Artificial neural networks: has the time come for their use in prostate cancer patients?
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Humans↗
Biomedical subjects
Carsten Stephan
Publications and source records attributed to Carsten Stephan.
Matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine: tumor-reducing effects on hormone-sensitive prostate cancer in rats.
Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor, Ro 28-2653 (5-biphenyl-4-yl-5-[4-(-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione), has been shown in various models of different tumor entities. The tumor growth-reducing effect has been demonstrated in the orthotopic rat prostate Dunning model (subline MatLyLu). Based on these results we investigated Ro 28-2653 in combination with estramustine on the G subline of the Dunning tumor. This subline is characterized by a low metastatic ability and androgen sensitivity. Efficacy was determined by recording tumor growth in vivo by magnetic resonance imaging (MRI). Tumor cells were injected into the prostates of 81 Copenhagen rats. MRI was performed at day 100 and at day 126 after tumor cell injection. The duration of therapy was 17 days with daily oral application of Ro 28-2653 (100 mg/kg) and four i.p. injections of estramustine (7.5 mg/kg). Histological evaluations were conducted to provide further information about the effects on tumor morphology. Orthotopic tumor induction was successful in 100% of the animals. Tumor volume calculations with MRI showed a significant difference between the control groups, the animals treated with Ro 28-2653, and the animals treated with the combination of Ro 28-2653 and estramustine. The new MMP inhibitor Ro 28-2653 reduces tumor growth and provides a compatible therapeutic alternative for patients with prostate cancer.
Animals↗
A multicenter clinical trial on the use of (-5, -7) pro prostate specific antigen.
PURPOSE: The determination of pro prostate specific antigen (proPSA) forms has been suggested to be promising in prostate cancer diagnosis. In this multicenter trial we evaluated the diagnostic usefulness of (-5, -7) proPSA. MATERIALS AND METHODS: A total of 2,055 white men, including 1,046 with and 1,009 without prostate cancer, with total PSA (tPSA) between 0.28 and 81 ng/ml were retrospectively analyzed. Of these men 2,026 and 1,727 had tPSA less than 20 and less than 10 ng/ml, respectively. All subjects were untreated for prostatic disease and underwent multisector needle biopsy of the prostate. An Elecsys 2010 analyzer was used to determine tPSA, free PSA (fPSA) and (-5, -7) proPSA in the 2,055 serum samples. ROC analyses were performed to discriminate men with biopsy positive and negative results in the entire and in select tPSA ranges. RESULTS: In the select tPSA range 2 to 4 ng/ml the area under the ROC curve for proPSA (0.53) and proPSA/fPSA (0.59) was not significantly larger than that for tPSA (0.60) or the fPSA/tPSA (f/tPSA) ratio (0.64). In the tPSA range 4 to 10 ng/ml the area under the curve for the ratio proPSA/fPSA (0.67) was larger than for tPSA (0.53) but not larger than for f/tPSA (0.69). The f/tPSA ratio demonstrated the best discriminatory power in this tPSA range of 4 to 10 ng/ml. CONCLUSIONS: In this multicenter study no improvement in diagnostic accuracy was shown when comparing (-5, -7) proPSA and the corresponding ratios with tPSA or f/tPSA. Further studies using other proPSA forms or tumor associated proteins should be done.
Adult↗
Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection.
OBJECTIVE: To assess, using artificial neural networks (ANNs), human glandular kallikrein 2 (hK2), prostate-specific antigen (PSA), and percentage free/total PSA (f/tPSA), for discriminating between prostate cancer and benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: Serum samples from 475 patients with prostate cancer (n = 347) or BPH (n = 128) within the PSA range of 1-20 ng/mL were analysed for tPSA, fPSA and hK2 (research assay, Toronto, Canada). Data were analysed in the ranges of 1-4, 2-4, 4-10, and 2-20 ng/mL tPSA. Back-propagation ANN models with the variables PSA, f/tPSA, and hK2, hK2/fPSA and hK2/(f/tPSA) were constructed. The diagnostic validity was evaluated by receiver-operating characteristic (ROC) curve analysis. RESULTS: Whereas the median concentration of hK2 was not significantly different between patients with BPH or prostate cancer in any of the tPSA ranges, the f/tPSA, hK2/fPSA and hK2/(f/tPSA), and the hK2-based ANN outputs were always significantly different between patients with prostate cancer or BPH. Using ROC curve comparison, all variables were significantly better than hK2 in all ranges. The hK2-based ANN performed better than f/tPSA except in the 4-10 ng/mL tPSA range. At 90% and 95% sensitivity, the hK2-based ANN was also significantly better than f/tPSA in the 1-4 ng/mL tPSA range. hK2/(f/tPSA) achieved equal results to the hK2-based ANN except in the range 2-20 ng/mL tPSA. CONCLUSIONS: The hK2-based ANN improves the outcome of f/tPSA but not hK2/(f/tPSA) in almost all analysed subgroups. When comparing the results at 90% and 95% sensitivity the hK2-based ANN only performed significantly better than f/tPSA in the lowest tPSA range. Only in lower tPSA ranges do hK2-based ANNs show an advantage for further improving prostate cancer detection.
Adult↗
Discordance analysis characteristics as a new method to compare the diagnostic accuracy of tests: example of complexed versus total prostate-specific antigen.
BACKGROUND: ROC curve analysis is used to compare the overall diagnostic accuracy of tests, but its application to subgroups selected by a concentration range of only one marker may show severe biases. We developed a new approach, which we have named discordance analysis characteristics (DAC). METHODS: The DAC method is based on a generalization of the McNemar test so that for a given pair of cutoff values only those patients are analyzed who are categorized differently by the two tests compared. The analyses are performed for all cutoff pairs that deliver identical sensitivities for both tests. We used data for total (tPSA) and complexed prostate-specific antigen (cPSA) from a recently published multicenter study to demonstrate the DAC method. RESULTS: The example shows that ROC analyses of subgroups can give contradictory results about the diagnostic accuracy of two markers, depending on the marker used for the selection of subgroups. The DAC method avoids artifacts attributable to questionable selection of subgroups and facilitates overall and local comparisons of the diagnostic accuracy of tests. The DAC results of the analyzed data set suggest that cPSA has higher diagnostic accuracy than does tPSA. CONCLUSIONS: The DAC method is a suitable tool for comparing the clinical usefulness of laboratory markers. The DAC method could be considered as an additional tool to ROC analysis and could replace comparative ROC analyses of diagnostic tests, especially within subgroups defined by only one of the markers.
Humans↗
Analysis of subforms of free prostate-specific antigen in serum by two-dimensional gel electrophoresis: potential to improve diagnosis of prostate cancer.
BACKGROUND: The aim of this study was to develop a method to separate and quantify subforms of free prostate-specific antigen (fPSA) in serum by two-dimensional electrophoresis and to assess the diagnostic accuracy of these subforms for prostate cancer (PCa) diagnosis in comparison with total PSA (tPSA) and the ratio of fPSA to tPSA (%fPSA). METHODS: Sera from 50 patients with and without PCa, respectively, were studied. PSA was isolated by immunoadsorption on streptavidin-coated magnetic beads with biotinylated anti-PSA antibodies and separated by two-dimensional electrophoresis. After semidry blotting, the intensities of the fPSA spots were quantified by chemiluminescence using an imager analyzer. RESULTS: The method detected subforms to a concentration of 0.1 mug/L fPSA with an imprecision (CV) <16%. We detected 15 immunoreactive fPSA spots of different intensities. Spots F2 and F3 were present in all samples. F2 was lower in samples from non-PCa patients (median, 23%) than in samples from PCa patients (49%), whereas F3 behaved inversely (non-PCa, 73%; PCa, 45%). Ratios of F2 to F3 and F2/F3 to %fPSA, respectively, showed improved diagnostic accuracy compared with tPSA and %fPSA. Better differentiation by F2/F3 or by F2/F3 to %fPSA was particularly evident in patients with %fPSA values >15%. There were no associations between the PCa grading scale and fPSA subforms. CONCLUSIONS: fPSA subforms separated by two-dimensional electrophoresis may improve both sensitivity and specificity in prostate cancer diagnostics compared with tPSA and %fPSA. The development of a practicable assay based on the immunologic properties of these different fPSA subforms seems to be promising.
Aged↗
Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications.
Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.
Adult↗
Polo-like kinase 1 is overexpressed in prostate cancer and linked to higher tumor grades.
BACKGROUND: Polo-like kinase 1 (PLK1) is known to be one of the key players in the regulation of mitosis of both normal and malignant transformed cells. Moreover, several studies reported an overexpression of PLK1 in human malignancies compared to the corresponding tissue of origin. METHODS: In this study, expression of PLK1 was investigated by immunohistochemistry in 78 tissue specimens of prostate carcinoma and in adjacent normal prostate tissue as well as in benign prostate hyperplasia. PLK1 expression was semiquantitavely scored and subsequently correlated to clinicopathological parameters and patient prognosis. RESULTS: No significant PLK1 expression was observed in normal prostate glandular epithelium and stroma. Specimens of benign prostate hyperplasia were PLK1-negative as well. In contrast, 52.6% of all prostate carcinomas showed strong expression of PLK1. High grade intraepithelial lesions, if present, stained almost invariably in the same manner as the respective invasive tumors. Expression of PLK1 correlated positively with Gleason grade (P = 0.011). No other significant correlations of PLK1 expression with either tumor stage, WHO tumor grade, preoperative PSA, age, or resection margins could be established. In an analysis for differences in PSA-relapse-free survival time, PLK1 expression was not a prognostic marker. CONCLUSIONS: These results demonstrate a high rate of PLK1-positivity in prostate cancer which suggests involvement of PLK1 in tumorigenesis and progression in this tumor entity. Therefore, targeted strategies focussing on PLK1 inhibition might represent a promising new chemotherapeutic approach in prostate cancer.
Aged↗
Predictive modeling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate-specific antigen levels < or = 10 ng/ml.
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Adenocarcinoma↗
Increased cell-free DNA in plasma of patients with metastatic spread in prostate cancer.
We compared the plasma DNA concentrations in patients with different prostate cancer (PCa) stages and with benign prostate hyperplasia (BPH) and in healthy persons. Patients with localized cancer had DNA plasma within the reference interval. Increased plasma DNA was found in patients with lymph node and distant metastases and also in BPH. The association between plasma DNA and the survival time was similarly strong as with prostate-specific antigen. It can be concluded that plasma DNA has a limited validity as metastatic marker in PCa patients but follow-up studies combined with the investigation of tumor-related characteristics of plasma DNA would be reasonable.
DNA↗
CD24 expression is a significant predictor of PSA relapse and poor prognosis in low grade or organ confined prostate cancer.
BACKGROUND: The prognostic impact of tumor grading and staging is markedly reduced in organ confined or moderately differentiated prostate cancer, which underscores the importance of new prognostic markers. Evaluating public expression data of prostate cancer, we found an upregulation of the candidate gene CD24. METHODS: We examined immunohistochemically the expression of CD24 protein in 31 nodal metastases and 102 adenocarcinomas of the prostate and correlated our findings to clinicopathological parameters. RESULTS: CD24 expression was found in 48% of primary prostate cancer cases and in 68% of lymph node metastases. Kaplan Meier curves and Cox regression analysis showed that CD24 expression was strongly linked to significantly earlier disease progression (relative risk = 3.2), which was especially pronounced in organ confined, or moderately differentiated primary prostate tumors. CONCLUSIONS: We conclude that CD24 is an important prognostic tissue marker for prostate cancer which could help to define patients of low or high risk of recurrence.
Adenocarcinoma↗
Re: Hessels D, Klein Gunnewiek JMT, van Oort I, Karthaus HFM, van Leenders GJL, van Balken B, Kiemeney LA, Witjes JA, Schalken JA. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003;44:8-16.
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Antigens, Neoplasm↗
Hepsin is highly over expressed in and a new candidate for a prognostic indicator in prostate cancer.
PURPOSE: Other cDNA microarray studies have shown that hepsin is one of the highly over expressed genes in prostate cancer tissue compared with nonmalignant and benign prostatic hyperplasia tissue. We quantitatively analyzed hepsin gene expression with real-time polymerase chain reaction and calculated its relationships with clinicopathological parameters in a large cohort of samples. MATERIALS AND METHODS: Matched prostate tissue samples from the cancerous and noncancerous parts of the same prostates were obtained from 90 patients with prostate cancer who underwent radical prostatectomy. Quantitative reverse transcriptase-polymerase chain reaction was performed using LightCycler Fast Start DNA Master SYBR Green I on a LightCycler (Roche Diagnostics GmbH, Mannheim, Germany) system. The ratio of hepsin-to-beta-actin (a housekeeping gene) was used to normalize data. RESULTS: Hepsin over expression in cancerous compared with noncancerous tissue was found in 81 of the 90 patient samples (90%, p <0.001). In 48 patients (53%) hepsin over expression was more than 10-fold in cancerous tissue. The ratio of cancerous-to-noncancerous hepsin expression was significantly higher in the 39 patients with grade 3 tumors compared with the 51 with grade 2 tumors (median 15.5 vs 9.6, p = 0.031). For the prognosis a cutoff at the 75th percentile provided a significant difference between patients at lower risk (pT2, G2 and Gleason score less than 7) and higher risk (pT3/4, G3 and Gleason score 7 or greater) for relapse. CONCLUSIONS: This report of the quantitative analysis of hepsin expression, which is the first to our knowledge, shows strong and significant over expression in prostate cancer tissue. Hepsin expression may be a new prognostic marker that could be used for assessing prostate cancer aggressiveness.
Adenocarcinoma↗
The membrane proteases adams and hepsin are differentially expressed in renal cell carcinoma. Are they potential tumor markers?
PURPOSE: ADAMs (a disintegrin and metalloproteinases) as cell surface proteins with adhesion and protease activity, and hepsin as a transmembrane protease have important roles in many biological processes. We assessed the expression of various ADAMs and of hepsin in human renal cell carcinoma (RCC), and correlated expression with clinicopathological data. MATERIALS AND METHODS: mRNA expression of ADAM-8, 17, 19, 28, TS1 and TS2, and of hepsin was investigated in paired tissue samples from cancerous and noncancerous parts of the kidneys of 27 patients with RCC who underwent tumor nephrectomy. Measurements were performed by quantitative real-time reverse transcriptase-polymerase chain reaction on a LightCycler instrument (Roche Applied Science, Mannheim, Germany). The data were related to housekeeping gene porphobilinogen deaminase mRNA. RESULTS: All ADAMs except ADAM-TS1 were significantly higher but hepsin was less expressed (at least p <0.05) in cancerous vs matched noncancerous tissue. Expression was differentially related to tumor stage. ADAM-8 and ADAM-TS2 over expression as well as decreased hepsin expression were associated with shorter patient survival. The Cox proportional hazards regression model revealed that ADAM-TS2 was an independent prognostic factor for cancer related death. ADAM-8 was the best predictor of distant metastases. CONCLUSIONS: The differential expression of hepsin and ADAMs suggests early and late involvement of membrane proteases in the development of RCC. Their association with the clinical outcome illustrates their potential usefulness as biomarkers for RCC.
ADAM Proteins↗
Serum macrophage migration inhibitory factor is not elevated in patients with prostate cancer.
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Aged↗
The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia.
Prostate-specific antigen (PSA) is the most useful tumor marker for diagnosis and monitoring of prostate cancer (CaP). Recently, we developed a specific immunoassay for human kallikrein 11 (hK11), one of the kallikrein gene family members, and found that hK11 was highly expressed in prostatic tissue and could be detected in seminal plasma (E. P. Diamandis et al., Cancer Res., 62: 295-300, 2002). The aim of this study was to investigate whether serum hK11 levels could be used to discriminate CaP from benign prostatic hyperplasia (BPH). We analyzed for hK11, total PSA, and percentage of free PSA, 150 serum samples from men with histologically confirmed BPH (n = 64) or CaP (n = 86). Total and free PSA levels were measured by the Immulite PSA assay, and hK11 levels were measured by our previously published immunofluorometric assay. Serum hK11 levels and the hK11:total PSA ratio were both significantly lower in CaP patients than in BPH patients. In the subgroup of patients with percentage of free PSA less than 20, an additional 54% of BPH patients could have avoided biopsies by using the hK11:total PSA ratio. Receiver operating characteristic (ROC) curve analysis demonstrated that the hK11:total PSA ratio [area under the curve (AUC), 0.83] and percentage of free PSA (AUC, 0.83) were much stronger predictors of CaP than total PSA (AUC, 0.69). These preliminary data suggest that the hK11:total PSA ratio could be a useful tumor marker for CaP and could be combined with percentage of PSA to further reduce the number of unnecessary prostatic biopsies.
Aged↗
Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues.
BACKGROUND: Many members of the human kallikrein gene family are differentially expressed in cancer and a few have potential as diagnostic/prognostic markers. KLK14 is a newly discovered human kallikrein gene that is mainly expressed in the central nervous system and endocrine tissues. Since KLK14 was found to be regulated by steroid hormones in prostate cancer cell lines, we hypothesized that it will be differentially expressed in prostate cancer tissues compared to their normal counterparts. METHODS: Matched prostate tissue samples from the cancerous and non-cancerous parts of the same prostates were obtained from 100 patients who underwent radical prostatectomy. Quantitative analysis of KLK14 expression levels were performed by real-time RT-PCR using SYBR Green I dye on the LightCycler trade mark system. Associations with clinico-pathological parameters were analyzed. RESULTS: KLK14 overexpression in the cancerous compared to non-cancerous tissue was found in 74% of patients (P < 0.001). Mean level of expression was 154 arbitrary units (Au) in cancerous tissues and 14.2 Au in the non-cancerous tissues. The ratio of the cancerous to non-cancerous KLK14 expression values was higher in patients with late stage (stage III) compared to stage II (P = 0.002), and in grade 3 compared to grade 1/2 tumors (P = 0.001). A statistically significant increase was also observed in patients with higher in Gleason score (>6) compared to Gleason score = 6 tumors (P = 0.027). No correlation was found between KLK14 tissue expression levels and serum prostate-specific antigen. CONCLUSIONS: KLK14 expression is significantly higher in cancerous compared to non-cancerous prostatic tissue. The up-regulation of the KLK14 gene in advanced and more aggressive tumors may indicate a possible role for the hK14 protein in tumor spread and opens the possibility of hK14 being a candidate new marker for prostate cancer diagnosis and prognosis.
Aged↗
ALCAM/CD166 is up-regulated in low-grade prostate cancer and progressively lost in high-grade lesions.
BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM, CD166) is expressed in various tissues, including malignant melanoma, prostate cancer cell lines, and prostate cancer. We aimed to clarify the expression patterns of ALCAM in normal and malignant prostate tissue. METHODS: RNA from 54 matched pairs of microdissected prostate tissue (tumor and normal) was hybridized to a custom built 4K GeneChip. Frozen section immunohistochemistry was used to confirm the ALCAM expression. RESULTS: Chip-based transcript analysis revealed an up-regulation of ALCAM in prostate cancer in 22% of cases. Immunohistochemistry showed a focally raised ALCAM expression in 81% and a decreased expression in 19% of cases. These expression patterns correlated significantly with Gleason tumor grade: ALCAM up-regulation was found in most low-grade tumors (Gleason grade 1-3), whereas down-regulation occurred preferentially in high-grade tumors (Gleason grade 4 and 5), although up-regulation of ALCAM expression was preserved in two Gleason grade 5 tumors. CONCLUSION: ALCAM expression is commonly disturbed in prostate cancer, which might indicate a role of ALCAM in the progression of this disease.
Activated-Leukocyte Cell Adhesion Molecule↗