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PubMed1997

Prospective evaluation of circulating hepatocytes by alpha-fetoprotein mRNA in humans during liver surgery.

OBJECTIVE: The objective of this study was to analyze the specificity of detecting liver tumor cell dissemination by alpha-fetoprotein (AFP) mRNA in peripheral blood. SUMMARY BACKGROUND DATA: Alpha-fetoprotein mRNA has been used for the detection of circulating micrometastatic tumor foci of hepatocellular carcinoma (HCC); however, the interpretation of the results has been equivocal. METHODS: Sixty-four consecutive patients with malignant HCC (n = 20), liver metastases (n = 27), or nonmalignant (n = 17) liver diseases undergoing partial or total hepatectomy and orthotopic liver transplantation were included in this prospective study from January to July 1995. Peripheral blood samples were obtained before surgery, during surgery, and after surgery (range, 6-15 months). Total mRNA was extracted from nucleated cells, and cDNA synthesis and polymerase chain reaction amplification (nested polymerase chain reaction in one tube) were performed with specific AFP primers. RESULTS: Preoperative AFP mRNA was detected in 20 patients (17%), of which 5 of 20 had HCC. Intraoperative assessment showed positive AFP mRNA values in a total of 34 patients (53%) with various causes, of which 8 of 20 (40%) had HCC, 17 of 27 (63%) had other malignancies, and 9 of 17 (53%) had nonmalignant diseases. Recurrent tumor in patients with HCC occurred in four cases after surgery (range, 6-15 months) and did not correlate with AFP mRNA positivity before surgery, during surgery, or after surgery. CONCLUSIONS: Alpha-fetoprotein mRNA in peripheral blood is not a specific marker of circulating micrometastases from HCC, especially in the context of surgical treatment of HCC.

Biomarkers, Tumor↗
PubMed2003

Real-time quantification of CK-19 mRNA-positive cells in peripheral blood of breast cancer patients using the lightcycler system.

PURPOSE: The purpose of this research was to develop a quantitative real-time reverse transcription-PCR (RT-PCR) for CK19-mRNA and evaluate its clinical potential for the molecular detection of occult carcinoma cells in the peripheral blood of breast cancer patients. EXPERIMENTAL DESIGN: The method is based on real-time monitoring during PCR of fluorescently labeled specific hybridization probes for CK19-mRNA. The breast cancer cell line MCF-7 was used for the development and analytical evaluation of the assay. We analyzed blood samples from 89 healthy blood donors, 77 patients with early breast cancer (stage I-II) postoperatively, and 47 patients with previously untreated metastatic disease (stage IV) before and after chemotherapy. All of the samples were also analyzed by nested RT-PCR. RESULTS: The method is highly sensitive and specific, because only 2 of 89 (2.2%) of the healthy control subjects had detectable CK19-mRNA+ cells. In 77 patients with early breast cancer, CK19-mRNA+ cells were detected in 24 (31.2%) before and 5 (6.5%) after adjuvant chemotherapy, and their levels differed significantly (P < 0.001, Wilcoxon test). In 47 patients with verified metastases 19 (40.4%) and 20 (42.6%) were found positive before and after chemotherapy, and no significant difference in CK19-mRNA+ cell levels was observed (P = 0.96, Wilcoxon test). Results obtained by the proposed real-time RT-PCR method correlated well with those obtained for the same samples by nested RT-PCR [concordance in 312 of 337 (92.6%); P = 0.69, McNemar test]. CONCLUSIONS: The developed method is highly sensitive and specific, and can be used for high-throughput continuous monitoring and quantification of circulating epithelial cells in the peripheral blood of breast cancer patients.

Adolescent↗
PubMed2002

Comparison of two density gradient centrifugation systems for the enrichment of disseminated tumor cells in blood.

BACKGROUND: The detection of disseminated tumor cells in peripheral blood is limited by the presence of very few tumor cells within a large number of blood cells. Therefore, tumor cell detection calls for enrichment systems with effective depletion of blood cells and high tumor cell recovery. METHODS: We compared the new density gradient centrifugation method OncoQuick with the standard method of Ficoll. The enriched cell fractions were quantified. Tumor cell spiking experiments examined the recovery of tumor cells as detected by immunocytochemistry and cytokeratin-20 reverse transcriptase-polymerase chain reaction (RT-PCR). Clinical application of OncoQuick was evaluated in 37 peripheral blood samples of patients with gastrointestinal carcinomas. RESULTS: The depletion of mononuclear cells (MNCs) in the enriched cell fraction after OncoQuick centrifugation was 632-fold, with an average cell number of 9.5 x 10(4), compared with Ficoll, with a depletion factor of 3.8 and a mean number of 1.6 x 10(7) MNCs. The mean tumor cell recovery rates were 87% for OncoQuick and 84% for Ficoll. The increased depletion of MNCs with OncoQuick centrifugation further simplified immunocytochemical evaluation by reducing the number of cytospins and increasing the tumor cell density. Due to the reduced number of co-enriched MNCs by OncoQuick, the blood volume, which could be analyzed in one RT-PCR reaction, was increased up to 30 ml. Examination of peripheral blood samples from 37 patients with gastrointestinal tumors showed a cytokeratin-20 detection rate of 30% and a significant correlation with the presence of distant metastases (P < 0.02). CONCLUSIONS: OncoQuick significantly reduced the co-enriched number of MNCs, with a high tumor cell recovery rate. Processing blood from tumor patients with OncoQuick increased the chance of detecting circulating tumor cells.

Cell Count↗
PubMedDate not supplied

Comparison of the expression profile of metastasis-associated genes between primary and circulating cancer cells in oral squamous cell carcinoma.

Tumor metastasis is a complex process involving several distinct steps such as escape from a primary tumor, dissemination through the circulation, lodgment in small vessels at distinct sites, penetration of the vessel wall and growth in the new site as a secondary tumor. To compare the expression profile of metastasis-associated genes between circulating cancer cells in peripheral blood and cells in the primary lesion of oral squamous cell carcinoma (OSCC), we employed a combination analysis of laser captured microdissection (LCM) and immunomagnetic separation (IMS) techniques for capturing primary and circulating cancer cells, respectively. Total RNAs were then extracted from each cell and mRNA expression of CK19, matrix metalloproteinases (MMP-1, -2, -7, -9) and CD44, including its variant forms (CD44s, v6, v9), were analyzed by RT-PCR. Although CD44 including its variant forms were expressed in 20%(CD44s) to 30%(v6, v9) of the primary lesion, 40%(v6) to 90%(CD44s) of blood samples were CD44-positive. Furthermore, MMPs were expressed in 30%(MMP-1, -2) to 60%(MMP-7) of primary samples, whereas most blood samples were negative for the expression of MMPs. These results suggested that circulating cancer cells might express different characteristics after being released from the primary lesion.

Aged↗
PubMed2003

Circulating blasts following chemotherapy in pediatric patients: implications for complete remission definition in acute leukemia.

We assessed the incidence of circulating blasts occurring post-chemotherapy in 1000 consecutive pediatric blood samples. Blasts with myeloid morphology (<1-3%) were present in post-chemotherapy samples in 19 of 294 (6.4%) patients with acute leukemia in remission and in 11 of 361 (3.4%) patients with solid tumors, non-Hodgkin or Hodgkin lymphoma, and were associated with ANC>1.5x10(9)/l in 13 of 30 (43%) samples, and platelets >100x10(9)/l in 25 of 30 (83%) samples. Our findings suggest that the absence of circulating blasts may not be a prerequisite for remission in acute myeloid leukemia (AML).

Acute Disease↗
PubMed1998

[Detection of urogenital malignant cells in the peripheral blood by nested RT-PCR using keratin 19 mRNA].

INTRODUCTION AND OBJECTIVES: It is reported that cytokeratin 19 (CK-19) mRNA is not expressed in the peripheral blood cells of the healthy subjects (Am. J. Pathol. 142: 1111. 1993). Detection of DNA fragments of CK-19 in the peripheral blood suggests the existence of epithelial malignant tumor cells. In this study, we detected CK-19 genes in peripheral blood of patients with urogenital malignancy, and thus clarified the possibility of understanding tumor expansion. METHODS: Mononuclear cells were separated from the peripheral blood of 39 patients with urogenital tumor and 9 controls. Total cellular RNA was extracted according to the method described elsewhere. The CK-19 gene expression was investigated using nested reverse transcription polymerase chain reaction (nested RT-PCR) and confirmed by Southern Blotting. These results were compared to the clinical stages. RESULTS: CK-19 mRNA was not detected in any of 9 controls. CK-19 mRNA was detected in 3 out of the 10 bladder cancer cases. Two had metastases and 1 had muscle invasion without metastasis. One of 6 urothelial cancer case of the upper urinary tract showed positive amplification, and had liver, bone and lymphnode metastases. After one course of chemotherapy, mRNA became negative. In prostate cancer cases, three among 7 were positive and all 3 cases had distant metastases. In renal, testicular and penile cancer cases, the positive ratio were 3/6, 1/8 and 2/2, respectively. All positive cases of renal and testicular cancer had distant metastases, but one case of penile cancer had no metastasis. CONCLUSION: The detection of CK-19 mRNA in the circulating blood by nested RT-PCR makes it possible to detect micrometastasis, to evaluate therapeutic effects and to predict the prognosis.

Adult↗
PubMed1996

Anatomic distribution of metastases in the vertebral body and modes of hematogenous spread.

STUDY DESIGN: A retrospective review of the magnetic resonance spine examinations of 49 patients with metastatic bone disease to the spine was performed. OBJECTIVES: To determine whether the pattern of metastatic distribution in the spine correlates with the type of primary tumor and theoretical mode of hematogenous spread by arterial or venous routes. SUMMARY OF BACKGROUND DATA: In 1940, Batson theorized a venous plexus route by which tumors spread to the spine from pelvic tumors such as prostatic carcinoma. It this theory is true, the venous vascular anatomy of the spine would result in metastases being deposited in the central or posterior vertebral body, whereas arterial deposits would occur near the end-plates. METHODS: Each vertebral body was divided into 27 equal cells in the magnetic resonance images; the central and posterior cells in the midsagittal view were defined as central, and the other cells were defined as peripheral. The primary tumor was assigned to either the arterial or venous group based on Batson's proposed mode of spread. The average number of lesions per involved vertebral body in the central and peripheral regions was calculated. RESULTS: There was no statistically significant correlation between tumors with proposed arterial/venous routes of metastasis and central/peripheral location of metastatic deposits. CONCLUSION: The mechanism by which tumors spread to the vertebral body may not be via a pure arterial or venous route. Other mechanisms such as tissue specificity, cascade system, and closed loop circulation system may be involved.

Adolescent↗
PubMed2006

Molecular screening for breast cancer prevention, early detection, and treatment planning: combining biomarkers from DNA, RNA, and protein.

The completion of the human genome project, along with the ancillary technologies derived from this effort, provides the ability to comprehensively analyze patient tumors as well as the individual patient's own genetic make-up at the DNA, RNA, and protein level. As a result, novel molecular screening techniques have the potential to push the boundaries of detection to even smaller tumors and also to allow accurate risk assessment, cancer prevention, and treatment planning in individual women. This review focuses on advances over the past 2 years in the use of molecular signatures and circulating tumor cells for early breast cancer detection and for prediction of response to therapy.

Biomarkers, Tumor↗
PubMed2000

Detection of circulating tumor cells in carcinoma patients by a novel epidermal growth factor receptor reverse transcription-PCR assay.

The epidermal growth factor receptor (EGFR) is overexpressed in 50-70% of human primary breast, lung, and colon carcinomas, whereas it is not usually expressed in hematopoietic cells. We developed a novel reverse transcription-PCR (RT-PCR)-Southern blot assay for the detection of circulating, EGFR mRNA-expressing tumor cells in carcinoma patients. The assay was set up by increasing the amount of cDNA step by step in the PCR reaction. The highest sensitivity and specificity were found when using 800 ng of cDNA in the PCR reaction. Peripheral blood samples from 91 patients with either colon (38), lung (30), or breast (23) carcinomas and from 38 healthy volunteers were analyzed. EGFR transcripts were found in 44 of 75 (59%) patients with metastatic carcinoma and in 4 of 38 (10.5%) healthy donors (P < 0.001; chi2 test). The expression of EGFR, cytokeratin 19, and carcinoembryonic antigen mRNA in blood samples from patients with metastatic colon carcinoma was compared. EGFR, cytokeratin 19, and carcinoembryonic antigen transcripts were found in 8 of 11 (73%), 3 of 11 (27%), and 5 of 11 (45%) patients, respectively. Furthermore, two of seven (29%) Dukes' B and five of nine (55%) Dukes' C colon carcinoma patients were found to express EGFR mRNA in the peripheral blood. All patients that expressed EGFR transcripts in the peripheral blood were found to express the EGFR protein in the corresponding primary carcinoma, as assessed by immunohistochemistry. These data suggest that the EGFR assay that we developed is a highly specific and sensitive technique to detect circulating tumor cells in patients affected by different carcinoma types.

Breast Neoplasms↗
PubMed1980

Role of natural killer cells in the destruction of circulating tumor emboli.

A close correlation was demonstrated between levels of host natural cytotoxic (NC) and/or natural killer (NK) cell activity and capacity to eliminate blood-borne tumor cells. The outcome of experimental metastasis of several tumors with defined biologic behavior was studied in syngeneic mice exhibiting low NK cell activity [3-wk-old normal mice and cyclophosphamide (Cy)-treated adult mice] and high NK cell activity (normal adult mice). An iv injection of metastatic tumor cells into 3-week-old or Cy-treated mice markedly enhanced experimental pulmonary metastasis. The increased incidence of metastasis in mice exhibiting low activity of NK cells was not due to enhanced tumor cell arrest in the lung but rather to increased tumor cell survival. Boosting the NK activity of 3-week-old, but not Cy-treated, mice with interferon inducers inhibited metastasis formation. The adoptive transfer of spleen cells from syngeneic mice or allogeneic nude mice that have high NK activity shortly before (but not after) iv tumor challenge abrogated the Cy-induced enhancement of metastasis. The reactive lymphoid cells were non-T, nonadherent to nylon wool, sensitive to Cy treatment, and endowed with a natural ability to kill tumor cells during a short (12-24 hr) period. The conclusions were that NC-NK cells are important in host defense against circulating tumor cells and therefore can prevent the development of tumor cells into metastases.

Adjuvants, Immunologic↗
PubMed2000

[Isolated tumor cells in primary malignant liver tumors].

The failure to reduce the mortality of patients with malignant liver tumors (hepatocellular carcinoma, cholangiocarcinoma) is probably a result of the early dissemination of cancer cells to secondary sites, which is usually missed by conventional diagnostic procedures used for tumor staging. Recent developments in the field of molecular biology enable us to detect tumor cells at a submicroscopic level. Therefore, over the past 10 years, sensitive assays have been developed to detect individual carcinoma cells disseminated to regional lymph nodes or distant organs. In contrast to colorectal and also breast cancer where disseminated tumor cells may be of additional prognostic value, few data exist for hepatocellular carcinomas. Until now, no relevant studies have been reported for cholangiocarcinoma. Alpha-fetoprotein and also albumin mRNA have been used for the detection of circulating micrometastatic tumor foci of hepatocellular carcinoma (HCC); however, the interpretation of the results has been equivocal. If hepatocyte-specific mRNAs are detected in the circulation, it is possible to infer the presence of circulating, presumably malignant, liver cells. The literature about the incidence of "micrometastases" and specificity of different assays for hepatocellular carcinomas varies tremendously. This clearly indicates the need for uniformity in protocols. For hepatocellular carcinoma, mRNA for alpha-fetoprotein and albumin is not a specific marker of circulating micrometastases, but may serve for treatment monitoring. Nevertheless, PCR-based techniques are a powerful tool in the therapeutical monitoring of hepatocellular carcinoma and will find their way into the daily practice of diagnostic histopathologists in the near future.

Bile Duct Neoplasms↗
PubMed2002

Molecular detection of micro-metastasis in breast cancer.

Metastatic spread of breast cancer begins with the dissociation of cancer cells from the primary tumour. The dissociated cancer cells either settle in or trespass through the tissues/organs that they encounter, thus leaving residual or micro-metastasis in the tissues or organs. Detection of the residual cells and micro-metastasis in tissues or organs other than the originating tissues and circulating cancer cells constitutes an important aspect in staging, predicting prognosis and design therapy. However, the size of micro-metastasis and number of tumour cells, particularly in the circulation and bone marrow have presented a challenge for reliably and sensitively detecting them. Recent development in technology, including quantitative DNA sequence detection has increased the prospect for detection in this area. Recent studies have shown that molecular detection of micro-metastasis disease from lymph nodes, bone marrow, and the blood circulation can provide very valuable information for the presence of micro-residual disease and its impact on tumour progression and clinical outcomes. The current article discusses recent developments, in the detection of micro-metastasis using molecular biology techniques.

Bone Marrow↗
PubMedDate not supplied

Expression and shedding of CD44 variant isoforms in patients with gynecologic malignancies.

OBJECTIVES: The presence of CD44 isoforms was evaluated in ascitic fluid and serum samples of patients with gynecologic malignancies. Previously, the shedding of tumor-associated cell surface antigens has been demonstrated in the blood and malignant effusions of gynecologic cancer patients. Thus, the shedding of CD44 was also studied in ascitic fluids and sera of these patients, to address variant isoform expression as a biomarker of gynecologic cancer. METHODS: The expression of CD44 isoforms by ovarian tumor cells was examined by flow cytometry using variant-specific monoclonal antibodies. The release of these isoforms into the peripheral circulation and ascites was assayed by Western immunoblot analysis. RESULTS: Flow cytometric analysis of ovarian tumor cell lines revealed a strong expression of CD44 with significant levels of v4/5 and v6 isoforms. The presence of circulating CD44 isoforms was detectable in the sera of six of eight cancer patients, as well as in 12 of 16 ascitic fluids. Of the CD44-positive specimens, all six positive sera expressed detectable levels of variant CD44. The CD44v6 was present in all of the positive sera samples tested. In the ascites, the "shed" CD44 appeared to be associated predominantly with shed particles (vesicles) of plasma membranes (membrane fragments). Of ten CD44-positive ascites samples, all expressed significant levels of variant CD44. CONCLUSIONS: In addition to mediating metastasis, the differential expression and shedding of CD44 isoforms into the circulation may represent important determinants in the escape of tumors from immune surveillance, and their detection may be a diagnostic or prognostic marker.

Aged↗
PubMed2002

Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis.

BACKGROUND: Ovarian carcinoma is apparently restricted for a long time to the peritoneal cavity. However, about 50% of patients with a surgically documented complete intraabdominal response experience later recurrence. Occult hematogenous micrometastases are common to most epithelial malignancies and have recently been found in 30% of bone marrow samples of ovarian carcinoma patients, as examined by immunocytochemistry. Moreover, these findings were associated with poor progression-free and overall survival. The aim of the current study was to evaluate the possible prognostic significance of tumor cells detected in the peripheral blood and bone marrow of ovarian carcinoma patients by an immunomagnetic method. METHODS: In a total of 90 patients with histologically proven epithelial ovarian carcinoma, blood and (in 73 cases) bone marrow samples were taken. Tumor cells were identified by a microbead coated with the antibody MOC-31, which recognizes an epitope regularly expressed on ovarian carcinoma cells. RESULTS: The authors detected carcinoma cells in the bone marrow in 21% of ovarian carcinoma patients, and in the peripheral blood in 12% of patients. Mean overall survival was 25 and 28 months for patients with or without circulating tumor cells, respectively. CONCLUSIONS: Ovarian carcinoma cells seem to reach peripheral circulation more frequently than expected. However, in contrast to an earlier report, detection of tumor cells in the bone marrow and/or blood was not associated with poor prognosis in ovarian carcinoma patients. This discrepancy remains unexplained, but characterization of circulating ovarian carcinoma cells for their malignant and metastatic capacity is clearly warranted.

Adult↗
PubMed2005

Tumor cell dynamics and metastasis in advanced neuroblastoma.

This study deals with the advancement process of neuroblastoma through clinical observations and circulating tumor cell exploration. Clinical feature, tumor biology, and circulating tumor cell detected by the previously described polymerase chain reaction (PCR) method were analyzed in 31 patients with advanced neuroblastoma treated in our department since 1991 through 2004. Treatment was completed in 28 patients, of whom 17 are alive without the disease and 11 died. The primary lesion was not confirmed in 2 patients with disseminated metastasis, both of whom showed positive circulating tumor cell. Circulating tumor cell was positive in 6 of 9 examined at their first appearance at the hospital, all had stage 4 disease, and 4 of the 6 (66.7%) died of systemic spread of the disease. N-myc was amplified in 15 patients, of whom only 2 (13.3%) died of systemic metastasis. N-myc amplification did not correlate with positive circulating tumor cell. A certain population of neuroblastoma may provide circulating tumor cells from the early period of the disease to form metastatic lesions independently of the primary lesion, which must be regulated by factors other than N-myc. Circulating tumor cells may suggest higher risk for systemic dissemination and poor prognosis.

Bone Neoplasms↗
PubMed2001

A PCR-ELISA assay for the detection of disseminated osteosarcoma cells in a mouse metastatic model.

Circulating tumor cells in the blood play a central role in the metastatic process. There have been no reports describing the relationship between lung metastasis and circulating osteosarcoma cells. We developed a system with a polymerase chain reaction assay based on an enzyme-linked immunosorbent assay (PCR-ELISA) to detect circulating osteosarcoma cells in a mouse metastatic model. Osf2/Cbfa1, hereafter called Osf2, a member of the runt family of transcription factors, was used as a target gene. One splicing variant of Osf2 mRNA was identified and its expression was restricted to the bones and osteosarcomas. The amount of the splicing variant of Osf2 mRNA was significantly higher in the blood of mice with metastasis than in the blood of the control group. The PCR-ELISA using Osf2 mRNA is a potential method to detect circulating osteosarcoma cells in peripheral blood.

Alternative Splicing↗
PubMed2006

Detection of Mammaglobin A-mRNA-positive circulating tumor cells in peripheral blood of patients with operable breast cancer with nested RT-PCR.

OBJECTIVES: The development and validation of a nested RT-PCR methodology for the detection of Mammaglobin A-mRNA-positive circulating tumor cells in peripheral blood of patients with operable breast cancer and evaluation of its prognostic significance. DESIGN AND METHODS: Different combinations of specific primers were in silico designed and selected, so that false positive results due to genomic DNA contamination were avoided. The specificity of the primers used was evaluated in 30 healthy individuals, 20 patients with colorectal cancer and 20 patients with non-small cell lung cancer. The method was applied in 101 patients with operable breast cancer before the administration of adjuvant chemotherapy and 39 patients with metastatic breast cancer. RESULTS: Mammaglobin A-mRNA-positive cells were detected in 14/101 (13.9%) of early breast cancer patients but not in the control population studied (0%); 9 of them (64.3%) relapsed during the follow-up period. Mammaglobin A was detected in 7/39 (17.9%) of patients with verified metastasis. Multivariate analysis revealed the detection of Mammaglobin A-mRNA-positive cells, as an independent risk factor for reduced DFI. CONCLUSIONS: Mammaglobin A is a highly specific molecular marker for the detection of circulating tumor cells in operable breast cancer, with important prognostic applications.

Biomarkers, Tumor↗