Independent Prognostic Indicator For Survival Research Articles

Prognostic value of 18F-FDG PET/CT tumor metabolic parameters and Ki-67 in pre-treatment diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive lymphoma. Rituximab-based conventional chemotherapy still leads to drug resistance or relapse in 30-40% of patients. Therefore, early identification of high-risk patients and accurate assessment of prognosis are very important for clinical decision-making. The aim of this study is to investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) of tumor metabolic, clinical and biological parameters in the prognostic risk stratification of DLBCL before treatment. We retrospectively collected clinical data on 63 patients with newly diagnosed DLBCL admitted to Shanxi Bethune Hospital during the period from November 2016 to April 2020 who underwent 18F-FDG PET/CT prior to treatment in a cohort study. Metabolic, clinical, and biological parameters were analyzed by Cox regression. Kaplan-Meier curves of patient survival were compared by the log-rank test. The median follow-up was 21 months. The 2-year progression-free survival (PFS) was 47.62%, and the overall survival (OS) was 53.97%. The subtype, double expression, Ann Abor stage, NCCN-IPI score, Ki-67, maximum standardized uptake value (SUVmax), bulk volume glycolysis (BVG), total lesion glycolysis (TLG), total metabolic tumor volume (TMTV) were the influencing factors for PFS and OS (P<0.050) in univariate analysis. BVG (PFS: HR =6.62, P<0.001; OS: HR =3.53, P=0.029), TLG (PFS: HR =8.56, P<0.001; OS: HR =5.20, P=0.004), TMTV (PFS: HR =12.02, P=0.001; OS: HR =5.05, P=0.033) and Ki-67 were found to be independent prognostic risk stratification parameters affecting PFS and OS by multivariate regression analysis. The 2-year PFS and OS rates for patients with high BVG (≥288.00 cm3), TLG (≥1,854.00 cm3), TMTV (≥103.00 cm3), and Ki-67 (≥85%) were 20% and 28.57%, 9.68% and 22.58%, 20.51%, and 30.77%, and 25% and 33.33%, respectively; and the 2-year PFS and OS rates for patients with low BVG (<288.00 cm3), TLG (<1,854.00 cm3), TMTV (<103.00 cm3), and Ki-67 (<85%) patients were 82.14% and 85.71%, 84.37% and 84.37%, 91.67% and 91.67%, and 61.54% and 66.67%, respectively. Patients with high BVG, TLG, TMTV, and Ki-67 had a worse 2-year PFS as well as OS rate (Ki-67: P=0.0018/P=0.0025; P<0.0001 for the rest of the groups). Our findings suggest that BVG, TLG, TMTV, and Ki-67 are independent prognostic indicators for survival in patients with pre-treatment DLBCL, especially BVG, which is a novel prognostic indicator that has to be validated in future research.

Association between marital status and all-cause mortality of patients with metastatic breast cancer: a population-based study

This study aimed to investigate the association between marital status and the prognosis of patients with metastatic breast cancer (MBC). Data of patients with MBC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into married and unmarried groups. Kaplan–Meier analysis with the log-rank test was conducted to compare breast cancer-specific survival (BCSS) and overall survival (OS) between the groups. Univariable and multivariable Cox proportional models were used to determine whether marital status was independently associated with OS, and the Fine–Gray subdistribution hazard method was performed to determine whether marital status was independently associated with BCSS. In total, 16,513 patients with MBC were identified, including 8949 married (54.19%) and 7564 unmarried (45.81%) patients. The married patients were significantly younger [median age (interquartile range), 59.0 (50.0–68.0) vs. 63.0 (53.0–75.0); p < 0.001] and received more aggressive treatments, such as chemotherapy (p < 0.001) and surgery (p < 0.001), than the unmarried patients. Moreover, married patients had higher 5-year BCSS (42.64% vs. 33.17%, p < 0.0001) and OS (32.22% vs. 21.44%, p < 0.0001) rates. Multivariable analysis revealed that marital status was an independent prognostic factor, and married status was associated with a significant reduction in the risk of breast cancer-specific (sub-hazard ratio, 0.845; 95% confidence interval, 0.804–0.888; p < 0.001) and all-cause (hazard ratio, 0.810; 95% confidence interval, 0.777–0.844; p < 0.001) mortality. Unmarried patients had a 15.5% increased risk of breast cancer-specific mortality and a 19.0% increased risk of overall mortality compared with married patients with MBC. BCSS and OS were superior in married populations compared with unmarried populations in most subgroups. Marital status was an independent prognostic indicator for survival in patients with MBC and was associated with significant survival benefits.

Cytoreductive Surgery and Hyperthermic Peritoneal Chemotherapy in Appendiceal and Colorectal Cancer: Outcomes and Survival.

We reviewed outcomes following cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with appendiceal or colorectal neoplasms and evaluated key prognostic indicators for treatment. All patients who underwent cytoreductive surgery/HIPEC for appendiceal and colorectal neoplasms were identified from an IRB-approved database. Patient demographics, operative reports, and postoperative outcomes were reviewed. 110 patients [median age 54.5 (18-79) years, 55% male] were included. Primary tumor location was colorectal (58; 52.7%) and appendiceal (52; 47.3%). 28.2%, .9%, and 12.7% had right, left, and sigmoid tumors, respectively; 11.8% had rectal tumors. 12/13 rectal cancer patients underwent preoperative radiotherapy. Mean Peritoneal Cancer Index was 9.6 ± 7.7; complete cytoreduction was achieved in 90.9%. 53.6% developed postoperative complications. Reoperation, perioperative mortality, and 30-day readmission rates were 1.8%, .09%, and 13.6%, respectively. Recurrence at a median of 11.1 months was 48.2%; overall survival at 1 and 2years was 84% and 56.8%, respectively; disease-free survival was 60.8% and 33.7%, respectively, at a median follow-up of 16.8 (0-86.8) months. Univariate analysis of preoperative chemotherapy, primary malignancy location, primary tumor perforated or obstructive, postoperative bleeding complication, and pathology of adenocarcinoma, mucinous adenocarcinoma and negative lymph nodes were identified as possible predictive factors of survival. Multivariate logistic regression analysis showed that preoperative chemotherapy (P < .001), perforated tumor (P = .003), and postoperative intra-abdominal bleeding (P < .001) were independent prognostic indicators for survival. Cytoreductive surgery/HIPEC for colorectal and appendiceal neoplasms has low mortality and high completeness of cytoreduction score. Preoperative chemotherapy, primary tumor perforation, and postoperative bleeding are adverse risk factors for survival.

Upregulation of NUAK2: A novel prognostic marker in breast cancer.

Breast cancer is the most commonly diagnosed neoplasm in women worldwide. New molecular biomarkers and effective prognostic models are being developed. This study aimed to investigate the clinical and prognostic significance of NUAK2 expression in patients with breast cancer. The expression of NUAK 2 was examined in breast cancer cells and tissues by real-time PCR, western blotting, and immunohistochemical staining. CCK-8 and colony formation assays were performed to verify the effect of NUAK2 on the proliferation and tumor progression of breast cancer cells. A tumor formation assay in nude mice was performed to analyze the effect of NUAK2 on the tumorigenicity of breast cancer cells. The expression of NUAK2 in breast cancer tissues was higher than that in paracarcinoma and normal breast tissues. The overall survival of patients with high NUAK2 expression was significantly lower than that of patients with low NUAK2 expression. Multivariate analyses indicated that NUAK2 was an independent prognostic indicator of survival in breast cancer. In vitro experiments demonstrated that knocking down NUAK2 in breast cancer cells inhibited cell proliferation and tumor-forming ability, and overexpression of NUAK2 showed the opposite effects. NUAK2 overexpression promoted the tumorigenicity of breast cancer cells in vivo. These findings suggest that NUAK2 is involved in breast cancer development and progression. NUAK2 may be a valuable prognostic indicator in patients with breast cancer.

Intratumoral CD73: An immune checkpoint shaping an inhibitory tumor microenvironment and implicating poor prognosis in Chinese melanoma cohorts.

BackgroundAs a novel immune checkpoint, CD73 has been reported to play prominent roles in several malignancies. However, the significance of CD73 in melanoma remains ambiguous. This study sought to reveal the impact of CD73 on the tumor microenvironment (TME) and patients’ prognosis, and to investigate whether CD73 could be a therapeutic target in Chinese melanomas, which were dominated by acral and mucosal subtypes.MethodsTwo independent Chinese cohorts of 194 patients with melanoma were enrolled. CD73 and PD-L1 expression as well as CD8+ and CD56+ cell infiltrations were evaluated by immunohistochemistry in 194 resected melanoma samples. Clinical outcomes of patients were assessed utilizing the Kaplan-Meier plotter and Cox proportional hazard analysis. RNA-seq data was obtained from TCGA database. Gene set functional annotations were performed based on GO, KEGG and GSEA analysis. CIBERSORT, ssGSEA and TIMER were used to explore the association between CD73 and immune infiltration. These findings were validated by establishing tumor xenograft model, and functions of tumor-infiltrating immune cells were examined by flow cytometry and immunofluorescence.ResultsHigh CD73 expression showed poorer clinical outcomes and was identified as an independent prognostic indicator for survival in two cohorts. Expression of CD73 was more prevalent than PD-L1 in Chinese melanoma cohorts (54.6% vs 23.2%). Co-expression of both immune checkpoints was infrequent (12.9%) in melanoma, and 54.4% of PD-L1 negative cases showed elevated expression of CD73. CD73high tumors showed a microenvironment with fewer CD8+ T cells and CD56+ NK cells infiltration, which displayed a dysfunctional phenotype. With the treatment of CD73 inhibitor APCP, the amount of CD8+ T cells and CD56+ NK cells infiltrated in tumors was elevated and the immunosuppressive effect of CD73 was eliminated.ConclusionsHigh CD73 expression was associated with an inhibitory TME and adverse clinical outcomes of melanoma. In comparison to PD-L1, CD73 was more prevalent and possessed more definite prognostic significance. Therefore, it may serve as a prognostic indicator and immunotherapeutic target next to PD-L1 in melanoma for Chinese population.

Radical Resection of Pediatric Fibrosarcoma Is Not Associated With Survival Benefit: A Nationwide Database Analysis

IntroductionFibrosarcoma is one of the most common nonrhabdomyosarcoma soft tissue sarcomas in the pediatric population. Surgical resection is the cornerstone of treatment; however, optimal factors regarding the extent of fibrosarcoma resection in localized versus regional disease is poorly understood. MethodsThe Surveillance, Epidemiology, and End Results database was queried for patients who are 19 y old or younger with a diagnosis of fibrosarcoma from 1975 to 2016. Kaplan–Meier analyses were performed for disease-specific survival on clinical and pathologic variables. Multivariate analysis was performed based on significant predictors of disease-specific survival. ResultsThere were 1290 patients (median age 13 [7-17] y) identified with fibrosarcoma. The overall survival rate at 20 y was 93%. Radical resection was performed on 22%, 40%, and 52% of patients with localized, regional, and distant Surveillance, Epidemiology, and End Results disease stage, respectively. Chemotherapy (P < 0.001), radiation (P < 0.001), histology (P < 0.001), and stage (P = 0.004) were significant predictors of increased mortality using univariate Kaplan–Meier analysis. Most patients (86%) with localized or regional stage who underwent radiation had fibrosarcomas of nondermatofibrosarcoma histology (P < 0.001). Dermatofibrosarcoma subtype comprised most radical resections (41%). Excluding distant stage, nondermatofibroma histology (hazard ratio 16.94, 95% confidence interval 3.77-76.01) and regional stage (hazard ratio 8.15, 95% confidence interval 2.93-22.69) were independent prognostic factors of mortality (both P < 0.001). Radical resection was not a significant independent prognostic indicator of survival. ConclusionsNondermatofibrosarcoma subtype is independently associated with increased mortality. Although surgery remains the mainstay of treatment, the extent of resection is not a predictor of survival for patients with the localized and regional stage of disease.

The nutritional management of people living with Amyotrophic Lateral Sclerosis (ALS): a cross-sectional survey of UK Dietitians’

People living with Amyotrophic Lateral Sclerosis (pwALS) face many challenges to taking adequate nutrition and hydration (1). Reduced dietary intake, combined with raised resting energy expenditure (REE) (2), contribute to the high prevalence of malnutrition in ALS (3), with low BMI and weight loss being independent prognostic indicators of survival (4). There is a lack of evidence focusing on the nutritional management of people living with ALS.

Prognostic impact of prognostic nutritional index on renal cell carcinoma: A meta-analysis of 7,629 patients.

BackgroundPrognostic nutritional index (PNI) is a parameter which reflects nutritional and inflammatory status. The prognostic value of PNI in renal cell carcinoma (RCC) remains in debate. The aim of this study is to evaluate the prognostic value and clinicopathological features of PNI in RCC.MethodsA literature search was performed in the databases of PubMed, Embase, Web of Science, and Cochrane Library. Hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were extracted for meta-analysis. The association between PNI and overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), progression-free survival (PFS), recurrence-free survival (RFS), and clinicopathological factors were evaluated.ResultsEleven studies involving 7,629 patients were included for meta-analysis. A decreased PNI was shown to be a significant predictor of worse OS (HR = 2.00, 95%CI = 1.64–2.42, p<0.001), CSS (HR = 2.54, 95%CI = 1.61–4.00, p<0.001), and DFS/PFS/RFS (HR = 2.12, 95%CI = 1.82–2.46, p<0.001) in RCC. Furthermore, a low PNI was correlated with Fuhrman grade III-IV (OR = 1.96, 95%CI = 1.27–3.02, p = 0.002), T stage T3-T4 (OR = 2.21, 95%CI = 1.27–3.87, p = 0.005), presence of sarcomatoid differentiation (OR = 5.00, 95%CI = 2.52–9.92, p<0.001), and presence of tumor necrosis (OR = 3.63, 95%CI = 2.54–5.19, p<0.001).ConclusionPNI is an independent prognostic indicator of survival and associated with Fuhrman grade, T stage, sarcomatoid differentiation, and tumor necrosis in patients with RCC.

Aberrant expression of the esophageal carcinoma related gene 4 as a prognostic signature for hepatocellular carcinoma

Background and objectiveHepatocellular carcinoma (HCC) is a lethal cancer with increasing incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain elusive. MethodsData mining approaches with a set of publicly accessible databases and immunohistochemistry were used to provide a novel insight into the expression pattern and prognostic significance of the esophageal cancer-related gene (ECRG) family members in HCC. ResultsWe found that elevated mRNA expression levels of ECRG factors were correlated with better overall survival, relapse-free survival and progression-free survival rates in patients with HCC. Subgroup analyses showed significant associations between ECRG expression and survival outcome in select HCC patients. In addition, immunohistochemical and multivariate analysis confirmed increased ECRG4 expression as an independent prognostic indicator for survival. ConclusionsOur data suggest that ECRG factors have significant impacts on the survival of HCC patients. The expression of ECRG factors may be involved in HCC progression and could serve as novel biomarkers for predicting more accurate prognosis.

Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas.

Background: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. Methods: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. Results: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (>0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031–2.927), 5.497 (95% CI: 1.818–16.615), and 0.176 (95% CI: 0.056–0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102–0.852). Conclusions: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies.

Malignant Tumor Purity Reveals the Driven and Prognostic Role of CD3E in Low-Grade Glioma Microenvironment.

The tumor microenvironment (TME) contributes to the initiation and progression of many neoplasms. However, the impact of low-grade glioma (LGG) purity on carcinogenesis remains to be elucidated. We selected 509 LGG patients with available genomic and clinical information from the TCGA database. The percentage of tumor infiltrating immune cells and the tumor purity of LGG were evaluated using the ESTIMATE and CIBERSORT algorithms. Stromal-related genes were screened through Cox regression, and protein-protein interaction analyses and survival-related genes were selected in 487 LGG patients from GEO database. Hub genes involved in LGG purity were then identified and functionally annotated using bioinformatics analyses. Prognostic implications were validated in 100 patients from an Asian real-world cohort. Elevated tumor purity burden, immune scores, and stromal scores were significantly associated with poor outcomes and increased grade in LGG patients from the TCGA cohort. In addition, CD3E was selected with the most significant prognostic value (Hazard Ratio=1.552, P<0.001). Differentially expressed genes screened according to CD3E expression were mainly involved in stromal related activities. Additionally, significantly increased CD3E expression was found in 100 LGG samples from the validation cohort compared with adjacent normal brain tissues. High CD3E expression could serve as an independent prognostic indicator for survival of LGG patients and promotes malignant cellular biological behaviors of LGG. In conclusion, tumor purity has a considerable impact on the clinical, genomic, and biological status of LGG. CD3E, the gene for novel membrane immune biomarker deeply affecting tumor purity, may help to evaluate the prognosis and develop individual immunotherapy strategies for LGG patients. Evaluating the ratio of differential tumor purity and CD3E expression levels may provide novel insights into the complex structure of the LGG microenvironment and targeted drug development.

Detection and characterization of lung cancer using cell-free DNA fragmentomes

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

Identification of Ferroptosis-Related Long Noncoding RNA and Construction of a Novel Prognostic Signature for Gastric Cancer.

Background Gastric cancer is the most common malignant tumor of the digestive system. It has a poor prognosis and is clinically challenging to treat. Ferroptosis is a newly defined mode of programmed cell death. The roles and prognostic value of ferroptosis-related long noncoding RNAs (lncRNAs) in gastric cancer remain unknown. Results In the current study, 20 ferroptosis-related lncRNAs were identified via univariate Cox analysis, least absolute shrinkage, and selection operator Cox regression analysis and used to construct a prognostic signature and classify gastric cancer patients into high-risk and low-risk groups. The signature was validated using TCGA training and testing cohorts. The risk signature was an independent prognostic indicator of survival and accurately predicted the prognoses of patients with gastric cancer. It was also associated with immune cell infiltration. Gene set enrichment analysis was used to investigate underlying mechanisms that the 20 ferroptosis-related lncRNAs were involved in. Chemosensitivity and immune checkpoint inhibitor analyses indicated that high-risk patients were more sensitive to the immune checkpoint inhibitor programmed cell death protein 1. Conclusions The important role of ferroptosis-related lncRNAs in immune infiltration identified in the current study may assist the determination of personalized prognoses and treatments in patients with gastric cancer. These 20 lncRNAs can be used as the diagnostic and prognostic markers for gastric cancer.

Bioinformatic analysis of PLOD family member expression and prognostic value in non-small cell lung cancer.

BackgroundProcollagen-lysine, 2-oxoglutarate 5-dioxygenases (PLODs) are a group of enzymes that can mediate the hydroxylation of lysyl to hydroxylysine and participate in the formation of stabilized collagen. Evidence has demonstrated that PLODs are involved in the steps of tumor progression, including proliferation, invasion, and metastasis. However, limited information is available on the function of PLOD1/2/3 in lung cancer. In this study, we investigated the expression patterns and prognostic values of PLODs in patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).MethodsThe Oncomine database and UALCAN were used to analyze the mRNA expression levels of PLOD family members in non-small cell lung cancer (NSCLC). The prognostic values of PLODs were investigated by the Kaplan–Meier Plotter database. We collected 33 patients with lung cancer to further verify the expression profiles and prognostic values of PLODs. The Kaplan-Meier method was used to perform survival curves, and the log-rank test was performed to evaluate the differences in survival. According to the GSE31210 databset, univariate and multivariate analyses were performed to identify whether PLODs were independent prognostic indicators for survival. Meanwhile, we investigated the mutations, potential biological functions and immune relevance of PLODs on the basis of the cBioPortal, Metascape and TIMER databases respectively.ResultsWe found that the mRNA and protein expression levels of PLODs in NSCLC tissues were higher than those in normal lung tissues. High PLOD1/2/3 expression had significant relevance to poor survival in LUAD but not in LUSC. In addition, the GSE31210 dataset showed that PLOD1 and PLOD3 were independent risk factors for relapse-free survival and overall survival (OS) in LUAD. We observed a high alteration rate of PLODs in LUSC patients, and the genetic alterations of PLODs had significant relevance to favorable OS. Furthermore, we observed that PLODs were significantly associated with tumor immunity in lung cancer. The enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed that the functions of the PLODs focused on cell cycle, DNA replication, and glycolysis/gluconeogenesis in LUAD.ConclusionsThese results indicated that PLODs were highly expressed in lung cancer and may be suitable prognostic markers.

Autophagy Gene Panel-Based Prognostic Model in Myelodysplastic Syndrome.

Abnormal autophagy is related to the pathogenesis and clinical symptoms of myelodysplastic syndrome (MDS). However, the effect of autophagy-related genes (ARGs) on the prognosis of MDS remains unclear. Here, we examined the expression profile of 108 patients with MDS from the GSE58831 dataset, and identified 22 genes that were significantly associated with overall survival. Among them, seven ARGs were screened and APIs were calculated for all samples based on the expression of the seven ARGs, and then, MDS patients were categorized into high- and low-risk groups based on the median APIs. The overall survival of patients with high-risk scores based on these seven ARGs was shorter than patients with low-risk scores in both the training cohort (P = 2.851e-06) and the validation cohort (P = 9.265e-03). Additionally, API showed an independent prognostic indicator for survival in the training samples [hazard ratio (HR) = 1.322, 95% confidence interval (CI): 1.158–1.51; P < 0.001] and the validation cohort (HR = 1.05, 95% CI: 1–1.1; P < 0.01). The area under the receiver operating characteristic curve (AUROC) of API and IPSS were 43.0137 and 66.0274 in the training cohorts and the AUC of the validation cohorts were 41.5361 and 72.0219. Our data indicate these seven ARGs can predict prognosis in patients with MDS and could guide individualized treatment.

Exosomal mRNAs and lncRNAs involved in multiple myeloma resistance to bortezomib.

The bone marrow microenvironment plays an essential role in multiple myeloma (MM) progression. We aimed to explore the alterations of levels of long noncoding RNAs and messenger RNAs (mRNAs), derived from exosomes in peripheral blood, in resistance to bortezomib (Btz) of MM patients. Peripheral blood samples were collected from five Btz‐resistant and five Btz‐sensitive MM patients. Exosomes in patients' peripheral blood were enriched, and the profiles of long noncoding RNAs (lncRNAs) and mRNAs in exosomes were determined using deep sequencing. Bioinformatics analysis was performed to explore biological function. MTS was employed to determine the viability of Roswell Park Memorial Institute (RPMI) 8226 and LP‐1 cells incubated with exosomes derived from Btz‐resistant patients. Quantitative polymerase chain reaction (qPCR) was used to evaluate the levels of exosomal FFAR1, SP9, HIST1H2BG, and ITIH2. Incubation with Btz‐resistant patient‐derived exosomes significantly increased the viability of Btz‐treated RPMI 8226 and LP‐1 cells in a dose‐dependent manner. We identified 482 lncRNAs and 2099 mRNAs deregulated in exosomes of the Btz‐resistance group; and 78 mRNAs were enriched in DR‐related pathways, including mammalian target of rapamycin, platinum drug resistance, and the cAMP and phosphoinositide 3‐kinase–Akt signaling pathways. qPCR results verified the increases in FFAR1 and SP9 and decreases in HIST1H2BG and ITIH2 in Btz‐resistant patient‐derived exosomes. Moreover, exosomal FFAR1 and SP9 exhibited potential as independent prognostic indicators of survival of MM patients. Our study reveals significant dysregulation of exosomal RNA components in the Btz‐resistant group of MM patients as well as several mRNAs that may be used as biomarkers of prognosis of MM patients that are resistant to Btz.

Correlation between MMP2 expression in lung cancer tissues and clinical parameters: a retrospective clinical analysis

BackgroundMatrix metalloproteinase 2 (MMP2) has been found to be related to malignant tumors; the aim of this study was to investigate the correlation between MMP2 expression in lung cancer tissues and clinical parameters of lung cancer.MethodsThe expression of MMP2 in lung cancer tissues and in adjacent non-malignant tissues was tested by immunohistochemistry. The correlation between the expression of MMP2 and clinical parameters of lung cancer was analyzed by Kaplan-Meier curve and multiple regression analysis.ResultsThe expression of MMP2 was higher in lung cancer tissues than that in adjacent non-malignant tissues (p = 0.002). Increased MMP2 was associated with low differentiation (p = 0.022), tumor size (p = 0.032), lymph node metastasis (p < 0.001), advanced stage (p = 0.002). The post-surgical survival time in patients with high MMP2 expression was shorter than that in patients with low MMP2 expression (p = 0.001). High expression of MMP2 (p = 0.006) and advanced stage (p = 0.003) were independent prognostic indicators for survival of lung cancer patients.ConclusionsIncreased MMP2 correlates with malignant biological behavior of lung cancer and it could be a potential biomarker for diagnosis and prognosis of the disease.

Clinicopathologic Features of Gastroenteropancreatic Neuroendocrine Tumors: A Single-center Experience

Background:Gastroenteropancreatic neuroendocrine tumors, a heterogeneous group of neoplasms, originates from the neuroendocrine system of the gastrointestinal tract and pancreas. There are limited number of studies investigating neuroendocrine tumors in Turkey.Aims:To define the clinicopathologic, demographic, and survival features of patients with gastroenteropancreatic neuroendocrine tumors.Study Design:A retrospective observational cohort study.Methods:We reviewed hospital records of patients and data was analyzed retrospectively. We investigated the clinical, pathological, survival features, and prognosis of patients with gastroenteropancreatic neuroendocrine tumors (n=128) admitted to the medical oncology department between year 2003 and 2014. Survival estimation was performed by the Kaplan-Meier method. Univariate and multivariate Cox regression models were utilized to investigate the prognostic factors for survival.Results:Of 128 patients with gastroenteropancreatic neuroendocrine tumors, 61 (47.7%) were female and 67 (52.3%) were male. The most common site of the tumor was stomach (36.7%), while the most common stage of tumor at diagnosis was stage 4 (40.9%). The median follow-up period was 37 months, while the 3- and 5-year overall survival rates were 78% and 69%, respectively. The factors significantly affecting overall survival rate were clinical stage, grade, presence of metastasis at diagnosis, and Ki-67 proliferation index. These factors were associated with the 3- and 5-year overall survival rate. Moreover, grade (hazard ratio: 8.34, 95% confidence interval: 2.16-32.22, p=0.01) and presence of metastasis at diagnosis (hazard ratio: 3.18, 95% confidence interval: 1.30-7.77, p=0.01) independently predicted overall survival in multivariate model following adjustment for age and gender.Conclusion:Higher-grade and presence of metastasis at diagnosis are negative independent prognostic indicators of survival in patients with gastroenteropancreatic neuroendocrine tumors.

Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma

Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA). This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA. We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013. Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group. The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model. There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival. Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.

OPN promotes the aggressiveness of non-small-cell lung cancer cells through the activation of the RON tyrosine kinase

Osteopontin (OPN) is identified as a diagnostic and prognostic biomarker of tumor progression and metastasis. In non-small-cell lung cancer (NSCLC), the functions of OPN have not been well characterized. The current study sought to investigate the clinical implications of OPN expression in NSCLC and the role of OPN in the aggressiveness of the lung cancer cells. Using a proteomics approach, we identified that phospho-RON (p-RON) was one of the most remarkably up-regulated proteins in OPN-overexpressing cells. The levels of OPN and RON transcripts were unveiled as independent prognostic indicators of survival in NSCLC (p = 0.001). Higher levels of OPN, RON and p-RON proteins were observed in tumor tissues. Knock down of the OPN gene suppressed the migration and invasion abilities of the A549 lung cancer cells which endogenously expresses OPN. While ectopic expression of OPN in the SK-MES-1 lung cancer cells increased levels of cellular invasion and migration. In addition, these changes were accompanied by a phosphorylated activation of RON. Small-molecule inhibition of RON or siRNA silencing of RON significantly reduced OPN-induced migration and invasion of lung cancer cells and had an inhibitory effect on the OPN-mediated cell epithelial-mesenchymal transition. Our study suggests that in NSCLC, the aberrant expression of OPN can be considered as an independent survival indicator and is associated with disease progression. OPN plays a crucial role in promoting migration and invasion properties of lung cancer cells through its phosphorylation activation of the RON signaling pathway, implying its potential as a therapeutic target in the treatment of NSCLC.