Monitoring the therapy of human tumor xenografts in nude mice by the use of lactate dehydrogenase.

With the use of circulating human lactate dehydrogenase (LDH) as a tumor marker, growth and remission of human tumor lines SW480, HEp-2, and Clouser, implanted into female BALB/c athymic nude mice, were followed during therapy. Three types of therapy were used: X-radiation, cyclophosphamide, and diphtheria toxin. After therapy tumor sizes were measured with calipers and compared to changes in the levels of circulating human LDH. Changes in LDH levels paralleled changes in tumor size, but the enzyme fluctuations were more pronounced. Mice bearing intraperitoneally growing SW480 and HEp-2 tumors were effectively treated with diphtheria toxin, and the measurement of circulating LDH was examined as a parameter for gauging the effectiveness of chemotherapy on tumors that could not be visualized. Circulating human LDH can be used to detect intraperitoneal tumor growth and/or remission and to predict death of the animal due to the tumor.

Preferential sites of growth of human tumors in nude mice following subcutaneous transplantation.

The growth characteristics and biological behavior of human tumors transplanted s.c. into two different anatomical regions of nude mice were studied. It was observed that tumors trnasplanted in the anterior lateral thoracic wall grew faster than did tumors transplanted in the posterior aspect of the trunk. Anteriorly growing tumors, in contrast to the posteriorly transplanted ones, were better vascularized, showed less necrosis, invaded the tumor bed, and metastasized to the regional lymph nodes. These findings were independent of their histogenetic and morphological characteristics. It is concluded that regional vascular supply is a key factor influencing the biological behavior of the transplanted tumors and that it may affect tumor response to treatment as well.

Enhanced therapeutic effect of cis-diamminedichloroplatinum(II) against nude mouse grown human pancreatic adenocarcinoma when combined with 1-beta-D-arabinofuranosylcytosine and caffeine.

We demonstrated previously that the effect of cis-diamminedichloroplatinum(II) (cisplatin) against pancreatic cancer was substantially enhanced by the addition to the chemotherapeutic regimen of 1-beta-D-arabinofuranosylcytosine and caffeine. To obtain information on the factors influencing tumor response to this combination treatment, we investigated two adenocarcinomas of the exocrine pancreas grown in the nude mouse, tumors Capan-1 and SW-1990. Tumor response to cisplatin, characterized by tumor regression and tumor growth arrest, was observed when it was given in the upper limits of tolerance (5 mg/kg). Caffeine and 1-beta-D-arabinofuranosylcytosine singly and in combination had no effect on tumor growth; neither did they influence the effect of cisplatin when combined singly with the latter. However, the triple combination of cisplatin, 1-beta-D-arabinofuranosylcytosine, and caffeine resulted in complete tumor regression. The enhancing effect of the triple combination depended on tumor sensitivity to cisplatin and the amount of cisplatin administered and required rather large amounts of caffeine. The present report indicates that certain combination regimens may enhance the therapeutic effect of cisplatin against pancreatic carcinoma.

Response of nude mouse-grown human urothelial cancer to cis-diamminedichloroplatinum(II), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum], and mitoguazone dihydrochloride.

A comparative study of the effect of cis-diamminedichloroplatinum(II) (cisplatin), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum] (carboplatin), and mitoguazone dihydrochloride on urothelial cancer was conducted using transitional cell carcinomas of the urinary bladder grown in the nude mouse. Tumors SW-780 and TCC-K1 represented transitional cell carcinoma, Grade II, whereas Tumor PR49 represented a fast-growing Grade III neoplasm. Of the agents studied, cisplatin was most effective, resulting in tumor response related to the dose administered. Response to carboplatin was clearly related to treatment schedule. For the same amount of total dose administered, better results were obtained when treatment was given three times weekly instead of once every week. Furthermore, cisplatin was more effective against the less differentiated PR49 tumor in contrast to carboplatin, which showed more activity against the better differentiated SW-780 and TCC-K1 tumors. None of the tumors tested responded to mitoguazone dihydrochloride. The results of the present study may assist in formulating better treatment modalities against urothelial cancer, taking into account factors such as tumor grade, growth rate, treatment schedule, and the patient's tolerance which may ultimately influence tumor response.

Morphological, biological, and biochemical characteristics of human bladder transitional cell carcinomas grown in tissue culture and in nude mice.

The morphological, biological, biochemical, and karyotypic characteristics of four human bladder transitional cell carcinoma lines, SW-780, SW-800, SW-1738, and SW-1710, were investigated. In tissue culture, each cell line presented a distinct phenotypic expression. All but line SW-1710 grew when transplanted in the nude mouse. Light and electron microscopic studies showed morphological characteristics similar to the tumors of origin, being independent of the passages in tissue culture medium, tumor cell extracts, and the plasma of nude mouse-grown tumors, showing isoenzyme quantitative distribution typical for each cell line. In addition, each cell line exhibited a unique genetically determined enzyme phenotypic profile which, along with the karyotypic analysis, makes their identification feasible. These characteristics make the described tumor lines a valuable tool in studying various aspects of the biology of human bladder transitional cell carcinoma.

Response of nude mouse-grown adenocarcinomas of the human exocrine pancreas to cis-diamminedichloroplatinum(II), diammine[1,1-cyclobutanedicarboxylato(2-)-O,O'-platinum], and mitoguazone dihydrochloride.

The effect of cisplatin, carboplatin, and mitoguazone dihydrochloride on pancreatic cancer was evaluated using pancreatic ductal adenocarcinomas Capan-1, Capan-2, and PR54 grown in the nude mouse. In single agent treatments, cisplatin, given in the amount of 5 mg/kg once/week for 4 consecutive weeks, was most effective, resulting in tumor regression, growth arrest, and a growth delay period of 6 and 4 months for tumors Capan-1 and PR54, respectively. Treatment with carboplatin was less effective, with a tumor response related to treatment schedule. For the same amount of total dose of carboplatin administered, best results were obtained when treatment was given 3 times weekly instead of in single weekly injections. Mitoguazone dihydrochloride exhibited no antitumor effect. The results of the present work may be of significance in the management of pancreatic cancer patients.

Conditions modifying development of tumors in mice at various sites by benzo(a)pyrene.

The modifying roles of age, sex, and strain of mice on the incidence, multiplicity, and spectrum of tumors induced by benzo(a)pyrene have been investigated. The first-generation (F1) hybrids of C57BL/6J X C3HeB/FeJ and C3HEB/Fej X A/J mice of both sexes were given single i.p. injections (75 or 150 mug/g) of benzo(a)pyrene at 1, 15, or 42 days of age. Experimental animals were allowed to live their life-spans, while animals in control groups were killed at 52, 90, 142, or 170 weeks of age. Animals treated with benzo(a)pyrene died, in general, by the 100th week of age due to development of liver, lung, stomach and lymphoreticular tumors. Few of the control animals died during that same observational period. The age of mice at the time of exposure to the carcinogen modified development of tumors at all the sites. The sex of animals influenced the development of liver and lymphoreticular tumors. The C3HeB/FeJ X A/J F1 hybrids developed lung tumors more readily than did the C57BL/6J X C3HeB/FeJ F1 mice, which had significantly more liver tumors and neoplasms of the lymphoreticular system than the former strain. No strain difference was observed in regard to tumors at other sites. Higher doses of benzo(a)pyrene were more effective in inducing lung, liver, and stomach tumors. In addition, 5 cases of pancreatic ductal adenoma and adenocarcinoma were observed in carcinogen-treated mice.

Factors influencing augmentation and/or acceleration of lymphoreticular tumors in mice by benzo(a)pyrene treatment.

The response of lymphoreticular tissues to a single i.p. injection of benzo(a)pyrene was studied in the first generation of C57BL/6J X C3HeB/FeJ F1 and C3HeB/FeJ X A/J F1 mice. Groups of 1-, 15-, and 42-day-old animals of both sexes received 75 or 150 mug of the carcinogen per g body weight. After a period of approximately 90 weeks, a high incidence (up to 43%) of reticulum cell sarcomas was observed in C57BL/6J X C3HeB/FeJ F1 mice treated with benzo(a)pyrene at 40 days of age. Animals treated with carcinogen at younger ages had a lower incidence of reticulum cell sarcomas. These sarcomas showed marked cellular pleomorphism and were classified into histiocytic, epitheloid-nodular, reticulocytic, and fibrocytic forms according to the predominant cell type. Lymphomas of thymic and extrathymic lymphoid origin and leukemia of granulocytic type were seen in a descending order of frequency. Control animals of either strain that were killed at 90 weeks of age were basically free of lymphoreticular tumors, while those kept under observation up to 170 weeks developed these tumors in 24% (C57BL X C3H F1) and 10% (C3H X A/J F1), respectively. Studies revealed that the augmentation and/or acceleration of development of the lymphoreticular neoplasms and specifically reticulum cell sarcomas by benzo(a)pyrene was dependent upon the strain and sex of mice used and the age at which the animals were exposed to carcinogen.

Biological behavior of human malignant tumors grown in the nude mouse.

The biological behavior of a number of nude mouse-grown human epithelial tumors of different histogenetic background was studied. They included three transitional cell carcinomas and a mucin-producing carcinoma of the urinary bladder, two pancreatic adenocarcinomas, a colon adenocarcinoma, a breast ductal carcinoma, and an epidermoid carcinoma. Microinvasion was a constant finding in all tumors examined. All but one of the tumors studied showed macroinvasion and metastases. Tumors transplanted s.c. in the anterior aspect of the lateral thoracic wall metastasized primarily to the regional and mediastinal lymph nodes. In certain cases, systemic metastases were observed affecting the submaxillary, contralateral axillary, and inguinal lymph nodes. Lung metastases occurred through the lymphatic and hematogenous routes. It is concluded that the nude mouse-grown human tumors investigated in the present study show overt malignant behavior recapitulating the biological characteristics of the tumor of origin.

Morphological, biological, biochemical, and karyotypic characteristics of human pancreatic ductal adenocarcinoma Capan-2 in tissue culture and the nude mouse.

Human pancreatic ductal adenocarcinoma Capan-2, derived from a 56-yr-old male Caucasian, has been studied in both tissue culture and the nude mouse. In tissue culture, tumor cells showed epithelial-like features, whereas in the nude mouse, the tumor grew as a well-differentiated adenocarcinoma, resembling histopathologically the original neoplasm. Ultrastructurally, the neoplastic cells showed characteristics of ductal epithelium. The allozyme phenotypic profile of Tumor Capan-2 was determined in eight genetically determined loci, and chromosome studies showed a hypotetraploid pattern with a number of morphological and numerical changes. Carcinoembryonic antigen was produced in trace amounts, and lactate dehydrogenase was represented only by Isoenzyme 5, regardless of environmental conditions. The characteristics of Capan-2 tumor make it a valuable addition to the small number of available pancreatic tumor lines in studies aiming at clarifying certain aspects of the biology of this type of malignancy.

Establishment and characterization of human pancreatic adenocarcinoma cell line SW-1990 in tissue culture and the nude mouse.

A new tumor line derived from a human pancreatic ductal adenocarcinoma of a 56-year-old Caucasian male was established in tissue culture and the nude mouse. In tissue culture, the neoplastic cells grew as large, epithelial-like, mucin-producing cells. Injection s.c. of 1 X 10(6) cultured neoplastic cells into nude mice resulted in tumor formation histologically closely resembling the original neoplasm. Ultrastructurally, the neoplastic cells showed characteristics of ductal epithelium. The allozyme phenotypic profile of the line was established in 14 genetically determined loci, and chromosome studies showed a near-tetraploid pattern. Production of macromolecules such as lactate dehydrogenase and carcinoembryonic antigen were present in measurable amounts in culture media, tumor cell extracts, nude mouse-grown tumors, and the serum of tumor-bearing mice in amounts relative to tumor size. Pancreatic enzymes were not detected. These characteristics make tumor line SW-1990 a valuable tool in studying various aspects of the biology of human pancreatic cancer.

Growth patterns and metastatic behavior of human tumors growing in athymic mice.

The growth characteristics and metastatic behavior of human tumors growing in athymic nude mice were studied. Human tumor cell lines HEp-2 (carcinoma or larynx) and SW480 (colon carcinoma) were transplanted into athymic nude mice of BALB/c origin. Tumor cells (1 x 10(6) and 2 x 10(7)) were given either s.c. or i.p. Following s.c. injection tumors developed rapidly to become easily palpable with 2 weeks forming a s.c. tumor focus surrounded by a thick fibrous capsule. Animals with s.c. transplants were little affected by the growing tumor. At the time they were sacrificed at Day 34 (HEp-2) and 62 (SW480), a large part of the tumor was necrotic. Capsular infiltration and invasion of lymphatic vessels and perineural and perivascular lymphatic spaces were observed. Metastases to regional lymph nodes were seen in animals kept alive for up to 6 months. Following i.p. transplantation, tumors spread widely in the peritoneal cavity, invaded intraabdominal organs, and metastasized to mediastinal lymph nodes and lungs. Fifteen of 26 animals (60%) developed metastases. Necrosis of the i.p. growing tumors was minimal. All animals in this group died as a result of tumor growth.

Ocular manifestations of canine transmissible venereal tumour: a retrospective study of 25 cases in Greece.

Transmissible venereal tumour (TVT) is a sexually transmitted neoplasm that frequently affects dogs of either sex, in tropical and subtropical regions. TVT primarily involves the external genitalia, although extragenital sites have also been reported. This study describes the ocular manifestations of TVT in 25 naturally infected dogs and their response to treatment. Seventeen male and eight female dogs were included in the study. TVT ocular lesions were either unilateral (21 dogs) or bilateral (four dogs). Ocular lesions as the single manifestation of TVT were seen in 22 animals. One dog presented external genitalia involvement while two others were found to have tumours in the oral and nasal mucosa. Variably sized multilobular tumour masses with irregular surface were noticed on the bulbar conjunctiva of the nictitating membrane in 17 dogs, on the conjunctiva of the upper eyelid in five dogs and on the conjunctiva of the lower eyelid and adjacent skin in three dogs. Deep ulcerative keratitis was observed in eight animals. TVT diagnosis was based on cytology and histopathology. The large eye masses were surgically excised. All dogs were treated with a single chemotherapeutic agent (vincristine). After four weeks of treatment, complete remission of the tumours was evident in all but one animal. Extragenital primary ophthalmic TVT can be completely eliminated by vincristine chemotherapy, while any further ocular damage is prevented with the combination of the above treatment and surgical excision.

Schedule dependency of the combination methotrexate-vinblastine against human urothelial cancer grown in nude mice.

The combination of methotrexate (MTX) and vinblastine (VLB) was evaluated using different doses and treatment schedules in human transitional cell carcinoma line SW-1738, TCC-K1 and TR-49 grown in the nude mouse. Maximally tolerated weekly doses of MTX, 30 mg/kg, and VLB, 3 mg/kg, were given intraperitoneally for four consecutive weeks singly, concurrently, and separated by 24, 48 and 72 hour intervals. MTX-VLB drug sequence was not a factor in determining tumor regression or response rates when the second agent was administered 24 or 48 hours after the first agent. However, when VLB was administered 72 hours after MTX, a significant statistical difference (0.005 greater than p greater than 0.001) was observed for all tumor lines studied compared to either controls, simultaneous administration of both agents and/or VLB administered 24 or 48 hours after MTX. Additionally, dose reduction of either agent by 30% proved ineffective. Thus, tumor response to MTX-VLB combination was dependent both on schedule and dose. Application of this schedule dependency may be beneficial in management of urothelial tract tumors.

Growth characteristics of tumors induced by transplantation into athymic mice of BALB/3T3 cells transformed in vitro by residue organics from drinking water.

The growth and histopathological characteristics of tumors produced in nude mice by injection of morphologically transformed or normal BALB/3T3 1-13 cells were studied. Subcutaneous injection of 5 X 10(6) cells transformed in vitro by organic residue mixtures from samples of drinking water resulted in tumor growth in all animals with an average latency period of 25 days. Of the 13 animals receiving non-treated cells, three developed tumors with an average latency period of 127 days. Tumors grew progressively at the site of injection, reaching an average size of 1141 mm2 within 8-37 days. Most of the tumors, primarily those deriving from transformed cells, invaded the tumor bed and extended into the surrounding tissues. In few cases, extension of the tumor into the peritoneal cavity was observed. Microscopically all tumors were characterized as fibrosarcomas.

Multiple cytomegalovirus-related intestinal perforations in patients with acquired immunodeficiency syndrome. Report of two cases and review of the literature.

We present two cases of patients with acquired immunodeficiency syndrome who, in the course of their disease, suffered multiple intestinal perforations that were directly related to cytomegalovirus infection. Biopsy and surgical specimens and autopsy findings in both cases revealed extensive lesions of gastroenteritis; the gastroenteritis was characterized by randomly distributed deep ulcers, resulting in multiple perforations. The main characteristic histopathologic finding was the association of intestinal lesions with a severe form of cytomegalovirus-related occlusive vasculitis. This report provides evidence that supports the contention that cytomegalovirus is the primary causal agent of gastrointestinal lesions affecting immunocompromised patients.

Uterine leiomyoblastoma (epithelioid leiomyoma) neoplasm of low-grade malignancy. A histopathologic study.

Uterine leiomyoblastomas are neoplasms of smooth muscle origin, which despite their benign histopathologic characteristics, have been shown to invade locally, metastasize, and recur, resulting in the patient's death. In an effort to define possible cellular changes that could explain the disparity between histopathologic features and biologic behavior, we have studied a series of three uterine leiomyoblastomas that, in routine sections, exhibited benign morphological characteristics. A detailed histopathologic study revealed, in all three cases, randomly distributed clusters of neoplastic cells with overt malignant features, such as cellular and nuclear atypia, abnormal mitoses, local infiltrating tendencies, and vascular invasion. These findings suggest that uterine leiomyoblastomas should be viewed as neoplasms of low-grade malignancy of a distinct clinicopathologic entity.

Primary rhabdomyosarcoma of the female breast: report of a case and review of the literature.

We report the case of a primary breast rhabdomyosarcoma in a 51-year-old white woman. The tumor occupied the upper outer quadrant of the right breast. There was no association with the underlying pectoral muscle, and the patient was free of any other benign or malignant neoplastic processes outside the breast. Microscopically, the breast tumor was composed of primitive myoblasts and numerous rhabdomyoblasts at various stages of development, many of which exhibited cytoplasmic cross striations on routine hematoxylin-eosin staining.

Morphologic, biologic and biochemical characteristics of three human pancreatic ductal adenocarcinomas established as xenotransplants in the nude mouse.

Three new human pancreatic adenocarcinomas of ductal origin, covering the spectrum of well differentiated to poorly differentiated neoplasms, have been established as xenotransplants in the nude mouse. Histopathological and ultrastructural features confirmed the neoplasms' ductal origin and were consistently reproduced through serial transplant generations. Carcinoembryonic antigen was only elaborated by the well differentiated neoplasms and production of lactate dehydrogenase isoenzymes was characteristic of each tumor. The morphological and biological features of these tumors make them a valuable addition to the very small number of available pancreatic tumor lines in studies aiming at clarifying many aspects of the biology of this type of neoplasia.

Intracystic papillary carcinoma of the female breast with secretory activity: the significance of aspiration cytology as diagnostic procedure.

We report the case of an intracystic papillary carcinoma of the breast in an elderly woman. Gross and microscopic observations support the contention that intracystic fluid is partly a result of secretory activity by the neoplastic epithelial cells and that, intracystic hemorrhage, which may contribute to it, is a secondary event complicating the primary process. Cytology of the aspirated fluid was negative for malignant cells. It is concluded that in the case of large cystic breast lesions, aspiration cytology may not be helpful in establishing the malignant nature of the lesion and that a negative cytology should be interpreted with caution, always taking under consideration the clinical picture of the disease. A concomitant adenocarcinoma was also present in the opposite breast, the second case reported in the literature.