nm23 in the primary and metastatic sites of gastric carcinoma. Relation to AFP-producing carcinoma

Tumor metastasis is the major cause of treatment failure and death in cancer patients. The present study was designed to extrapolate the association of nm23 expression with acquisition of metastatic potential of gastric carcinoma with special reference to the alpha-fetoprotein-producing gastric carcinoma (APGC). The primary tumor with surrounding normal mucosa and metastatic lymph nodes of 30 patients with APGC and 29 randomly selected matched controls of non-AFP gastric carcinoma (NAGC) were immunostained for nm23 and an image analyzer system was used for quantitative evaluation. Overexpression of nm23 was noted in 71% (42/59) of the primary tumors and 18% (10/55) of the metastatic tumors and there was no difference between the APGC and NAGC groups. The overexpression of nm23 in the primary tumors correlated with tumor invasion, metastasis and progression in all cases and similar results were obtained in the APGC and NAGC groups except for the tumor stage which was insignificant in the APGC group. The patient survival was adversely affected by the overexpression of nm23 in the primary sites and downregulation in the metastatic sites in all cases but lost their significance in the multivariate analysis. However, nm23 status did not affect patient survival in the APGC group.     

Differences in the recognition of tumor-specific CD8+ T cells derived from solid tumor, metastatic lymph nodes and ascites in patients with gastric cancer

We established gastric cancer-specific CD8+ T-cell (T(CD8+)) lines derived from different lymphocyte sources in the same patients by repeated stimulation with mitomycin-C-treated autologous tumor cells with low-dose interleukin-2, and we compared recognition patterns among the T(CD8+) derived from solid tumor, lymph node metastasis and ascites in the same patient (n = 3) to determine their similarities and differences for therapeutic purposes. We confirmed that gastric cancer-specific T(CD8+) lines can be isolated, in a MHC class I-restricted manner, from solid tumors, metastatic lymph nodes and malignant ascites. T(CD8+) lines derived from tumor-infiltrating lymphocytes (TIL) in solid tumor recognized autologous tumor cells derived from solid tumor, but not autologous tumor cells derived from ascites or metastatic lymph node, while T(CD8+) lines derived from tumor-associated lymphocytes (TAL) in malignant ascites recognized autologous tumor cells derived from ascites, but not tumor cells from solid tumor or metastatic lymph node. Furthermore, T(CD8+) lines derived from regional lymph node lymphocytes (RLNL) recognized autologous tumor cells derived from metastatic lymph nodes, but not tumor cells derived from ascites. No significant differences were seen in MHC class I expression among the tumors derived from solid tumor, lymph node metastasis or ascites in the same patient. This suggests that there are differences of recognition patterns among the TILs, TALs and RLNLs in the same patient and that it is important to consider the source of lymphocytes, e.g., a combination of TILs, TALs and RLNLs, for adoptive immunotherapy in gastric cancer patients.     

Gastric cancer with p53 overexpression has high potential for metastasising to lymph nodes

Overexpression of the tumour suppressor gene p53 was investigated immunohistochemically in 96 primary gastric carcinomas and 26 corresponding metastatic perigastric lymph nodes. Abnormalities in p53 expression were found in 52 (54%) of the 96 primary carcinomas. Tumours stained positively for p53 frequently metastasised to lymph nodes (the metastatic rate: 85%) compared to findings in those with negative p53 staining (64%, P < 0.05). Ninety-two percent (24/26) of the malignant cells in the lymph nodes stained positively for p53. When the DNA ploidy pattern of the tumour was determined by flow cytometry, the aneuploid tumours in p53 positive and negative groups accounted for 69% and 45%, respectively (P < 0.05). Proliferative activity of the tumour, as measured by Ki-67 labelling, was significantly higher (30.6 +/- 12.0%) in the p53 positive group than that (25.1 +/- 10.7%) in the p53 negative group (P < 0.05). Thus, gastric cancer with a mutant p53 has high proliferative activity and metastasis to lymph nodes will probably occur.     

Microsatellite instability in gastric cancer with varied structure

BACKGROUND: The intratumoral histological heterogeneity of cancer has been investigated by many pathologists. Although microsatellite alteration has been reported in gastric cancer, the significance of genomic instability in these histologically heterogeneous cases has not been elucidated. METHODS: Microsatellite alteration detected by polymerase chain reaction (PCR) in 13 primary advanced gastric cancers with varied structure was examined at 8 microsatellite loci. RESULTS: We were able to detect a greater prevalence of replication errors (RER) (6/13, 46.2%) at the primary site of gastric cancer than previously reported and loss of heterozygosity (LOH) at 17p (4/13, 30.8%) was demonstrated at the primary sites. All the same time, we also examined metastatic tumors in the regional lymph nodes in 12 of these cases. The frequency of RER (8/12, 66.7%) in metastatic lesions was higher than that in primary tumors. Detectability of RER was more frequent in the poorly differentiated portions than the well-differentiated portions of lymph node metastases. CONCLUSIONS: These findings suggest that gastric cancer with varied structure acquired frequent microsatellite instability during progression and metastasis, and we reasoned that the mutator phenotype detected by microsatellite alterations may represent heterogeneous tumor clones in gastric cancer and lymph node metastases.     

Cell therapy of a highly invasive human breast carcinoma implanted in immunodeficient (SCID) mice

Although enormous progress has been made in the detection and treatment of localized (nonmetastatic) breast cancer, there has been relatively moderate progress toward the effective treatment of advanced disease. This study investigates the antitumor efficacy of a potent MHC nonrestricted cytotoxic human T cell line (TALL-104) upon transfer into a clinically relevant mouse model of metastatic breast cancer. Fragments from a surgical specimen of a patient with infiltrating ductal carcinoma were implanted s.c. in the flank region of severe combined immunodeficient (SCID) mice. One hundred % of the animals developed a local tumor mass that metastasized to subaxillary and inguinal lymph nodes, bones, lungs, liver, kidneys, ovaries, and brain, very closely mimicking the human disease. Multiple i.p. transfers of gamma-irradiated (nonproliferating) TALL-104 cells into mice bearing low tumor burden (the primary tumor mass weighed only 150 mg) completely arrested local tumor growth and prevented systemic spread into local lymph nodes and distant organs. Remarkably, cell therapy administered in an advanced disease stage (when the tumor weighed 2 g) induced a significant or total regression of established metastasis with no obvious effects on the primary tumor mass. Profound antitumor effects against both local and systemic disease were instead seen in mice that received cell therapy after surgical excision of the primary tumor. The implications of these data in adjuvant breast cancer therapy are discussed.     

Synchronous hepatocellular carcinoma or metastatic hepatic tumor with primary gastric cancer

BACKGROUND/AIMS: When a solitary hepatic tumor occurs synchronously with gastric cancer, it is usually presumed to be metastatic. However, this may not be true in a place like Taiwan, where hepatocellular carcinoma (HCC) is prevalent. This study was conducted to examine the clinicopathological factors of both conditions. METHODOLOGY: A retrospective analysis of 14 patients who underwent a synchronous hepatectomy in combination with radical gastrectomy over the past 15 years was performed. RESULTS: Seven patients had metastatic gastric cancer, and seven had concomitant gastric and hepatic cancer. Serosal invasion and lymph node metastasis were the major features in the patients with metastatic gastric cancer. Early gastric cancer was found in three of the patients with the coexisting primary cancers. No patient with solitary metastatic cancer survived more than one year, but long-term survival of more than two years was achieved in two patients with the two forms of cancer. CONCLUSIONS: Double cancer of the stomach and liver should be kept in mind in patients with gastric cancer concomitant with a solitary hepatic tumor, in order to provide optimal treatment.     

Intra-operative diagnosis of N2 lymph node metastasis of gastric cancer

BACKGROUND/AIMS: Limited lymph node dissection for gastric cancer, which is prevalent in Western countries, leaves cancer cells in the second tier of nodes in patients who have metastasis in those nodes. It is, however, difficult to correctly diagnose nodal status during surgery. The present study was, therefore, designed to examine how to detect N2 metastasis intra-operatively. METHODOLOGY: Five hundred and eight patients undergoing extended lymph node dissections for gastric cancer were retrospectively analyzed. Accuracy of the intraoperative diagnosis of node involvement based on macroscopic findings was investigated, according to the N stage and histological type of the tumor. Furthermore, the distributions of N2 metastasis were clarified, according to tumor site. RESULTS: Intra-operative macroscopic findings were frequently assessed as being less severe than histological findings in cases with N2 metastasis (61.9%, 39/63). Intra-operative recognition of N2 metastasis was significantly lower in the cases with undifferentiated adenocarcinoma (28.2%, 11/39) than in those with differentiated adenocarcinoma (56.5%, 13/23). The distributions of N2 metastasis revealed nodes along the left gastric and common hepatic arteries to be the key junctions for lymphatic flow from the middle and lower thirds of the stomach, respectively. CONCLUSIONS: Intra-operative diagnosis of N2 metastasis is difficult to make based on macroscopic findings, especially in undifferentiated tumors. To detect N2 metastasis intra-operatively, the nodes along the left gastric or common hepatic artery should be submitted to frozen section examination for primary tumors located in the middle or lower third of the stomach, respectively.     

A case of advanced gastric cancer resembling submucosal tumor of the stomach

We report a case of primary gastric carcinoma with a macroscopic appearance indistinguishable from that of a submucosal tumor. A 48-year-old man visited our hospital with a chief complaint of epigastric discomfort. Endoscopic examination revealed a protruding lesion with a well defined margin on the anterior wall of the gastric antrum. Most of the tumor surface was covered with apparently normal gastric mucosa and a shallow recess with mild erosion was observed on the top. Abdominal ultrasonography showed a hypoechoic lesion with an irregular margin under the gastric mucosa. Laboratory examination revealed an elevated CA19-9 level of 106.9 U/ml. In spite of repeated bouling biopsies, no histological diagnosis could be obtained before surgery. However, gastrectomy with regional lymph node dissection was performed because of the high likelihood of gastric cancer, in view of the markedly elevated CA19-9 level and irregular tumor margin demonstrated by abdominal ultrasonography. The tumor was diagnosed histologically as papillo-tubular adenocarcinoma invasive to the serosa with marked vessel infiltration. No metastasis was found in the regional lymph nodes. Gastric cancer resembling submucosal tumor is rare and often difficult to diagnose. Careful estimation of the possibility of gastric cancer and the informed consent of the patient are critically important, in cases of suspected primary gastric cancer resembling submucosal tumor, in order to decide the form of treatment.     

NM23 gene expression in human breast carcinomas: loss of correlation with cell proliferation in the advanced phase of tumor progression

NM23 is a protein associated with tumor progression, expressed in all tissues and in human tumors. Reduced expression of NM23.H1 is related to high incidence of lymph node and distant metastasis or to poor prognosis of the patient in several human malignant tumors. In this study we analyze NM23 expression in non-neoplastic mammary tissues surrounding the tumoral lesions, in human mammary carcinomas and in lymph node metastasis. Our analysis shows that NM23.H1 expression is lower in the mammary cells surrounding the tumor than in the tumor itself. In the primary tumors we observed a negative trend between degree of local invasion and level of NM23.H1 expression. A further decrease of NM23.H1 was detected in the invasive tumors that metastasized to axillary lymph nodes and in the metastasis. NM23.H2 was always more highly expressed than NM23.H1, and reduced expression of NM23.H1 but not NM23.H2 was concordant with the presence of lymph node metastasis or local invasiveness of the primary tumor. A positive correlation between NM23.H1 mRNA content and cell growth rate of breast tumor cells has been confirmed. However, this trend was not maintained in cancer cells from tumors that metastasized to axillary lymph nodes and in metastatic cells; in these 2 situations the NM23.H1 mRNA content varied without any relationship to the proliferative rate of the cells. In addition, in comparison with the initial tumor, the metastatic cell population showed a strong decrease of NM23.H1 expression and increased proliferative activity.     

A case of advanced gastric carcinoma with disappearance of cancer cells by neoadjuvant chemotherapy

A 74-year-old man was diagnosed by preoperative X-ray and endoscopy with biopsy as having type 2 advanced gastric carcinoma (poorly differentiated adenocarcinoma) in the antrum. CT scan revealed swelling of the paraaortic lymph nodes, which was considered to be metastasis from the gastric carcinoma. As the cancer was judged to be stage IV and too advanced for a curative surgical resection, a neoadjuvant chemotherapy was initiated. One course of the regimen consisted of 10 mg of CDDP (day 1-5, drip) and 300 mg of UFT (day 1-7, oral), and the patient underwent the regimen three times in succession. After the chemotherapy, the swelling of para-aortic lymph nodes disappeared on CT scan. A distal gastrectomy with D2 lymph nodes dissection and sampling of the para-aortic lymph nodes was performed. Histopathological examination revealed that the cancer cells had completely vanished both in the primary tumor and lymph nodes. The effect of this neoadjuvant chemotherapy was judged to be Grade 3 histopathologically.     

Metastatic adenocarcinoma to the uterine cervix from gastric cancer. A clinicopathologic analysis of 16 cases

BACKGROUND: Metastatic adenocarcinoma to the uterine cervix from gastric cancer is rare, and the clinicopathologic features of this metastasis are unclear. METHODS: A clinicopathologic review of 16 patients with metastatic adenocarcinoma to the uterine cervix from gastric cancer was performed. RESULTS: The ages of the patients ranged from 29 to 57 years, and 81.3% of the patients were premenopausal. Nine of the patients had undergone gastrectomy previously. In 11 patients the histologic type of the gastric cancer was poorly differentiated adenocarcinoma and, in 5 patients, signet ring cell carcinoma. The cervical metastasis was diagnosed 11-121 months (mean, 57.5 months) after the diagnosis of the gastric cancer in 10 of the patients. In six patients, the cervical metastasis was discovered synchronously or before the diagnosis of the gastric cancer. The colposcopic findings were normal in 57.1%, but 56.3% had abnormal cervical smears. In all patients, tumor cells were present in the dilated lymphatics of the cervix. Metastases to the uterine body and bilateral ovaries were common, and half of the patients had metastases to the paraaortic lymph nodes. Extirpation of the cervix was performed in six patients. The prognosis was poor, regardless of the treatment method. CONCLUSIONS: The route of metastasis to the cervix is surmised to be retrograde lymphatic, and this extension is often slow. Periodic gynecologic examinations should be performed indefinitely for premenopausal female patients with advanced gastric cancer.     

Expression of CD44 variant 6 and lymphatic invasion: importance to lymph node metastasis in gastric cancer

Lymph node metastasis is a critical prognostic factor for gastric cancer. In the present investigation we examined clinicopathologic factors influencing the metastatic processes to the lymph mode and their prognostic importance. A randomly selected group of 98 patients with adenocarcinomas of the stomach who underwent gastrectomy plus systematic lymph node dissection at Osaka Police Hospital from 1991 to 1996 were analyzed. Altogether 37 (38%) cancers were positive for CD44 variant 6 (v6) staining, 31 (32%) were intermediately stained, and 30 (30%) were negative. CD44-v6 expression correlated well with lymph node metastasis. Expression of CD44-v6 and lymphatic invasion were independent risk factors for metastatic lymph nodes. Among the patients with CD44-v6-positive and lymphatic invasion-positive cancers, 88% had lymph node metastasis, whereas only 13% of patients negative for both factors had lymph node metastasis. Although CD44-v6 expression and lymphatic invasion have been reported to be risk factors for recurrence and a poor prognosis, in this investigation these factors were found not to be significant for hematogenous and lymphatic recurrences or overall survival rates. Thus expression of CD44-v6 and lymphatic invasion may regulate lymph node metastases from gastric cancer.     

Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumor recurrence and tumor death within three years after the initial operation

We investigated whether the presence of a fibrotic focus (FF) in the primary lesion and in lymph node metastasis is a good predictor of early tumor recurrence or death in patients with invasive ductal carcinoma (IDC). Multivariate relative risk (RR) of tumor recurrence and death according to the presence of FF in the primary tumor was estimated using the Cox proportional hazards regression model with adjustment for other prognostic factors (histologic grade, T classification, nodal status, tumor necrosis, DNA ploidy, c-erbB-2 protein expression, p53 protein expression, and labeling index of proliferating cell nuclear antigen). For the evaluation of the metastatic status in the axillary lymph nodes, RR of multivariate analysis was adjusted for the presence of FF in the metastatic tumor and the number of lymph nodes involved (1-3 and > 3). The presence of FF increased the RR of tumor recurrence significantly for the cases in all stages, and especially for those in stages I and II (RR = 6.9, P < 0.05 and RR = 25.0, P < 0.005, respectively). All cases that died of disease had FF. Among IDCs with FF, 24 cases had FF in lymph node metastasis. Significantly higher RRs of tumor recurrence and death were observed in cases with FF in lymph node metastasis than in those without it (RR = 2.0, P < 0.001 and RR = 5.9, P < 0.05, respectively). It was suggested that the presence of FF is an important predictor of early tumor recurrence or death in patients with IDCs. The presence of FF in lymph node metastatic lesions is also a significant prognostic parameter.     

Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer

In a subset of patients with early gastric cancer, there were recurrences of the disease after a curative resection had been done. Direct evidence of tumor seeding in distant organs at the time of surgery for gastric cancer is not available. An immunocytochemical assay for epithelial cytokeratin protein may fill this gap because it is a feature of epithelial cells that would not normally be present in bone marrow. From 1994-1997, the bone marrow of 45 patients with early gastric cancer was examined for tumor cells, using immunocytochemical techniques and an antibody reacting with cytokeratin, a component of the intracytoplasmic network of intermediate filaments. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. Clinicopathological characteristics were determined for subjects with cytokeratin-positive cells in the bone marrow. Of these 45 patients, 9 (20.0%) had cytokeratin-positive cells in the bone marrow at the time of primary surgery. These positive findings were not related to tumor advance-related factors of lymph node metastasis and distinct lymphatic and vascular invasion. Microvessel density in the primary tumor exceeded 2-fold in cytokeratin-positive cells, compared with findings in negative cells (P < 0.05). Tumor cells in bone marrow are indicative of the general disseminative metastasis in patients with early gastric cancer, and the metastatic potential was closely related to angiogenesis in the primary tumor.     

Accuracy of endoscopic ultrasonography in the diagnosis and staging of gastric cancer and lymphoma

BACKGROUND: There is a need to assess the sensitivity, specificity, and predictive value of endoscopic ultrasonography (EUS) in the diagnosis and staging of gastric cancer and lymphoma. METHODS: A prospective study was performed on 86 patients with endoscopic gross appearance suspicious for cancer or lymphoma. Biopsies with endoscopic forceps were always carried out before EUS. All patients underwent laparotomy for final diagnosis, staging, and eventually treatment. The results of EUS were correlated with the histologic findings of the resected specimens, when possible, or with the surgical findings. There were 42 gastric cancers and 44 primary gastric lymphomas. RESULTS: EUS made a correct diagnosis of cancer in 35 of 42 patients, with a sensitivity of 83%. Positive predictability was 87%, specificity was 97%, and negative predictability was 96%. Diagnostic accuracy was 95%. In the evaluation of cancer depth invasion, EUS was correct in 91% of cases. EUS displayed perigastric metastatic lymph nodes in 14 of 25 patients, with a sensitivity of 56%. Positive predictive value was 93%, specificity was 93%, and negative predictive value was 54%. Diagnostic accuracy was 69%. EUS made a correct diagnosis of lymphoma in 39 of 44 patients, with a sensitivity of 89%. Positive predictability was 87%, specificity was 97%, and negative predictability was 97%. Diagnostic accuracy was 95%. In the evaluation of lymphoma depth invasion, EUS was correct in 92% of cases. EUS displayed metastatic perigastric lymph nodes in 8 of 18 patients, with a sensitivity of 44%. Positive predictability was 100%, specificity was 100%, and negative predictability was 72%. Diagnostic accuracy was 77%. CONCLUSIONS: From these data it appears that in these diseases EUS has demonstrated specific ultrasonographic features that allow correct diagnosis and staging in the majority of patients. In difficult cases EUS may help to achieve the correct diagnosis. EUS also appear to be a useful tool for staging of gastric cancer and lymphoma. It shows not only tumor depth and local spread but also the passage from a pathologic to a normal wall and lymph node metastasis. With this accurate noninvasive staging procedure, in the near future many patients will no longer undergo exploratory laparotomy for surgical staging. Thanks to EUS, the choice of conservative or surgical treatment can be strongly affected. In case of surgery, EUS can orient the kind of surgical approach. Moreover, the use of EUS for evaluation of therapy during follow-up will probably become of major importance.     

In vitro diagnosis of axillary lymph node metastases in breast cancer by spectrum analysis of radio frequency echo signals

Axillary lymph node status is of particular importance for staging and managing breast cancer. Currently, axillary lymph node dissection is performed routinely in cases of invasive breast cancer because of the lack of accurate noninvasive methods for diagnosing lymph node metastasis. We investigated the diagnostic ability of ultrasonic tissue characterization based on spectrum analysis of backscattered echo signals to detect axillary lymph node metastasis in breast cancer in vitro compared with in vitro B-mode imaging. Immediately after surgery, individual lymph nodes were isolated from axillary tissue. Each lymph node was scanned in a water bath using a 10-MHz instrument, and radio frequency data and B-mode images were acquired. Spectral parameter values were calculated, and discriminant analysis was performed to classify metastatic and nonmetastatic lymph nodes. Forty histologically characterized axillary lymph nodes were enrolled in this study, including 25 nonmetastatic and 15 metastatic lymph nodes. A significant difference existed in the spectral parameter values (slope and intercept) for metastatic and nonmetastatic lymph nodes. Spectral parameter-based discriminant function classification of metastatic vs. nonmetastatic lymph nodes provided a sensitivity of 93.3%, specificity of 92.0%, and overall accuracy of 92.5%. In comparison, B-mode ultrasound images of in vitro lymph nodes provided a sensitivity of 73.3%, specificity of 84.0%, and overall accuracy of 80.0%. Receiver operating characteristic (ROC) analysis comparing the efficacy of both methods gave an ROC curve area of 0.9888 for spectral methods, which was greater than the area of 0.8980 for B-mode ultrasound. Hence, this in vitro study suggests that the diagnostic ability of spectrum analysis may prove to be markedly superior to that of B-mode ultrasound in detecting axillary lymph node metastasis in breast cancer. Because of these encouraging results, we intend to conduct an investigation of the ability of spectral methods to classify metastatic axillary lymph nodes in vivo.     

Administration of recombinant interleukin 12 prevents outgrowth of tumor cells metastasizing spontaneously to lung and lymph nodes

The present study investigates the ability of recombinant interleukin 12 (rIL-12) to modulate the growth of a primary tumor as well as the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor displayed rapid growth of the primary tumor mass, high incidence of metastases to lung and lymph nodes, and invasion from the primary s.c. site to the peritoneal cavity. Starting 12 days after s.c. tumor cell implantation, several i.p. injections of rIL-12 at 2-3 day intervals resulted in regression of growing tumors. These treated mice did not show signs of metastases or tumor recurrence at the original site. One month after tumor implantation, untreated mice did not have visible lung metastasis, but some did have palpable lymph nodes. At this stage, the primary tumors of animals without palpable lymph nodes were surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injections after tumor resection inhibited the development of metastases in both lung and lymph nodes. This contrasted with the failure of IL-2 to prevent metastases. Even for mice already showing signs of lymph node metastases or invasion of the abdominal wall, rIL-12 administration after tumor resection prevented further invasion to the peritoneal cavity and growth of metastatic tumor cells in lung. It was somewhat surprising that the IL-12 treatment of animals after 1 month of tumor growth without resection also resulted in complete tumor regression, as well as eradication of micrometastasis that would have occurred before the treatment. Moreover, they exhibited resistance to a rechallenge with the same tumor but not with a second tumor. Thus, this tumor system provides a relevant model to clinical situations in terms of treatment of advanced tumors and metastases. These results also indicate that IL-12 can induce a curative immune response, even in the face of an aggressive micrometastasizing tumor.     

Traffic to lymph nodes of PC-3 prostate tumor cells in nude mice visualized using the luciferase gene as a tumor cell marker

Tumor cell traffic between intramuscular tumors experimentally induced in nude mice and lymph nodes was studied using PC-3.luc prostate adenocarcinoma cells permanently transfected with the luciferase gene as a tumor cell marker. This sensitive approach allowed the detection of 1 luminescent tumor cell mixed with 1 x 10(7) unlabeled PC-3 cells and of 1 tumor cell/lymph node. PC-3.luc cells inoculated in nude mice showed a 1000-fold expansion, accompanied by a 4.5-fold increase in tumor cell density (tumor cell number/gram of tumor), during the first 90 days of primary tumor growth. No macroscopic secondary tumors were found in organs, other than lymph nodes, by the end of the experiment. Tumor cell spread to lymph nodes was detected at Day 21, when there were 2 x 10(5) tumor cells at the inoculation sites, before discrete primary tumors could be identified. The total tumor cell burden in the tested lymph nodes was modeled by a power function of primary tumor cell number (determination coefficient R2 = 0.9472). By the end of the experiment, on Day 110, there were 1.8 metastatic cells in the studied lymph nodes for every 1000 primary tumor cells. These results suggest that empirically obtained tumor-specific indexes could be used to characterize the invasion of lymph nodes by tumor cells. The path of spread for PC-3.luc cells from intramuscular sites appears to follow the lymphatic system, and at no time during the experiment were tumor cells found in blood. An upper limit of no more than 16 blood-circulating tumor cells was established for these experiments. The observation of tumor cells that were invading the lymphatic system from the onset of tumor growth but unable to establish secondary tumors in other organs emphasizes the potential of this procedure in studying the multi-step nature of metastasis.     

A dominant negative mutant of the insulin-like growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer

The 5-year survival rate for women with metastatic breast cancer is only 25-30%; thus, the need to improve treatment is apparent. Overexpression of insulin-like growth factor-I receptor (IGF-IR) correlates with poor prognosis and local recurrence. In this study, we addressed whether functional impairment of IGF-IR affects adhesion, invasion, and metastasis of breast cancer. Impairment of IGF-IR function was achieved by transfecting a dominant negative form of the receptor, termed 486stop, into MDA-MB-435 metastatic breast cancer cells. The protein product of 486stop is secreted extracellularly, resulting in a bystander effect. Cellular adhesion to laminin and collagen was inhibited 94 and 88%, respectively. Furthermore, 486stop inhibited insulin-like growth factor-I-stimulated invasion through collagen IV by 75%. The dominant negative receptor was secreted, as evidenced by the observation that MDA-MB-435 and MDA-MB-231 cells were prevented from binding to laminin by 90% when treated with conditioned medium (CM) from 486stop-transfected cells. CM also inhibited the invasion of MDA-MB-231 cells across collagen IV by 80%. Finally, CM made MDA-MB-231 cells 30% more sensitive to Taxol-induced cell death. Growth in soft agar was suppressed by 486stop, but growth in monolayer was unaffected. When injected into the mammary fat pad, 486stop did not significantly suppress growth of the primary tumor, but metastasis to the lungs, livers, lymph nodes, and lymph vessels was significantly decreased compared to the vector control. In conclusion, inhibition of IGF-IR resulted in suppression of adhesion, invasion, and metastasis, providing a mechanistic rationale for targeting IGF-IR in the treatment of metastatic breast cancer.     

Lymph node dissection for T1 esophageal cancer

Proper mucosal cancer of esophagus of esophageal has no lymph node metastasis, and lymph node metastasis occurs when the tumor invades to muscularis mucosa. Submucosal cancer of esophagus has lymph node metastasis in the rate of 44.4% (40/90). The incidence and number of metastatic lymph node increase with the depth of invasion. Lymph node metastasis of esophageal cancer spreads widely to cervix, mediastinum and abdomen. It's same in submucosal cancer and first metastasis occurs also appears at everywhere from cervix to abdomen. There are high rate of lymph node metastasis in 101L, 105, 106rR, 106rL, 108, 110, 1, 2, 3, 7 lymph nodes. The cancer in upper thoracic esophagus has high rate of lymph node metastasis in cervix and upper mediastinum and lymph node metastasis of lower thoracic esophageal cancer is liable to appear in lower mediastinum and abdomen. Then the cancer in middle thoracic esophagus should be performed the lymph node dissection in cervix, mediastinum and abdomen, especially 101, 102m, 104, 105, 106r, 106t, 107, 108, 110, 1, 2, 3, 7 lymph nodes. On the other hand, cancers limited to proper mucosal layer should be treated with endoscopic mucosal resection. And its same as in the greater part of cancers invaded to muscularis mucosa and shallow layer of esophageal submucosa. The 5 year survival rate of T1 cancers of esophagus is 85.6%, which were performed surgical treatment.