Prediction of Immune-Checkpoint Blockade Monotherapy Response in Patients With Melanoma Based on Easily Accessible Clinical Indicators

BackgroundImmune checkpoint blocker (ICB) has shown significant clinical activity in melanoma. However, there are no clinically approved biomarkers to aid patient selection. We aimed to identify patients with advanced or metastatic melanoma who are likely to benefit from ICB monotherapy using easily accessible clinical indicators.Materials and MethodsWe retrospectively reviewed the records of 134 patients with advanced or metastatic melanoma who received ICB monotherapy between 2014 and 2018. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were determined using Cox regression analysis.ResultsDuring the median follow-up of 13.7 months, the median OS and PFS were 18.4 and 3.4 months, respectively. Visceral/central nervous system (CNS) metastasis (OS: adjusted hazards ratio [HR], 1.82; p=.014; PFS: HR, 1.59; p=.024), lymphopenia (<1000 cells/µL) within 3 months (OS: HR, 1.89, p=.006; PFS: HR, 1.70; p=.010), and elevated baseline lactate dehydrogenase (LDH) level (OS: HR, 2.61; p<.001; PFS: HR, 2.66; p<.001) were independent prognostic factors for both poor OS and PFS. Development of immune-related adverse events (irAE; e.g., hypothyroidism or vitiligo) within 6 months showed a trend toward better OS in multivariable analysis (HR, 0.37; p=.058). Patients with normal LDH levels and no visceral/CNS metastasis had a substantially better OS than the others (median, 40.4 vs. 13.6 months; p<.001). Among others, patients who developed irAE within 6 months achieved long-term OS (median, 43.6 vs. 13.1 months; p=.008). A decision tree was suggested using four risk factors, and the risk stratification provided significant distinction between the survival curves.ConclusionThe four easily accessible clinical indicators associated with better treatment outcomes after ICB monotherapy in patients with advanced or metastatic melanoma were LDH level, the extent of disease, lymphopenia, and irAE. The combined use of these indicators can be clinically useful in improving risk stratification of patients treated with ICB monotherapy.

Download Full-text

Prediction of Immune-Checkpoint Blockade Monotherapy Response in Patients with Melanoma Based on Easily Accessible Clinical Indicators

10.21203/rs.3.rs-91123/v1 ◽

2020 ◽

Author(s):

Hwa Kyung Byun ◽

Jeesuk Chang ◽

Minkyu Jung ◽

Woong Sub Koom ◽

Kee Yang Chung ◽

...

Keyword(s):

Prognostic Factors ◽

Risk Stratification ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Cox Regression ◽

Immune Checkpoint Blockade ◽

Clinical Activity ◽

Clinical Indicators ◽

Cox Regression Analysis ◽

Cns Metastasis

Abstract Background: Immune checkpoint blocker (ICB) has shown significant clinical activity in melanoma. However, there are no clinically approved biomarkers to aid patient selection. We aimed to identify patients with advanced or metastatic melanoma who are likely to benefit from ICB monotherapy using easily accessible clinical indicators. Methods: We retrospectively reviewed the records of 134 patients with advanced or metastatic melanoma who received ICB monotherapy between 2014 and 2018. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were determined using Cox regression analysis. Results: During the median follow-up of 13.7 months, the median OS and PFS were 18.4 and 3.4 months, respectively. Visceral/central nervous system (CNS) metastasis (OS: adjusted hazards ratio [HR], 1.82; p=.014; PFS: HR, 1.59; p=.024), lymphopenia (<1000 cells/µL) within 3 months (OS: HR, 1.89, p=.006; PFS: HR, 1.70; p=.010), and elevated baseline lactate dehydrogenase (LDH) level (OS: HR, 2.61; p<.001; PFS: HR, 2.66; p<.001) were independent prognostic factors for both poor OS and PFS. Development of immune-related adverse events (irAE; e.g., hypothyroidism or vitiligo) within 6 months showed a trend toward better OS in multivariate analysis (HR, 0.37; p=.058). Patients with normal LDH levels and no visceral/CNS metastasis had a substantially better OS than the others (median, 40.4 vs. 13.6 months; p<.001). Among others, patients who developed irAE within 6 months achieved long-term OS (median, 43.6 vs. 13.1 months; p=.008). A decision tree was suggested using four risk factors, and the risk stratification provided significant distinction between the survival curves. Conclusion: The four easily accessible clinical indicators associated with better treatment outcomes after ICB monotherapy in patients with advanced or metastatic melanoma were LDH level, the extent of disease, lymphopenia, and irAE. The combined use of these indicators can be clinically useful in improving risk stratification of patients treated with ICB monotherapy.

Download Full-text

Identification of Prognostic RBPs in Osteosarcoma

Technology in Cancer Research & Treatment ◽

10.1177/15330338211004918 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110049

Author(s):

Bei Li ◽

Long Fang ◽

Baolong Wang ◽

Zengkun Yang ◽

Tingbao Zhao

Keyword(s):

Regression Analysis ◽

Prognostic Factors ◽

Differential Expression ◽

Ribosome Biogenesis ◽

Rna Binding ◽

Cox Regression ◽

Rna Binding Proteins ◽

Malignant Tumors ◽

Differential Expression Analysis ◽

Cox Regression Analysis

Osteosarcoma often occurs in children and adolescents and causes poor prognosis. The role of RNA-binding proteins (RBPs) in malignant tumors has been elucidated in recent years. Our study aims to identify key RBPs in osteosarcoma that could be prognostic factors and treatment targets. GSE33382 dataset was downloaded from Gene Expression Omnibus (GEO) database. RBPs extraction and differential expression analysis was performed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to explore the biological function of differential expression RBPs. Moreover, we constructed Protein-protein interaction (PPI) network and obtained key modules. Key RBPs were identified by univariate Cox regression analysis and multiple stepwise Cox regression analysis combined with the clinical information from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Risk score model was generated and validated by GSE16091 dataset. A total of 38 differential expression RBPs was identified. Go and KEGG results indicated these RBPs were significantly involved in ribosome biogenesis and mRNA surveillance pathway. COX regression analysis showed DDX24, DDX21, WARS and IGF2BP2 could be prognostic factors in osteosarcoma. Spearman’s correlation analysis suggested that WARS might be important in osteosarcoma immune infiltration. In conclusion, DDX24, DDX21, WARS and IGF2BP2 might play key role in osteosarcoma, which could be therapuetic targets for osteosarcoma treatment.

Download Full-text

Prognostic values, ceRNA network, and immune regulation function of SDPR in KRAS-mutant lung cancer

Cancer Cell International ◽

10.1186/s12935-021-01756-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaoqing Luo ◽

Shunli Peng ◽

Sijie Ding ◽

Qin Zeng ◽

Rong Wang ◽

...

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Cox Regression ◽

Tissue Array ◽

Lung Cancers ◽

Cox Regression Analysis ◽

Immune Checkpoint Molecules ◽

Cerna Network ◽

Kaplan Meier ◽

Infiltration Models

Abstract Background Serum Deprivation Protein Response (SDPR) plays an important role in formation of pulmonary alveoli. However, the functions and values of SDPR in lung cancer remain unknown. We explored prognostic value, expression pattern, and biological function of SDPR in non-small cell lung cancer (NSCLC) and KRAS-mutant lung cancers. Methods SDPR expression was evaluated by quantitative real-time PCR (RT-qPCR), immunohistochemistry (IHC), and Western blot on human NSCLC cells, lung adenocarcinoma tissue array, KRAS-mutant transgenic mice, TCGA and GEO datasets. Prognostic values of SDPR were evaluated by Kaplan–Meier and Cox regression analysis. Bioinformatics implications of SDPR including SDPR-combined transcription factors (TFs) and microRNAs were predicted. In addition, correlations between SDPR, immune checkpoint molecules, and tumor infiltration models were illustrated. Results SDPR expression was downregulated in tumor cells and tissues. Low SDPR expression was an independent factor that correlated with shorter overall survival of patients both in lung cancer and KRAS-mutant subgroups. Meanwhile, ceRNA network was constructed to clarify the regulatory and biological functions of SDPR. Negative correlations were found between SDPR and immune checkpoint molecules (PD-L1, TNFRSF18, TNFRSF9, and TDO2). Moreover, diversity immune infiltration models were observed in NSCLC with different SDPR expression and copy number variation (CNV) patterns. Conclusions This study elucidated regulation network of SDPR in KRAS-mutant NSCLC, and it illustrated correlations between low SDPR expression and suppressed immune system, unfolding a prognostic factor and potential target for the treatment of lung cancer, especially for KRAS-mutant NSCLC.

Download Full-text

FRI0248 PROGNOSTIC FACTORS FOR STEROID-FREE REMISSION IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES: IMPORTANCE OF ANTHROPOMETRIC MEASUREMENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3010 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 708.1-708

Author(s):

J. S. Lee ◽

S. H. Nam ◽

S. J. Choi ◽

W. J. Seo ◽

S. Hong ◽

...

Keyword(s):

Prognostic Factors ◽

Cox Regression ◽

Idiopathic Inflammatory Myopathies ◽

Inflammatory Myopathies ◽

Immunosuppressant Therapy ◽

Muscle Enzymes ◽

Cox Regression Analysis ◽

Factors Associated ◽

Early Use

Background:Several studies have been conducted on factors associated with mortality in idiopathic inflammatory myopathies (IIM), but few studies have assessed prognostic factors for steroid-free remission in IIM.Objectives:We investigated the various clinical factors, including body measurements, that affect IIM treatment outcomes.Methods:Patients who were newly diagnosed with IIM between 2000 and 2018 were included. Steroid-free remission was defined as at least three months of normalisation of muscle enzymes and no detectable clinical disease activity. The factors associated with steroid-free remission were evaluated by a Cox regression analysis.Results:Of the 106 IIM patients, 35 displayed steroid-free remission during follow-up periods. In the multivariable Cox regression analyses, immunosuppressants’ early use within one month after diagnosis [hazard ratio (HR) 6.21, 95% confidence interval (CI) 2.61–14.74, p < 0.001] and sex-specific height quartiles (second and third quartiles versus first quartile, HR 3.65, 95% CI 1.40–9.51, p = 0.008 and HR 2.88, 95% CI 1.13–7.32, p = 0.027, respectively) were positively associated with steroid-free remission. Polymyositis versus dermatomyositis (HR 0.21, 95% CI 0.09–0.53, p = 0.001), presence of dysphagia (HR 0.15, CI 0.05–0.50, p = 0.002) and highest versus lowest quartile of waist circumference (WC) (HR 0.24, 95% CI 0.07–0.85, p = 0.027) were negatively associated with steroid-free remission.Conclusion:The early initiation of immunosuppressant therapy, type of myositis and presence of dysphagia are strong predictors of steroid-free remission in IIM; moreover, height and WC measurements at baseline may provide additional important prognostic value.Disclosure of Interests:None declared

Download Full-text

Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer

Biological Chemistry ◽

10.1515/hsz-2016-0177 ◽

2016 ◽

Vol 397 (12) ◽

pp. 1265-1276 ◽

Cited By ~ 14

Author(s):

Nancy Ahmed ◽

Julia Dorn ◽

Rudolf Napieralski ◽

Enken Drecoll ◽

Matthias Kotzsch ◽

...

Keyword(s):

Ovarian Cancer ◽

Mrna Expression ◽

Cox Regression ◽

Multivariable Analysis ◽

Progression Free Survival ◽

Predictive Marker ◽

Residual Tumor ◽

Mrna Levels ◽

Serous Ovarian Cancer ◽

Cox Regression Analysis

Abstract Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients’ outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

Download Full-text

A nomogram based on pretreatment levels of serum bilirubin and total bile acid levels predicts survival in colorectal cancer patients

BMC Cancer ◽

10.1186/s12885-021-07805-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yinghao Cao ◽

Shenghe Deng ◽

Lizhao Yan ◽

Junnan Gu ◽

Jia Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factors ◽

Bile Acid ◽

Bile Acids ◽

Cancer Patients ◽

Serum Bilirubin ◽

Cox Regression ◽

Total Bile Acid ◽

Cox Regression Analysis ◽

Colorectal Cancer Patients

Abstract Background Serum bilirubin and total bile acid (TBA) levels have been reported to be strongly associated with the risk and prognosis of certain cancers. Here, we aimed to investigate the effects of pretreatment levels of serum bilirubin and bile acids on the prognosis of patients with colorectal cancer (CRC). Methods A retrospective cohort of 1474 patients with CRC who underwent surgical resection between January 2015 and December 2017 was included in the study. Survival analysis was used to evaluate the predictive value of pretreatment levels of bilirubin and bile acids. X-Tile software was used to identify optimal cut-off values for total bilirubin (TBIL), direct bilirubin (DBIL) and TBA in terms of overall survival (OS) and disease-free survival (DFS). Results DBIL, TBIL, and TBA were validated as significant prognostic factors by univariate Cox regression analysis for both 3-year OS and DFS. Multivariate Cox regression analyses confirmed that high DBIL, TBIL and TBA levels were independent prognostic factors for both OS (HR: 0.435, 95% CI: 0.299–0.637, P < 0.001; HR: 0.436, 95% CI: 0.329–0.578, P < 0.001; HR: 0.206, 95% CI: 0.124–0.341, P < 0.001, respectively) and DFS (HR: 0.583, 95% CI: 0.391–0.871, P = 0.008; HR:0.437,95% CI: 0.292–0.655, P <0.001; HR: 0.634, 95% CI: 0.465–0.865, P = 0.004, respectively). In addition, nomograms for OS and DFS were established according to all significant factors, and the c-indexes were 0.819 (95% CI: 0.806–0.832) and 0.835 (95% CI: 0.822–0.849), respectively. Conclusions TBIL, DBIL and TBA levels are independent prognostic factors in colorectal cancer patients. The nomograms based on OS and DFS can be used as a practical model for evaluating the prognosis of CRC patients.

Download Full-text

Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia

Blood ◽

10.1182/blood-2011-07-367961 ◽

2012 ◽

Vol 119 (24) ◽

pp. 5824-5831 ◽

Cited By ~ 165

Author(s):

Ana Flávia Tibúrcio Ribeiro ◽

Marta Pratcorona ◽

Claudia Erpelinck-Verschueren ◽

Veronika Rockova ◽

Mathijs Sanders ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cox Regression ◽

Multivariable Analysis ◽

Gene Expression Signature ◽

Mutation Status ◽

Cox Regression Analysis ◽

Prognostic Effect ◽

Or Gene ◽

Acute Myeloid

Abstract The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3Amutant AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13-2.05) than DNMT3Awild-type AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3Amutant AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3Awild-type AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML.

Download Full-text

Prognostic Significance of PD-L1 and mTOR Expression in Oral Squamous Cell Carcinoma

Journal of Health Science and Medical Research ◽

10.31584/jhsmr.2020745 ◽

2020 ◽

Author(s):

Nattinee Charoen ◽

Kitti Jantharapattana ◽

Paramee Thongsuksai

Keyword(s):

Squamous Cell Carcinoma ◽

Regression Analysis ◽

Prognostic Factors ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cox Regression ◽

Prognostic Significance ◽

P Value ◽

Cox Regression Analysis

Objective: Programmed cell death ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) are key players in host immune evasion and oncogenic activation, respectively. Evidence of the prognostic role in oral squamous cell carcinoma (OSCC) is conflicting. This study examined the associations of PD-L1 and mTOR expression with 5-year overall survival in OSCC patients. Material and Methods: The expressions of PD-L1 and mTOR proteins were immunohistochemically evaluated on tissue microarrays of 191 patients with OSCC who were treated by surgery at Songklanagarind Hospital, Thailand from 2008 to 2011. Cox regression analysis was used to determine independent prognostic factors. Results: PD-L1 expression was observed in 14.1% of cases while mTOR expression was present in 74.3% of cases. Females were more likely to have tumors with PD-L1 (p-value=0.007) and mTOR expressions (p-value=0.003) than males. In addition, lower clinical stage and well differentiated tumor are more likely to have mTOR expression (p-value= 0.038 and p-value<0.001, respectively). Cox regression analysis showed that age, tumor stage, nodal stage, combined surgical treatment with radiation or chemoradiation therapy, surgical margin status, PD-L1 expression and mTOR expression are independent prognostic factors. High PD-L1 expression (hazard ratio (HR) 3.14, 95% confidence interval (CI), 1.26–7.79) and high mTOR expression (HR 1.69, 95% CI, 1.00–2.84) are strong predictors of poor outcome. Conclusion: A proportion of OSCC expressed PD-L1 and mTOR proteins. Expression of PD-L1 and mTOR proteins are strong prognostic factors of OSCC.

Download Full-text

Subdivision of metastatic colorectal cancer for identifying patients who benefit more from primary tumor resection

10.21203/rs.3.rs-62901/v2 ◽

2021 ◽

Author(s):

Dakui Luo ◽

Zezhi Shan ◽

Zhiqiang Li ◽

Simin Chen ◽

Sanjun Cai ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factors ◽

Primary Tumor ◽

Cox Regression ◽

Tumor Resection ◽

Signet Ring Cell ◽

Normal Serum ◽

Primary Tumor Resection ◽

Cox Regression Analysis ◽

Serum Cea

Abstract Background Stage IV colorectal cancer (CRC) patients are heterogeneous with distinctive clinicopathologic features and prognosis. Radical resection of primary tumor and distant metastases is associated with improved survival outcomes in metastatic CRC. The value of palliative primary tumor resection is controversial. The present study explored which subgroups benefited more from primary tumor resection in metastatic CRC. Methods Between 2004 and 2015, patients with metastatic CRC were identified using the surveillance, epidemiology, and end results (SEER) database. Uni- and multivariable Cox regression analysis were performed to identify factors associated with decreased cancer-specific mortality. The subgroups were divided based on the independent prognostic factors. Results Age, marital status, race, serum CEA, histologic type, differentiation, tumor location, surgery of primary or metastatic lesion, site of metastases, number of metastatic sites, chemotherapy and radiotherapy were identified as independent prognostic factors. Patients with non-white race, normal serum CEA, non-signet ring cell carcinoma, well or moderate differentiation, surgery of metastases, isolated liver metastasis, single metastasis, receiving chemotherapy or radiotherapy presented more survival benefit from primary tumor resection. Conclusion Subgroup of metastatic CRC optimizes decision-making and selected patients will benefit more from primary tumor resection.

Download Full-text

Incidence, Survival, and Associated Factors Estimation in Osteosarcoma Patients with Lung Metastasis: A Single-center Experience of 11 Years in Tianjin, China

10.21203/rs.3.rs-1071152/v1 ◽

2021 ◽

Author(s):

Chao Zhang ◽

Haixiao Wu ◽

Guijun Xu ◽

Wenjuan Ma ◽

Lisha Qi ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Regression Analysis ◽

Prognostic Factors ◽

Lung Metastasis ◽

Associated Factors ◽

Cox Regression ◽

Cancer Center ◽

Single Center ◽

Cox Regression Analysis

Abstract Background: Osteosarcoma is the most common primary malignant bone tumor. The current study was conducted to describe the general condition of patients with primary osteosarcoma in a single cancer center in Tianjin, China and to investigate the associated factors in osteosarcoma patients with lung metastasis. Methods: From February 2009 to October 2020, patients from Tianjin Medical University Cancer Institute and Hospital, China were retrospectively analyzed. The Kaplan–Meier method was used to evaluate the overall survival of osteosarcoma patients. Prognostic factors of patients with osteosarcoma were identified by the Cox proportional hazard regression analysis. Risk factor of lung metastasis in osteosarcoma were investigated by the logistic regression model. Results: A total of 203 patients were involved and 150 patients were successfully followed up for survival status. The 5-year survival rate of osteo-sarcoma patients was 70.0%. Surgery, bone and lung metastasis were the significant prognostic factors in multivariable Cox regression analysis. Twenty-one (10.3%) patients showed lung metastasis at the diagnosis of osteosarcoma and 67 (33%) lung metastases during the later course. T3 stage (OR=11.415, 95%CI 1.362-95.677, P=0.025) and synchronous bone metastasis (OR=6.437, 95%CI 1.69-24.51, P=0.006) were risk factors of synchronous lung metastasis occurrence. Good necrosis (≥90%, OR=0.097, 95%CI 0.028-0.332, P=0.000) and elevated Ki-67 (≥50%, OR=4.529, 95%CI 1.241-16.524, P=0.022) were proved to be significantly associated with metachronous lung metastasis occurrence. Conclusion: The overall survival, prognostic factors and risk factors for lung metastasis in this single center provided insight about osteosarcoma management.

Download Full-text