Clinical potential role of circulating microRNAs in early diagnosis of colorectal cancer patients.

Current procedures for diagnosis and biomarker examination of colorectal cancer (CRC) are invasive and unpleasant. There is a great need to identify sensitive and specific biomarkers for early diagnosis of CRC. Circulating microRNAs (miRNAs) are promising molecular markers for CRC prediction. We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of circulating miRNAs in diagnosing CRC patients. Furthermore, we conducted an independent validation set of 49 CRC patients and 49 healthy controls. In our meta-analysis, we found that miR-21 yielded a pooled area under ROC curve (AUC) of 0.867 (sensitivity: 76%, specificity: 82%) in discriminating CRC from controls, and miR-92a yielded a summary AUC of 0.803 (sensitivity: 77%, specificity: 68%); miR-21 had a higher diagnostic efficiency than miR-92a. In the further validation, plasma miR-21 levels in CRC patients were significantly higher than levels observed in healthy subjects. A ROC curve analysis showed a consistent result. However, this phenotype was not present in miR-92a. Moreover, the expression trend of miR-21 in plasma samples was in line with that of tissue samples, along with the cellular level. Current evidences suggest that plasma miR-21 could be a reliable and non-invasive biomarker for CRC diagnosis. Studies with larger cohorts that include the diagnostic value of plasma miR-21 for CRC are warranted.

Diagnostic ability of %p2PSA and prostate health index for aggressive prostate cancer: a meta-analysis.

The role of [-2]proPSA (p2PSA) based diagnostic tests for the detection of aggressive prostate cancer (PCa) has not been fully evaluated. We conducted a meta-analysis to evaluate the diagnostic performance of p2PSA/free PSA (%p2PSA) and prostate health index (Phi) tests for PCa and to evaluate their ability in discriminating between aggressive and non-aggressive PCa. A total of 16 articles were included in this meta-analysis. For the detection of PCa, the pooled sensitivity, specificity, and AUC were 0.86 (95% CI, 0.84-0.87), 0.40 (95% CI, 0.39-042) and 0.72 (95% CI, 0.67-0.77) for %p2PSA respectively, and were 0.85 (95% CI, 0.83-0.86), 0.45 (95% CI, 0.44-0.47) and 0.70 (95% CI=0.65-0.74) for Phi, respectively. In addition, the sensitivity for discriminating PCa between higher Gleason score (≥7) and lower Gleason score (<7) was 0.96 (95% CI, 0.93-0.98) and 0.90 (95% CI, 0.87-0.92) for %p2PSA and Phi respectively, and the specificity was low, only 0.09 (95% CI, 0.06-0.12) and 0.17 (95% CI, 0.14-0.19) for %p2PSA and Phi, respectively. Phi and %p2PSA have a high diagnostic accuracy rates and can be used in PCa diagnosis. Phi and %p2PSA may be useful as tumor markers in predicating patients harboring more aggressive disease and guiding biopsy decisions.

Retroperitoneal laparoscopic nephrectomy for acute blunt grade 4 renal injuries.

OBJECTIVE: To first describe laparoscopic nephrectomy (LN) for patients with acute blunt Grade 4 renal injuries using a retroperitoneal approach. PATIENTS AND METHODS: Three patients (2 males and 1 female) with acute blunt renal trauma underwent retroperitoneal LN successfully. The revised American Association for Surgery of Trauma grading system was used to grade renal injuries. All three patients with Grade 4 renal injuries required blood transfusions preoperatively and angiographic embolization because of hemodynamic instability. Given the severity of the renal injuries, failure of angiographic embolization, and persistent blood loss, surgical intervention was used. We performed retroperitoneal LN using four trocars within 24 hours after trauma for the patients. RESULTS: Pure retroperitoneal LN was successfully performed in all 3 patients without requiring hand-assisted or open surgery. The renal hematoma dimension for the patients was 7.5, 8.4, and 9.2 cm, respectively. Operative time was 80, 110, and 130 minutes, respectively. Estimated blood loss was 100, 140, and 300 mL, respectively. The incision size was 4.2, 4.2, and 4.5 cm, respectively. The average hospital stay was 6 days. Pathology showed renal injuries without incidental renal tumors. CONCLUSIONS: Despite the technical challenges, LN for patients with acute blunt Grade 4 renal injuries using a retroperitoneal approach is safe and feasible in carefully selected patients if conservative measures and angiographic embolization fail. However, it is important to note that one should keep a low threshold for open conversion or the hand-assisted approach whenever necessary.

Pure retroperitoneal laparoscopic radical nephrectomy for right renal masses with renal vein and inferior vena cava thrombus.

PURPOSE: To describe our pure retroperitoneal laparoscopic radical nephrectomy (LRN) with thrombectomy for right renal masses with renal vein (RV) and inferior vena cava (IVC) thrombus. PATIENTS AND METHODS: Five patients with right renal masses with RV and IVC thrombus underwent pure retroperitoneal LRN. Three patients had a history of abdominal surgery. In one patient with a RV thrombus, the RV was ligated and dissected with Hem-o-lok clips; in four patients with IVC thrombus, the IVC was partially occluded with a laparoscopic vascular clamp and incised distal to its junction with the right RV, and the thrombus was delivered intact. The IVC was closed with a running 3-0 polypropylene suture. RESULTS: Pure retroperitoneal LRN with thrombectomy was successfully performed for all the patients without hand-assisted or open conversion. The mean tumor size was 6.2 cm, and mean thrombus length was 2.8 cm; four thrombi extended 0.6-1.0 cm into the IVC, and the mean operative time was 127 minutes with the average estimated blood loss at 148 mL. The mean hospital stay was 5 days. Histology revealed two renal-cell carcinomas, one angiomyolipoma, one renal pelvic transitional-cell carcinoma, and one renal infarction. All the surgical margins were negative. With a mean follow-up of 35 months, metastatic diseases did not develop in any patient. CONCLUSIONS: Despite the technical challenges, pure retroperitoneal LRN for right renal masses with a RV and IVC thrombus is safe and feasible in appropriately selected patients using a retroperitoneal approach. In patients with minimal caval involvement, our surgical approach provided an alternative treatment option, especially when the patients had a history of abdominal surgery.

Comparison of ESWL and ureteroscopic holmium laser lithotripsy in management of ureteral stones.

BACKGROUND: There are many options for urologists to treat ureteral stones that range from 8 mm to 15 mm, including ESWL and ureteroscopic holmium laser lithotripsy. While both ESWL and ureteroscopy are effective and minimally invasive procedures, there is still controversy over which one is more suitable for ureteral stones. OBJECTIVE: To perform a retrospective study to compare the efficiency, safety and complications using ESWL vs. ureteroscopic holmium laser lithotripsy in management of ureteral stones. METHODS: Between October 2010 and October 2012, 160 patients who underwent ESWL or ureteroscopic holmium laser lithotripsy at Suzhou municipal hospital for a single radiopaque ureteral stone (the size 8-15 mm) were evaluated. All patients were followed up with ultrasonography for six months. Stone clearance rate, costs and complications were compared. RESULTS: Similarity in stone clearance rate and treatment time between the two procedures; overall procedural time, analgesia requirement and total cost were significantly different. Renal colic and gross hematuria were more frequent with ESWL while voiding symptoms were more frequent with ureteroscopy. Both procedures used for ureteral stones ranging from 8 to 15 mm were safe and minimally invasive. CONCLUSION: ESWL remains first line therapy for proximal ureteral stones while ureteroscopic holmium laser lithotripsy costs more. To determining which one is preferable depends on not only stone characteristics but also patient acceptance and cost-effectiveness ratio.

Pure retroperitoneal laparoscopic radical nephrectomy for left renal cell carcinoma with differential extensions of level I renal vein tumor thrombus.

OBJECTIVES: To describe a large clinical series of pure laparoscopic radical nephrectomy (LRN) for left renal cell carcinoma (RCC) with differential extensions of level I renal vein (RV) tumor thrombus using a retroperitoneal approach. METHODS: Ten left RCC patients with RV tumor thrombus underwent pure retroperitoneal LRN. Operation procedures were different for patients with varying length of the RV tumor thrombus. Based on our experience, four grades were defined based on the distal limit of the thrombus. Grade 1: tip of the thrombus was located between the renal sinus and the left gonadal vein (or adrenal vein); Grade 2: tip of the thrombus was located between the left gonadal vein and the abdominal aorta; Grade 3: tip of the thrombus was riding on the abdominal aorta; Grade 4: tip of the thrombus was located in the interaortocaval region. According to this classification, grade 1 in 3 patients, grade 2 in 2, grade 3 in 3, and grade 4 in 2. RESULTS: Pure retroperitoneal LRN and thrombectomy were successfully performed for all the patients without requiring open surgery. The mean tumor size for each of the four grades was 5.9, 6.4, 5.8, and 7.6 cm, respectively; the mean thrombus length was 2.1, 3.5, 5.2, and 7.1 cm, respectively; the mean operative time was 85, 103, 137, and 190 minutes, respectively; the average surgical bleeding volume was 67, 110, 143, and 225 mL, respectively. Better procedures are needed to increase the working space for patients with higher grades of thrombus. Surgical margins were negative for all patients. With a mean follow-up of 29 months, two patients developed metastatic disease. CONCLUSIONS: Despite the technical challenges, pure retroperitoneal LRN for left RCC patients with differential extensions of RV tumor thrombus is safe and feasible in selected patients. However, it is important to note that surgery will be more difficult for patients with higher grades of thrombus.

Genetic variants and family history predict prostate cancer similar to prostate-specific antigen.

PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.

Association of prostate cancer risk variants with clinicopathologic characteristics of the disease.

PURPOSE: Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain. EXPERIMENTAL DESIGN: We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum prostate-specific antigen (PSA) levels were tested. RESULTS: After adjusting for multiple testing, none of the single nucleotide polymorphisms was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for single nucleotide polymorphism rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86; nominal P = 0.03) or in controls (0.86; nominal P = 0.04). Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening. CONCLUSIONS: Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed to discover genetic variants that predict tumor aggressiveness.

Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12.

We carried out a fine-mapping study in the HNF1B gene at 17q12 in two study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hot spot. We confirmed the association with a SNP in the second locus (rs11649743) in five additional populations, with P = 1.7 x 10(-9) for an allelic test of the seven studies combined. The association at each SNP remained significant after adjustment for the other SNP.

A support vector machine approach for detecting gene-gene interaction.

Although genetic factors play an important role in most human diseases, multiple genes or genes and environmental factors may influence individual risk. In order to understand the underlying biological mechanisms of complex diseases, it is important to understand the complex relationships that control the process. In this paper, we consider different perspectives, from each optimization, complexity analysis, and algorithmic design, which allows us to describe a reasonable and applicable computational framework for detecting gene-gene interactions. Accordingly, support vector machine and combinatorial optimization techniques (local search and genetic algorithm) were tailored to fit within this framework. Although the proposed approach is computationally expensive, our results indicate this is a promising tool for the identification and characterization of high order gene-gene and gene-environment interactions. We have demonstrated several advantages of this method, including the strong power for classification, less concern for overfitting, and the ability to handle unbalanced data and achieve more stable models. We would like to make the support vector machine and combinatorial optimization techniques more accessible to genetic epidemiologists, and to promote the use and extension of these powerful approaches.

DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies.

BACKGROUND: Identifying genomic regions that are commonly deleted or gained in neoplastic cells is an important approach to identify tumor suppressor genes and oncogenes. Studies in the last two decades have identified a number of common DNA copy number alterations in prostate cancer. However, because of various sample sizes, diverse tumor types and sources, as well as a variety of detection methods with various sensitivities and resolutions, it is difficult to summarize and fully interpret the overall results. METHODS: We performed a combined analysis of all published comparative genomic hybridization (CGH) studies of prostate cancer and estimated the frequency of alterations across the genome for all tumors, as well as in advanced and localized tumors separately. A total of 41 studies examining 872 cancers were included in this study. RESULTS: The frequency of deletions and gains were estimated in all tumors, as well as in advanced and localized tumors. Eight deleted and five gained regions were found in more than 10% of the prostate tumors. An additional six regions were commonly deleted and seven were commonly gained in advanced tumors. While 8p was the most common location of deletion, occurring in about a third of all tumors and about half of advanced tumors, 8q was the most commonly gained region, affecting about a quarter of all tumors and about half of all advanced tumors. CONCLUSIONS: The large number of tumors examined in this combined analysis provides better estimates of the frequency of specific alterations in the prostate cancer cell genome, and offers important clues for prioritizing efforts to identify tumor suppressor genes and oncogenes in these altered regions.

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array.

Although multiple recurrent chromosomal alterations have been identified in prostate cancer cells, the specific genes driving the apparent selection of these changes remain largely unknown. In part, this uncertainty is due to the limited resolution of the techniques used to detect these alterations. In this study, we applied a high-resolution genome-wide method, Affymetrix 100K SNP mapping array, to screen for somatic DNA copy number (CN) alterations among 22 pairs of samples from primary prostate cancers and matched nonmalignant tissues. We detected 355 recurrent deletions and 223 recurrent gains, many of which were novel. As expected, the sizes of novel alterations tend to be smaller. Importantly, among tumors with increasing grade, Gleason sum 6, 7, and 8, we found a significant trend of larger number of alterations in the tumors with higher grade. Overall, gains are significantly more likely to occur within genes (74%) than are deletions (49%). However, when we looked at the most frequent CN alterations, defined as those in > or =4 subjects, we observed that both gains (85%) and deletions (57%) occur preferentially within genes. An example of a novel, recurrent alteration observed in this study was a deletion between the ERG and TMPRSS2 genes on chromosome 21, presumably related to the recently identified fusion transcripts from these two genes. Results from this study provide a basis for a systematic and comprehensive cataloging of CN alterations associated with grades of prostate cancer, and the subsequent identification of specific genes that associated with initiation and progression of the disease. This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/1045-2257/suppmat

A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Serum levels of phytanic acid are associated with prostate cancer risk.

BACKGROUND: Recent findings of over-expression of the AMACR gene in prostate cancer and association between sequence variants in the AMACR gene and prostate cancer risk, along with the well established findings of association between prostate cancer risk and over-consumption of dairy products and red meat, indirectly suggest that phytanic acid, which primarily comes from dietary intake of dairy and red meat and requires the AMACR enzyme for its metabolism, may be associated with prostate cancer risk. In this small case-control study, we assessed the association between phytanic acid levels and prostate cancer risk. METHODS: One hundred and four prostate cancer patients and controls were recruited in North Carolina. Serum levels of phytanic acid were measured using a gas liquid chromatography/mass spectroscopy analysis, and a food frequency questionnaire was administered to each individual to assess dietary intake. RESULTS: Three key findings are reported. First, there was a high correlation between two independent measurements of phytanic acid levels from the same individuals and the levels of phytanic acid were within the expected range, suggesting that serum levels of phytanic acid levels can be reliably measured in large epidemiological studies. Second, serum levels of phytanic acid among prostate cancer patients were significantly higher than that of unaffected controls, suggesting an association between phytanic acid and prostate cancer risk. Lastly, there was a significantly positive correlation between serum levels of phytanic acid and dietary intake of dairy and red meat servings during the year prior to the serum measurement. CONCLUSIONS: Although the results from our study suggest phytanic acid levels may be associated with prostate cancer risk, they were based on a study with a small sample size. Much larger studies are required to confirm these important findings.

Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study.

Inflammation has been implicated as an etiological factor in several human cancers. Growing evidence suggests that chronic inflammation may also play a role in the etiology of prostate cancer. Considering that genetic susceptibility is a major risk factor for this disease, we hypothesize that sequence variants in genes that regulate inflammation may modify individual susceptibility to prostate cancer. The lipopolysaccharide receptor Toll-like receptor 4 (TLR4) is a central player in the signaling pathways of the innate immune response to infection by Gram-negative bacteria and is an important candidate inflammatory gene. We performed a systematic genetic analysis of TLR4 sequence variants by evaluating eight single-nucleotide polymorphisms that span the entire gene among 1383 newly diagnosed prostate cancer patients and 780 age- and residence-matched controls in Sweden. We found an association between a sequence variant (11381G/C) in the 3'-untranslated region of the TLR4 gene and prostate cancer risk. The frequency of the variant genotypes (CG or CC) was significantly higher in the patients (24.1%) than in the controls (19.7%; P = 0.02). The frequency of risk genotypes among patients diagnosed before the age of 65 years was even higher (26.3%). Compared with men who had the wild-type genotype of this single-nucleotide polymorphism (GG), those with GC or CC genotypes had a 26% increased risk for prostate cancer (odds ratio, 1.26; 95% confidence interval, 1.01-1.57) and 39% increased risk increased risk for early onset prostate cancer (before age 65 years; odds ratio, 1.39; 95% confidence interval, 1.02-1.91). The risk attributable to this variant for prostate cancer in Sweden was estimated to be 4.9%. Although the biological mechanism of the observed association remains to be elucidated, our finding supports a role for a bacteria-associated response pathway, possibly acting via inflammation, in the development of prostate cancer.