In vivo isolation of circulating tumor cells in patients with different stages of prostate cancer.

Circulating tumor cells (CTCs) provide accurate information on the clinical stage of cancer progression. The present study examined the clinical validity and feasibility of a new medical device for the in vivo isolation of CTCs from the blood of patients with prostate cancer (PCa). The GILUPI CellCollector® (DC01) was applied in 188 cases. The CTC/prostate-specific antigen (PSA) profile of each patient was checked for therapeutic monitoring of patients with PCa. The CellCollector, which is a unique in vivo approach for the isolation of CTCs, was compared with the CellSearch® system, which is the current standard. Overall survival (OS) and diagnostic performance were evaluated. By in vivo isolation, 78.9% (56/71) of patients with metastatic disease (PCa-m) and 46.3% (24/53) of patients with localized disease (PCa-l) had ≥1 captured CTC. Kaplan-Meier analysis revealed that patients with PCa-m that had ≥5 CTCs had a significantly different OS compared with those with <5 CTCs (27.5 months vs. 37 months; HR 2.6; 95% CI 0.78-8.3). Patients with a higher number of CTCs at all time-points had the shortest median OS of 25 months (HR 1.9; 95% CI 0.4-11.6). The effectiveness of CTC isolation technologies demonstrated that in 65.7% of the applications, patients with cancer were positive for CTCs using the CellCollector. By contrast, the CellSearch system detected CTCs in 44.4% of applications. In vivo isolation of CTCs demonstrated the clinical viability of the CellCollector, related to the current standard for the isolation of CTCs from patients with PCa. The advantage of the in vivo device is that it overcomes the blood volume limitations of other CTC assays. Furthermore, the present study revealed that the CellCollector was well tolerated, and no adverse events (AEs) or serious AEs were reported.

The Use of a New CellCollector to Isolate Circulating Tumor Cells from the Blood of Patients with Different Stages of Prostate Cancer and Clinical Outcomes - A Proof-of-Concept Study.

BACKGROUND AND METHODS: Circulating tumor cells (CTCs) constitute a useful approach for personalized medicine. Nevertheless, the isolation of these cells remains very challenging because they rarely circulate in the blood. Another current problem is the cancer-specific characterization of these cells, which requires a method that allows for the molecular and immunocytochemical profiling of all captured cells. The purpose of our proof of concept study was to investigate the use of a medical wire (CellCollector, GILUPI) to isolate CTCs in the blood of prostate cancer (PCa) patients, which allowed CTCs to be counted and molecularly characterized. Forty-three PCa patients in different stages and 11 control subjects were studied. Some randomized samples were used to detect tumor-associated transcripts, such as prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA) and epidermal growth factor receptor (EGFR), in the isolated CTCs. RESULTS: The mean CTC counts were 4.6 CTCs [range, 0-8] in patients with localized PCa, 16.8 CTCs [range, 10-25] in patients with locally advanced PCa, and 26.8 CTCs [range, 0-98] in patients with metastatic PCa. The median follow-up time was 24 months, and there was a significant difference in the cancer-specific survival rates. Patients with CTC counts under 5 CTCs lived significantly longer (p = 0.035) than patients with more than 5 CTCs. We also demonstrated that the captured CTCs could be molecularly characterized. We detected tumor-associated transcripts of EGFR and PSMA in patients with metastatic PCa in 42.8% and 14.3% of the analyzed samples, respectively. CONCLUSION: Our results indicate that the sensitive isolation and molecular characterization of CTCs can be achieved ex vivo using the wire. Patients with more than 5 CTCs had a mortality risk that was 7.0 times greater that of those with fewer than 5 CTCs (hazard ratio 7.0 95%, CI 1.1-29.39). This proof of concept was required for the approval of the use of the CellCollector in a clinical study for the in vivo isolation of CTCs from the blood stream of PCa patients by the Federal Institute for Drugs and Medical devices (Germany, BfArM).

Serum amyloid A: a biomarker for renal cancer.

BACKGROUND/AIM: Serum amyloid A (SAA) has been identified as a potential biomarker for renal cell carcinoma. We examined its diagnostic value in patients of different tumor stages. PATIENTS AND METHODS: In our study, 48 patients with localized and 67 patients with advanced renal tumors were included. 24 patients served as a control group. Interleukine 6 (IL-6), C-reactive protein (CRP) and SAA levels were measured preoperatively and at day 5 after nephrectomy. RESULTS: The IL-6, CRP and SAA levels in patients with advanced tumors are significantly higher than those of patients with localized tumors. Advanced tumors were identified with a sensitivity of 78% (SAA), 69% (CRP) and 44% (IL-6). The specificity was 82%, 82% and 94% for SAA, CRP and IL-6, respectively. CONCLUSION: Our results indicate that advanced renal cancers are accompanied by increased levels of acute-phase proteins such as CRP and SAA. SAA is found to be more sensitive than CRP for the indication of advanced renal cancer.

Monitoring peri-operative immune suppression in renal cancer patients.

The aim of this study was the identification of surrogate markers of host immunity in renal cell carcinoma (RCC) patients. Using 4-color flow cytometry the immunophenotype of blood immune cells of RCC patients was compared to that of healthy volunteers and correlated with staging and grading of patients. Furthermore, the time course of these immune markers was compared in RCC patients undergoing either open surgery or laparoscopy. Compared to the healthy control group, blood of RCC patients contained more granulocytes and higher percentages of CTLA4+CD8+ T lymphocytes, but reduced numbers of dendritic cells (DCs) and of CD28+ CD8+ T cells. Tumor progression was associated with a higher white blood cell count, a reduced frequency of blood DCs and increased numbers of CD57+ T and NK cells. Monocytes of patients with advanced RCC showed a reduced HLA-DR surface expression associated with higher aminopeptidase N(APN)/CD13 expression. Tumor surgery caused an increase of granulocytes and a decrease of all lymphocytic and DC subpopulations within 24 h, whereas the number of HLA-DR low monocytes was up-regulated. As demonstrated by time kinetic analysis, laparoscopic intervention caused a more moderate immunosuppression and an enhanced restoration of immune activity than open surgery. These results suggest that the composition and the phenotype of innate immune cells reflect well the differences in the cellular immunity of RCC patients associated with tumor disease as well as surgery. The monocytic HLA-DR intensity represents a suitable marker for monitoring tumor stage and surgery-associated immunosuppression in RCC patients.

A clinical study of annular geometry and dynamics in patients with ischemic mitral regurgitation: new insights into asymmetrical ring annuloplasty.

OBJECTIVE: Recent studies in animals showed that regional annulus distortion is a major determinant of ischemic mitral regurgitation (IMR) and accordingly suggested new surgical approaches with asymmetrical annuloplasty rings. As accurate measurement of annulus in patients is still a challenge, we performed this study to analyze the changes in three-dimensional annular geometry in patients with IMR compared to primary valvular lesions. METHODS: We studied 110 patients divided into three groups: (1) 30 with coronary artery disease without IMR, (2) 38 with chronic IMR, and (3) 42 with MR due to primary valvular lesions. Longitudinal and septal-lateral annulus diameters; global diastolic and systolic annular area and its percentual shortening, diastolic and systolic areas of six regions corresponding to the segmental Carpentier classification were measured by 3D-echocardiography. The degree of MR was assessed by three-dimensional color Doppler. Global and regional left ventricular geometry were assessed by sphericity index and by measuring anterior and posterior tethering of papillary muscles. RESULTS: Patients with significant IMR (group 2) showed larger longitudinal (52.7+/-3.9 mm vs 41.8+/-2.9 mm; p<0.01) and antero-lateral (31.8+/-3.5mm vs 26.7+/-2.8mm; p<0.01) annular diameters than the patients with MR due to primary valvular lesions (group 3). Diastolic (997.8+/-64.9 mm(2) vs 700.7+/-46.8mm(2); p<0.01) and systolic (894.9+/-57.3mm(2) vs 547.3+/-35.0mm(2); p<0.01) annular areas were larger in group 2 than in group 3. Annular area change was significantly lower in the group with ischemic mitral regurgitation than in the group with primary valvular lesions (10.3+/-1.1% vs 21.9+/-1.6%; p<0.01). Regional annular areas of the six sectors were homogeneously larger in group 2 than in group 3. The sector P3 did not show larger area than the other ones. The degree of MR, as assessed by the volumes of regurgitant jets, was higher in the group with primary valvular lesions than in the patients with IMR (32.6+/-13.4 cm(3) vs 23.1+/-11.1cm(3); p<0.01). CONCLUSIONS: This study showed that annular enlargement in patients with IMR affects the different annular regions to the same extent. An ideal surgical repair of IMR should be individually tailored after quantitative assessment measurement of geometry and function of each single component of the mitral valve complex.