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A case of rhabdomyosarcoma presenting with circulating tumour cells (carcinocythemia) is discussed. Tumor cells must be differentiated from leukemic cells or a leukemoid reaction. If the abnormal cells appear as syncytia, tumor should be strongly suspected. Cytochemical and/or histochemical stains should also be employed to differentiate tumor cells from hematopoietic cells.
OBJECTIVES: The detection of circulating prostatic cells by molecular biology techniques (RT-PCR) can be useful in the staging of localized prostate cancer prior to radical prostatectomy in some institutions. After describing their technique, the authors report their results. PATIENTS: 80 RT-PCR were performed: 32 in a control group (including 11 women free of any neoplastic disease, 11 healthy men, and 10 men with benign prostatic hyperplasia before resection), and 48 in patients with prostate cancer (43 with clinically localized cancer and 5 with metastatic cancer). RESULTS: In the control group, none of 11 women had a positive RT-PCR, 1 of the healthy men was positive (orchidopexy) and 3 of the 11 patients with benign prostatic hyperplasia were positive, but none of them had tumour on the resection chips. None of the 5 metastatic patients were positive. In the patients treated by radical prostatectomy, no correlation was observed between RT-PCR results, pathological stage, positive resection margin status and laboratory progression after radical prostatectomy. CONCLUSION: This PSA RT-PCR technique developed in this institution does not appear to be useful for the molecular staging of prostate cancer. This study demonstrates the difficulty of standardization of this technique which limits its routine use.
A 58 year-old male was scheduled for surgery of his hepatic cancer. Tumor invaded to the right atrium through the inferior vena cava. The operative method of removing the tumor in the right atrium was scheduled under extracorporeal circulation after the left lobe hepatectomy. Since there was a tumor in the right atrium, central venous pressure monitoring could not be reliable. Transesophageal echocardiography (TEE) was employed in order to detect the part of the tumor flowing into the pulmonary artery or occluding the tricuspid valve. Due to massive blood loss during hepatectomy, the capacity in the right atrium decreased and the tumor was often about to engage the tricuspid valve. After the rapid fluid therapy, the right atrium capacity increased preventing the engagement of the tumor. TEE was useful not only to observe the movement of the tumor in the right atrium but also to monitor the circulating blood volume.
BACKGROUND: Many viral and neoplastic diseases are resistant to interferon-alpha/beta (IFN-alpha/beta) therapy or develop resistance during the course of IFN treatment. In patients with viral diseases, the authors identified four IFN inhibitors, of which the most important, most likely is a free IFN receptor of type 1 appearing in the circulation that captures and neutralizes IFN-alpha/beta. METHODS: Ninety-one cancer patients and 25 healthy individuals were studied. Free circulating IFN receptor-alpha/beta type 1 was studied. The patients were ages 35-75 years. The diagnoses were 24 cases of colon carcinoma, 7 cases of prostate carcinoma, 16 cases of breast carcinoma, 8 cases of ovarian carcinoma, 9 cases of uterine carcinoma, 5 cases of lung carcinoma, 3 cases of astrocytoma, 4 cases of transitional cell carcinoma of the bladder, 1 case of osteosarcoma, 3 cases of multiple myeloma, 4 cases of Hodgkin disease, 2 cases of non-Hodgkin lymphoma, 3 cases of myelodysplastic syndrome, and 2 disseminated tumors of unknown origin. RESULTS: All patients were found to have increased free IFN receptor-alpha/beta type 1 in the circulation, with the highest levels reported in patients with adenocarcinoma. CONCLUSIONS: High IFN inhibitory activity in patients with cancer may be a significant factor in their increased susceptibility to progressive disease, infectious complications, and resistance to IFN therapy. Ongoing studies are being performed with the objective of overcoming this inhibitory activity.
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OBJECTIVES: Studies in several solid tumors have shown that the presence of occult metastasis in the bone marrow or peripheral blood is highly predictive of decreased disease-free and overall survival. Our objective was to determine the incidence of circulating ovarian or primary peritoneal cancer cells in the peripheral blood at the time of disease diagnosis, or recurrence, and to determine the prognostic significance of these occult metastasis. METHODS: Peripheral blood was drawn preoperatively from 91 women thought to have newly diagnosed or recurrent epithelial ovarian or primary peritoneal carcinoma. All samples underwent a tumor-enriched immunocytochemical assay. RESULTS: Sixty-four women were found to have epithelial ovarian or primary peritoneal cancer. Of the 64 women with cancer, 12 had evidence of circulating cancer cells in their peripheral blood (18.7%). Characteristics were compared between those with circulating cancer cells and those without, using Fisher's exact test or the Wilcoxon-Mann-Whitney test, as appropriate. Women with circulating cancer cells had statistically more grade 3 tumors than women without. At a mean follow-up of 18.7 months (SD 6.7 months), analysis using Kaplan-Meier estimation and the log-rank test indicated that survival curves did not differ between patients with and without circulating cancer cells. CONCLUSIONS: Ovarian and primary peritoneal cancer, which historically has been thought to spread primarily by direct cell seeding throughout the abdominal cavity, can have circulating cancer cells in the peripheral blood. The clinical utility of identifying circulating cancer cells is yet to be defined.
We analyzed the peripheral blood of patients with gastrointestinal tract cancer at different stages to assess the presence of carcinoembryonic antigen (CEA) mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR), which we used as an indicator for micrometastatic malignant cells. A total of 35 gastric, 24 colorectal, 4 esophageal and 4 biliary tract cancer patients and nine normal healthy subjects were studied. No CEA mRNA was detected in the nine normal healthy volunteers. CEA mRNA was detected in 100% (10/10) of metastatic, 33.3% (3/9) of early gastric cancer (EGC), and 18.8% (3/16) resectable gastric cancer patients, respectively. In colorectal cancer, 55.6% (5/9) of metastatic cancers were positive for CEA mRNA, and 26.7% (4/15) Duke stage B/C showed positive. One patient with stage III gastric cancer who was negative CEA mRNA initially and turned positive during follow-up, developed multiple bone metastasis one month later. Another stage III patient, who was positive for CEA mRNA, preoperatively revealed early relapse in two months. These results suggest that the identification of circulating tumor cells using RT-PCR for the detection of CEA mRNA is feasible and this analysis may be a promising tool for early detection of micrometastatic circulating malignant cells in patients with gastrointestinal tract cancer.
OBJECTIVE: To study the changes and significance of circulating hepatocellular carcinoma cells in recurrent hepatocellular carcinoma (HCC) patients after combined treatment of transarterial chemo-embolization(TACE) and percutaneous ethanol injection(PEI). METHODS: We detected 19 blood samples from the recurrent HCC patients by nested RT-PCR to find out AFP mRNA before and after the treatment. RESULTS: There were 7 patients with AFP mRNA positive before treatment (36.8%), and none of patients with AFP mRNA positive after treatment. CONCLUSIONS: Combined treatment of TACE and PEI can effectively eliminate circulating hepatocellular carcinoma cells and thereby prevent metastasis and recurrence of HCC.
PURPOSE: In this study, we evaluated the correlation between the postoperative detection of circulating cancer cells and the risk of recurrence in patients with gastric cancer. METHODS: Total RNA was extracted from 1.5 ml of peripheral blood from 59 patients with gastric cancer and 15 patients with cholecystolithiasis (control) before and after operation. Carcinoembryonic antigen (CEA) messenger RNA (mRNA) was used as a probe to detect gastric cancer cells in samples using a real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Carcinoembryonic antigen mRNA-positive cells were not found in the peripheral blood of the control patients either before or after operation, nor in the peripheral blood of the gastric cancer patients before operation. However, CEA and mRNA-positive cells were detected in 46% of the patients just after a gastrectomy, though these circulating cancer cells disappeared from peripheral blood within 2 postoperative days. In 55 patients who underwent a curative operation, the risk for cancer recurrence (10/30; 33%) in 30 patients who did not show circulating cancer cells postoperatively was higher than that for cancer recurrence (3/25; 12%) in 25 patients with positive for circulating cancer cells (P = 0.064). As a result, the presence of blood circulating tumor cells just after surgery tends to correlate with a low rate of tumor recurrence in patients operated on for gastric cancer. CONCLUSION: These findings indicate that a gastrectomy may spread gastric cancer cells into the peripheral blood from primary tumors; however, such circulating cancer cells may be destroyed within a short time. The detection of circulating cancer cells may therefore be a marker for a possibly better prognosis in patients with gastric cancer.
In this article we report inhalation effects of nitrogen dioxide (NO2) and ozone (O3) mixture as well as O3 alone on blood-borne cancer cell colonization of lungs. The findings are discussed in light of our earlier studies with NO2 exposure alone. In all of these studies the mouse B16 melanoma model was used. Animals were exposed to ambient concentrations of pollutants before melanoma-cell infusion. The results have indicated that inhalation of NO2 played a significant role in facilitation of blood-borne cancer cell spread, while O3 inhalation did not. With respect to mechanisms involved, the role of natural immunity was investigated and its was postulated that nitrogen dioxide may affect cells of the immune system and may in part account for the results. These findings may have direct bearing on dissemination of human cancer cells, since many cancer patients have circulating cancer cells and are exposed daily to noxious air pollutants. Most importantly, this effect may be preventable by reducing air pollution in urban areas.
Recently published protocols using Reverse Transcriptase Polymerase Chain reaction (RT-PCR) for prostate specific antigen (PSA) provide a sensitive means for detecting circulating prostate cancer cells. Attempts to use these assays for staging of prostate cancer have produced conflicting results. As a first step towards rectifying these discrepancies, a modified immunobead-RT-PCR assay capable of detecting as few as 10 prostate cancer cells in 8cc of blood was developed. This 10 fold increase in sensitivity was achieved in part by introducing two target cell enrichment steps. As a model system to assess sensitivity of the modified assay, template RNA was extracted from PSA positive human carcinoma cells suspended in human blood and isolated with immunomagnetic beads following incubation with an epithelium specific antibody. After 45 cycles of PCR, product from as few as 10 target cells could be readily detected when displayed on a 2% agarose gel stained with SYBR Green fluorescent dye. The identity of amplified DNA fragments was confirmed by Southern blot hybridization. When applied to blood samples from patients with proven metastatic disease, the immuno-bead RT-PCR assay was successful in detecting circulating PSA positive epithelial cells, suggesting this assay may be useful for assessment of disease progression or recurrence.
OBJECTIVE: Magnetic-activated cell separation (MACS) for the enrichment of tumor cells was evaluated with immunocytochemistry (ICC) and flow cytometry (FCM). METHODS: Blood (20 ml) was sampled in 36 affected patients before surgery. Nucleated blood cells were obtained with the removal of red blood cells in the buffy coat. Nucleated blood cells (2 x 10(6)) from breast cancer patients were aliquoted before enrichment for direct immunostaining (ICC group), while all remaining cells were enriched and then immunostained (MACS/ICC group). Breast cancer cell lines were spiked serially in normal nucleated blood cells for FCM evaluation of the enrichment efficiency of MACS. RESULTS: The enrichment rate of spiked tumor cells was 37- to 2,300-fold and was negatively correlated with the ratio of tumor cells to normal nucleated cells (p < 0.05). The positive rate was only 5.6% (2/36) in the ICC group and was as high as 38.9% (14/36) in the MACS/ICC group (p < 0.001). The positivity in the enriched fraction was 0% (0/4), 33.3% (8/24), 60% (3/5) and 100% (3/3) for tumors at stages I, II, III and IV, respectively (p < 0.05). CONCLUSION: MACS can enrich circulating tumor cells, and the presence of circulating breast cancer cells correlates with clinical staging.
In a pilot study the effect of palliative chemotherapy on the detection rates of circulating tumour cells in peripheral venous blood of stage IV colorectal cancer patients was investigated. The results indicate a recruitment of tumour cells during chemotherapy and suggest a poorer survival for tumour cell positive patients. Circulating tumour cells have been shown to be a potential prognostic factor in patients who undergo curative resection for colorectal cancer. The effect of chemotherapy on the detection rates of disseminated tumour cells in blood has not yet been adequately investigated. Objective of this pilot-study was to analyze circulating tumour cells in peripheral venous blood of colorectal cancer patients undergoing chemotherapy in order to evaluate its potential value as a surrogate-marker for predicting clinical outcome after chemotherapy. Our hypothesis was that chemotherapy results in a reduction of the detection rates of circulating tumour cells in colorectal cancer patients. Forty-two Stage IV patients were examined at three different time points before and during palliative chemotherapy for the presence of disseminated tumour cells, using a previously described RT-PCR-assay for cytokeratin 20. 80.1% of the patients showed disseminated tumour cells at least once. Before chemotherapy, patients with multi-organ metastases were positive in 62.5%, patients with locally limited disease in only 14.3%. After the first chemotherapy, the detection rates in the latter group increased to 62.5%, for all patients in the same time from 46.3% to 57.5%. Clinical therapy responders showed an increase in the detection rates from 28.5% before to 71.4% after chemotherapy. In contrast, chemotherapy had no effect on tumour cell detection rates of patients with progressive disease (57% before vs. 60% after therapy). Patients with detected circulating tumour cells showed a shorter overall survival than patients without circulating tumour cells (83 vs. 53 weeks). Clinical therapy responders on average lived only 3 weeks longer than non-responders. In contrast to the original hypothesis, our data suggest a recruiting of circulating tumour cells during chemotherapy in advanced colorectal cancer. Further investigations are needed to clarify the potential role of circulating tumour cells for monitoring chemotherapy in these patients.
Previously, the human high mobility group protein member HMGA2 mRNA was reported to be expressed in peripheral blood of patients with breast cancer, but not in healthy individuals. Expression of HMGA2 in blood was suggested to be an independent indicator of poor prognosis in metastatic breast cancer. These very promising findings propose HMGA2 as a potential marker for the detection of circulating tumor cells in peripheral blood. Therefore, we analyzed peripheral blood specimens from healthy controls and patients with breast tumors for HMGA2 expression using TaqMan real-time RT-PCR to test if HMGA2 is a suitable marker for the early detection of breast cancer and monitoring therapy response in peripheral blood. Furthermore, we examined the possible involvement of HMGA2 expression in invasion investigated by an in vitro invasion assay using established breast cell lines. HMGA2 expression was detected in peripheral blood of breast cancer patients as well as of healthy individuals. No significant association of HMGA2 expression with any clinical or histopathological data was apparent. However, there was a significant correlation of HMGA2 expression in invasive and non invasive breast cell lines (p=0.0056). Although, HMGA2 obviously contributes to invasion it is not a specific marker for the detection of circulating tumor cells in peripheral blood.
Iatrogenic metastasis of bone tumor is reportedly increased if aggregates of tumor cells enter the circulation. The current study used a previously developed animal model to explore the movement of 25-, 50-, and 100-micron-diameter particles from an experimental femur biopsy site into the circulation. The results indicate that cell aggregate-sized particles can enter the circulation from the femur at a rate similar to that of the 15-micron particles used in previous studies. Arterial blood samples collected during and after the injection of particles contained no 50- or 100-micron particles, suggesting that the lung is an effective filter for these larger particles.
BACKGROUND: Detection of circulating malignant cells (CMCs) through a reverse transcriptase-polymerase chain reaction (RT-PCR) assay seems to be a demonstration of systemic disease. We here evaluated the prognostic role of RT-PCR assays in serially-taken peripheral blood samples from patients with malignant melanoma (MM). METHODS: One hundred forty-nine melanoma patients with disease stage ranging from I to III were consecutively collected in 1997. A multi-marker RT-PCR assay was used on peripheral blood samples obtained at time of diagnosis and every 6 months during the first two years of follow-up (total: 5 samples). Univariate and multivariate analyses were performed after 83 months of median follow-up. RESULTS: Detection of at least one circulating mRNA marker was considered a signal of the presence of CMC (referred to as PCR-positive assay). A significant correlation was found between the rate of recurrences and the increasing number of PCR-positive assays (P = 0.007). Presence of CMC in a high number (> or =2) of analysed blood samples was significantly correlated with a poor clinical outcome (disease-free survival: P = 0.019; overall survival: P = 0.034). Multivariate analysis revealed that presence of a PCR-positive status does play a role as independent prognostic factors for overall survival in melanoma patients, adding precision to the predictive power of the disease stage. CONCLUSION: Our findings indicated that serial RT-PCR assay may identify a high risk subset of melanoma patients with occult cancer cells constantly detected in blood circulation. Prolonged presence of CMCs seems to act as a surrogate marker of disease progression or a sign of more aggressive disease.
A prospective pretreatment staging evaluation was done on 49 consecutive patients with mycosis fungoides or the Sézary syndrome to study patterns of disease spread and prognostic factors. Routine staging procedures included complete blood count, blood chemistries, chest roentgenogram, lymphangiogram, radionuclide scans, bone marrow aspiration and biopsy, liver biopsy, and lymph node biopsy. Special evaluations included cytogenetic analysis, electron microscopy, and T-cell cytology. Extracutaneous lymphoma was documented by light microscopy in 51% of patients and by the three special procedures in 88%. Extracutaneous lymphoma was most frequent in blood and lymph nodes; 18% of patients had visceral involvement. Patients with generalized erythroderma had a higher frequency of extracutaneous disease than did patients with cutaneous plaques and tumors by both light microscopy and special studies. Survival was directly related to the type of skin involvement and the presence or absence of extracutaneous disease. Systemic dissemination of cutaneous T-cell lymphoma is frequent, generally asymptomatic, and develops early via the circulation. These findings may explain why cutaneous therapies are associated with a high frequency of relapse.
OBJECTIVE: We tested whether circulating tumor cells can be detected in the peripheral blood of patients with resectable non-small-cell lung cancer (NSCLC) by reverse transcriptase-polymerase chain reaction (RT-PCR) of carcinoembryonic antigen (CEA) mRNA. METHODS: We assayed for CEA mRNA by RT-PCR in the peripheral blood, taken at the time of diagnosis before surgical intervention and again 2 to 3 weeks postoperatively, from 103 patients with NSCLC who underwent curative lobectomy. Blood samples taken from 15 patients with interstitial pulmonary fibrosis who underwent an open-lung biopsy and from 32 healthy subjects served as controls. RESULTS: No control samples were positive for CEA by RT-PCR. Sixty-two (60%) of the preoperative blood samples from the 103 patients with NSCLC were positive. Of these 62 samples, 27 (44%) remained positive even after surgical intervention, whereas the remaining 35 samples (56%) became negative. The incidence of positive CEA mRNA correlated highly with pathologic TNM stage of disease in both the preoperative and postoperative blood samples. CONCLUSIONS: Many patients with resectable NSCLC have detectable levels of circulating cells expressing carcinoembryonic antigen even after surgical intervention. Such patients may have a higher rate of relapse.