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Two cases of renal cell carcinoma, metastatic to the pancreas, are presented. The lesions were hypoechoic with ultrasound examination, and were mixed iso- and hypodense with computed tomography. Angiography was performed in one case, and showed a typical hypervascular pattern of the metastatic tumor.
OBJECTIVE: Our purpose was to depict the characteristics of the global vasculature of cervical lymphadenopathies and to clarify the efficiency of Doppler spectral analysis and power Doppler sonography in the differential diagnosis. SUBJECTS AND METHODS: Prospectively, 289 lymph node lesions underwent Doppler flow studies and were grouped as metastasis, lymphoma, tuberculosis, and benign lymphadenopathies. Sonographic assessments included vascular pattern and vascular density (presented as vascularity index) as revealed by power Doppler sonography. Vascular resistive index and pulsatility index were assessed by at least three flow samplings. Values of both the highest and the lowest resistance were analyzed. Vascularity index, resistive index, pulsatility index, nodal size, and age were correlated. RESULTS: Most benign lymphadenopathies (87%), tuberculous lymphadenopathies (72%), and lymphomas (71%) revealed an avascular or hilar vascular pattern. Vascular patterns of most metastatic lymphadenopathies (90%) were of spotted (26%), peripheral (11%), or mixed (53%) type. The vascularity indexes of metastatic lymphadenopathy (mean, 0.176) and lymphoma (mean, 0.122) were significantly higher than those of tuberculous and benign lymphadenopathy (mean, 0.054 and 0.042, respectively). In vascular resistance studies, the highest pulsatility index and resistive index in metastatic lymphadenopathy statistically exceeded those of benign lymphadenopathy, whereas no difference was found in the lowest values. Negative correlation was found between the vascularity index of metastatic lesions and their lowest vascular resistance, and positive correlation was found between vascularity index and nodal size in benign lymphadenopathies. CONCLUSION: In addition to vascular resistance assessed traditionally with Doppler spectral analysis, vascular pattern and vascular density assessed with power Doppler sonography can better differentiate the nature of lymphadenopathies.
Tumour and metastatic phenotypes, the pattern of mouse mammary tumour virus (MMTV) integration and expression, and the expression of a metastasis associated gene, nm23, were examined in three mammary tumour cell subpopulations, 66, 168 and 4526. Tumour growth, host survival, metastatic aggressiveness, and the distribution of different cell types in metastasis resulting from mixed cell inocula were also analysed. The results of these studies indicated that the cell lines were distinguishable from each other both phenotypically and genotypically. However, a rearrangement of the mammary tumour specific protooncogene, int-1, caused by MMTV was found to be a unique characteristic of the cell line 4526. Therefore, int-1 was used as a stable marker to examine the genotype of the metastatic colonies that developed in mice bearing tumours of mixed cell inocula. Highly metastatic 4526 cells influenced the metastatic range of poorly metastatic 66 cells. Line 66 cells that normally colonize only to lungs were also found to colonize liver when inoculated together with the liver-metastasizing 4526 cells. This acquired metastatic phenotype of 66 cells was transient. On the contrary, mixed cell inocula of 4526 and non-metastatic 168 cells did not produce any colony of 168 cells. The metastatic aggressiveness of 4526 cells was inhibited by both 66 and 168 cells. Furthermore, the metastatic behaviour of mixed inocula differed depending on the relative abundance of the component populations in the mixtures. These findings suggest that interaction between cells of different metastatic phenotypes may result in changes of their metastatic behaviour.
A case in which hepatic artery perfusion scintigraphy (HAPS) correctly predicted the outcome of chemotherapy in a patient with metastatic liver disease is presented. In spite of angiography showing "proper" position of the Infusaid catheter, HAPS showed preferential perfusion to the right lobe of the liver. Computed tomography pre- and postchemotherapy showed a changing pattern of the metastatic foci correlating with the perfusion demonstrated by HAPS.
We investigated the relationship between telomere length and various characteristics of tumor cells in 46 lung cancer specimens (40 primary lesions and six metastatic lesions). Three variant patterns of telomere length were observed in 16 cases (34.8%): reduction in 13 cases, elongation in two cases, and convergence in one case. These variant patterns were frequently observed in small cell carcinomas, in metastatic lesions, and in cases which possessed the S-type allele of the L-myc gene. All three cases with telomere elongation or convergence were associated with a poor prognosis. This is compatible with the previous report suggesting that telomerase activity may be an indicator of immortality in vitro. In adenocarcinoma, telomere reduction or elongation was also observed in the early stages with a low percentage of cells in the S-phase, while in cases with other histologic types, these changes were observed only in late stage, in metastatic lesions, or in cancerous tissues with a high percentage of cells in the S-phase. Although the reduction of telomere length in these tissues may be a result of many cell divisions, it may represent another stage of carcinogenesis in early-stage adenocarcinoma.
We have developed animal models of breast cancer that allow the direct examination of the behavior of individual green fluorescent protein-expressing carcinoma cells in live nonmetastatic and metastatic primary tumors in situ. We have combined this model with multiphoton microscopy to image differences in cell behavior within the primary tumor. Differences in cell behavior between nonmetastatic and metastatic cells in culture and within live primary tumors were correlated with results from cDNA microarray analyses to identify potentially important genetic determinants for breast cancer invasion and metastasis. Using multiphoton microscopy, we found five major differences in carcinoma cell behavior between the nonmetastatic and metastatic primary breast tumors involving extracellular matrix, cell motility, and chemotaxis. Behavioral differences were correlated with seven categories of molecules that were differentially expressed and related to these behaviors. We have found that extracellular matrix composition, actin nucleation factors, molecules involved in mechanical stability and survival, and cell polarity and chemotaxis showed large and consistent differences in gene expression. We conclude that aligning cell behavior in vivo with patterns of gene expression can lead to new insights into the microenvironment of carcinoma cells in the primary tumor and the molecular mechanisms behind cell behavior.
Samples of 130 metastatic melanomas from 92 patients were analyzed by DNA flow cytometry. DNA aneuploidy was observed in 67% of the patients. DNA indices were evenly distributed from 0.6 to 2.6 Tumors originating from primary lesions in the lower extremities were more frequently DNA aneuploid than those of other sites. S-phase fraction (SPF) was evaluable from 73 tumors. DNA aneuploid tumors had a significantly higher SPF than diploid tumors, and females had a higher SPF than males. Furthermore, distant metastases had a higher SPF than metastases in regional lymph nodes and in transit metastases, probably indicating a higher growth potential in metastases spreading to distant sites.
Breast cancer frequently metastasizes to bone, resulting in osteolytic lesions. These lesions, formed by activated osteoclasts, cause pain, an increased susceptibility to fractures, and hypercalcemia. It has been shown that breast cancer cells communicate with osteoblasts and subsequently stimulate osteoclast activity; however, little research has focused on understanding the interaction between breast cancer cells and osteoblasts. We recently reported that conditioned medium from MDA-MB-231 breast cancer cells inhibited the differentiation of MC3T3-E1 osteoblasts through the secretion of transforming growth factor beta (TGFbeta). In addition, the breast cancer conditioned medium altered MC3T3-E1 morphology, the pattern of actin stress fibers, and reduced focal adhesion plaques. In the current study, we identified the mechanism used by MDA-MB-231 cells to cause these effects. When MC3T3-E1 osteoblasts were cultured with MDA-MB-231 conditioned medium preincubated with neutralizing antibodies to platelet derived growth factor (PDGF), insulin-like growth factorII (IGFII), and TGFbeta, focal adhesion plaques and actin stress fiber formation were restored. These cytokines were further found to signal through PI3Kinase and Rac. In conclusion, TGFbeta, PDGF, and IGFII might be good therapeutic targets for treating breast cancer-induced osteolytic lesions.
In an attempt to assess the development or progression of symptoms in patients with metastatic bladder cancer we reviewed 41 patients who died of the disease but who did not undergo cystectomy. Therapy for the local tumor was used when indicated. Of the 41 patients 9 experienced worsening of symptoms, while the others were either stable or improved. Only 1 of 10 asymptomatic patients suffered symptoms during the course of the illness.
BACKGROUND: We have reported that N-(phosphonacetyl)-L-aspartic acid (PALA) 1266 mg/m2 can safely be given 24 hours prior to the start of a 72-hour infusion of fluorouracil (FUra) and leucovorin (LV) at doses of 2000 and 500 mg/m2/day. Since inhibition of aspartate carbamoyltransferase (ACTase) activity was evident 4 hours post PALA, we wished to evaluate PALA given 1 hour prior to FUra. Further, we studied the toxicity and pharmacokinetics with FUra given by either fixed- or variable-rate infusion. PATIENTS AND METHODS: Twenty-seven patients with gastrointestinal tract adenocarcinomas were treated with PALA 1266 mg/m2/15 min followed by a 72-hour infusion of FUra and LV (1750 & 500 mg/m2/day) given by fixed- or variable-rate (peak at 4:00 A.M.). RESULTS: Clinical toxicity was similar in two consecutive cycles in 17 patients receiving fixed- and variable-rate infusion at the same FUra dose. Overall, grade 3 stomatitis and hand-foot syndrome occurred in 12% and 4% patients receiving fixed- and in 16% and 10.5% of patients receiving variable-rate infusions. Six of 24 evaluable patients (25%) had a partial response. The profile of FUra plasma levels (Cp) over a 24-hour period during fixed- and variable-rate infusions were strikingly different, but the average Cp and area under the concentration-time curves were comparable. ACTase activity was significantly decreased at 4 and 24 hours after PALA (12% and 18% of baseline; P < 0.001), but enzyme activity had recovered to 40% by 72 hours. CONCLUSIONS: This regimen was active and well tolerated with similar toxicities with FUra given by either fixed- or variable rate infusion. PALA 1266 mg/m2 significantly inhibited ACTase activity for at least 24 hours.
Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormone-refractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy. Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway.
BACKGROUND: The metastatic ability of tumor cells is determined by level of expression of specific genes that may be identified with the aid of cDNA microarray containing thousands of genes and can be used to establish the expression profile of disease related genes in complex biological system. MATERIALS AND METHODS: Salivary adenoid cystic carcinoma cell line and its high metastases adenoid cystic carcinoma clone were used as model systems to reveal the gene expression alteration related to metastasis mechanism by cDNA microarray analysis. The correlation of metastatic phenotypic changes and expression levels of 4 selected genes (encoding CD98, L6, RPL29, and TSH) were further validated by using RT-PCR analysis of human tumor specimens from primary adenoid cystic carcinoma and corresponding metastasis lymph nodes. RESULTS: Of the 7,675 clones of known genes and expressed sequence tags (ESTs) that were analyzed, 30 showed significantly different (minimum 3 fold) expression levels in two cell lines. Out of 30 genes found differentially expressed, 18 were up regulated (with ratio more than 3) and 12 down regulated (with ratio less than 1/3). CONCLUSION: Some of these genes are known to be involved in human tumor antigen, immune surveillance, adhesion, cell signaling pathway and growth control. It is suggested that the microarray in combination with a relevant analysis facilitates rapid and simultaneous identification of multiple genes of interests and in this study it provided a profound clue to screen candidate targets for early diagnosis and intervention.
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For the study of invasion of tumor cells in vitro and in vivo methods were used to observe the invasion process and morphological characteristics of tumor cells. The different animal tumor cells and cell lines from human tumors were used. The process of cancer cells in vitro invasion can be divided into 5 stages. We suggest that filopodia protruding from the tumor cell margin seem to play an important role in the initiation of cell invasion. For experimental study of cancer metastasis we established three spontaneous metastatic models, including spontaneous lymphatic and hematogenous metastasis of mouse uterine cervix carcinoma No 14(U14) and No 27(U27), and third spontaneous lung metastasis in mouse forestomach carcinoma (FC). Two tumor cell lines are established: One is MFC cell line which is derived from FC tumor; second cell line is MUCC which is derived from the U27 tumor. These metastasis models and their cell lines are very useful for studying the mechanism of metastasis, tumor heterogenicity and antimetastatic agents of tumor. The results are discussed.
OBJECTIVE: After identifying a metastatic glycogen-rich balloon cell malignant melanoma, originally thought to be a benign clear cell tumor of the lung, we investigated the extent of positive reactions, or "positivity," of malignant melanoma to periodic acid-Schiff (PAS) staining. METHODS: Frequency, intensity, and distribution of PAS positivity was studied in 61 excisional biopsy specimens from 58 patients with malignant melanoma. For comparison, 17 benign nevi from 10 patients were examined. RESULTS: Positivity for PAS was seen in all cases. All malignant melanomas and benign nevi were characterized by weak, diffuse, diastase-resistant PAS positivity. Additionally, focal or diffuse, strong diastase-sensitive PAS positivity was observed in 9 of 61 melanomas (15%); 7 were metastatic and 2 were primary invasive melanomas. Strong diastase-sensitive PAS positivity was seen in all lesions with 30% or more balloon cell features and only in advanced primary or metastatic lesions. The presence of glycogen was confirmed by transmission electron microscopy. CONCLUSIONS: Cutaneous malignant melanomas have weak, diastase-resistant PAS positivity. Strong diastase-sensitive PAS positivity, consistent with the presence of intracytoplasmic glycogen, is seen in many primary and metastatic melanomas with balloon cell features. Depending on the content of the balloon cells, these melanomas are best categorized as either glycogen-rich malignant melanomas or glycogen-rich balloon cell malignant melanomas. Because many tumors with clear cell features contain glycogen, such content often is an unreliable differential feature.
The metastatic capacity of intravenously injected human FEMX-I melanoma cells in athymic nude mice and rats was compared. Young rats given 1 x 10(6) ascites tumor cells all died of lung tumors with a life span of 50 +/- 10 days (mean +/- SD). In contrast, in accordance with previous findings, only extrapulmonary metastases developed in mice. This host-dependent difference in metastasis pattern permitted studies on the role of factors that may influence the organ specificity of metastases. The tissue distribution of 125I-labeled FEMX-I cells did not differ in the two nude species during the first 12 hours after cell injection. The plating efficiency of FEMX-I cells in soft agar was increased by the addition of conditioned medium prepared from rat lungs, resulting also in a significant increase in colony size. In contrast, conditioned medium prepared from mouse lungs reduced the clonogenic capacity of the FEMX-I cells in a dose-dependent manner. Conditioned media prepared from rat and mouse liver, kidney, and spleen tissues either inhibited or had no effect on colony formation. The results suggest that the unexpected differential metastatic patterns observed in vivo may reflect differences in the presence of growth-modulating paracrine factors in the host lungs.
The objective of this study was to investigate the key genetic changes and molecular mechanisms in the process of invasion and metastasis of human epithelial ovarian cancers. The in vitro invasion assay was used to further testify that the human epithelial ovarian cancer cell line SKOV3.ip1 is more invasive and metastatic compared with its parental line SKOV3. A total of 17,000 human genome complementary DNA microarrays were used to compare the gene expression patterns of the two cell lines. Reverse transcription-polymerase chain reactions and Western blotting were performed to validate the results of the microarray. Totally, 1557 twofold differentially expressed genes were screened out by 17,000 human genome complementary DNA microarrays between the two cell lines, including some important genes such as, nm23, c-erbB-2, and other unknown genes or expressed sequence tags with remarkable fold changes. The results of the microarray experiment were further confirmed by reverse transcription-polymerase chain reactions and Western blotting of the nm23-H2 gene. SKOV3.ip1 is more invasive and metastatic than its parental line. The invasion and metastasis mechanism of epithelial ovarian cancer is a very complex process in which many important genes like nm23, c-erbB-2, as well as other unknown genes or expressed sequence tags were involved.
The distribution of DNA content in 12 cases of metastatic brain tumor, 6 cases of primary lung cancer and 6 cases of primary breast cancer were studied by flow cytometry. According to the pattern of DNA histogram, 12 specimens of metastatic brain tumors were classified into 3 types. Six cases of type I showed a sharp peak in 2C with large numbers of cells in 4C, 4 cases of type II showed the highest peak near 3C with a small peak in 2C, and 2 cases of type III showed a shift of the peak to the right near 4-5C. Type II and III seemed to have two different kinds of the cells which were mixed with normal brain cells or blood cells showing small peak in 2C and tumor cells showing the highest peak in 3C to 5C. Primary lung cancer and breast cancer were also divided into 2 types of DNA histogram, which were similar to those of metastatic brain tumors as type I and type II. Although there was no case of metastatic brain tumor having a DNA histogram of primary tumor in the same case, DNA patterns of metastatic brain tumors might be related to those of primary tumors because of the similarity of the histograms. It was difficult to disclose the primary sites or histological types of metastatic brain tumors from the type of DNA histograms but flow cytometric analysis revealed the characteristic patterns such as type II and III in metastatic brain tumors. We consider that these patterns might be of clinical diagnostic value in flow cytometric study.