Predictor Of Poor Prognosis Research Articles

Nucleolin Overexpression Predicts Patient Prognosis While Providing a Framework for Targeted Therapeutic Intervention in Lung Cancer

Simple SummaryDespite the clinical benefit of new anticancer therapies, such as immune checkpoint inhibitors, lung cancer remains the most frequent cause of cancer-related death worldwide, thus supporting the need to develop novel anticancer treatments. Endothelial cells of the tumor-associated vasculature are easily accessible to drugs administered intravenously, besides having greater genetic stability than neoplastic cells and thus lowering the risk of developing drug resistance. In this respect, the identification of alternative targets, and therapeutic strategies, within the tumor vasculature is of high relevance. Accordingly, this work aimed at characterizing nucleolin expression in patient-derived pulmonary carcinomas and further validating nucleolin as a novel target to mediate successful therapeutic interventions against human lung cancers. The highlighted prognostic value of nucleolin points towards the applicability of nucleolin-based targeting strategies against nucleolinhigh pulmonary carcinomas, present in every disease stage, in a clinical trial setting.Notwithstanding the advances in the treatment of lung cancer with immune checkpoint inhibitors, the high percentage of non-responders supports the development of novel anticancer treatments. Herein, the expression of the onco-target nucleolin in patient-derived pulmonary carcinomas was characterized, along with the assessment of its potential as a therapeutic target. The clinical prognostic value of nucleolin for human pulmonary carcinomas was evaluated through data mining from the Cancer Genome Atlas project and immunohistochemical detection in human samples. Cell surface expression of nucleolin was evaluated by flow cytometry and subcellular fraction Western blotting in lung cancer cell lines. Nucleolin mRNA overexpression correlated with poor overall survival of lung adenocarcinoma cancer patients and further predicted the disease progression of both lung adenocarcinoma and squamous carcinoma. Furthermore, a third of the cases presented extra-nuclear expression, contrasting with the nucleolar pattern in non-malignant tissues. A two- to twelve-fold improvement in cytotoxicity, subsequent to internalization into the lung cancer cell lines of doxorubicin-loaded liposomes functionalized by the nucleolin-binding F3 peptide, was correlated with the nucleolin cell surface levels and the corresponding extent of cell binding. Overall, the results suggested nucleolin overexpression as a poor prognosis predictor and thus a target for therapeutic intervention in lung cancer.

N6-methyladenosine (m6A) reader IGF2BP1 accelerates gastric cancer aerobic glycolysis in c-Myc-dependent manner

The N6-methyladenosine (m6A) is involved in the regulation of cell proliferation and metastasis formation in multiple cancers. However, the biological significance of RNA m6A reader IGF2BP1 and the modification of IGF2BP1 itself have not been fully investigated. Here, we analyzed the functions and mechanism of IGF2BP1 in gastric cancer (GC). Results showed that IGF2BP1 upregulated in GC tissue and acted as a predictor of poor prognosis for GC patients. Functionally, IGF2BP1 promoted the migration and aerobic glycolysis of GC cells in vitro. Moreover, IGF2BP1 knockdown repressed the tumor growth in vivo. We also demonstrated that IGF2BP1 directly interacted with c-MYC mRNA via m6A-dependent manner to by stabilize its stability. Overall, these findings demonstrated that m6A reader IGF2BP1 facilitated the carcinogenic of GC in m6A/c-Myc-dependent manner, which might provide critical therapeutic strategy for GC.

Cyclin-dependent kinase 8 is an independent prognosticator in uterine leiomyosarcoma

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7–30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and β-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p < 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not significantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.

ADAMTS12 promotes migration and epithelial-mesenchymal transition and predicts poor prognosis for pancreatic cancer

BackgroundADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family, a group of extracellular multifunctional enzymes, has been proven to play a pivotal role in the tumor. In pancreatic cancer, the role and mechanism of this family remain unclear. The present study aimed to figure out the hub gene of ADAMTSs and explore the exact roles in the prognosis and biological functions in pancreatic ductal adenocarcinoma (PDAC). MethodsWe used several databases to analyze the ADAMTS family and then screen out the hub genes. The expression of ADAMTS12 in 106 pairs of PDAC tumors and adjacent normal tissues was examined by immunohistochemistry, and its correlations with clinical parameters were further analyzed. The impacts of ADAMTS12 on the migration of PDAC cells were predicted by gene set enrichment analysis and confirmed by transwell assays. The potential impacts of ADAMTS12 on the epithelial-mesenchymal transition (EMT) were identified by database analysis and experimental proof of real-time quantitative polymerase chain reaction (qPCR) and Western blotting. ResultsOur study found that ADAMTS12 was a crucial gene in PDAC, and it was highly expressed in tumor tissues when compared to that in the adjacent tissues. ADATMS12 had predictive value of a poor prognosis for PDAC. The elevation of ADAMTS12 was parallel to the progression of PDAC. Inhibition of ADAMTS12 suppressed the migration of PDAC cells and interfered with the process of EMT. ConclusionsADAMTS12 is a crucial member of ADAMTSs in PDAC and a predictor of poor prognosis. Additionally, based on its impacts on migration and metastasis in PDAC and the relationship with EMT, ADAMTS12 plays a role of an oncogene in PDAC and may be a promising target for treatment.

Relationship between Neurological Deterioration and Blood Pressure/Heart Rate Variability in Patients with Acute Cerebral Infarction

ObjectivesNeurological deterioration (ND) during hospitalization is an independent predictor of poor prognosis after stroke. Risk factors affecting early ND within 48 h post stroke have been intensively investigated, while few data are available on those for late ND after transfer to a wheelchair. Therefore, it was investigated whether hemodynamic factors may affect the late ND during hospitalization. Materials and methodsA retrospective study was conducted on 135 patients with atherothrombotic or cardiogenic cerebral infarction who were admitted to our hospital between April 1st, 2014 and July 31st, 2017. During hospitalization, average, maximum, and minimum values were determined for systolic blood pressure (sBP), diastolic BP (dBP), and heart rate (HR), respectively.135 patients were classified into two groups; ND (+) group, in which modified Barthel index score at the time of transfer to a wheelchair showed five points or more decrease between wheelchair transfer and discharge, and ND (−) group, which did not. Vital indices were compared between the two groups and subjected to ROC-curve analysis. ResultsThe ND (+) group included 32 patients, and the ND (−) 103. Significant differences were found between the groups in four items; sBPmin (p = 0.029), dBPmin (p = 0.019), HRave (p = 0.028), and HRmax (p < 0.01). The ND (+) group showed lower sBPmin and dBPmin, and higher HRave and HRmax than the ND (−) group. ConclusionsLate ND after transfer to a wheelchair is related to the vital indices during hospitalization and should be cautiously managed to prevent late ND

ADAM12 is an independent predictor of poor prognosis in liver cancer

Disintegrin and metalloproteinase 12 (ADAM12) is thought to trigger the occurrence and development of numerous tumours, including colorectal, breast, and pancreatic cancers. On the basis of The Cancer Genome Atlas (TCGA) datasets, in this study, the relationship between ADAM12 gene expression and hepatocellular carcinoma (HCC), the prognostic value of this relationship, and the potential mechanisms influencing HCC development were evaluated. The results showed that the ADAM12 gene was significantly and highly expressed in liver cancer tissue. The high expression of the ADAM12 gene in liver cancer tissue significantly and positively correlated with T stage, pathological stage, and residual tumour. Kaplan–Meier and Cox regression analyses revealed that ADAM12 gene expression is an independent risk factor influencing the prognosis of patients with liver cancer. Pathway analyses of ADAM12 in HCC revealed ADAM12-correlated signalling pathways, and the expression level of ADAM12 was associated with immune cell infiltration. In vitro experiments demonstrated that the expression level of ADAM12 in Huh-7 and Hep3B cells was significantly higher than that in other HCC cells. ShRNA transfection experiments confirmed that the expression levels of TGF-β and Notch pathway-related proteins were significantly decreased. An EdU cell proliferation assay showed that a low level of ADAM12 gene expression significantly inhibited the proliferative activity of HCC cells. Cell cycle experiments showed that low ADAM12 expression blocked the G1/S phase transition. Overall, this research revealed that high ADAM12 gene expression implies a poor prognosis for patients with primary liver cancer. In addition, it is a potential indicator for the diagnosis of liver cancer.

Major postoperative complications are associated with early recurrence of hepatocellular carcinoma following hepatectomy.

Early recurrence (ER) is a strong predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to examine manageable factors associated with ER. Overall, 475 consecutive patients with primary HCC who underwent curative hepatectomy were included (R0/R1). We defined ER as recurrence within 2years after hepatectomy and analyzed predictors for ER. We also defined postoperative complication as Clavien-Dindo classification grade III or IV. ER after hepatectomy was observed in 209 cases (44.0%). Patients with ER had a significantly poor prognosis compared with those with late recurrence (log-rank p < 0.0001) and were more likely to be diagnosed with extrahepatic metastasis (p = 0.009). Significant predictors for ER were des-γ-carboxyprothrombin > 40 mAU/mL (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.36-3.14, p = 0.001), multiple tumors (OR 2.80 95%CI 1.83-4.32, p < 0.0001), cirrhosis (OR 1.53, 95%CI 1.01-2.32, p = 0.043), and postoperative complications (OR 1.72, 95% CI 1.05-2.85, p = 0.032). Blood loss (OR 1.09, 95%CI 1.05-1.13, p < 0.0001) and cirrhosis (OR 1.74, 95%CI 1.05-2.86, p = 0.031) were significant predictors for postoperative complications. We should pay close attention to surgical associated- and disease-specific factors in hepatectomy for HCC to prevent ER.

Influence of skeletal muscle volume loss during lenvatinib treatment on prognosis in unresectable hepatocellular carcinoma: a multicenter study in Tohoku, Japan

Sarcopenia is associated with poor prognosis of patients with hepatocellular carcinoma (HCC). We investigated the association of skeletal muscle volume (SMV) and its change in HCC patients taking lenvatinib. In 130 HCC patients, psoas mass index (PMI) was calculated as the left–right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared. Patients were classified into two groups (low and normal PMI) based on indices of < 6.0 cm2/m2 for man and < 3.4 cm2/m2 for women. Change in PMI per month during the lenvatinib administration period (ΔPMI/m) was calculated; and patients were classified into two groups (severe and mild atrophy) based on the ΔPMI/m rate, as ≥ 1% or < 1%, respectively. There was no significant difference in Overall survival (OS) between the low and normal PMI groups at the start of lenvatinib administration. OS was significantly lower in the severe atrophy group than in the mild atrophy group (median; 15.2 vs. 25.6 months, P = 0.005). Multivariate analysis revealed a significant association of severe atrophy with OS (hazard ratio 1.927, P = 0.031). Progressive loss of SMV is a strong predictor of poor prognosis in HCC patients taking lenvatinib.

Methylation Subtypes of Primary Prostate Cancer Predict Poor Prognosis.

Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.

The Sonographic Features of Malformation in Fetal Echogenic Bowel and Its Relationship With Chromosome Abnormalities.

The aims of this study were to analyze the sonographic features and clinical prognosis of fetal echogenic bowel (FEB) and to evaluate the value of FEB in the prediction of fetal chromosomal abnormalities. Eight hundred eighty-two fetuses with FEB were selected. The ultrasonographic features and the chromosomal examination were retrospectively analyzed. Among the 882 FEB, 272 (30.8%) cases had malformation. The most common malformation was cardiovascular malformation (21.6%), followed by urinary malformation (9.0%), craniocerebral malformation (6.8%), and gastrointestinal malformations (5.6%). According to other combined ultrasound abnormalities, the FEBs were divided into 4 groups: isolated FEB group (490 cases), ultrasound soft indicators group (130 cases), single malformation group (117 cases), and multiple malformation group (145 cases). A total of 45 cases (5.1%) were detected with chromosomal abnormalities. Compared with isolated FEB group, the rate of chromosomal abnormality in other 3 groups was significantly higher. Among 490 cases of isolated FEB, 114 cases of isolated FEB group with adverse pregnancy outcomes were selected as the experimental group, and 376 cases of FEB group with good prognosis were selected as the control group. There were significant differences of the location, shape, intensity, and progression between the 2 groups. Multivariate logistic regression analysis showed that central location and progression of FEB were independent risk predictors of poor prognosis. The combined malformation rate is high for FEB fetuses. The fetal systems should be carefully examined when FEB is found in prenatal ultrasound.

Outcomes of Minority COVID-19 patients managed with ECMO: A single-center experience.

BackgroundThe coronavirus disease 2019 (COVID‐19) pandemic has significantly burdened the global healthcare system since December 2019. Minority populations are found to have a higher incidence of hospitalization and higher mortality when compared to Caucasians. Extracorporeal membrane oxygenation (ECMO) is reserved for COVID‐19 patients who develop respiratory failure refractory to conventional management. To our knowledge, no data has been reported on outcome differences between Minority COVID‐19 patients and Caucasian COVID‐19 patients managed with ECMO. We aimed to investigate the outcome differences between these two groups.MethodsOur retrospective cohort study had 23 adults (aged 18 and older) diagnosed with COVID‐19 by polymerase chain reaction. All patients developed acute respiratory distress syndrome (ARDS), refractory to conventional treatment, and were managed on ECMO support. The primary outcome of interest was mortality; the secondary outcome was the rate of ECMO‐related complications.ResultsThe overall mortality rate of our study was higher (70%) than other reports of the COVID‐19 population on ECMO. Caucasians in our study had more severe respiratory acidosis with carbon dioxide retention and appeared to have a higher mortality rate of 85.7% compared to Minorities (62.5%). No differences in complication rates between these two groups were identified.ConclusionsOur cohort revealed a high overall mortality rate of COVID‐19 patients on ECMO support. The Caucasian group was observed to have higher mortality than the Minority group. The high overall mortality was likely attributed to the Caucasian group, which had more severe respiratory acidosis before ECMO initiation, a known predictor of poor prognosis in ARDS patients. Our cohort's ethnic composition may also partially explain the high mortality rate since COVID‐19 Minorities are reported to have worse outcomes than Caucasians. Larger and randomized studies are needed to investigate further the mortality and complication differences between Minority and Caucasian patients diagnosed with COVID‐19 and managed by ECMO.

Prevalence, Associated Factors, and Survival Outcomes of Small-Cell Neuroendocrine Carcinoma of the Gynecologic Tract: A Large Population-Based Analysis.

Small-cell carcinomas are highly malignant tumors with neuroendocrine function and which often occur in the lungs. Primary small-cell neuroendocrine carcinomas of the gynecologic tract are extremely rare. This study aimed to evaluate the prevalence of independent predictors related to the prognosis and overall survival of patients with small-cell neuroendocrine carcinomas of the gynecologic tract. Patients with gynecologic small-cell neuroendocrine carcinomas diagnosed between 1973 and 2015 were identified from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox risk regression analyses were performed to determine the independent predictors of overall survival. Overall survival was calculated using the Kaplan–Meier method, and the log-rank test was used for comparison. We included 5,15,393 eligible carcinomas in the present study; the prevalence of gynecologic small-cell neuroendocrine carcinomas was 0.121% (N = 622). Multivariate analysis indicated that advanced age, stage III and IV cancer, and no chemotherapy treatment may be predictors of poor small-cell neuroendocrine cervical carcinoma prognosis. Stage III and IV cancer and lack of surgery, radiotherapy, or chemotherapy were identified as potential predictors of poor prognosis in patients with ovarian small-cell neuroendocrine carcinoma. Kaplan–Meier analysis suggested that the median survival was 19, 11, and 12 months for cervical, ovarian, and endometrial small-cell neuroendocrine carcinomas, respectively. The 1-, 3-, and 5-year overall survival rates were as follows: 58.8, 31.4, and 26.1%, respectively, for small-cell neuroendocrine cervical carcinoma; 46.3, 23.5, and 22.0%, respectively, for ovarian small-cell neuroendocrine carcinoma; and 49.4, 29.4, and 25.9%, respectively, for endometrial small-cell neuroendocrine carcinoma. Our findings indicate that comprehensive and individualized treatment of small-cell neuroendocrine carcinomas of the gynecologic tract may prolong patient survival, although further studies are required.

In-Hospital and Long-Term Outcomes of ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention

Introduction: We evaluated in-hospital and long-term outcomes of patients who underwent primary percutaneous coronary intervention (PCI) in a tertiary center. Patients and Methods: We examined 1550 patients (mean age= 58.5 years, 83.1% male) admitted with acute ST-segment elevation myocardial infarction (AMI) who underwent primary PCI and were followed-up prospectively. The primary outcomes were in-hospital death and major adverse cardiac events (MACE) at follow-up. Results: The mean duration of ischemia at admission was 2.85 ± 2.49 hours; 10.3% of the patients were Killip class III or IV. The mean door-to-device time was 43 (29-52) minutes. During hospitalization, all-cause mortality occurred in 73 patients (4.7%). Multivariate analysis revealed that advanced age, impaired left ventricular ejection function, high Killip functional class, hemoglobin level at admission, ventricular arrhythmias, and advanced atrioventricular block were independent predictors of poor prognosis (OR= 1.07, 0.93, 15.34, 1.44, 3.79, and 4.26 respectively). Among discharged patients with a median 49.5 (25-73) months follow-up, 12.4% of them died, 12.5% had a recurrent myocardial infarction (MI), and 2.3% had a cerebrovascular accident. The strongest independent MACE predictors were impaired left ventricular function, poor glomerular filtration rate, low albumin level, and a history of cerebrovascular disease (HR= 0.97, 0.99, 0.65, and 2.50, respectively). Secondary outcomes were contrast-induced acute kidney injury (16.7%), ventricular arrhythmias (6.1%), advanced atrioventricular block (3.7%), atrial fibrillation (7.6%), and major bleeding (1.6%). Conclusion: AMI still has a poor long-term prognosis. These results emphasize the advantages of rapid, non-delayed revascularization. Patients should be followed-up closely after discharge in both the short- and long-term.

Combining Pre- and Postoperative Lymphocyte-C-Reactive Protein Ratios Can Better Predict Hepatocellular Carcinoma Prognosis After Partial Hepatectomy.

BackgroundVarious preoperative inflammatory indicators have been identified as potential predictors of poor prognosis in patients with hepatocellular carcinoma (HCC), but the role of postoperative inflammatory indicators remains unclear. This study aimed to explore the prognostic value of the postoperative lymphocyte–C-reactive protein ratio (PostLCR) on its own and combined with preoperative LCR (PreLCR).MethodsA total of 290 patients with primary HCC were retrospectively enrolled in the study. Univariate analysis was used to identify factors significantly associated with poor disease-free survival (DFS) and overall survival (OS), then multivariate analysis was performed to identify independent prognostic indicators of poor survival. Prognostic models based on preoperative, postoperative, and both types of indicators were then constructed, and their predictive performance were evaluated using time-dependent receiver operating characteristic curves and the concordance index (C-index).ResultsPreLCR and PostLCR levels correlated with DFS and OS more strongly than other pre- and postoperative inflammatory indicators, respectively. Decreased PreLCR and PostLCR were independent prognostic factors for both DFS and OS, while HCC patients with decreased PreLCR and PostLCR had worse prognosis than patients with increased PreLCR and PostLCR. Patients into three groups based on their cut-off values of PreLCR and PostLCR, Kaplan–Meier survival analysis indicated that HCC patients with low PreLCR and PostLCR had the worst DFS and OS. The combined model showed better predictive performance at 1 and 3 years post-surgery than individual pre- and postoperative models, the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system and the Barcelona Clinic Liver Cancer system. The combine model demonstrated a markedly superior C-index compared with the other models in DFS and OS.ConclusionOur study showed PreLCR and PostLCR are independent predictors of DFS and OS in HCC patients after partial hepatectomy. Models that include both PreLCR and PostLCR can predict prognosis better than well-established clinical staging systems.

Tumor-suppressive role of Smad ubiquitination regulatory factor 2 in patients with colorectal cancer

Smad ubiquitination regulatory factor 2 (Smurf2) plays various roles in cancer progression. However, the correlation between Smurf2 and clinical outcomes has not been determined in patients diagnosed with colorectal cancer and colorectal liver metastases. We analyzed 66 patients with colorectal cancer who developed liver metastases. Smurf2 expression was assessed using immunohistochemical analysis of primary and metastatic liver tumors. High Smurf2 expression in both primary and metastatic tumors was significantly associated with longer overall survival time and time to surgical failure. Multivariate analyses revealed that low Smurf2 expression in primary tumors was an independent predictor of poor prognosis. In vitro experiments using colon cancer cell lines demonstrated that short interfering RNA knockdown of Smurf2 increased cell migration and tumor sphere formation. Western blot analyses revealed that Smurf2 knockdown increased the protein expression of epithelial cell adhesion molecule (EpCAM). Thus, in summary, high Smurf2 expression in cancer cells was found to be an independent predictor of better prognosis in patients with primary colorectal cancer and consequent liver metastases. The tumor-suppressive role of Smurf2 was found to be associated with cell migration and EpCAM expression; hence, Smurf2 can be considered a positive biomarker of cancer stem cell-like properties.

CD133(+)HIF-1α(-) Expression After Chemoradiotherapy Predicts Poor Prognosis in Rectal Cancer.

CD133 and hypoxia-inducible factor 1α (HIF-1α) have been reported to be affected by chemoradiotherapy (CRT), but the combinatorial assessment of these markers for prognosis after CRT has not been fully investigated. Therefore, we aimed to predict recurrence and prognosis in patients with rectal cancer by assessing changes in the expression of both CD133 and HIF-1α after CRT. CD133 and HIF-1α expression was evaluated by immunohistochemistry in surgical specimens from 243 patients with advanced low rectal cancer who received CRT followed by curative resection. The positivity rate of CD133 expression showed increase with increased HIF-1α expression. The combination of these two markers showed that the CD133(+)HIF-1α(-) group exhibited a markedly shorter relapse-free survival (p=0.007), higher liver recurrence (p=0.004), and higher local recurrence (p=0.006). CD133(+)HIF-1α(-) expression after CRT is a promising marker to predict recurrence in rectal cancer.

PRPF8 Expression is an Independent Predictor for Poor Prognosis in Patients with Kidney Renalclear Cell Carcinoma

Background: Alternative splicing is an important process associated with disease including tumors. PRPF8 is a conserved protein in splice some component U5 snRNP that plays an important role in tumor cell growth. Materials and Methods: The data in The Cancer Genome Atlas was downloaded and analyzed by R Studio. The box plots showed the expression pattern of PRPF8. The chi-square test was used to manifest the association between PRPF8 expression and clinical parameters. The diagnostic value was assessed using ROC curve. The Kaplan-Meier curves and the Cox regression analysis elucidated the difference of overall survival and relapse-free survival between high expression and low expression and the prognostic value. Results: We downloaded the PRPF8 expression and the clinical data of 50 healthy individuals and 537 patients from TCGA database. We found PRPF8 expression is lower in tumor tissues than that in normal tissues and is related to age, histologic grade, pathologic stage, M classification, T classification and vital status. The Kaplan Meier curves showed the patients with lower PRPF8 expression has a poorer overall survival and relapse-free survival. The Univariate and Multivariate analysis suggested PRPF8 expression was an independent prognostic factor for overall survival and relapse-free survival in kidney renal clear cell carcinoma. Conclusion: Low PRPF8 expression is an independent predictor for overall survival and relapse-free survival in kidney renal clear cell carcinoma.

Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis

A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival. A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival. A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr=0.0099]; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr= 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr= 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr= 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41-24.98; Pfdr= 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr= 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr= 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr= 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P= 0.008). HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.

The Prognostic Role of CDK9 in Bladder Cancer.

Simple SummaryIn this article, we investigated the prognostic role of cyclin-dependent kinase 9 expression in urothelial carcinoma. High CDK9 expression has recently been associated with shorter patient survival time, but its role in urothelial carcinoma has not yet been explored. The expression of CDK9 was higher in cancer than in normal urothelial tissue and correlated with tumor grade, stage, and invasiveness. To our surprise, patients with high CDK9 expression lived longer than patients with low CDK9 expression. In The Cancer Genome Atlas database cohort, high CDK9 RNA concentration correlates with longer survival of patients and CDK9 status remained a statistically significant prognostic factor in multivariate analysis. It seems that CDK9 not only regulates the expression of anti-apoptotic genes, leading to longer survival of cancer cells, it also facilitates DNA repair, preventing the build-up of genomic instability, crucial in the initiation and progression of bladder cancer. The results suggest that CDK9 overexpression is not always associated with a worse prognosis, while cell maturity and disease stage may influence the efficacy of potential targeted therapy.Introduction: Most patients with urothelial carcinoma are diagnosed with non-invasive tumors, but the prognosis worsens with the progression of the disease. Overexpression of cyclin-dependent kinase 9 has been recently linked to increased cancer proliferation, faster progression, and worse prognosis. However, some cancers seem to contradict this rule. In this work, we explored the prognostic role of CDK9 expression in urothelial carcinoma. Materials and Methods: We performed immunohistochemical analysis on 72 bladder cancer samples. To assess a larger group of patients, the Cancer Genome Atlas (TCGA) database containing 406 cases and transcriptomics information through the Human Pathology Atlas were analyzed. Results: CDK9 is overexpressed in urothelial cancer tissues when compared to normal urothelial tissues (p < 0.05). High CDK9 expression was observed in low-stage, low-grade, and non-muscle-invasive tumors (p < 0.05). The patients with high CDK9 expression had a significantly higher 5-year overall survival rate than those with low CDK9 expression (77.54% vs. 53.6% in the TMA group and 57.75% vs. 35.44% in the TCGA group, respectively) (p < 0.05). The results were consistent in both cohorts. Multivariate Cox regression analysis indicated that low CDK9 status was an independent predictor for poor prognosis in the TCGA cohort (HR 1.60, CL95% 1.1–2.33, p = 0.014). Conclusions: High CDK9 expression predicts a favorable prognosis in urothelial carcinoma and is associated with clinicopathological features characteristic for early-stage disease. The decrease in CDK9 expression can be associated with the build-up of genetic instability and may indicate a key role for CDK9 in the early stages of urothelial carcinoma.

3-Mercaptopyruvate sulfurtransferase represses tumour progression and predicts prognosis in hepatocellular carcinoma.

AIMS: The prognosis of hepatocellular carcinoma (HCC) remains dismal, and its molecular pathogenesis has not been completely defined. The enzyme 3-mercaptopyruvate sulfurtransferase (MPST) regulates endogenous hydrogen sulfide (H2 S) biosynthesis. However, the role of MPST in HCC has never been intensively investigated. MPST protein expression was analysed in HCC tumour tissues and matched adjacent tissues. The effect of MPST on HCC progression was studied in vitro and in vivo. The mRNA and protein expression of MPST was significantly downregulated in HCC samples compared with their paired nontumour counterparts. A low MPST expression was associated with larger tumour size and a worse overall survival. Overexpression of MPST in HCC cells inhibited cell proliferation and induced apoptosis. MPST overexpression also significantly suppressed the growth of tumour xenografts in nude mice, whereas silencing MPST by intratumour delivery of siRNA substantially promoted tumour growth. Moreover, diethylnitrosamine-induced mouse HCC was aggravated by MPST gene knockout. Mechanistically, MPST suppressed the cell cycle associated with H2 S production and inhibition of the AKT/FOXO3a/Rb signalling pathway in HCC development. In addition, MPST expression negatively correlated with that of pRb in HCC specimens and the combination of these two parameters is a more powerful predictor of poor prognosis. MPST may function as a tumour suppressor gene that plays an essential role in HCC proliferation and liver tumorigenesis. It is a candidate predictor of clinical outcome in patients with HCC and may be used as a biomarker and intervention target for new therapeutic strategies.