year PFS rates were 59.2% and 89.9% (p=0.006), 1-year CI rates of NRM were 21.7% and 3.33% (p=0.035), and 1-year CI rates of relapse were 19.1% and 6.8% (p=0.145) in the low and high eosinophil groups, respectively (Figures C-E).Conclusion: Low PB eosinophil counts before systemic corticosteroid therapy is associated with inferior 1-year OS after aGVHD due to elevated NRM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Influence of FLT3-ITD Mutation and Length on the Prognosis in Acute Myeloid Leukemia

Objective: To explore the influence of FLT3-ITD mutation and ITD mutation length on the prognosis in non-M3 acute myeloid leukemia (AML), overall survival (OS) and relapse free survival (RFS) were followed to evaluate the prognosis in AML patients. Methods: Clinical features and therapeutic effect were retrospectively analyzed in 75 AML patients with FLT3-ITD mutation and 76 AML patients without FLT3-ITD with normal karotype from June 2011 to April 2016. Genomic DNA was amplified by PCR, and FLT3-ITD mutation length was analyzed by DNA sequences. Results: AML patinets with FLT3-ITD mutation had higher WBC and the bone morrow (BM) blast than wild type without FLT3 mutation (WT ) (95.13 vs 10.85, P=0.000; 72% vs 59%, P=0.003). The incidence of complete remission (CR) in AML with FLT3-ITD mutation less than that in WT (70.42% vs 94.7%, P=0.001). OS (P=0.000) and RFS (P=0.000) were significantly longer in FLT3-ITD mutated AML who received allo-HSCT compared with these who received consolidation chemotherapy, and which were similar to patients with WT after allo-HSCT. Patients with maintenance sorafenib after allo-HSCT had longer OS (P=0.038) and RFS (P=0.048) than control group. AML patients with FLT3-ITDs exceeding 60 bp in length were associated with shorter OS compared with these with FLT3-ITDs less than 60 bp (P=0.028). OS and RFS were similar betwen the two groups with diferent ITD lengths which just received consolidation chemotherapy. Besides, AML patients with shorter ITDs who received allo-HSCT had longer OS than these patients with ITDs exceeding 60 bp (P=0.042), and which were also similar to patients with WT after allo-HSCT. Conclusion: AML patients with FLT3-ITD mutation had poor prognosis, even worse in patients with ITD exceeding 60bp. Chemotherapy alone didn't improve the survival of patients with FIT3-ITD mutation. Allo-HSCT is an effective therapeutic strategy for FLT3-ITD mutated AML patients. Sorafenib was approved to be an effective maintenance therapy after allo-HSCT in AML patients with FLT3-ITD mutation. DisclosuresNo relevant conflicts of interest to declare.

Gender and Marital Status Influence Survival of Myelodysplastic Syndrome and Risk of Secondary Acute Myeloid Leukemia: A Population-Based Study of Patients in the Surveillance, Epidemiology, and End Results (SEER) Database

The myelodysplastic syndromes (MDS) are a cluster of clonal hematopoietic disorders with diverse origins. MDS frequently progresses to secondary acute myeloid leukemia (sAML). sAML is unique from de novo AML and is associated with a poorer response to induction chemotherapy and decreased survival (Granfeldt Ostgard, et al 2015). To remedy this situation, we conducted a retrospective study of the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) database. A logistic regression analysis was performed to determine the significant risk factors associated with transformation of MDS into sAML. In addition, a Cox proportional hazard regression model was used to analyze the prognostic factors for survival of the included patients. Leukemic transformation was fitted in the Cox model as a time-dependent covariate.A total of 36,558 patients with primary, newly-diagnosed MDS were identified in the SEER database during the study period (January 1, 2001 to December 31, 2013) and grouped on the basis of age (≤ 40 and > 40 years). This population is among the largest of any population based-study of MDS or sAML. Table 1 presents a summary of patient demographics and clinical characteristics for the 2 groups of patients, who differed significantly in gender, race, marital status, WHO classification, type of follow-up, and rate and time interval of leukemic transformation. Transformation occurred more frequently (3.7% vs. 2.5%) and more quickly (median time of transformation: 4 vs. 13 months) for patients in the under 40 group. Other studies have also identified a detrimental effect of age on the progression of MDS to sAML (Hulegardh, et al 2015, Shi, et al 2004). Table 2 summarize our analysis of overall survival (OS) and cancer-specific survival (CSS), respectively. For both groups of patients, refractory anemia with excess blasts had the worst prognosis for OS and CSS. Most histological types of MDS including therapy-related myeloid neoplasms were all significant indicators of poor survival when compared to refractory anemia, with the exception of refractory thrombocytopenia. We also found that the negative impact on survival of a subtype other than refractory anemia was greater for patients under 40, particularly for CSS.Regarding demographic factors, older age and female gender were predictors of shorter and longer survival, respectively, with similar effects for each age group. Black race was positively associated with survival, when compared to being white and over 40 (the influence of race was not examined in the under 40 group). This study is among the first to assess the influence of marital status on the outcomes of patients with MDS. Our analysis revealed that being married was positively associated with OS and CSS for patients older than 40, when compared to being single, separated, divorced, or widowed.However, the effect of marital status could be related to race, as Martinez et al found that non-married white patients in the California Cancer Registry (CCR) had a greater risk of mortality than did non-married black, Hispanic, or Asian/Pacific Islander patients (Martinez, et al 2016).In conclusion, we have conducted a retrospective analysis of the SEER cancer registry database. Our results indicate that younger patients not only had a greater likelihood of developing sAML than did older patients but also had a shorter time interval to transformation. Survival among older patients is influenced by demographic factors including age, gender, race, and marital status. Accordingly, the accuracy of current risk assessment systems may be improved by including these types of data.*Correspondending author information: Dr. Jian Huang, Department of Hematology, The fourth Affiliated Hospital, College of Medicine, Zhejiang University. Email: househuang@zju.edu.cn.Funding: Social development project of public welfare technology research, Zhejiang Provincial Department of science and technology, Zhejiang Province, China (2016C33160). Public technology research projects of Yiwu City, Zhejiang Province, China (2016-S-05). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mutant p53 and Twist1 Co-Expression Predicts Poor Prognosis and Is an Independent Prognostic Factor in Breast Cancer.

PurposeThe basic helix-loop-helix transcription factor (bHLH) transcription factor Twist1 plays a key role in embryonic development and tumorigenesis. p53 is a frequently mutated tumor suppressor in cancer. Both proteins play a key and significant role in breast cancer tumorigenesis. However, the regulatory mechanism and clinical significance of their co-expression in this disease remain unclear. The purpose of this study was to analyze the expression patterns of p53 and Twist1 and determine their association with patient prognosis in breast cancer. We also investigated whether their co-expression could be a potential marker for predicting patient prognosis in this disease.MethodsTwist1 and mutant p53 expression in 408 breast cancer patient samples were evaluated by immunohistochemistry. Kaplan-Meier Plotter was used to analyze the correlation between co-expression of Twist1 and wild-type or mutant p53 and prognosis for recurrence-free survival (RFS) and overall survival (OS). Univariate analysis, multivariate analysis, and nomograms were used to explore the independent prognostic factors in disease-free survival (DFS) and OS in this cohort.ResultsOf the 408 patients enrolled, 237 (58%) had high mutant p53 expression. Two-hundred twenty patients (53.9%) stained positive for Twist1, and 188 cases were Twist1-negative. Furthermore, patients that co-expressed Twist1 and mutant p53 (T+P+) had significantly advanced-stage breast cancer [stage III, 61/89 T+P+ (68.5%) vs. 28/89 T-P- (31.5%); stage II, 63/104 T+P+ (60.6%)vs. 41/104 T-P- (39.4%)]. Co-expression was negatively related to early clinical stage (i.e., stages 0 and I; P = 0.039). T+P+ breast cancer patients also had worse DFS (95% CI = 1.217–7.499, P = 0.017) and OS (95% CI = 1.009–9.272, P = 0.048). Elevated Twist1 and mutant p53 expression predicted shorter RFS in basal-like patients. Univariate and multivariate analysis identified three variables (i.e., lymph node involvement, larger tumor, and T+P+) as independent prognostic factors for DFS. Lymph node involvement and T+P+ were also independent factors for OS in this cohort. The total risk scores and nomograms were reliable for predicting DFS and OS in breast cancer patients.ConclusionsOur results revealed that co-expression of mutant p53 and Twist1 was associated with advanced clinical stage, triple negative breast cancer (TNBC) subtype, distant metastasis, and shorter DFS and OS in breast cancer patients. Furthermore, lymph nodes status and co-expression of Twist1 and mutant p53 were classified as independent factors for DFS and OS in this cohort. Co-evaluation of mutant p53 and Twist1 might be an appropriate tool for predicting breast cancer patient outcome.

Prognostic Significance of Hematopoietic-cell Serglycin for the Survival of Hepatocellular Carcinoma: A Single-center Retrospective Study.

Inflammation-related changes in peripheral blood cells and blood proteins are prognostic factors for survival in hepatocellular carcinoma (HCC), but their usefulness is limited by an active bacterial infection. This study investigated whether infection interfered with the predictive value of serglycin, a proteoglycan found in hematopoietic cells, on survival in HCC. Patients with hepatitis B virus (HBV)-induced HCC, 100 without and 30 with a bacterial infection, and 30 healthy adult controls were enrolled retrospectively. Baseline clinical data collected before treatment with transarterial chemoembolization (TACE) was evaluated, and serglycin expression was assayed by flow cytometry. Receiver operating characteristic (ROC) curve analysis identified serglycin cutoff values for patient stratification. Cox regression and Kaplan-Meier analyses were performed to identify predictors of overall survival (OS). Serglycin levels in peripheral blood cells were higher in both groups of HCC patients than in the control group. Cholinesterase, lung metastasis, average neutrophil serglycin fluorescence intensity, and aspartate aminotransferase levels were associated with survival risk. Barcelona Clinic Liver Cancer stage A was associated with a good prognosis of OS. The intensity of serglycin fluorescence in peripheral neutrophils was independently predictive of survival in HCC, and its value was not limited by a bacterial infection. The method presented here is a simple and feasible way to predict prognosis in HCC patients with TACE.

Automated Quantification of sTIL Density with H&E-Based Digital Image Analysis Has Prognostic Potential in Triple-Negative Breast Cancers.

Simple SummaryAround 15% of breast cancer patients are diagnosed as triple-negative (TNBC), which have significantly lower 5-year survival rates (77%) than other types of breast cancer (93%). Our study aimed at developing an image analysis-based biomarker to assess how the immune system interacts with the tumor and investigate the potential added value of stromal tumor-infiltrating lymphocytes (sTIL) for the prognosis of overall survival compared to the manual approach. In a large retrospective cohort of 257 patients, we found that our fully automated hematoxylin and eosin (H&E) image analysis pipeline can quantify sTIL density showing both high concordance with manual scoring and association with the prognosis of patients with TNBC. It also overcomes natural limitations of manual assessment that hinder clinical adoption of the immune biomarker. We conclude that sTIL scoring by automated image analysis has prognostic potential comparable to manual scoring and should be further investigated for future use in a clinical setting.Triple-negative breast cancer (TNBC) is an aggressive and difficult-to-treat cancer type that represents approximately 15% of all breast cancers. Recently, stromal tumor-infiltrating lymphocytes (sTIL) resurfaced as a strong prognostic biomarker for overall survival (OS) for TNBC patients. Manual assessment has innate limitations that hinder clinical adoption, and the International Immuno-Oncology Biomarker Working Group (TIL-WG) has therefore envisioned that computational assessment of sTIL could overcome these limitations and recommended that any algorithm should follow the manual guidelines where appropriate. However, no existing studies capture all the concepts of the guideline or have shown the same prognostic evidence as manual assessment. In this study, we present a fully automated digital image analysis pipeline and demonstrate that our hematoxylin and eosin (H&E)-based pipeline can provide a quantitative and interpretable score that correlates with the manual pathologist-derived sTIL status, and importantly, can stratify a retrospective cohort into two significant distinct prognostic groups. We found our score to be prognostic for OS (HR: 0.81 CI: 0.72–0.92 p = 0.001) independent of age, tumor size, nodal status, and tumor type in statistical modeling. While prior studies have followed fragments of the TIL-WG guideline, our approach is the first to follow all complex aspects, where appropriate, supporting the TIL-WG vision of computational assessment of sTIL in the future clinical setting.