Using microRNA profiling in urine samples to develop a non‐invasive test for bladder cancer

Current standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC) are invasive or have low sensitivity. The incorporation into clinical practice of a non‐invasive tool for UCC assessment would enormously improve patients' quality of life and outcome. This study aimed to examine the microRNA (miRNA) expression profiles in urines of UCC patients in order to develop a non‐invasive accurate and reliable tool to diagnose and provide information on the aggressiveness of the tumor. We performed a global miRNA expression profiling analysis of the urinary cells from 40 UCC patients and controls using TaqMan® Human MicroRNA Array followed by validation of 22 selected potentially diagnostic and prognostic miRNAs in a separate cohort of 277 samples using a miRCURY LNA? qPCR system. miRNA‐based signatures were developed by multivariate logistic regression analysis and internally cross‐validated. In the initial cohort of patients, we identified 40 and 30 aberrantly expressed miRNA in UCC compared with control urines and in high compared with low grade tumors, respectively. Quantification of 22 key miRNAs in an independent cohort resulted in the identification of a six miRNA diagnostic signature with a sensitivity of 84.8% and specificity of 86.5% (AUC = 0.92) and a two miRNA prognostic model with a sensitivity of 84.95% and a specificity of 74.14% (AUC = 0.83). Internal cross‐validation analysis confirmed the accuracy rates of both models, reinforcing the strength of our findings. Although the data needs to be externally validated, miRNA analysis in urine appears to be a valuable tool for the non‐invasive assessment of UCC.     

A comparison of EBV serology and serum cell-free DNA as screening tools for nasopharyngeal cancer: Results of the Singapore NPC screening cohort

We aimed to evaluate the effectiveness of nasopharyngeal cancer (NPC) screening by comprehensive clinical follow-up and adjunctive Epstein–Barr virus (EBV) testing. In a prospective cohort study, 524 individuals with a first-degree family history of NPC were recruited at a university clinical center in Singapore. The cohort was evaluated at baseline and at 6 monthly intervals, with a complete head and neck examination including nasopharyngeal endoscopy. Blood was taken at baseline and at yearly intervals for EBV Viral Capsid Antigen (VCA) IgA, EBV Early Antigen (EA) IgA serology and serum cell-free EBV DNA. Nasopharyngeal biopsy was performed when any irregularity in the nasopharynx was observed, or when EBV markers were elevated. The mean duration of follow-up was 57.7 months, with an average of 8.6 clinical visits per participant. Five participants (0.96%) were identified to have NPC, giving a prevalence of 199 per 100,000 person-years of screening. Four of the five NPC cases identified had asymptomatic T1 disease, at an earlier stage compared to NPC patients diagnosed in the clinic during the same time period (p = 0.0297). All NPC cases identified had elevated EBV-EA IgA titers ≥1:10, with a specificity of 94.6% and a positive predictive value of 15.2%, outperforming EBV-VCA IgA and serum EBV DNA. Two NPC cases were biopsied only because of elevated EBV serology titers, with increasing EBV-EA IgA titers preceding the diagnosis of NPC. In conclusion, screening for NPC is effective in identifying early-stage disease. Adjunctive EBV-EA IgA testing improved the effectiveness of screening.     

Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker

BACKGROUND:

Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell‐free DNA.

METHODS:

Preoperative serum samples from 200 consecutive patients with sporadic, solid renal tumors were analyzed (157 patients with RCC and 43 patients with benign renal tumors). Quantitative real‐time polymerase chain reaction was used to assess total cell‐free DNA (ring finger protein 185 [RNF185]) and CpG island methylation of Ras association domain family member 1A (RASSF1A) von Hippel‐Lindau (VHL), prostaglandin‐endoperoxidase synthase 2 (PTGS2), and P16 (cyclin‐dependent kinase inhibitor 2A). Associations with RCC, pathologic variables, and disease‐specific survival were evaluated.

RESULTS:

Total cell‐free DNA levels and CpG island methylation of RASSF1A and VHL were highly diagnostic for RCC with an area under the receiver operating characteristic curve of 0.755, 0.705, and 0.694, respectively. VHL methylation was detected more frequently in patients with clear cell RCC than in those with other subtypes (P = .007). Total cell‐free DNA levels were higher in patients with metastatic RCC (P < .001) and necrotic RCC (P = .003) and were associated with poorer disease‐specific survival (P < .001). In multivariate analysis, the tumor stage, size, grade, and necrosis (SSIGN) score (P < .001) and categorized total cell‐free DNA levels (P = .028) were retained as independent prognostic factors.

CONCLUSIONS:

The current results indicated that cell‐free DNA represents a novel serum‐based diagnostic and prognostic biomarker for RCC. Total serum cell‐free DNA levels and CpG island methylation of RASSF1A and VHL may be useful diagnostic biomarkers for RCC. VHL methylation of cell‐free DNA is suggestive of clear cell RCC. Total serum cell‐free DNA may be a useful prognostic biomarker that may assist in tailoring postoperative surveillance and therapy. External prospective validation of these data will be required. Cancer 2012;. © 2011 American Cancer Society.     

Staging investigations for oesophageal cancer: a meta-analysis

The aim of the study was to compare the diagnostic performance of endoscopic ultrasonography (EUS), computed tomography (CT), and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in staging of oesophageal cancer. PubMed was searched to identify English-language articles published before January 2006 and reporting on diagnostic performance of EUS, CT, and/or FDG-PET in oesophageal cancer patients. Articles were included if absolute numbers of true-positive, false-negative, false-positive, and true-negative test results were available or derivable for regional, celiac, and abdominal lymph node metastases and/or distant metastases. Sensitivities and specificities were pooled using a random effects model. Summary receiver operating characteristic analysis was performed to study potential effects of study and patient characteristics. Random effects pooled sensitivities of EUS, CT, and FDG-PET for regional lymph node metastases were 0.80 (95% confidence interval 0.75-0.84), 0.50 (0.41-0.60), and 0.57 (0.43-0.70), respectively, and specificities were 0.70 (0.65-0.75), 0.83 (0.77-0.89), and 0.85 (0.76-0.95), respectively. Diagnostic performance did not differ significantly across these tests. For detection of celiac lymph node metastases by EUS, sensitivity and specificity were 0.85 (0.72-0.99) and 0.96 (0.92-1.00), respectively. For abdominal lymph node metastases by CT, these values were 0.42 (0.29-0.54) and 0.93 (0.86-1.00), respectively. For distant metastases, sensitivity and specificity were 0.71 (0.62-0.79) and 0.93 (0.89-0.97) for FDG-PET and 0.52 (0.33-0.71) and 0.91 (0.86-0.96) for CT, respectively. Diagnostic performance of FDG-PET for distant metastases was significantly higher than that of CT, which was not significantly affected by study and patient characteristics. The results suggest that EUS, CT, and FDG-PET each play a distinctive role in the detection of metastases in oesophageal cancer patients. For the detection of regional lymph node metastases, EUS is most sensitive, whereas CT and FDG-PET are more specific tests. For the evaluation of distant metastases, FDG-PET has probably a higher sensitivity than CT. Its combined use could however be of clinical value, with FDG-PET detecting possible metastases and CT confirming or excluding their presence and precisely determining the location(s).     

The association between physical activity and bladder cancer: systematic review and meta-analysis

Background:

Physical activity may protect against bladder cancer through several biologic pathways, such as enhanced immune function and decreased chronic inflammation. Physical activity may also indirectly prevent bladder cancer by reducing obesity. A sizeable number of epidemiologic studies have examined the association between physical activity and bladder cancer, but the available evidence has not yet been formally summarised using meta-analysis.

Methods:

We performed a systematic literature review and meta-analysis of English-language studies published from January 1975 through November 2013. We followed the PRISMA guidelines and used a random effects model to estimate the summary risk estimates for the association between physical activity and bladder cancer.

Results:

A total of 15 studies with 5 402 369 subjects and 27 784 bladder cancer cases were included. High vs low levels of physical activity were related to decreased bladder cancer risk (summary relative risk (RR)=0.85, 95% confidence interval (CI)=0.74–0.98; I²=83% P-value for heterogeneity across all studies<0.001). Results were similar for cohort studies (RR=0.89, 95% CI=0.80–1.00; I²=64%) and case–control studies (RR=0.71, 95% CI=0.43–1.16; I²=87% P-value for difference=0.108) and they were comparable for women (RR=0.83, 95% CI=0.73–0.94; I²=0%) and men (RR=0.92, 95% CI=0.82–1.05; I²=67; P-value for difference=0.657). Findings were also comparable for recreational (RR=0.81, 95% CI=0.66–0.99; I²=77%) and occupational physical activity (RR=0.90, 95% CI=0.76–1.0; I²=76% P-value for difference=0.374), and they were largely consistent for moderate (RR=0.85, 95% CI=0.75–0.98; I²=76%) and vigorous activity (RR=0.80, 95% CI=0.64–1.00;I²=87% P-value for difference=0.535).

Conclusions:

Physical activity is associated with decreased risk of bladder cancer. Further studies are required to assess the relations of intensity, frequency, duration, and timing in life of physical activity to bladder cancer risk.     

Circulating cell-free DNA in serum as a biomarker for diagnosis and prognostic prediction of colorectal cancer

Background:

To verify whether the concentrations and integrity index of circulating cell-free DNA (ccf-DNA) in serum may be clinically useful for the diagnosis and progression monitoring of colorectal cancer (CRC) patients.

Methods:

Serum samples were collected from 104 with primary CRC, 85 with operated CRC, 16 with recurrent/metastatic CRC, 63 patients with intestinal polyps and 110 normal controls. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats (ALU-qPCR). Serum carcinoembryonic antigen (CEA) level was detected by ARCHITECT assay.

Results:

The median absolute serum ALU115 and ALU247/115 in primary CRC group was significantly higher than those in intestinal polyp and normal control groups (both P<0.0001), in recurrent/metastatic CRC was significantly higher compared with primary CRC (P=0.0021, P=0.0018) or operated CRC (P<0.0001, respectively) and during follow-up, ALU115 and ALU247/115 were increased before surgery and decreased significantly after surgery.

Conclusions:

Combined detection of ALU115, ALU247/115 and CEA could improve the diagnostic efficiency for CRC. Serum DNA concentrations and integrity index may be valuable in early complementary diagnosis and monitoring of progression and prognosis of CRC.     

Breast cancer diagnosis by scintimammography: a meta-analysis and review of the literature

Scintimammography is a relatively new, non-invasive diagnostic modality in the evaluation of breast cancer. The purpose of the current study was to review the existing literature on the accuracy of scintimammography in the diagnosis of breast cancer. A search of all articles published between 1st January 1967 and 31st December 1999 was conducted. A total of 64 unique studies were selected. Each scientific paper was reviewed for scientific merit by an epidemiologist, a surgeon and a surgical resident. Assessment of scientific merit was based on a scoring scheme developed for the study. The articles included in this review reported data on a total of 5340 patients assessed for breast cancer with scintimammography. The aggregated summary estimates on these patients were sensitivity: 85.2% and specificity: 86.6%. For patients with a palpable mass the sensitivity and specificity were 87.8 and 87.5%, respectively. For patients without a palpable mass the sensitivity was 66.8% and that for specificity was 86.9%. The results of this review have shown that scintimammography may be used effectively as an adjunct to mammography and physical examination in the diagnosis of breast cancer.     

Diagnostic value of lncRNAs as potential biomarkers for oral squamous cell carcinoma diagnosis: a meta-analysis

Objective Several studies have revealed the critical role of long non-coding RNAs (lncRNAs) as biomarkers for diagnosing oral squamous cell carcinoma (OSCC). However, the data remain inconsistent. This meta-analysis was performed to summarize the potential of lncRNAs as OSCC biomarkers. Methods We searched PubMed, Cochrane Library, Web of Science, and China National Knowledge Infrastructure databases for literature published until December 10, 2020. Study quality was assessed using Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, and other measures regarding lncRNAs for OSCC diagnosis were pooled using bivariate meta-analysis models. Data analyses were performed using STATA 14.0. Results Overall, 8 studies with 981 cases and 585 controls were included in the pooled analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the receiver operating characteristic curve values were as follows: 0.76 [95％ confidence interval (CI), 0.65–0.84], 0.90 (95％ CI, 0.82–0.95), 7.5 (95％ CI, 4.20–13.40), 0.27 (95％ CI, 0.18–0.39), 28 (95％ CI, 13.00–58.00), 0.90 (95％ CI, 0.87–0.93), respectively. Deeks' funnel plot asymmetry test (P = 0.56) indicated no potential publication bias. Conclusion Our meta-analytical evidence suggests that lncRNAs could be employed as a potential non-invasive diagnostic tool for OSCC.     

Potential of urinary biomarkers in early bladder cancer diagnosis

Carcinoma of urinary bladder ranks among the top ten most common cancers worldwide. Approximately 80% of the disease is superficial (limited to mucosa and lamina propria) at the time of presentation. However, the majority of these tumors recur and 15–20% progress into muscle-invasive disease. Cystoscopic surveillance of the urinary bladder remains the standard of care to identify these recurrences on follow-up. Not only is this an invasive procedure, but the sensitivity of cystoscopy can be as low as 70%, so there can be up to 30% of tumors that are missed. Urinary cytology, with recognized limitations, has been used as an adjunct to this procedure, pending discovery of alternate urinary biomarkers. In the past decade there has been tremendous advancement in producing urinary biomarkers for urinary bladder cancer research, reflecting advancements in genomics and proteomics. An ideal biomarker should be able to replace cystoscopic examination and be cost effective. Unfortunately, most of the identified protein or molecular biomarkers have failed this test. This article critically appraises the status of these urinary biomarkers in urinary bladder cancer, in addition to highlighting some of the difficulties in this research area.     

P53 as a prognostic marker for bladder cancer: a meta-analysis and review

BACKGROUND: P53 is the most widely investigated molecular marker in bladder cancer. We aimed to review comprehensively the evidence for use of changes in P53 to predict bladder-cancer recurrence, progression, and mortality. METHODS: We reviewed 168 publications from 117 studies. Estimates of significance were extracted from association tests, and hazard ratios with 95% CI from actuarial curves and Cox regression analyses. A meta-analysis was done on the studies that applied Cox models. FINDINGS: The methods used to assess significance varied widely between studies. 27% (nine of 34) of studies that assessed the prognostic value of P53 overexpression in recurrence by use of multivariate tests showed a significant association. The corresponding values for progression and mortality were 50% (12 of 24) and 29% (ten of 35), respectively. In the studies that used Cox models, the overall risk of recurrence was 1.6 (95% CI 1.2-2.1), of progression was 3.1 (1.9-4.9), and of mortality was 1.4 (1.2-1.7). These findings could be overestimates because of publication and reporting bias. INTERPRETATION: After 10 years of research, evidence is not sufficient to conclude whether changes in P53 act as markers of outcome in patients with bladder cancer.     

Next-generation sequencing reveals mutational accordance between cell-free DNA from plasma,malignant pleural effusion and ascites and directs targeted therapy in a gastric cancer patient

Cell-free DNA (cfDNA) has been a research hotspot in molecular tumor profiling. In advanced gastric cancer patients, malignant pleural effusion (MPE) and ascites provide a wealth of tumor cells that can be investigated. Here we conducted next-generation sequencing (NGS) on matched cfDNA from plasma, MPE and ascites from a stage-IV gastric cancer patient to identify potential therapeutic targets. In all three samples, we detected an amplification in the cellular-mesenchymal to epithelial transition factor (MET) gene, a truncation mutation in SMAD3 (p.R368X), and four ataxia telangiectasia-mutated gene (ATM) variants, including a missense mutation (p.E2351A), an in-frame deletion (p.NPAVIM2353delinsK), a frame-shift deletion (p.D1758fs) and an ATM- BPI fold containing family B member 1 (BPIFB1) gene fusion. In contrast, we detected amplification of TEK only in malignant ascites. The patient was subjected to Crizotinib to counter MET amplification. Our study demonstrates high accordance in mutational spectra of matched cfDNA from plasma, MPE and ascites, and suggests that it is feasible to utilize these tumor sources in clinical decision-making.     

保留膀胱的综合治疗与根治性手术治疗肌层浸润性膀胱癌预后的荟萃分析

目的 比较保留膀胱手术+术后化疗与根治性手术治疗肌层浸润性膀胱癌的预后.方法 检索保留膀胱手术+术后化疗与根治性手术治疗肌层浸润性膀胱癌(muscle-invasive bladder cancer,MIBC)的对照研究,比较两种治疗方案的术后5年生存率,计算合并优势比(OR)和95%CI.结果 共纳入7项研究,累积876例患者.1组研究的OR=1.03,95%CI为1.03(0.52~2.02),4组研究的OR及其95%CI﹤1,2组研究的OR及其95%CI﹥1;7个研究的总OR=1.05,95%CI为1.05(0.53~2.06),跨过"无差异线",故认为根治性膀胱全切术(radical cystectomy,RC)与保留膀胱的综合治疗预后差异无统计学意义(Z=0.13,P=0.89).结论 对于部分肌层浸润性膀胱癌患者,保留膀胱的综合治疗不会降低患者的5年生存率,且能保留患者膀胱的正常功能,提高了患者的生存质量,但适应证需严格把握.     

Breast cancer and NSAID use: a meta-analysis

Recent epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of several cancers including breast cancer. This meta-analysis examined the studies on NSAID use and breast cancer. The estimators of relative risk and associated variances, which have been adjusted for the greatest number of confounders, were abstracted and included in the meta-analysis. Combined estimators of relative risk (RR) were calculated using either fixed or random effect models. Meta-analyses were performed on 6 cohort studies (number of cases ranged from 14 to 2414) and 8 case-control studies (number of cases ranged from 252 to 5882). The combined estimate of relative risk was 0.82 (95% confidence interval [CI] = 0.75-0.89). The combined estimate for cohort studies was 0.78 (95% CI = 0.62-0.99) and was 0.87 (95% CI = 0.84-0.91) for case-control studies. The findings of this meta-analysis suggest that NSAID use may be associated with a small decrease in the risk of breast cancer. However, the available data are insufficient to estimate the dose-response effect for duration and frequency of use of any particular types of NSAID.     

外周血循环miRNA诊断卵巢癌的Meta分析

目的 综合评价外周血循环微小RNA(microRNA,miRNA)对卵巢癌的诊断价值.方法 全面检索PubMed、The Cochrane Library、ISIWeb of Science、CNKI、万方和维普数据库,按照纳入与排除标准收集从各数据库建库至2015年5月发表的关于运用外周血循环miRNA表达水平诊断卵巢癌的文献,应用Meta-DiSc 1.4软件进行Meta分析.结果 共9项关于外周血循环miRNA诊断卵巢癌的研究纳入本次分析,共1 068例研究对象.Meta分析结果显示,外周血循环miRNA诊断卵巢癌的合并敏感度和合并特异性分别为0.74(95％ CI:0.71～0.78)和0.76(95％ CI:0.72 ～0.80),合并诊断阳性似然比和阴性似然比分别为3.03(95％ CI:2.17 ～4.21)和0.32(95％CI:0.25～0.43),合并诊断比值比为10.70(95％ CI:6.82～16.78).总受试者工作特征曲线下面积为0.83,Q*值为0.77.结论 外周血循环miRNA对卵巢癌具有一定的诊断价值.