Clinical Prognostic Predictors Research Articles

Patient-specific computational models predict prognosis in B cell lymphoma by quantifying pro-proliferative and anti-apoptotic signatures from genetic sequencing data

Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and cell fates in diffuse large B cell lymphoma and multiple myeloma. Simulations predicted adverse impact on clinical prognosis when combinations of mutations induced both anti-apoptotic (AA) and pro-proliferative (PP) signalling. We integrated patient-specific mutational profiles into personalised lymphoma models, and identified patients characterised by simultaneous upregulation of anti-apoptotic and pro-proliferative (AAPP) signalling in all genomic and cell-of-origin classifications (8-25% of patients). In a discovery cohort and two validation cohorts, patients with upregulation of neither, one (AA or PP), or both (AAPP) signalling states had good, intermediate and poor prognosis respectively. Combining AAPP signalling with genetic or clinical prognostic predictors reliably stratified patients into striking prognostic categories. AAPP patients in poor prognosis genetic clusters had 7.8 months median overall survival, while patients lacking both features had 90% overall survival at 120 months in a validation cohort. Personalised computational models enable identification of novel risk-stratified patient subgroups, providing a valuable tool for future risk-adapted clinical trials.

Identification and validation of m5c-related lncRNA risk model for ovarian cancer

Ovarian cancer (OC) is one of the common malignant tumors that seriously threaten women's health, and there is a lack of clinical prognostic predictors, while m5c and lncRNA have been shown to be predictive of multiple cancers, including OC. Therefore, our goal was to construct a risk model for OC based on m5c-related lncRNA.340 m5c-related lncRNA were identified and a novel risk model of OC ground on nine m5C-related lncRNA was constructed using LASSO-COX regression analysis. Kaplan–Meier analysis showed there was a significant difference in prognosis between risk groups. We established a nomogram which was a good predictor of overall survival. In addition, GSEA was enriched in multiple pathways and immune function analysis suggested that immune infiltration varies depending on the risk group. In vitro experiments show that AC005562.1, a key lncRNA of the risk model, is highly expressed in OC cells and promotes OC cell proliferation. Finally, we further explored the potential biological markers of m5c-related lncRNA in OC with WGCNA analysis and established a ceRNA network. In conclusion,we have developed a reliable m5c-related prediction model and performed systematic validation and exploration of various aspects. These results can be used for the assessment of OC prognosis and the discovery of novel biomarkers.

Advanced Dementia: Brain-State Characteristics and Clinical Indicators of Early Mortality.

There is an urgent need in advanced dementia for evidence-based clinical prognostic predictors that could positively influence ethical decisions allowing health provider and family preparation for early mortality. Accordingly, the authors review and discuss the prognostic utility of clinical assessments and objective measures of pathological brain states in advanced dementia patients associated with accelerated mortality. Overall, due to the paucity of brain-activity and clinical-comorbidity predictors of survival in advanced dementia, authors outline the potential prognostic value of brain-state electroencephalography (EEG) measures and reliable clinical indicators for forecasting early mortality in advanced dementia patients. In conclusion, two consistent risk-factors for predicting accelerated mortality in terminal-stage patients with advanced dementia were identified: pressure ulcers and paroxysmal slow-wave EEG parameters associated with cognitive impairment severity and organic disease progression. In parallel, immobility, malnutrition, and co-morbid systemic diseases are highly associated with the risk for early mortality in advanced dementia patients. Importantly, the authors' conclusions suggest utilizing reliable quantitative-parameters of disease progression for estimating accelerated mortality in dementia patients entering the terminal disease-stages characterized by severe intellectual deficits and functional disability.

Identification of Hypoxia-Related Differentially Expressed Genes and Construction of the Clinical Prognostic Predictor in Hepatocellular Carcinoma by Bioinformatic Analysis

Background. Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research is aimed at mining the hypoxic-related genes (HRGs) and constructing a prognostic predictor (PP) model on clinical prognosis in HCC patients. Methods. RNA-sequencing data about HRGs and clinical data of patients with HCC were obtained from The Cancer Genome Atlas (TCGA) database portal. Differentially expressed HRGs between HCC and para-carcinoma tissue samples were obtained by applying the Wilcox analysis in R statistical software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene functional enrichment analyses. Then, the patients who were asked to follow up for at least one month were enrolled in the following study. Cox proportional risk regression model was applied to obtain key HRGs which related to overall survival (OS) in HCC. PP was constructed and defined, and the accuracy of PP was validated by constructing the signature in a training set and validation set. Connectivity map (CMap) was used to find potential drugs, and gene set cancer analysis (GSCA) was also performed to explore the underlying molecular mechanisms. Results. Thirty-seven differentially expressed HRGs were obtained. It contained 28 upregulated and 9 downregulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer, and 2 genes were protective factors. The PP was composed by 12 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, HMOX1, PGK1, ERO1A, LDHA, ENO2, SLC6A6, and TPI1). GSCA results showed the overall activity of these 12 key genes in 10 cancer-related pathways. Besides, CMap identified deferoxamine, crotamiton, talampicillin, and lycorine might have effects with HCC. Conclusions. This study firstly reported 12 prognostic HRGs and constructed the model of the PP. This comprehensive research of multiple databases helps us gain insight into the biological properties of HCC and provides deferoxamine, crotamiton, talampicillin, and lycorine as potential drugs to fight against HCC.

Prognostic Value of Nutritional and Inflammatory Indicators in Female With Esophageal Squamous Cell Cancer: A Retrospective Cohort Study

Background: Esophageal squamous cell cancer (ESCC) was a disease with a male predominance. Accordingly, the applicability of prognostic indicators values previously set for the general population with ESCC have not been reported for determining physical state in female. Methods: A total of 2660 patients with ESCC were pooled in this study. We analyzed clinicopathologic features and clinical prognostic predictors to determine the associations with outcome by sex. We also evaluated the relationship between total cholesterol and overall survival (OS) and further assessed the influence of total cholesterol on OS was affected by other clinicopathologic variables in female cohort. We explore the interacting with gender-specific genes and TC in ESCC by bioinformatics analysis. Findings: Compared with male, female has better overall survival (log-rank P < 0.001; HR, 0.59; 95% CI, 0.51-0.67). In addition, the results confirmed that survival outcome was significantly deteriorated in male patients with low TC level (log-rank P < 0.001; HR, 1.20; 95% CI, 1.03-1.39). Interestingly, our findings, which were based on a female population, suggested a protective role of low TC level in ESCC. In accordance with the gene expression profiles from The Cancer Genome Atlas (TCGA), differential expression genes analysis shown 20 significant differential expression genes were associated with cholesterol metabolism. Subsequently, Gene ontology (GO) analysis shown these genes were mainly enriched in cholesterol transport etc. Interpretation: In our study, we suggest patients with ESCC may benefit from targeted treatments after adjusting TC concentrations based on sex-stratified, in addition to routine cancer therapies. Funding Information: Sichuan Cancer Hospital and Institution of China. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This was a retrospective clinical study and approved by Sichuan Cancer Hospital (SCCHEC-02-2020-015).

A novel DNA repair-related nomogram predicts survival in low-grade gliomas.

AimsWe aimed to create a tumor recurrent‐based prediction model to predict recurrence and survival in patients with low‐grade glioma.MethodsThis study enrolled 291 patients (188 in the training group and 103 in the validation group) with clinicopathological information and transcriptome sequencing data. LASSO‐COX algorithm was applied to shrink predictive factor size and build a predictive recurrent signature. GO, KEGG, and GSVA analyses were performed for function annotations of the recurrent signature. The calibration curves and C‐Index were assessed to evaluate the nomogram's performance.ResultsThis study found that DNA repair functions of tumor cells were significantly enriched in recurrent low‐grade gliomas. A predictive recurrent signature, built by the LASSO‐COX algorithm, was significantly associated with overall survival and progression‐free survival in low‐grade gliomas. Moreover, function annotations analysis of the predictive recurrent signature exhibited that the signature was associated with DNA repair functions. The nomogram, combining the predictive recurrent signature and clinical prognostic predictors, showed powerful prognostic ability in the training and validation groups.ConclusionAn individualized prediction model was created to predict 1‐, 2‐, 3‐, 5‐, and 10‐year survival and recurrent rate of patients with low‐grade glioma, which may serve as a potential tool to guide postoperative individualized care.

The Oncogenic Potential of SUV39H2: A Comprehensive and Perspective View.

Epigenetic modifications at the histone level have attracted significant attention because of their roles in tumorigenesis. Suppressor of variegation 3-9 homolog 2 (SUV39H2, also known as KMT1B) is a member of the SUV39 subfamily of lysine methyltransferases (KMTs) that plays a significant role in histone H3-K9 di-/tri-methylation, transcriptional regulation and cell cycle. Overexpressions of SUV39H2 at gene, mRNA and protein levels are known to be associated with a range of cancers: leukemia, lymphomas, lung cancer, breast cancer, colorectal cancer, gastric cancer, hepatocellular cancer and so on. Accumulating evidence indicates that SUV39H2 acts as an oncogene and contributes to the initiation and progression of cancers. It could, therefore, be a promising target for anti-cancer treatment. In this review, we focus on the dysregulation of SUV39H2 in cancers, including its clinical prognostic predictor role, molecular mechanism involved in cancer occurrence and development, relevant inhibitors against cancer, and its epigenetic modification interaction with immunotherapy. A better understanding of the SUV39H2 will be beneficial to the development of molecular-targeted therapies in cancer.

Increased expression of BPI fold-containing family A member 1 is associated with metastasis and poor prognosis in human colorectal carcinoma.

Bactericidal or permeability-increasing protein fold-containing family A member 1 (BPIFA1) has been demonstrated to be involved in inflammatory responses in the upper airway and the progression of non-small cell lung cancer. However, the expression levels of BPIFA1 and its clinical prognostic significance in colorectal carcinoma (CRC) has not yet been elucidated. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to analyze the expression levels of BPIFA1 in CRC and normal mucosal tissues. The associations between BPIFA1 expression levels and clinicopathological characteristics, and its predictive value for prognosis in CRC, were statistically evaluated as appropriate. The expression levels of BPIFA1 were revealed to be upregulated at the transcriptional and translational levels in CRC tissues, compared with in normal mucosal tissues. A high expression level of BPIFA1 is significantly associated with invasion depth (P=0.040), lymph node metastasis (P=0.035) and distant metastasis (P=0.010). Furthermore, Kaplan-Meier analysis indicated that BIPFA1 overexpression is associated with short survival time, and the Cox proportional hazards model of risk analysis indicated that BPIFA1 is an independent prognostic factor for patients with CRC. The results of the present study suggested that BPIFA1 expression is upregulated in CRC tissues, and that an increased expression level of BPIFA1 is associated with tumor invasion, metastasis and poor prognosis, indicating that BPIFA1 may be a potential clinical prognostic predictor and therapeutic target for patients with CRC.

Sleep convulsive seizures predict lack of remission in genetic generalized epilepsies: A retrospective study from a single epilepsy center in Egypt.

Genetic generalized epilepsies (GGEs) represent 15-20% of all epilepsies. There are no studies on the outcome of GGEs in the Middle East. To investigate the long-term prognosis of GGEs and identify prognostic predictors in Egypt. This is a retrospective cohort study of consecutive children and adults with GGEs seen in an epilepsy clinic in Cairo, Egypt, followed for 10+ years. Follow-up visits were scheduled every 3-6 months or earlier. Demographic and clinical prognostic predictors were collected. Presence and number of seizure types were noted along with the number and doses of drugs. The outcome was defined as 5-year remission (5yrR), relapse, or no remission. The probability of 5yrR was calculated using Kaplan-Meier curves. Prognostic predictors were assessed with Cox proportional models. Included were 120 patients (males, 41.7%), mean age at onset 13.6 years, followed for a mean of 12.5 years (range 10-20). Generalized tonic-clonic seizures were present in 93.3% of cases, followed by myoclonic (65%) and absence seizures (37.5%). 85 cases (70.8%) attained 5yrR (18 of them off-medications) and 59.1% had a relapse. The cumulative probability of starting 5yrR was 6.7%, 30.8%, and 50% at onset, 5 and 10 years. Only absence of sleep seizures was an independent predictor of 5yrR (Hazard ratio, 2.08; 95% CI 1.01-4.33). Our findings are in keeping with others. The negative effects of sleep seizures are not unexpected because further unrecognized seizures might be expected. Prolonged remission of GGEs is high and compatible with treatment discontinuation. Sleep seizures are negative prognostic predictors.

CD5 positivity is an independent adverse prognostic factor in elderly patients with diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Age over 60 years is one of the five parameters of the International Prognostic Index (IPI), which is the most important clinical prognostic predictor in DLBCL. A previous study on German DLBCL patients over 60 years of age showed that immunoblastic morphology, but not germinal center B cell-like (GCB)/non-GCB subtype, correlated with short survival. We collected 174 DLBCL cases over 60 years of age in Taiwan and performed immunophenotyping and detection of Epstein-Barr virus (EBV)-encoded RNA (EBER) by in situ hybridization. Of the cases, 5.2 % were positive for CD5 and 5.7 % positive for EBER. Neither immunoblastic morphology nor GCB/non-GCB subtype correlated with survival. In univariate analysis, adverse prognostic factors included IPI ≥ 3 (P < 0.000001), B symptoms (P = 0.000075), bone marrow/peripheral blood involvement (P = 0.017), EBER positivity (P = 0.0013), and CD5 positivity (P = 0.016). In multivariate analysis, CD5 positivity was the only independent adverse prognostic factor (HR = 3.16; 95 % CI = 1.34-7.47; P = 0.0087) in addition to IPI ≥ 3 (HR = 3.07; 95 % CI = 1.84-5.11; P = 0.000018). Surprisingly, despite an overall 5.2 % incidence of central nervous system (CNS) relapse in our patients, none of the CD5+ cases experienced CNS relapse (P = 1.00). This is in stark contrast to the more frequent CNS relapse in Japanese CD5+ DLBCL patients. EBER positivity was associated with IPI ≥ 3 (P = 0.010), stage III-IV (P = 0.0082), and B symptoms (P = 0.011). In multivariate analysis, EBER positivity was not an independent adverse prognostic factor (P = 0.81), its effect being due likely to accompanying adverse clinical parameters.

Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard

Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. The aims of this study were to describe HCC tumor characteristics and different therapeutic approaches, to evaluate patient survival time from HCC diagnosis, and to identify clinical prognostic predictors in patients with and without HIV infection. A multicenter observational retrospective comparison of 104 HIV-infected patients and 484 uninfected patients was performed in four Italian centers. HCC was staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria. Tumor characteristics of patients with and without HIV were significantly different for age, Eastern Cooperative Oncology Group performance status (PS) score ≤1, and etiology of chronic liver disease. Despite the similar potentially curative option rate and better BCLC stage at diagnosis, the median survival time was significantly shorter in HIV(+) patients. HIV(+) patients were less frequently retreated at relapse. Independent predictors of survival were: BCLC stage, potentially effective HCC therapy, tumor dimension ≤3 cm, HCC diagnosis under a screening program, HCC recurrence, and portal vein thrombosis. Restricting the analysis to HIV(+) patients only, all positive prognostic factors were confirmed together with HAART exposure. This study confirms a significantly shorter survival time in HIV(+) HCC patients. The less aggressive retreatment at recurrence approach does not balance the benefit of younger age and better BCLC stage and PS score of HIV(+) patients. Thus, considering the prognosis of HIV(+) HCC patients, effective screening techniques, programs, and specific management guidelines are urgently needed.

Sex differences in incidence and outcome of chronic lymphocytic leukemia patients

Observational studies have consistently reported a reduced incidence and superior survival for female patients with chronic lymphocytic leukemia (CLL). These results were corroborated by different national cancer database reports and confirmed in recent prospective trials. Whether improved survival for women is attributable to increased comorbidities in men, better response and/or tolerance of therapy in women or an intrinsic difference in the molecular biology of the disease (or a combination thereof) is unknown. It is through prospective trials that evaluate known molecular, genetic and clinical prognostic predictors that one will better understand these differences and determine whether treatment should be tailored to biological clinical profiles or more to sex.

Serum IFN-inducible protein-10: A new clinical prognostic predictor of hepatocyte death in biliary atresia

Purpose : The aim of this study was to determine whether chemokines such as serum IP-10 levels in patients with biliary atresia (BA) correlate with liver function and histology and assess its value as a medium to long-term prediction of prognosis in postoperative BA patients. Methods : Thirty postoperative BA patients (mean age, 10.8 ± 3.5 years) and eight normal controls (mean age, 10.3 ± 3.3 years) were studied. The BA patients were divided into three groups according to liver function. Group I (n = 8) was jaundice free, had normal liver function and no evidence of severe cholangitis or portal hypertension. Group II (n = 12) had moderate liver dysfunction. Group III (n = 10), had severe liver dysfunction. Hepatic histology was assessed using conventional needle biopsy. Serum IP-10 levels were determined using a specific enzyme-linked immunosorbent assay (ELISA). Results : Serum levels of IP-10 in group III (458.0 ± 240.0 pg/mL) were significantly higher than those in group II (233.6 ± 126.9 pg/mL; P < .0001). Levels in group II were also significantly higher than those in group I (144.8 ± 23.4 pg/mL; P < .05), but there was no significant difference between group I and controls (107.9 ± 34.0 pg/mL). Liver biopsy findings showed a progression of fibrosis and mononuclear cell infiltration from group I to group III. There was intimal hyperplasia and swelling of endothelial cells of branches of the hepatic artery in the portal area in group III. Conclusion : Because IP-10 levels correlate closely with histological findings in postoperative BA patients, it would appear to play a specific role in hepatocyte death and hepatic artery changes, thus providing important information about progressive fibrosis in BA patients that facilitates treatment decision making and prediction of prognosis.

A new clinical prognostic predictor for patients with biliary atresia

The excretion of D-glucaric acid (DGA), a metabolite of the cytochrome P-450 pathway, is considered a marker of the viability of hepatocytes. Twelve cases of biliary atresia (BA) have been investigated, correlating the level of DGA, degree of histological alteration of liver parenchyma, and clinical outcome. Urine was collected in the preoperative period. Five patients had good bile flow after the Kasai operation and demonstrated mild liver fibrosis. The urine excretion level of DGA in this group was 17.2 + 3.1 μmol/d (control, 15.2 + 2.2 [67od] mmol/d). Seven patients had partial bile drainage or prolonged jaundice. They also had altered liver parenchyma and a very low level of DGA in the urine preoperatively (4.2 + 2.2 μmol/d). Urine excretion of DGA reflected the degree of alteration of liver parenchyma and closely correlated with clinical outcome. Measurement of DGA before the Kasai operation provides information concerning the present hepatic function and the postoperative prognosis. Once the activity of hepatocytes deteriorates, this test is quicker than the other liver function tests. It is noninvasive and is a useful clinical prognostic predictor in BA.