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PubMed1997

Detection of circulating tumor cells in patients with prostate cancer using prostate specific membrane-derived primers in the polymerase chain reaction.

BACKGROUND: Prostate specific membrane antigen (PSM) is a transmembrane glycoprotein that has been described as human prostate specific. It is possible that PSM could be used as a biomarker for staging prostate cancer. METHODS: Peripheral blood mononuclear cells from 2 groups of patients with prostate cancer were used for the detection of PSM messenger ribonucleic acid (mRNA) using the reverse transcriptase-polymerase chain reaction (RT PCR) method. Group 1 consisted of 29 untreated patients (13 stage B cancer, 5 stage C, and 11 stage D cancers). Group 2 consisted of 40 treated patients (23 responded well and 17 had recurrence after treatment). In addition, blood specimens from 30 patients with benign prostatic hyperplasia, 5 women, and 5 men undergoing cystoprostatectomy for invasive bladder cancer were used as controls. We then correlated patient and disease characteristics with PCR assay results. RESULTS: Samples of all 40 controls were negative for PSM-mRNA. Thirteen of 29 patients of group 1 (45%) were positive for PSM-mRNA. The PCR positive rate did not correlate with clinical stage, pathologic stage, tumor grade, or serum PSA levels. Nine of 40 patients (22%) in group 2 were positive for PSM-mRNA, and the majority (8 of 9) were derived from the group of patients with recurrent disease. CONCLUSIONS: A nested RT PCR assay for PSM mRNA can detect circulating tumor cells in the peripheral blood of patients with prostatic cancer. These results suggest that the detection of circulating tumor cells could be useful for monitoring disease progression of prostatic cancer.

Adenocarcinoma↗
PubMed2001

Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review.

BACKGROUND: The central nervous system (CNS) can be a sanctuary site for cancer cells, because the blood-brain barrier impedes penetration of most chemotherapeutic agents. The authors hypothesized that, with improved survival from childhood metastatic neuroblastoma (NB), the incidence of CNS (intraparenchymal and leptomeningeal) spread may increase. They undertook this study to assess the frequency of CNS NB, to analyze risk factors and treatment options, and to review the literature. METHODS: The authors retrospectively analyzed all patients with metastatic NB who were treated on protocols N4, N5, N6, and N7 from 1980 to 1999 at Memorial Sloan-Kettering Cancer Center (MSKCC), during which time there was an increase in the overall survival rate. RESULTS: Two hundred fifty-one patients with Stage 4 NB (Group 251) were studied, of which 127 (Group 127) were newly diagnosed patients who were treated initially at MSKCC. None had CNS NB at the time of diagnosis. Eleven patients developed documented CNS disease; 8 of these 11 recurrences were isolated in the CNS. For Group 127, the overall incidence rate of CNS NB was 6.3%, with an increase in incidence from N4-N5 to N6-N7 of from 1.7% to 11.7%. Seven patients had isolated CNS disease recurrences. Only lumbar punctures (LP) performed near the time of diagnosis in patients with known bone marrow involvement were associated with subsequent development of CNS disease. For the entire group of 251 patients, lumbar puncture at the time of diagnosis and elevated serum lactic dehydrogenase levels were prognostic. Among the larger series reported in the literature, CNS involvement from metastatic lesions was rare at the time of diagnosis and remained an uncommon complication. CONCLUSIONS: The incidence of CNS NB may be increasing. Because it is the sole site of disease recurrence in 64% of patients, the CNS may represent a sanctuary site for NB. CNS NB is associated with diagnostic lumbar punctures in patients with known bone marrow disease, raising the possibility that circulating or epidural microscopic tumor cells may seed the craniospinal axis.

Adrenal Gland Neoplasms↗
PubMed2000

[The expression and clinical significance of keratin 19, 20 mRNA in different tumor cell lines and tumor tissues].

OBJECTIVE: To study the expression of keratin 19, 20 (K19, K20) in different tumor cell lines and tumor tissues and its clinical implication. METHODS: Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was employed to examine the specific expression of K19 and K20 mRNA in eleven tumor cell lines and 33 corresponding tumor tissue specimens. RESULTS: The expression of K19 mRNA was detected in 4 kinds of tumor cell lines and all tumor tissues examined, but the magnitude of expression differed, with a difference ranging from 1.7 to 10 folds for the same type of cancer. In some patients, the level of expression was as low as 12% of the positive control. K20 mRNA expression was negative for lung and esophageal tumor cell lines and the corresponding carcinoma specimens. In one of 6 bladder cancer specimens and in 4 of 5 colorectal cancer tissues, K20 expression was positive, at a level of 41%-77% of the positive control. There was no expression of K20 in bladder tumor cell line EJ1 and colorectal tumor cell line SW480. CONCLUSION: These results demonstrate that K19 and K20 may be used as a valuable marker for detecting circulating cancer cells, but the low level of expression in some cases of carcinoma would probably result in false negative results.

Biomarkers, Tumor↗
PubMed1992

[Portal blood levels of mitomycin C after intraperitoneal administration].

Portal blood levels of mitomycin C (MMC) were measured after intraperitoneal administration of 10 or 20 mg of mitomycin C following pancreatoduodenectomy. The portal concentration of MMC increased rapidly to the maximum concentration of 826 +/- 364 ng/ml at 5 minutes after administration, when the dosage was 20 mg (four cases). The peripheral blood levels followed the portal levels and the maximum concentration was 397 +/- 123 ng/ml at 15 minutes. Then the MMC levels of both portal and peripheral blood decreased gradually, but concentration higher than 100 ng/ml was maintained for 90 minutes after administration. In four patients given 10 mg of MMC, the patterns of the blood levels were similar, but the concentration was lower than in the group given 20 mg. In both groups, the AUC values were higher in portal than in peripheral blood. MMC administered intraperitoneally was absorbed rapidly through portal circulation and a high MMC level of portal blood was obtained. Therefore, it would prevent the dissemination of cancer cells into the liver which may well occur during operation for pancreatic carcinoma.

Humans↗
PubMed2006

Development and evaluation of a colorimetric membrane-array method for the detection of circulating tumor cells in the peripheral blood of Taiwanese patients with colorectal cancer.

Early detection is the hallmark of successful cancer treatment. Evidence is accumulating that primary cancers begin shedding neoplastic cells in the circulation at an early stage. To date, a high-sensitivity and high-throughput method for the detection of circulating tumor cells (CTCs) is deficient. In this study, we have developed a high-sensitivity colorimetric membrane-array method to detect CTCs in the peripheral blood of colorectal cancer (CRC) patients as a potential diagnostic tool. Previously, we identified a set of 18 oligonucleotide clones, significantly overexpressed in CRC, which were synthesized and applied to a nylon membrane. Digoxigenin (DIG)-labeled cDNA were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) from the peripheral blood of 88 Taiwanese CRC patients and 50 healthy subjects, and were then hybridized to the membrane-array. Hybridization signals were detected by color development. Meanwhile, blood samples were analyzed by real-time quantitative PCR (Q-PCR). Subsequently, both methods were compared regarding their correlation, sensitivity and specificity in the detection of CTCs by statistics. The results of membrane-arrays were demonstrated to be closely related to that of Q-PCR (P<0.001). The sensitivity and specificity of membrane-arrays for the detection of CTCs were 94.3% (95% CI, 86.4-102.2%) and 94% (95% CI, 85.9-102.1%), respectively. Moreover, the accuracy of membrane-arrays is higher than that of any one gene by Q-PCR. The detection rate of membrane-arrays was significantly associated with the depth of tumor invasion (P=0.002), the presence of lymph node metastasis (P=0.016), and TNM stage (P=0.005). The preliminary results indicated that the accuracy of membrane-arrays was sufficient to distinguish Taiwanese CRC patients from normal individuals with the advantages of time-saving, cost-effectiveness and high-throughput. Thus, the constructed colorimetric membrane-array could be a promising approach for the future detection of CTCs.

Adult↗
PubMed1997

Detection of colorectal carcinoma cells in circulating peripheral blood by reverse transcription-polymerase chain reaction targeting cytokeratin-20 mRNA.

For the detection of circulating colorectal carcinoma cells, we investigated the presence of cytokeratin 20 (CK 20) mRNA in the peripheral blood of colorectal carcinoma patients. Application of our published technique resulted in analysis by reverse transcription followed by three-step nested polymerase chain reaction. This analysis could detect a single Colo 205 colon cancer cell mixed with 1 ml of blood. Our system also successfully detected the presence of CK 20 mRNA in actual patients' peripheral blood samples. Our highly sensitive and specific system for the detection of CK-20 mRNA from patients' peripheral blood thus seems to be useful for screening for circulating colorectal carcinoma cells.

Adult↗
PubMed2004

Circulating tumour cells in breast cancer.

By use of modern immunological and molecular analytical techniques, cells with the characteristics of tumour cells can be detected in the blood of many patients with breast cancer. The ability to detect and characterise such cells routinely could have a profound influence on the early diagnosis of breast cancer, risk stratification in the adjuvant setting, early detection of relapse, and the development of new targeted strategies. In this review we discuss current techniques to detect circulating breast-cancer cells and the limitations of these approaches. We also review the clinical studies in breast cancer and discuss the potential relevance of this research to the future management of the disorder.

Breast Neoplasms↗
PubMed2004

Microphthalmia-associated transcription factor and tyrosinase as markers of melanoma cells in blood of patients with melanoma.

AIM: To investigate whether analysis of microphthalmia-associated transcription factor (MITF) as an additional marker to tyrosinase in melanoma patients can improve the detection of circulating melanoma cells by reverse-transcription-polymerase chain reaction (RT-PCR). METHODS: Blood samples were taken from 33 patients with metastatic melanoma. RNA was isolated from mononuclear cell fraction of the blood and reversely transcribed into the complementary DNA (cDNA). The cDNA was assayed by PCR for the expression of tyrosinase and MITF. Peripheral blood samples from 15 healthy subjects were used as controls. RESULTS: The threshold for detection of both tyrosinase and MITF was set low enough to detect 50 melanoma cells in 10 mL of healthy volunteer blood in the relative ratio of one melanoma cell in 0.82 x 106 peripheral blood leukocytes. Out of 33 blood samples from metastatic melanoma patients, 5 were positive for both tyrosinase and MITF, 7 for tyrosinase only, and 5 for MITF only. All samples from healthy volunteers were negative for both tyrosinase and MITF. CONCLUSION: Determination of MITF marker in addition to tyrosinase improved the detection of circulating melanoma cells in patients with metastatic melanoma.

Adult↗
PubMed2004

Detection of circulating Tg-mRNA in the follow-up of papillary and follicular thyroid cancer: how useful is it?

To investigate the usefulness of thyroglobulin mRNA (Tg-mRNA) detection in peripheral blood in the follow-up of papillary and follicular (differentiated) thyroid cancer, a literature study was performed. Both evidence for and evidence against the usefulness of Tg-mRNA detection were found. Also, evidence for the expression of Tg-mRNA in cells other than normal or neoplastic thyroid follicular cells was found. It is concluded that currently Tg-mRNA detection is not a useful tool in the follow-up of differentiated thyroid carcinoma, but that the concept of using RT-PCR measurements during follow-up still warrants further research.

Adenocarcinoma, Follicular↗
PubMed1997

Transrectal ultrasound-guided biopsy causes hematogenous dissemination of prostate cells as determined by RT-PCR.

OBJECTIVES: To determine if transrectal ultrasound-guided (TRUS) prostate biopsy causes dissemination of prostate cells into the circulation as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) targeted against prostate-specific antigen (PSA) mRNA. METHODS: RT-PCR PSA analysis was performed before and after prostatic invasive manipulations in 50 men. The cases consisted of 47 patients with TRUS and 3 with transurethral resection of the prostate (TURP). Peripheral venous blood (8 mL) was drawn before and within 60 minutes after the procedure. Total RNA was extracted from fractionated blood, and RNA/cDNA quality was assured and normalized with beta-actin RT-PCR analysis. The PSA primers hybridize exons 3 and 5, yielding a 254-basepair PCR product. The assay detects one LNCaP cell in a background of 100 million lymphoid cells and a single copy of PSA cDNA on an ethidium bromide gel. RESULTS: Among the 47 TRUS cases, 43 specimens were evaluable. Forty-two cases were negative before biopsy; among these patients, 4 cases (9.5%) converted to a positive RT-PCR PSA result. Both benign and malignant TRUS biopsies were capable of producing a positive RT-PCR PSA signal implicating iatrogenic dissemination of cells. All three TURP cases converted from a negative to a highly intense positive signal. CONCLUSIONS: We conclude that a positive RT-PCR PSA signal may result from release of prostate cells into the peripheral circulation after a TRUS biopsy and TURP. TURP causes greater dissemination than TRUS. Based on these preliminary data, we recommend that future molecular staging studies should be based on blood specimens drawn before performance of TRUS biopsy. This may be an important mechanism of prostate cancer dissemination meriting further investigations.

Aged↗
PubMed1999

Characterization of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry.

Studies of metastasis can be accelerated and provide more mechanistic information using cell lines which reproducibly and aggressively metastasize, and which are accurately and easily detected in tissues at all stages of the metastatic process. Although reporter proteins such as green fluorescent protein (GFP) and beta-galactosidase have improved the tracking of tumor cells in vivo, their measurement has often been limited to visual observation and manual counting. In this study, we exploited the highly sensitive and objective quantitation provided by flow cytometry to characterize, in detail, the sequence of events associated with orthotopic metastasis in a highly aggressive mouse model. Following stable transfection of the MDA-MB-435 breast carcinoma cell line with GFP, we utilized an in vivo selection process to isolate a variant exhibiting increased primary tumor growth and metastasis. As few as one fluorescent tumor cell per 200,000 host cells could be accurately detected in dissociated tissues by flow cytometry, allowing us to demonstrate that metastatic cells migrate to the lungs of SCID mice very early after orthotopic implantation. Tumor burden in lungs increased in a smooth continuous manner, until death approximately eight weeks later. Levels of circulating tumor cells in blood were also detectable at an early timepoint, but remained relatively low throughout the course of secondary tumor development in the lungs. Surgical removal of the primary tumor at various times after inoculation significantly affected lung tumor burden, supporting the concept that circulating tumor cells in blood inefficiently initiate distal metastases. Furthermore, the continuing contribution to metastasis by the primary tumor was independent of tumor mass. The combined characteristics of enhanced orthotopic metastasis and quantitative detection in blood and tissues will make this a useful new model for the characterization of the multi-stage progression of cancer, and the preclinical evaluation of anti-neoplastic therapies.

Breast Neoplasms↗
PubMedDate not supplied

Effect of pneumoperitoneum on circulating tumor DNA.

BACKGROUND: Release and circulation of tumor DNA could be favored by surgery. No data is available for the effect of laparoscopy on this phenomenon. MATERIAL AND METHODS: The aim of this study was to assess the impact of CO2 laparoscopy on circulating tumor DNA. Two xenografts of ovarian cancer were obtained by intraperitoneal inoculation (IP) of IGR-OV1 or NIH:OVCAR-3 cells in nude rats. CO2 laparoscopy (L), gasless laparoscopy (GL), midline laparotomy (ML) or general anesthesia as a control (C) were randomly carried out when the tumor graft was present in the peritoneal cavity. A sterile blood sample was taken in each case as soon as the experiment was completed. DNA was subsequently extracted and amplified (PCR, primers HLA GH 26 and HLA GH 27 specific for human DNA). In each model, we compared the influence of each surgical approach on circulating tumor DNA. Statistics were performed with the Wilcoxon test and Fisher exact test. 1: RESULTS: Eighteen rats were included in each group. Our protocol could detect an amount of tumor DNA equivalent to 10 cells/ml of blood. This technique was specific. Circulating tumor DNA was frequently observed in the IGR-OV1 model (45 to 50%), without significant difference between groups (p=0.6). In the NIH: OVCAR-3 model, the detection rate ranged from 22% (control group) to 64% (gasless group); but the overall comparison between the four groups was not significant (p = 0.2). CONCLUSION: In this experimental trial, CO2 laparoscopy had no deleterious effect on circulating tumor DNA. Biologic characteristics of tumors could also play a role.

Animals↗
PubMed1997

A quantitative reverse transcriptase polymerase chain reaction-based assay to detect carcinoma cells in peripheral blood.

The presence of tumour cells in the circulation may predict disease recurrence and metastasis. To improve on existing methods of cytological or immunocytological detection, we have developed a sensitive and quantitative technique for the detection of carcinoma cells in blood, using the reverse transcriptase polymerase chain reaction (RT-PCR) identifying transcripts of the pancarcinoma-associated tumour marker EGP-2 (KSA or 17-1A antigen). The amount of EGP2 mRNA was quantified using an internal recombinant competitor RNA standard with known concentration and which is both reversely transcribed and co-amplified in the same reaction, allowing for a reliable assessment of the initial amount of EGP2 mRNA in the sample. Calibration studies, seeding blood with MCF-7 breast carcinoma cells, showed that the assay can detect ten tumour cells among 1.0 x 10(6) leucocytes. The PCR assay revealed that normal bone marrow expresses low levels of EGP2 mRNA, although immunocytochemistry with the anti-EGP2 MAb MOC31 could not identify any positively stained cell. Analyses using this RT-PCR assay may prove to have applications to the assessment of circulating tumour cells in clinical samples.

Antigens, Neoplasm↗
PubMed2002

A novel method for monitoring response to chemotherapy based on the detection of circulating cancer cells: a case report.

We describe a novel method for detecting micrometastasis in the blood stream of cancer patients based on RT-PCR amplification of tumor-associated carcinoembryonic antigen (CEA) mRNA. To increase sensitivity and specificity of RT-PCR, CEA transcript was selectively up-regulated in cancer cells by exposure of peripheral blood to non-toxic concentrations of staurosporine (ST). Thereafter, polyA(+) RNA was extracted from tumor cells captured by means of magnetic beads coated with a monoclonal antibody against a common human epithelial antigen. Finally, RNA was subjected to RT-PCR analysis of CEA transcript. Using this approach, we demonstrated an ST-mediated increase in CEA transcript in blood specimens collected from a patient with metastatic colon cancer before receiving treatment with 5-fluorouracil/leucovorin. After a few cycles of chemotherapy, CEA-positive tumor cells were no longer detected. Clinical follow-up of this patient indicated that treatment with chemotherapy induced a dramatic reduction in liver metastasis. Therefore, it can be hypothesized that lack of CEA transcript detection might be consistent with disappearance or at least marked reduction of circulating tumor cells.

Adenocarcinoma↗
PubMed2000

Detection of circulating cancer cells with von hippel-lindau gene mutation in peripheral blood of patients with renal cell carcinoma.

Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene have been detected in up to 60% of sporadic clear cell renal carcinomas (RCCs). Even patients with RCCs believed to be curable with radical nephrectomy sometimes develop distant metastasis 5-10 years after surgery, suggesting hematogenous circulation of cancer cells. Useful tumor markers have not yet been established for RCC. To detect patients at high risk of metastasis after surgery, we developed a highly sensitive and specific nested reverse transcription-PCR method using VHL gene mutation to detect circulating cancer cells. We screened 29 sporadic clear cell RCCs from patients for mutations of the VHL gene by direct sequencing. We next examined blood samples from patients with the VHL gene mutation using mutation-specific nested reverse transcription-PCR. Somatic mutations were detected in 20 of 29 (69.0%) sporadic clear cell RCCs. The VHL gene mutations were detected in peripheral and/or renal venous blood from 15 of 20 (75%) patients. The mutations were detected in the peripheral blood in 2 of 17 (11.8%) patients before surgery, 6 of 16 (37.5%) patients within 24 h after surgery, 3 of 16 (18.8%) patients on day 7 after surgery, and 2 of 11 (18.2%) patients on day 30 after surgery. In seven of nine (77.8%) patients, mutations were detected in renal venous blood during surgery. These findings indicate the presence of circulating cancer cells with VHL gene mutation. Although much larger studies are needed to determine the clinical significance, our study shows that this technique is feasible for detecting circulating RCC cells.

Adult↗
PubMed2002

Detection of epithelial tumour RNA in the plasma of colon cancer patients is associated with advanced stages and circulating tumour cells.

BACKGROUND: Although circulating tumour DNA has been detected in patients with different types of cancer, little is known of free RNA in cancer patients. AIMS: We investigated the presence of RNA from epithelial tumours in plasma from patients with colorectal carcinomas, and its correlation with tumour characteristics and circulating tumour cells. METHODS: beta-actin mRNA was analysed to assess the viability of plasma RNA in samples from 53 patients with colonic cancer and 25 controls. Subsequently, nested primers were used to detect the presence of cytokeratin 19 (CK19) and carcinoembryonic antigen (CEA) RNA in the same samples. Nine clinicopathological parameters were studied to correlate the molecular and clinical parameters. Additionally, we investigated for micrometastases in blood in 18 of these patients and in 10 of the controls samples. RESULTS: All samples had detectable quantities of beta-actin RNA. In the controls, one case (4%) was positive for CEA and five (20%) for CK19 RNA; of the 53 patients, 17 cases (32%) were positive for CEA and 39 (73.6%) for CK19 RNA. This was statistically significant (p=0.000001). Advanced stages (p=0.03) and soluble CEA status (p=0.03) were associated with the presence of CEA, CK19, or both RNAs in plasma. Lymph node metastases (p=0.06) and vascular invasion (p=0.07) were almost significant. On the basis of these results, we examined the possible presence of micrometastases in blood in several of these patients. The presence of plasma tumour RNA was found to be associated with circulating tumour cells in blood (p=0.04). CONCLUSIONS: Epithelial tumour RNA is detectable in plasma from colon cancer patients. This molecular event is associated with advanced stages and circulating tumour cells. Our results could offer new approaches in the diagnosis and monitoring of colon cancer.

Actins↗
PubMed2003

Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in metastatic prostate cancer: a nested study within CALGB 9583.

PURPOSE: To determine whether reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating prostate-specific antigen (PSA)-positive cells is a prognostic factor for survival in hormone refractory prostate cancer and to validate the prognostic importance of this test in relation to other known prognostic factors. PATIENTS AND METHODS: A single centralized laboratory received and analyzed whole blood for RT-PCR for PSA for a subset of patients enrolled on two Cancer and Leukemia Group B (CALGB) randomized trials (CALGB 9583 and CALGB 9480). Using 9583, a prognostic model was developed and an independent data set (CALGB 9480) was used to validate the fitted model. RESULTS: Of 162 patients in 9583, 91 (56%) patients were negative for RT-PCR for PSA and 71 (44%) patients were positive. The median survival time was 21 months (95% confidence interval [CI], 18 to 27 months) for RT-PCR-negative patients compared with 11 months (95% CI, 8 to 15 months) for RT-PCR-positive patients (P < or =.001). In multivariable analysis, the hazard ratio (HR) for death was 1.7 (95% CI, 1.2 to 2.4; P =.006) for positive RT-PCR patients compared with negative RT-PCR patients. A fitted model that incorporated RT-PCR for PSA and other factors was used to classify patients from 9480 into one of two risk groups: low or high. We observed good agreement between the observed and predicted survival probabilities for the two risk groups. CONCLUSION: RT-PCR to detect PSA-positive circulating cells is confirmed to be a significant prognostic factor of survival in patients with hormone refractory prostate cancer. This model could be used to stratify patients in randomized phase III trials.

Aged↗