Prognostic Role of Survivin in Bladder Cancer: A Systematic Review and Meta-Analysis

Purpose

The objective of the present study was to conduct a systematic review and meta-analysis of published literature investigating the survivin expression and its effects on bladder cancer prognosis.

Materials and Methods

We carefully searched online Pubmed, Cochrane Library and SCOPUS database from August 1997 to May 2013.

Results

A total of 14 articles met the eligibility criteria for this systematic review. The eligible studies included a total of 2,165 patients with a median number of 155 patients per study (range: 17–726). Of the 14 studies, nine evaluated immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks. In non-muscle invasive bladder tumor, the pooled hazard ratio (HR) was statistically significant for recurrence-free survival (pooled HR, 1.81; 95% confidence interval [CI], 1.30–2.52), progression-free survival (pooled HR, 2.12; 95% CI, 1.60–2.82), cancer-specific survival (pooled HR, 2.01; 95% CI, 1.32–3.06), and overall survival (pooled HR, 1.53; 95% CI, 1.02–2.29). The overall HRs by survivin status were robust across advanced stages. When only adjusted survival data were included, statistically significant differences were identified for all survival subgroup analyses. There was no between-study heterogeneity in the effect of survivin status on the majority of meta-analyses. There was no clear evidence of publication bias in this meta-analysis.

Conclusions

Survivin expression indicates worse prognosis in patients with bladder cancer but the results should be interpreted with caution. It is necessary that better-designed studies with standardized assays need to provide a better conclusion about the relationship between survivin expression and the outcome of patients with bladder cancer.     

Panobinostat synergizes with zoledronic acid in prostate cancer and multiple myeloma models by increasing ROS and modulating mevalonate and p38-MAPK pathways

Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism.     

Stress and survival after cancer: a prospective study of a Finnish population-based cohort

Stress has been suggested to reduce survival after cancer, but the results of previous studies have been contradictory. We investigated the hypothesis in a national cohort of adults in Finland. Of those who completed the Stressful Life Events scale and the Stress of Daily Activities scale, 1470 and 1882, respectively, later had cancer and were included in the analysis, covering 23 years of follow-up between 1982 and 2004. In Cox regression analysis, the multivariate hazard ratio (HR) was 0.99 (95% confidence interval [CI], 0.96-1.01) for total number of life events and the HR for the life change score was 0.99 (95% CI, 0.95-1.03). Further, the HR was 0.92 (95% CI, 0.69-1.22) for severe daily stress. Overall, the results of the current study do not support the hypothesis that stress reduces cancer survival.     

Serum Vitamin D in Patients with Chronic Obstructive Lung Disease Does Not Correlate with Mortality – Results from a 10-Year Prospective Cohort Study

Background

Recent studies have found vitamin D (25-OHD) deficiency and insufficiency to be common among patients with COPD. Serum level of 25-OHD seems to correlate to pulmonary function, COPD disease staging, and increased susceptibility to respiratory infections. We wanted to investigate whether vitamin D deficiency or insufficiency was associated with mortality rate in patients suffering from advanced COPD.

Methods

25-OHD serum levels were measured in 462 patients suffering from moderate to very severe COPD. Patients were stratified into three groups according to serum levels of 25-OHD. Outcome measure was mortality in a 10 year follow-up period. Kaplan-Meier curves (KM) were plotted and mortality hazard ratios (HR) were calculated using Cox Proportional Hazard regression (Cox PH).

Results

Serum 25-OHD deficiency and insufficiency were prevalent. We were unable to demonstrate any association between baseline serum levels of 25-OHD and mortality rate. We found an association between mortality and age [HR 1.05 (CI 95%: 1.03–1.06)], Charlson score [HR 1.49 (CI 95%: 1.06–2.09)], increasing neutrophil count [HR 1.05 (CI 95%: 1.02–1.09)], severe [HR 1.41 (CI 95%: 1.06–1.86)]/very severe COPD [HR 2.19 (CI 95%: 1.58–3.02)] and a smoking history of more than 40 pack years [HR 1.27 (CI 95%: 1.02–1.70)].

Conclusions

Serum level of 25-OHD does not seem to be associated with mortality rate, suggesting no or only a minor role of 25-OHD in disease progression in patients with moderate to very severe COPD.     

Lymphatic microvessel density and vascular endothelial growth factor-C and -D as prognostic factors in breast cancer: a systematic review and meta-analysis of the literature

The use of lymphatic microvessel density (LVD) and pro-lymphangiogenic mediators as prognostic factors for survival in breast cancer remains controversial. We searched the electronic databases PubMed and EMBASE without language restrictions for relevant literature to aggregate the survival results. To be eligible, every study had to include the assessment of the LVD or the expression of vascular endothelial growth factor (VEGF)-C or -D in patients with breast cancer and provide a survival comparison, including disease-free survival (DFS) or overall survival (OS), according to the LVD, VEGF-C or VEGF-D status. Across all studies, 56.64?% of patients were considered to have a VEGF-C-positive tumor, and 65.54?% of patients had VEGF-D-positive tumors. High LVD had an unfavorable impact on DFS, with a pooled hazard ratio (HR) of 2.222 (95?% CI 1.579–3.126) and an OS with a HR of 2.493 (95?% CI 1.183–5.25). According to the different lymphatic makers, the subgroup HR in the D2-40 studies was 2.431 (95?%?CI 1.622–3.644) for DFS and 4.085 (95?% CI 1.896–8.799) for OS. VEGF-C overexpression, as assessed by immunochemistry, was a prognostic factor for decreased DFS (HR 2.164; 95?% CI 1.256–3.729) and for decreased OS (HR 2.613; 95?% CI 1.637–4.170). VEGF-D overexpression was a significant although weak prognostic factor for DFS only when assessed by immunochemistry, with a HR of 2.108 (95?% CI 1.014–4.384). Our meta-analysis demonstrated that LVD, VEGF-C and VEGF-D could predict poor prognosis in patients with breast cancer. However, standardization of the assessment of LVD and for the expression of lymphangiogenesis factors is needed.     

Diagnostic and prognostic value of circulating miR-21 for cancer: A systematic review and meta-analysis

Background

MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with cancer. Many studies have shown that circulating miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the role of circulating miR-21 as a biomarker in patients with a variety of carcinomas.

Material and methods

Eligible studies were identified and assessed for quality through multiple search strategies. For diagnostic meta-analysis, the sensitivity, specificity, and other measures of miR-21 in the diagnosis of cancer were pooled using bivariate random-effects approach models. For prognostic meta-analysis, pooled hazard ratios (HRs) of circulating miR-21 for survival were calculated.

Results

A total of 36 studies dealing with various carcinomas were included for the systemic review. Among them, 23 studies were finally enrolled in the global meta-analysis (17 studies for diagnosis and 6 studies for prognosis). For diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, positive likelihood ratio (LRP), negative likelihood ratios (LRN) and diagnostic odds ratio (DOR) were 75.7% (95% CI: 67.1%–82.6%), 79.3% (95% CI: 74.2%–83.5%), 3.65 (95% CI: 2.83–4.70), 0.31 (95% CI: 0.22–0.43), and 11.88 (95% CI: 6.99–20.19), respectively. For prognostic meta-analysis, the pooled HR of higher miR-21 expression in circulation was 2.37 (95% CI: 1.83–3.06, P < 0.001), which could significantly predict poorer survival in general carcinomas. Importantly, subgroup analysis suggested that higher expression of miR-21 correlated with worse overall survival (OS) significantly in carcinomas of digestion system (HR, 5.77 [95% CI: 2.65–12.52]).

Conclusions

Our findings suggest that circulating miR-21 may not suitable to be a diagnostic biomarker, but it has a prognostic value in patients with cancer.     

ACUTE PHASE REACTIONS AFTER ZOLEDRONIC ACID INFUSION: PROTECTIVE ROLE OF 25-HYDROXYVITAMIN D AND PREVIOUS ORAL BISPHOSPHONATE THERAPY

Objective: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naïve patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naïve patients and to investigate the role of 25(OH)D for the time of APR onset.Methods: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded.Results: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, P = .08).Conclusion: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort.Abbreviations: APR = acute phase reaction; BPs = amino-bisphosphonates; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; OP = osteoporosis; OR = odds ratio; PTH = parathyroid hormone; ROC = receiver operating characteristic; ZOL = zoledronic acid     

Impact of Bisphosphonate-related Osteonecrosis of the Jaw on Osteoporotic Patients after Dental Extraction: A Population-Based Cohort Study

Background and Aims

Little is currently known about the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study sought to determine the incidence of BRONJ in osteoporotic patients. We also sought to identify the nature and types of risk factors of osteonecrosis of jaw (ONJ) related to the use of oral bisphosphonates (BPs).

Materials and Methods

Data from the National Health Insurance system of Taiwan. This cohort study included 19,399 adult osteoporosis patients received dental extraction in 2000-2010 (osteoporosis cohort) and 38,669 age and gender matched comparisons selected from dental extraction people without osteoporosis and osteonecrosis history (comparison cohort). All study subjects were followed from the date of their dental extraction (index date) to the development of ONJ and were included in the study up to 2011 or were lost to the study, whichever occurred first. Cox proportional hazard regression was used to estimate the hazard ratio and 95% confidence intervals for the two cohorts.

Results

Patients with osteoporosis had a significantly higher risk to develop ONJ than healthy persons (adjusted HR, 2.05; 95% confidence interval, 1.58–2.65). The risk of ONJ increased with the severity of osteoporosis, no matter whether patient with cancer or not. A cumulative effect of dental extraction frequency may increase the risk of ONJ.

Conclusions

We concluded that ONJ is caused by a number of factors. Osteoporosis and past dental history play the very important roles, while BPs play the synergistic effect.     

Prognostic Significance of the Metabolic Marker Hexokinase-2 in Various Solid Tumors: A Meta-Analysis

ObjectiveRecently, numerous studies have reported that hexokinase-2 (HK2) is aberrantly expressed in cancer, indicating that HK2 plays a pivotal role in the development and progression of cancer. However, its prognostic significance in solid tumor remains unclear. Accordingly, we performed a meta-analysis to assess the prognostic value of HK2 in solid tumor.MethodsEligible studies were identified using PubMed, Embase, and Web of Science databases. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) or progression-free survival (PFS)/disease-free survival (DFS)/relapse-free survival (RFS) were estimated with random effects or fixed effects models, respectively. Subgroup analysis was also performed according to patients’ ethnicities, tumor types, detection methods, and analysis types.ResultsData from 21 included studies with 2532 patients were summarized. HK2 overexpression was significantly associated with worse OS (pooled HR = 1.90, 95% CI = 1.51–2.38, p < 0.001) and PFS (pooled HR = 2.91, 95% CI = 2.02–4.22, p < 0.001) in solid tumor. As to a specific form of cancer, the negative effect of HK2 on OS was observed in hepatocellular carcinoma (pooled HR = 2.06, 95% CI = 1.67–2.54, p < 0.001), gastric cancer (pooled HR = 1.72, 95% CI = 1.09–2.71, p = 0.020), colorectal cancer (pooled HR = 2.89, 95% CI = 1.62–5.16, p < 0.001), but not in pancreatic cancer (pooled HR = 1.13, 95% CI = 0.28–4.66, p = 0.864). No publication bias was found in the included studies for OS (Begg’s test, p = 0.325; Egger’s test, p = 0.441).ConclusionIn this meta-analysis, we identified that elevated HK2 expression was significantly associated with shorter OS and PFS in patients with solid tumor, but the association varies according to cancer type.     

Relationship Between the Use of Statins and Patient Survival in Colorectal Cancer: A Systematic Review and Meta-Analysis

Background

Studies have indicated that statins influence the risks and mortality rates of several types of solid tumors. However, the association between statin use and survival in patients with colorectal cancer (CRC) remains unclear.

Methods

We searched the PubMed and Embase databases for relevant studies published up to September 2014 that assessed statin use and CRC prognosis. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). The secondary outcomes were disease-free survival (DFS) and recurrence-free survival (RFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled with Mantel–Haenszel random-effect modeling. All statistical tests were two-sided.

Results

Four studies on post-diagnosis statin therapy and five studies on pre-diagnosis statin use were included in our meta-analysis of 70,608 patients. Compared with the non-users, the patients with post-diagnosis statin use gained survival benefits for OS (HR 0.76; 95% CI: 0.68 to 0.85, P<0.001) and CSS (HR 0.70; 95% CI: 0.60 to 0.81, P<0.001). In addition, we observed that pre-diagnosis statin use prolonged the survival of patients with CRC for OS (HR 0.70; 95% CI: 0.54 to 0.91, P=0.007) and CSS (HR 0.80; 95% CI: 0.74 to 0.86, P<0.001). However, we did not observe a survival benefit for DFS (HR 1.13; 95% CI: 0.78 to 1.62, P=0.514) or RFS (HR 0.98; 95% CI: 0.36 to 2.70, P=0.975) in the CRC patients with post-diagnosis statin use.

Conclusions

Statin use before or after cancer diagnosis is related to reductions in overall and cancer-specific mortality in colorectal cancer survivors.     

Pre-treatment prognostic nutritional index may serve as a potential biomarker in urinary cancers: a systematic review and meta-analysis

Background

To investigate the potential prognostic role of pre-treatment prognostic nutritional index (PNI) in urinary cancers.

Methods

Relevant articles were searched comprehensively from PubMed, Embase and Web of Science, up to November 2018. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to evaluate their associations.

Result

A total of 12 related articles including 6561 patients were ultimately enrolled. Our results indicated that a relatively lower level of pre-treatment PNI was associated with decreased OS, CSS/DSS and DFS/RFS/PFS (pooled HR?=?1.68, 95% CI 1.45–1.95; pooled HR?=?1.57, 95% CI 1.33–1.86; pooled HR?=?1.75, 95% CI 1.53–1.99, respectively). Subsequent stratified analysis by cancer type for OS showed that PNI could also be a predictor no matter in renal cell cancer (RCC) or bladder cancer (BC) (pooled HR?=?1.65, 95% CI 1.37–1.97 and pooled HR?=?1.67, 95% CI 1.20–2.33). Similar results could be found in DFS/RFS/PFS (RCC: HR?=?1.81, 95% CI 1.54–2.13 and BC: HR?=?1.68, 95% CI 1.32–2.12) and in CSS/DSS (RCC: HR?=?1.50, 95% CI 1.23–1.82 and upper tract urothelial carcinoma: HR?=?1.61, 95% CI 1.13–2.28). As for the treatment subgroup, a relatively lower level of PNI could also be a positive predictor for OS (surgery: HR?=?1.64, 95% CI 1.40–1.93; target therapy: HR?=?1.88, 95% CI 1.34–2.63) and DFS/RFS/PFS (surgery: HR?=?1.69, 95% CI 1.47–1.95; target therapy: HR?=?2.14, 95% CI 1.50–3.05).

Conclusion

The outcomes of us shed light on that elevated pre-treatment PNI was positively associated with OS, CSS/DSS and DFS/RFS/PFS, indicating that it could be an independent prognostic factor in urinary cancers.

     

The impact of rheumatological disorders on lymphomas and myeloma: a report on risk and survival from the UK’s population-based Haematological Malignancy Research Network

BackgroundAutoimmune inflammatory disease increases the risk of diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), but findings for other mature B-cell malignancies are equivocal. Furthermore, it has been suggested that the increase in DLBCL is due to the activated B-cell (ABC) subtype; but data on this, and the impact of inflammatory co-morbidities on survival, are sparse and contradictory.MethodsData are from an established UK population-based cohort. Patients (n = 6834) diagnosed between 01/2009 and 08/2015 are included; DLBCL (n = 1771), myeloma (n = 1760), chronic lymphocytic leukaemia (CLL, n = 1580), MZL (n = 936), and follicular lymphoma (FL, n = 787). Information on rheumatological disorders and deaths was obtained by record-linkage to nationally compiled Hospital Episode Statistics, with age-and sex-matched individuals (n = 68,340) from the same catchment population (˜4 million people) providing the comparator.ResultsSignificantly increased risks for DLBCL (OR = 2.3, 95% CI 1.8–2.8) and MZL (OR = 2.0, 95% CI 1.5–2.7) were found for those with rheumatological disorders; the site distribution of those with/without rheumatological conditions differing for DLBCL (p = 0.007) and MZL (p = 0.002). No increases in risk were observed for the remaining mature B-cell malignancies, and no associations with survival were detected for DLBCL (age-adjusted HR = 1.2, 95% CI 0.9–1.6) or MZL (age-adjusted HR = 1.0, 95% CI 0.6–1.9). Furthermore, whilst our findings provide evidence for an association with rheumatological disease severity for DLBCL, they offer little support for the notion that the association is driven by an increase in the incidence of the ABC subtype.ConclusionOur findings support the hypothesis that the chronic activation and proliferation of specific B-cell populations which characterize autoimmune disease increase the potential for the lymphomagenic events that lead to DLBCL and MZL in both males and females; but have no impact on the development of CLL, FL or MM, or on survival.     

A systematic review and meta-analysis of higher expression of folate receptor alpha (FOLR1) predicts poor cancer prognosis

Abstract

Folate receptor alpha (FOLR1), a glycosylphosphatidylinositol-linked protein, is a well characterized folate transporter. However, the prognostic power of FOLR1 in cancer remains controversial. We conducted a meta-analysis to assess the prognostic roles of FOLR1 on different cancers. Twelve studies involving 4471 patients were included in this meta-analysis. The pooled analysis indicated that high FOLR1 significantly predicted poor overall survival (OS) (pooled hazard ratio (HR)?=?0.78, 95% confidence interval (CI)?=?0.64–0.94, p?=?0.009) and the disease-free survival (DFS) (HR?=?1.25, 95% CI?=?1.07–1.47, p?=?0.005). Subgroup analyses based on tumour type found that high FOLR1 level was associated with poor OS in breast cancer (HR?=?2.66, 95% CI?=?1.54–4.59, p?=?0.0005) and endometrial carcinoma (HR?=?1.30, 95% CI?=?1.05–1.61, p?=?0.02). However, FOLR1 has relatively weakly correlation with gender, tumour size and chemotherapy. Additionally, overexpression of FOLR1 was correlated with grade, FIGO stage, vital status and nodule status. The present meta-analysis indicated that the high expression of FOLR1 is associated with the poor survival of cancer patients, which is helpful for the clinical decision-making process.     

Clinicopathological and prognostic value of lncRNA PANDAR expression in solid tumors: Evidence from a systematic review and meta-analysis

PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76–3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25–6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11–2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17–3.44 and pooled HR 2.62; 95% CI, 1.98–3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.     

The role of pretreatment prognostic nutritional index in esophageal cancer: A meta-analysis

Clinicopathological characteristics and prognosis of esophageal cancer (EC) patients with decreased prognostic nutritional index (PNI) have not been well investigated. So, we conducted this meta-analysis. We performed comprehensive research in PubMed, Embase, and Cochrane databases. The effect size was hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS) and cancer-specific survival (CSS). The pooled odds ratio (OR) with 95% CI were used to assess the association between PNI and clinicopathological features. A total of 3,425 EC patients were included in the present meta-analysis. Male patients, advanced age, higher tumor stage, and lymph node metastases were associated with reduced PNI level (OR = 1.40, 95% CI: 1.10-1.79; OR = 1.35, 95% CI: 1.10-1.66; OR = 2.37, 95% CI: 1.91-2.94; OR = 1.63, 95% CI: 1.04-2.56). And, the EC patients with decreased PNI held a worse OS and CSS compared with those who carried a higher PNI (HR = 1.29, 95% CI: 1.10-1.50; HR = 2.53, 95% CI: 1.15-5.57). This meta-analysis demonstrated PNI level was associated with tumor stage and lymph nodes metastases and was an independent prognostic factor in EC.     

The Prognostic Value of Epigenetic Silencing of p16 Gene in NSCLC Patients: A Systematic Review and Meta-Analysis

Background

The prognostic significance of p16 promoter hypermethylation in patients with non-small cell lung cancer (NSCLC) is still controversial. This analysis presents pooled estimates of the association to better elucidate whether p16 methylation has a prognostic role in NSCLC.

Methods

Relevant studies were identified by searching PubMed, Embase and Web of Science databases until June 2012. The association of p16 methylation with both overall survival (OS) and disease-free survival (DFS) was preformed. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses, sensitivity analysis and publication bias were also conducted.

Results

A total of 18 studies containing 2432 patients met the inclusion criteria and had sufficient survival data for quantitative aggregation. The results showed that p16 methylation was an indicator of poor prognosis in NSCLC. The HR was 1.36 (95% CI: 1.08–1.73, I² = 56.7%) and 1.68 (95% CI: 1.12–2.52, I² = 38.7%) for OS and DFS, respectively. Subgroup analyses were carried out. The HRs of fresh and paraffin tissue were 1.50 (95% CI: 1.11–2.01) and 1.10 (95% CI: 0.77–1.57). The pooled HR was 1.40 (95% CI: 1.02–1.92) for methylation-specific PCR (MSP) and 1.26 (95% CI: 0.87–1.82) for quantitative MSP (Q-MSP). The combined HR of the 16 studies reporting NSCLC as a whole indicated that patients with p16 hypermethylation had poor prognosis. No significant association was found when adenocarcinoma subtype pooled. When seven studies on DFS were aggregated, the HR was 1.68 (95% CI: 1.12–2.52) without significant heterogeneity. Moreover, no obvious publication bias was detected on both OS and DFS.

Conclusion

The meta-analysis findings support the hypothesis that p16 methylation is associated with OS and DFS in NSCLC patients. Large well-designed prospective studies are now needed to confirm the clinical utility of p16 methylation as an independent prognostic marker.     

Prognostic Value of miR-21 in Various Cancers: An Updating Meta-Analysis

Background

Recently, more and more studies investigated the value of microRNA (miRNA) as a diagnostic or prognostic biomarker in various cancers. MiR-21 was found dysregulated in almost all types of cancers. While the prognostic role of miR-21 in many cancers has been studied, the results were not consistent.

Methods

We performed a meta-analysis to investigate the correlation between miR-21 and survival of general cancers by calculating pooled hazard ratios (HR) and 95% confidence intervals (CI).

Results

The pooled results of 63 published studies showed that elevated miR-21 was a predictor for poor survival of general carcinomas, with pooled HR of 1.91 (95%CI: 1.66–2.19) for OS, 1.42 (95% CI: 1.16–1.74) for DFS and 2.2 (95% CI: 1.64–2.96) for RFS/CSS. MiR-21 was also a prognostic biomarker in the patients who received adjuvant therapy, with pooled HR of 2.4 (95%CI: 1.18–4.9) for OS.

Conclusions

Our results showed that miR-21 could act as a significant biomarker in the prognosis of various cancers. Further studies are warranted before the application of the useful biomarker in the clinical.     

Association of T174M polymorphism of angiotensinogen gene with essential hypertension: A meta-analysis

The association between T174M polymorphism of angiotensinogen gene and essential hypertension risk remains controversial. We herein performed a meta-analysis to achieve a reliable estimation of their relationship. All the studies published up to May 2013 on the association between T174M polymorphism and essential hypertension risk were identified by searching the electronic repositories PubMed, MEDLINE and EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Ultimately, nine eligible studies, including 2188 essential hypertension cases and 2459 controls, were enrolled in this meta-analysis. No significant associations were found under the overall ORs for M-allele comparison (M vs. T, pooled OR 0.92, 95% CI 0.62–1.37), MM vs. TT (pooled OR 0.86, 95% CI 0.29–2.51), TM vs. TT n (pooled OR 0.91, 95% CI 0.63–1.32), recessive model (MM vs. TT+TM, pooled OR 0.89, 95% CI 0.35–2.30), dominant model (MM+TM vs. TT, pooled OR 0.91, 95% CI 0.60–1.38) between T174M polymorphism and risk for essential hypertension. This meta-analysis suggested that the T174M polymorphism of the angiotensinogen gene might not be associated with the susceptibility of essential hypertension in Asian or European populations.     

Accelerated Partial Breast Irradiation for Breast Cancer: A Meta-Analysis

To evaluate the long-term effect of breast conservation with accelerated partial breast irradiation (APBI) for early-stage breast cancer, PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journals Full-text Database, and China Journal Full-text Database were searched to identify relevant original published trials. Randomized controlled trials in any language comparing APBI with whole-breast radiotherapy in patients with early-stage breast cancer were included. RevMan 5 software was used for statistical analysis. Four trials involving 919 patients were included. The rate of 5- and 7-year excellent/good cosmetic results was significant {odds ratio (OR) = 2.09 [95% confidence interval (CI) = 1.21–3.62]} between two groups. The 5- and 8-year overall survival had no significant difference [OR = 1.76 (95% CI = 0.67–4.62) and OR = 0.86 (95% CI = 0.44–1.66)]. The 10-year overall survival had significant differences [OR = 0.56 (95% CI = 0.35–0.91)]. There were no differences in the 5-year local recurrence (LR)-free survival [OR = 0.65 (95% CI = 0.18–2.34)], cancer-specific survival [OR = 1.67 (95% CI = 0.39–7.12)], disease-free survival [OR = 0.84 (95% CI = 0.38–1.84)], LR [OR = 1.36 (95% CI = 0.46–3.99)], the rate of contralateral breast cancer [OR = 2.82 (95% CI = 0.73–10.89)], and distant metastasis [OR = 0.71 (95% CI = 0.22–2.31)]. APBI significantly improved the rate of excellent/good cosmetic results anywhere in the breast, shortened the treatment time, alleviated the pain, and improved the quality of life. Future large-scale, high-quality, and double-blind trials are needed.     

Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data

This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression‐free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first‐line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28 days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted = 0.79 [0.65–0.96]; drug withdrawn = 1.18 [0.71–1.96]; p = 0.032), PFS (HR [95% CI]: dose reduced/interrupted = 0.82 [0.67–0.99]; drug withdrawn = 1.58 [0.97–2.58]; p = 0.017) and objective response (odds ratio (OR) [95% CI]: dose reduced/interrupted = 1.35 [0.99–1.85]; drug withdrawn = 0.17 [0.06–0.43]; p = <0.001). Arthralgia occurring within the first 28 days of vemurafenib or vemurafenib plus cobimetinib therapy was also significantly associated with favourable OS (p = 0.026), PFS (p = 0.042) and objective response (p = 0.047).