Purpose: Several preoperative prostate cancer nomograms have been developed that predict risk of progression using pretreatment prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason grade. We describe the development and performance of a new nomogram. The nomogram adds new markers to the standard clinical predictors that reflect the biologic behavior of prostate cancer: pretreatment plasma levels of interleukin-6 soluble receptor (IL6SR) and transforming growth factor beta₁ (TGF-β₁). Patients and Methods: Between November 7, 1994 and December 22, 1997, 714 patients with stage cT1c to cT3a prostate cancer and no prior therapy were treated with radical prostatectomy at the Methodist Hospital, Houston TX. Plasma levels of IL6SR and TGF-β₁ were measured in banked preoperative plasma. With these data, a nomogram was developed to predict the probability of PSA progression within 5 years of surgery. The nomogram was validated with bootstrapping to assess its discrimination and calibration performance. Results: In the multivariable Cox model, PSA (P = .004), IL6SR (P < .001), TGF-β₁ (P < .001), primary Gleason grade (P < .002), and secondary Gleason grade (P = .029) were associated with PSA progression, whereas clinical stage (P = .696) was not. The nomogram seemed to be well calibrated and had a bootstrap-corrected area under the receiver operating characteristic curve (ie, concordance index) of 0.83. For comparison, a nomogram that omitted IL6SR and TGF-β₁ achieved a concordance index of only 0.75. Conclusion: We found that pretreatment plasma levels of IL6SR and TGF-β₁ improved the ability to predict biochemical progression by a prognostically substantial margin. A nomogram including the pretreatment levels of these molecular markers, along with standard clinical markers, has been developed and internally validated.

Purpose: We have shown that preoperative plasma levels of transforming growth factor-β₁ (TGF-β₁), interleukin 6 (IL)-6, and its receptor (IL-6sR) are associated with prostate cancer progression and metastasis. The objectives of this study were to confirm these findings and to examine the association of changes in plasma levels of these markers after surgery with disease progression in a large consecutive cohort of patients. Experimental Design: Plasma levels of TGF-β₁, IL-6, and IL-6sR were measured pre- and postoperatively (6–8 weeks after surgery) in 302 consecutive patients who underwent radical prostatectomy for clinically localized disease. Results: Pre- and postoperative levels of TGF-β₁ were significantly elevated in patients with extraprostatic extension, seminal vesicle involvement, and metastases to lymph nodes. In contrast, preoperative levels of IL-6 and IL-6sR, but not postoperative levels, were significantly associated with tumor volume, prostatectomy Gleason sum, and metastases to lymph nodes. In a postoperative model that included pre- and postoperative TGF-β₁, IL-6, and IL-6sR and standard postoperative parameters, postoperative TGF-β₁ and prostatectomy Gleason sum were significant predictors of overall and aggressive disease progression. Although, for all patients, plasma levels of all three markers declined significantly after prostate removal, for patients that experienced disease progression, only IL-6 and IL-6sR levels decreased significantly. Conclusions: For patients undergoing radical prostatectomy, preoperative plasma levels of TGF-β₁ and IL-6sR are associated with metastases to regional lymph nodes, presumed occult metastases at the time of primary treatment, and disease progression. After prostate removal, postoperative TGF-β₁ level increases in value over preoperative levels for the prediction of disease progression.

MicroRNAs (miRNAs) regulate many cellular activities, including cancer development, progression, and metastasis. Some miRNAs are involved in breast cancer (BC) migration and invasion, thus affect patients’ prognosis. Microarray analysis was performed to compare miRNA expression in BC tissues, and results confirmed by qPCR. BC cell migration and invasion were studied in vitro with MDA‐MB‐231 cells using microplate transwell assays. miRNA targeting was investigated using luciferase assays, qPCR, and Western blot analysis in cells with overexpression of miRNA mimics. Knockdown of miRNA targets was performed using target siRNA lentiviral infection. Results show that microRNA‐141 (miR‐141) was downregulated in breast cancer tumor tissues compared with matched surrounding tissues. Downregulation of miR‐141 expression correlated with tumor stage, lymph node involvement, and expressions of PCNA, Ki67, and HER2. Overexpression of miR‐141 inhibited BC cell proliferation, migration, and invasion in vitro. ANP32E gene was selected as one putative target for further studies based on results from in silico analysis. Results from a dual‐luciferase reporter system suggested ANP32E as a direct target of miR‐141. Overexpression of miR‐141 downregulated ANP32E expression at both mRNA and protein levels in BC cells. Knockdown of ANP32E inhibited BC cell proliferation, migration, and invasion in vitro, mimicking the effect of the overexpression of miR‐141. Our study revealed important roles miR‐141 plays in BC growth and metastasis. Moreover, for the first time, we identified ANP32E as one of the miR‐141 targets, and demonstrated its involvement in the regulation of cell proliferation, migration, and invasion.

To explore new molecular diagnosis approaches for early detection and differential diagnosis of hepatocellular carcinoma (HCC), we analyzed genomic copy number variations (CNV) using plasma cell-free DNA from patients with HCC by next generation DNA sequencing. Plasma samples from 31 patients with HCC and 8 patients with chronic hepatitis or cirrhosis were analyzed. In HCC group, most samples with large tumor size (tumor dimension greater than 50 mm) showed CNVs that are visually recognizable at chromosome CNV plots, few samples with small tumor and none samples with chronic liver diseases showed CNVs recognizable at CNV plots. CNV Z score analysis showed significant CNVs in samples with HCC and chronic liver diseases although more significant changes were found in HCC group, some are differentially valuable (such as gain in 1q, 7q, and 19q in HCC), while others are less differentially valuable (such as loss in 4q, 13q, gain in 17q, 22q). We proposed a CNV scoring method that generated positive result in 26 of the 31 HCC patients (83.9%) or 11 of the 16 HCC with tumor dimension 50 mm or less (68.8%) or 4 of the 7 HCC with tumor dimension 30 mm or less (57.1%), while all the 8 samples with chronic hepatitis or cirrhosis scored negative. Ten HCC patients had normal or low serum AFP levels, among them, 7 were scored positive by CNV analysis, including 4 with tumor dimension 50 mm or less. Our study suggested that non-invasive genomic CNV analysis using plasma samples could be a valuable tool for early detection and differential diagnosis of HCC. Although CNV analysis itself cannot establish the diagnosis, it can help identify patients at high risk for HCC among patients with chronic liver diseases, which would prompt closer and more frequent surveillance for early tumor detection and intervention.