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Novel experimental models of human cancer metastasis in nude mice: lung metastasis, intraabdominal carcinomatosis with ascites, and liver metastasis.

The ability of RPMI 4788 cells, a human colon cancer cell line, to produce experimental metastases in the lung, intraperitoneal cavity, and liver was studied in nude mice. Injection of 2 X 10(6) tumor cells into the tail vein of nude mice produced metastatic lung tumors, and an intraportal injection of 5 X 10(6) cells produced metastatic liver tumors. An intraabdominal carcinomatosis with ascites was formed after an i.p. injection of 5 X 10(6) tumor cells. The nude mice with lung metastasis or intraabdominal carcinomatosis always died within a few weeks. Macroscopic observation showed that the number of lung metastatic nodules on day 21 after tumor inoculation was 311.3 +/- 78.2 (mean +/- SD) in BALB/C nude mice, and 187.5 +/- 26.7 in ICR nude mice. In survival experiments, the mice with intraabdominal carcinomatosis showed a mean survival of 29.0 +/- 1.7 (mean +/- SD) days in BALB/C nude mice and 43.6 +/- 6.1 days in ICR nude mice. These novel experimental models of metastases in nude mice produced by injection of RPMI4788 cells had high reproducibility and may be useful not only for the study of the metastatic process but also for testing anticancer drugs.

Animals

[Clinical study of renal cell carcinoma with bony metastasis: comparative study with lung metastasis].

For the purpose of clinical analysis of renal cell carcinoma with bony metastasis (59 cases) the cases with lung metastasis (146 cases) were selected for comparison. The analyzed items were the distribution of bony metastatic portions, the results of radiotherapy for bony metastasis, comparative study with lung metastasis on clinical background, comparative study with lung and bony metastasis on the survival rate, comparative study with solitary bony and lung metastasis on the survival rate, comparative study with bony and lung metastasis on the grade of primary lesion. The most frequent metastatic portion was lower extremities, spine, upper extremities and pelvic bone in this order. The survival rate of the cases with bony metastasis was better than that of lung, especially with solitary metastatic cases. The effects of radiotherapy for bony metastasis were not so good for prolonging the survival. The grade of kidney malignancy did not influence the survival of patients with bony metastasis, on the contrary, in patients with lung metastasis, there was a good prognostic factor for survival.

Adult

[Experimental study of lymph node metastasis in thoracic esophageal carcinoma--regarding lymph node metastasis and changes in lymphatic flow by ultrafine charcoal in rabbit esophageal carcinoma model].

Esophageal carcinoma models were created by transplanting VX2 cells to rabbit esophagus endoscopically. By injecting finely divided activated charcoal into normal rabbit esophagus and tumor sites of esophageal carcinoma model, lymph flow was observed directly. Existence of lymph node metastasis was studied in detailed pathology. In 30 rabbits with upper esophageal carcinoma, lymph node metastasis was seen in 77%. Metastasis to bilateral intrathoracic paratracheal lymph node was seen in 50%, and also concentration of lymphatic flows from tumor site was seen. However, there were no metastasis and no lymph flow to abdominal lymph nodes. While, metastasis to cervical lymph nodes showed around 13%. Esophageal lymphatic flows were also seen reaching the cervical area along the esophagus. In 40 models with mid lower esophageal carcinoma, lymph node metastasis were seen in 88%. Metastasis to right and left thoracic paratracheal lymph nodes was 75% and 53%, respectively, and 25% of metastasis went to cardia lymph nodes. The lymph flows were going up and down around these lymph nodes, and reaching to lymph nodes at upper highest mediastinum or left gastric artery. The metastatic rate to the cervical lymph nodes was about 5%. There were no significant differences in lymphatic metastasis between right and left mediastinum. These findings suggest the necessity of radical dissection for both sides of the mediastinum.

Animals

Colorectal Liver Metastasis Pathomics Model: Integrating Single-Cell and Spatial Transcriptome Analysis With Pathomics for Predicting Liver Metastasis in Colorectal Cancer.

The liver is the primary target organ for hematologic metastasis of colorectal cancer (CRC), and CRC liver metastasis (CRLM) often precludes radical resection, making it the leading cause of death in patients with CRC. To improve the identification and prediction of liver metastasis risk, we identified a cell type of liver metastasis--triggering malignant cells (LMTMCs) through integrating single-cell RNA sequencing and spatial transcriptome analysis. Multiomics cell communication analysis indicated that the interaction between fibroblasts and LMTMCs through the COL1A1-CD44/SDC4 and LAMA4-CD44 signaling axes could promote CRLM. By applying the one-class logistic regression algorithm, we developed a CRLM scoring system in the bulk RNA-sequencing data according to the abundance of LMTMCs in each individual. Using the grouping labels derived from the CRLM scoring system in the bulk data and the corresponding whole-slide images without any manual annotations at the region or pixel level, processed via slide-level weakly supervised learning, a deep-learning model based on the ResNet18 architecture, called Colorectal Liver Metastasis Pathomics Model, was developed to predict the risk of liver metastasis in patients with CRC. The Colorectal Liver Metastasis Pathomics Model achieved an area under the curve of 0.84 at the internal test set of The Cancer Genome Atlas-CRC histology images. In the external independent validation sets, namely the Affiliated Hospital of Southwest Medical University and the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University cohorts, the areas under the curve were 0.89 and 0.72, respectively, indicating effective classification performances. This study provided new insights and tools for the early identification of CRLM and demonstrated the potential of combining multiomics with deep learning-based pathomics in cancer research.

Humans

Cervical lymph node metastasis in carcinoma of the tongue. Correlation between clinical and histopathological findings and metastasis.

The factors relating to lymph node metastasis occurring in association with carcinoma of the tongue have been investigated clinically and histopathologically by many authors. Nevertheless, accuracy in predicting lymph node metastasis has not yet been attained. The present study describes the results of analysis performed in an attempt to predict lymph node metastasis of carcinoma of the tongue. Ninety-eight patients with squamous cell carcinoma of the tongue who were treated at our institution were investigated. Among the 98 patients, lymph node metastases were histologically proven after neck dissection in 40 patients. For statistical analysis in the present study, the quantification theory Type II of Hayashi (1954) was employed for discriminatory analysis. According to this discriminatory analysis, the correlations between the clinical (age, tumour size, N-category) and histopathological (degree of keratinization, mitoses, structure, mode of invasion) findings and metastasis were assessed on the basis of the partial correlation coefficients; these coefficients for each finding were not greatly different from each other and 74 out of 98 patients (76%) could be differentiated between patients with metastasis and without metastasis accurately. The prediction of lymph node metastasis by such discriminatory analysis had significant validity.

Adult

Should all the N3 lymph nodes group metastasis be regarded as distant metastasis (M1) in curatively resected gastric cancer?

Recently, metastasis to N3 lymph nodes group was regarded as distant metastasis by the new TNM staging system due to poor overall survival. However, the 5-year overall survival rate of patients with metastasis to N3 groups was 34.5% after curative surgery. Moreover, in patients with metastasis to lymph node subgroups of #12, #13, #14, the overall 5-year survival rate increased upto 47.2% after curative resection and adjuvant chemotherapy. This was similar to that of the patients with metastasis to N1 and N2 lymph nodes groups. But in these highly tumor burden states, no survival benefit was found with the addition of immunotherapy to chemotherapy as we achieved in stage II and III. Therefore, we suggest that, at least, metastasis to #12, #13, #14 lymph nodes subgroups should not be categorized as a distant metastasis. And in these situations, active curative radical surgery with extended lymphadenectomy and adjuvant chemotherapy are recommended.

Adult

[Metastasis into the paracystium of urinary bladder carcinoma--the rate position and morphology of metastasis].

Twenty-three patients, who underwent radical cystectomy and pelvic lymph node dissection for bladder carcinoma from November 1985 to November 1987, were studied pathologically. We evaluated the rate, position and morphology of metastasis into the neurovascular corridor or paracystium. The stages of the twenty-three patients were G1 1, G2 10, G3 12 and pT1a 1, pT1b 4, pT2 8, pT3a 2, pT3b 7, pT4 1. Of the 23 specimens, 22 (95%) were found to contain metastasis in the connective tissue of the paracystium. Lymph node metastasis was recognized in four patients (17%). Metastasis in connective tissue around the iliac lymph node was recognized in 5 patients (22%). Of these 5 patients, 3 were free from lymph node metastasis. The morphological pattern of metastasis was ranged from a few tumor cells to massive tumor cells with proliferation of fibroblasts. The existence of metastasis in the paracystium should be evaluated morphologically for urinary bladder carcinoma.

Adult

[A clinical study of 76 cases in carcinoma of the colon and rectum with metastasis to the peri-aortic lymph nodes. With particular reference to the skip metastasis in carcinoma of the sigmoid colon to the peri-aortic lymph nodes].

The therapeutic result by tumorous site were evaluated in 76 cases of carcinoma of the colon and rectum with the confirmed presence of metastasis to the peri-aortic lymph nodes. The results revealed that significant good out-comes were noted in the relatively non-curative cases of carcinoma of the sigmoid colon, with particularly good prognosis being found in six cases with skip metastasis. There was a 26.1% (6/23) incidence of the skip metastasis in carcinoma of the sigmoid colon with the peri-aortic lymph nodes metastasis. We confirmed two lymphatic routes of the skip metastasis; one route was from the lymph nodes near the tumor to the para-aortic lymph nodes directly, and the other was from the lymph nodes near the tumor to the lymph nodes at the aortic diffract directly and finally to the para-aortic lymph nodes. In the all six cases, the peri-aortic lymph nodes metastasis occurred only in inferior site of the inferior mesenteric artery. The average number of the peri-aortic lymph nodes metastasis were as few as 1.7 in these cases. The prognosis was favorable with three of the six cases scoring a three-year survival and included a five-year survival case.

Adult

Lymph node metastasis in squamous cell carcinoma of the oral cavity: correlation between histologic features and the prevalence of metastasis.

A retrospective study was made of the correlation between preoperative clinical or histologic findings and the prevalence of lymph node metastasis in 60 patients with squamous cell carcinoma of the oral cavity who had histologically confirmed neck metastasis. Of these 60 patients, 39 with clinically N+ necks underwent immediate therapeutic neck dissection, and 21 whose necks were initially N0 but progressed to N+ during observation underwent subsequent therapeutic neck dissection. The primary site, TNM staging, histologic grade of malignancy of biopsy specimen, and location and number of histologically positive lymph nodes were reviewed in each case. The results were as follows: (1) The prevalence of neck metastasis was not significantly correlated with primary site and T stage; however, there was an apparent correlation between histologic grade of malignancy and the prevalence of neck metastasis. Patients with grade I-II histologic malignancy showed limited metastases that involved lymph nodes in levels I-II. On the other hand, patients showing grade III-IV histologic malignancy often had metastases that extended beyond level III, regardless of T stage. These results suggest that histologic grade of malignancy, as well as clinical features, must be taken into consideration when deciding whether supraomohyoid neck dissection is indicated. (2) The group that underwent subsequent neck dissection exhibited less advanced neck metastasis and a better prognosis than the group which underwent immediate neck dissection. These findings show that if they are closely followed up, it is possible to delay neck dissection in N0 patients until a neck metastasis is detected.

Adult

[Studies on pulmonary metastasis of renal cell carcinoma--pulmonary embolism revealed by lung-perfusion imaging and metastasis].

Invasion of renal cell carcinoma to veins is known to have a close relation with pulmonary metastasis. We speculated that a tumor thrombus would lodge in the pulmonary artery before establishment of a clinically apparent pulmonary metastasis. This may be particularly true in patients with renal vein or vena cava involvement of renal cell carcinoma. In this instance, it is crucial to know the clinical consequence of tumor thrombi in the pulmonary artery. Thus, we investigated these issues with the aid of lung-perfusion imaging in 22 renal cell carcinoma patients with and without vein involvement. The lung-perfusion imaging revealed positive in 8 of the patients examined prior to treatment. The incidence of positive finding was well correlated with an extensive vein invasion. Patients with positive imaging prior to treatment were associated with pulmonary metastasis at a higher rate than those with negative findings. These findings have indicated that vein invasion should be related with tumor thrombus formation in the pulmonary artery, and such a status in the lung would, in part, result in pulmonary metastasis. Two different clinical courses were found by an analysis of patients with the positive imaging prior to treatment. One is the clinical course in which positive findings were correlated with a newly developed metastasis in the lung. Thus, care should be taken in development of the metastasis during the follow-up when patients show the positive lung-perfusion imaging prior to treatment. On the other hand, we found two patients in whom the positive findings disappeared during the follow-up.

Adult

Drug treatments for metastasis of the Lewis lung carcinoma: lack of correlation between inhibition of lung metastasis and survival.

The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These compounds represent widely varied structures and were evaluated because they have been found to inhibit thromboxane synthetase, cyclooxygenase, and thrombin activation, respectively. These biochemical processes have been proposed in the literature as targets for antimetastatic drugs. The purpose of this investigation was twofold: (a) to compare the antimetastatic activities of the Eli Lilly compounds to those of the reference antimetastatic compounds nafazatrom and RA233, and (b) to examine the correlation between inhibition of spontaneous lung metastasis and survival. Spontaneous metastasis of the Lewis lung carcinoma was used to evaluate the antimetastatic activity of the compounds. In this model 5 x 10(5) tumor cells were implanted into the gastrocnemius muscle, the primary tumor was resected on Day 14, and metastatic lung lesions were counted on Day 25. Compounds were administered every 12 h on Days 5 through 19. Nafazatrom, LY150310, LY189332, and LY135305 were found to inhibit spontaneous lung metastasis in a dose-dependent manner. The ED50 values for the respective inhibitions with these compounds were 50, 0.5, 2, and 0.35 mg/kg/day; the respective therapeutic indexes (LD50/ED50) were 7, 180, 255, and 511. To evaluate the effect of nafazatrom, LY150310, LY189332, and LY135305 on animal survival, the compounds were given at maximally antimetastatic doses of 200, 60, 20, and 6 mg/kg/day, respectively. Two dosing schedules were used: (a) on Days 5 through 19 and (b) on Day 5 until death. Neither the median survival times nor the numbers of long-term survivors were significantly changed with any of the compounds at any dosing schedule. RA233, given to a maximally tolerated dose of 200 mg/kg/day on Day 5 until death, did not inhibit lung metastasis and did not increase median survival time. Postmortem examination of animals dosed with nafazatrom, LY150310, LY189332, and LY135305 showed complete inhibition in lung lesions and the appearance of lesions in the liver, kidney, spleen, and brain. The results of this investigation show that the effect a compound has on the number of metastatic lesions in a target organ may not be predictive of its effect on survival. To successfully translate laboratory data into the clinic, survival should be considered as a predictor of a compound's potential clinical utility.

Aniline Compounds

A novel Arg-Gly-Asp containing peptide specific for platelet aggregation and its effect on tumor metastasis: a possible mechanism of RGD peptide-mediated inhibition of tumor metastasis.

A novel cyclic tetrapeptide containing L-arginine-glycine-L-aspartic acid-L-phenylglycine (cyclo-RGDPhg) was synthesized and found to be a potent inhibitor of platelet aggregation induced by highly metastatic murine squamous cell carcinoma (SCCVII) cells (IC50 = 3.3 microM) as well as ADP (1.5 microM). This cyclic peptide, however, showed similar or less inhibitory activities on adhesion of SCCVII cells to fibronectin, vitronectin and type IV collagen as compared with those of parent linear tetrapeptide, RGDS. These results show that cyclo-RGDPhg peptide is a highly specific antagonist for gpIIb/IIIa on platelets. Moreover, this peptide failed to suppress pulmonary metastasis of SCCVII cells in an experimental metastasis model. These results indicate that RGD peptide-mediated inhibition of tumor metastasis is attributed to the suppression of cell adhesion but not platelet aggregation. These also suggest that platelet aggregation is not an essential step during blood circulation of tumor cells for the completion of metastasis.

Animals

[Metachronous hematogenous metastasis of gastric cancer--histopathologic characteristics of gastric cancer developing of the liver, lung or bone metastasis].

Fifty-seven gastric cancer patients developing metachronous hematogenous metastasis were histopathologically analyzed. In 37 patients who developed metachronous liver metastasis as the main pattern of recurrence, papillary adenocarcinoma was the most frequent histologic type, followed by poorly differentiated adenocarcinoma of the medullary type. In 20 patients with metachronous lung or bone metastasis, poorly differentiated adenocarcinoma of the scirrhous type was the common histologic pattern. From the present data, we assume that liver metastasis of gastric cancer occurs when cancer cell clusters are transported to the liver, where they attach and proliferate, whereas single cells passed through the portal system tend to establish secondary deposits in the lung or bone.

Bone Neoplasms

[A case of alveolar soft-part sarcoma with recurrent cerebral metastasis--operative management of the cerebral metastasis].

A female patient noticed a painless swelling at the right thigh at the age of 12. Two years later, she had total removal for the tumor and irradiation. The diagnosis of the tumor was alveolar soft-part sarcoma. At the age of 16 she had left pneumonectomy for its metastasis. The next year the metastatic tumor is detected in the right lung. At 21 she was admitted to our service with a diagnosis of cerebral metastasis. Her chief complaints were headache, nausea and visual disturbance. Neurological examination revealed advanced choked disc and left homonimous hemianopsia. CT scan revealed a large vascular tumor in the right occipital lobe and chest film showed multiple metastatic shadows in right lung. A large bloody tumor was removed totally through right occipital craniotomy. She was discharged with a marked improvement of neurological symptom. Since then she had had 8 times of surgical removal for 10 cerebral metastatic tumors. Several chemotherapy was attempted for three times. At first adriamycin was administered after the first removal of cerebral metastasis. Methyl-CCNU and Picibanil was administered after the second removal. Soon after the chemotherapy, metastatic tumor recurred. Cisplatin was administered for the ninth metastasis. None of these chemotherapy had seemed to be benefit in the management. At 27 she had removal of metastatic tumor on chest wall. She died of respiratory embarrassment in thorax at 30. At autopsy she had metastatic tumors in right frontal lobe, right lung, mediastinum, heart, chest wall, and intestine. During her illness, she graduated from high school and college, and got a good job as a secretary.

Adult

[Clinical characteristics and prognosis of renal cell carcinoma. Statistical evaluation of possible determinants for distant metastasis, venous tumor thrombi, and lymph node metastasis].

To clarify the recent clinical characteristics of renal cell carcinomas and to evaluate possible determinants for metastasis and venous tumor thrombi, the authors reviewed data from 99 renal cell carcinoma patients treated at Nagoya University Hospital between 1980 and 1989. According to Robson's classification, stage I tumors were found in 48 patients, stage II in 9, stage III in 16, and stage IV in 26. Incidentally detected tumors appeared to be on the increase in recent years. Grade 1 tumors were significantly associated with low-stage tumors and expansive growth. Univariate and multivariate analyses using a logistic regression model demonstrated that venous tumor thrombi and histological grade were significantly related to distant metastasis. Univariate analysis revealed relative risks of 4.7 for venous tumor thrombus presence (pV1b-pV2 vs. pV0-pV1a, p = 0.005) and 8.5 for histological grade (grades 2 and 3 vs. grade 1, p = 0.04). Local invasion (pT3 vs. pT2a-pTb: a relative risk of 7.5, p = 0.0009) and infiltration pattern (INF beta and INF gamma vs. INF alpha: a relative risk of 11.5, p = 0.002). were associated with venous tumor thrombi. Local invasion (pT3 vs. pT2a-pT2b: a relative risk of 6.6, p = 0.03) was the only significant determinant for lymph node metastasis. The 5-year actuarial survival rate was 60.0% for all 99 patients. The 5-year survival rates for stage I and II tumors were, respectively, 91.8% and 64.8%.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Renal Cell

Merkel cell carcinoma. Long term survival in a patient with proven brain metastasis and presumed choroid metastasis.

Merkel cell carcinoma (Trabecular carcinoma) is a rare malignant tumor of the skin. Because these tumors tend to spread locally via the lymphatic system, very few papers have dealt with the treatment of distant metastasis. Systemic disease is uncommon and usually fatal. In this paper, we report a case of Merkel cell carcinoma with proven brain metastasis and a solid choroidal tumor. The patient responded well to radiation and chemotherapy and is alive and neurologically intact three years after diagnosis. All previous patients with metastatic Merkel cell carcinoma to the brain died within two months of the diagnosis. We use this case to discuss possible routes of metastatic dissemination and to review the treatment options in patients with distant metastatic disease. To our knowledge, this is the first reported case of presumed choroidal metastasis of Merkel cell carcinoma and the longest documented survival in a patient with brain involvement.

Brain Neoplasms

Metastasis induction by incomplete tumor resection. A new metastasis model using inoculation sarcomas in adult nude mice after long-term cultivation of sarcoma cells.

In searching an animal model to study metastasis formation we used cultured cells of experimental rhabdomyosarcomas and their inoculation tumors in adult nude mice. Supplementing earlier observations (Katenkamp et al. 1987) we found that long-term cultured sarcoma cells induce tumors in adult nude mice which do not metastasize spontaneously but produce lung metastases after repeated incomplete tumor removal. Possible factors and mechanisms responsible for metastasis emergence are discussed. The metastasis model introduced may be apt to study cellular changes at cytogenetic and molecular biological level that occur during tumor progression and metastatic dissemination.

Animals

An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer.

We examined resected specimens from 40 cases of advanced rectal cancer to determine the extent of microtubular cancer nests and undifferentiated cancer cells (budding). We investigated the relationship between this budding and lymphatic invasion (ly), venous invasion (v), and lymph node metastasis (n), respectively. Moreover, we examined the relationship between ly, budding, and n in the preoperative biopsy specimens of 112 patients, including those of the 40 cases mentioned above. The degree of budding, which was abundant in the actively invasive region, showed a strong correlation with the degree of ly and the existence of n in the resected specimens. Also, budding was recognized in a relatively large portion of the biopsy specimens (52 of 112 [46.4%]) and lymph node metastasis was found in 41 of 52 specimens (78.8%). In 57 specimens, neither ly nor budding was found, and 16 of these specimens (28.1%) had positive lymph nodes. These results implied that the degree of budding in the actively invasive region can be a great help in predicting the presence of n. The presence or absence of budding in preoperative biopsy specimens also can be an important factor (along with the degree of differentiation and ly) in estimating the probability of n.

Adult