Alan S. Rabson

Classification of Proliferative Pulmonary Lesions of the Mouse Recommendations of the Mouse Models of Human Cancers Consortium

Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated by a panel of human, veterinary, and experimental pathologists during the Mouse Models of Human Cancers Consortium (NIH/National Cancer Institute) workshop on mouse models of lung cancer held in Boston on June 20–22, 2001. The panel performed a comparative evaluation of 78 cases of mouse and human lung proliferative lesions, and recommended development of a new practical classification scheme that would (a) allow easier comparison between human and mouse lung neoplasms, (b) accommodate newly emerging mouse neoplasms, and (c) address the interpretation of benign and preinvasive lesions of the mouse lung. Subsequent discussions with additional experts in pulmonary pathology resulted in the current proposal of a new classification. It is anticipated that this classification, as well as the complementary digital atlas of virtual histological slides, will help investigators and pathologists in their characterization of new mouse models, as well as stimulate further research aimed at a better understanding of proliferative lesions of the lung.

A Method for Dinitrochlorobenzene Contact Sensitization: A Clinicopathological Study

Abstract To facilitate measurement of cell-mediated immune responses, a method for quantitative clinical evaluation of contact sensitization to dinitrochlorobenzene (DNCB) was devised and used in 40 patients with cancer. When a sensitizing dose is applied, the immediate reaction produced expresses a general inflammatory response. Sensitization is expressed by the occurrence of a spontaneous flare seven to 14 days later, or by the reaction to a challenge dose of DNCB. Equivocal reactions require histologic examination. Use of a sensitizing dose of 2000 μg and a relatively weak challenge dose of 50 μg yielded a satisfactory incidence of sensitization with a low proportion of irritative inflammatory reactions.

ENHANCEMENT OF ADENOVIRUS GROWTH IN AFRICAN GREEN MONKEY KIDNEY CELL CULTURES BY SV40.

Summary SV40 enhances the growth of adenovirus 12 in African green monkey kidney (AGMK) cell cultures. In the absence of SV40, adenovirus 12 produces CPE; however, after 72 hours, less than 1% of the cells contain adenovirus particles by electron microscopy, and titrations show no increase in virus. When similar cultures are infected with both SV40 and adenovirus 12, after 72 hours 75% of the cells contain adenovirus particles and there is an increase in virus by titration. A similar enhancement of the growth of adenovirus 5 in AGMK cultures by SV40 has been observed. The development of progressive adenovirus-type cytopathic changes without demonstrable adenovirus particles in cells of AGMK cultures infected with adenoviruses alone suggests the possibility of some type of incomplete virus formation which is able to go to completion in the presence of SV40.

Ewing's sarcoma: an autopsy study.

An autopsy study of 26 cases of Ewings sarcoma treated with radiation to the primary site plus adjuvant chemotherapy has shown metastatic tumor in 23 cases. Metastases were found typically in lungs, pleura, bones and regional lymph nodes. In three cases no tumor could be found at autopsy, and death was due to complications of treatment. Tumor was found in the irradiated primary site in 13 of the 20 cases in which the primary site was examined at autopsy. Histologically, the tumor at autopsy frequently had increased pleomorphism and increased numbers of bizarre giant cells; however, these changes did not affect the presence of glycogen in tumor cells, thus reaffirming the importance of intracytoplasmic glycogen in the diagnosis of Ewings sarcoma.

Induction of malignancy in vitro in newborn hamster kidney tissue infected with simian vacuolating virus (SV40).

Summary Cell cultures derived from explants of newborn hamster kidney infected with simian vacuolating virus (SV40) consisted of sheets of rapidly growing polygonal, cuboidal and elongated cells. Cultures derived from similar explants free of SV40 consisted initially of slowly growing polygonal and elongated cells, and, after 12 weeks in vitro, only a few scattered elongated cells remained. Cell suspensions from infected cultures injected into newborn hamsters produced tumors at the sites of injection, the tumors becoming apparent as early as 17 days after injection of cells. Histologically, in contrast to the sarcomas produced after malignant transformation of hamster tissue in vitro by polyoma virus, the tumors were predominantly undifferentiated carcinomas with areas of adenocarcinoma, sarcoma and, in one animal, well-differentiated epidermoid carcinoma. SV40 was recovered from the infected cultures and from one of 2 tumors tested.

Adenovirus Tumorigenesis: Role of the Viral Genome in Determining Tumor Morphology

Adenovirus type 12 transforms the fibroblastic BHK21 (baby hamster kidney) cell line into rounded or cuboidal cells that give rise in hamsters to undifferentiated small cell sarcomas indistinguishable from those induced in newborn hamsters by inoculation of the virus itself. In contrast. cells from this line transformed by polyoma virus retain their fibroblastic morphology and induce fibrosarcomas in hamsters. This suggests that the morphology of tumors induced by the adenovirus-transformed cells from this line may be determined by the viral genome and that such mechanism may also explain the remarkably uniform microscopic appearance which seems to characterize tumors induced in hamsters by direct inoculation of adenovirus type 12.

Oncogenic activity of adenovirus 12 in thymectomized balb/c and c3h/hen mice.

Summary Newborn BALB/c and C3H HeN mice inoculated subcutaneously with human adenovirus 12 developed tumors only when thymectomized at birth. Tumors developed in 5 of 30 BALB/c and 3 of 18 C3H/HeN thymectomized mice. These results suggest that neonatally thymectomized animals may be useful in evaluation of the oncogenic potential of viruses which have not produced tumors when injected into non-thymectomized animals.

Viral Neoplastic Transformation of Hamster Prostate Tissue in vitro

Cultures of hamster prostatic tissues infected with simian virus 40 undergo transformation in vitro, and the transformed cells produce malignant tumors when injected into homologous hosts. Tartrate-inhibited acid phosphastase is found in the cultures of transformed cells and in the tumors they produce. Tartrate-inhibited acid phosphatase activity is elevated in the serum of tumor-bearing animals.

Occult metastases to the scalene lymph nodes in patients with clinically operable carcinoma of the cervix

The left scalene fat pad was excised and examined microscopically in 84 consecutive patients with clinically operable carcinoma of the cervix. Eleven, or 13%, of the specimens contained metastatic tumor. The metastases were associated with patients who had tumors in relatively more advanced stages of local growth and usually with parametrial spread, yet exhibited no clinical evidence of local or regional metastasis. Seven of 36 patients with Stages IIB, III, and IV carcinomas of the cervix, and 4 of 22 patients with radiation‐recurrent tumors had scalence lymph node metastases as their only evidence of incurability. No metastases were identified in 26 patients with Stage I and IIA cancer. The complications of biopsy were few and minor. The 13% incidence of metastases to clinically benign scalene lymph nodes of patients with advanced but clinically operable carcinoma of the cervix demonstrated in this preliminary study is considered sufficient to justify routine biopsy of these lymph nodes in patients who, on the basis of clinical examination, may require radical surgery for removal of the tumor.

Growth of Ultraviolet-Damaged Herpesvirus in Xeroderma Pigmentosum Cells

Summary The growth of ultravioletirradiated herpes simplex virus was studied in cultures of skin fibroblasts from a patient with xeroderma pigmentosum and compared with growth in WI-38 cells, skin fibroblasts from people with no evidence of xeroderma pigmentosum and in HeLa cells. The irradiated virus grows less efficiently in the xeroderma pigmentosum cells than it does in the other cell lines examined, suggesting that mechanisms for repair of the UV-damaged viral DNA may be deficient in the xeroderma pigmentosum cells. This is consistent with previous observations of others that repair mechanisms for UV-damaged cellular DNA may be defective in skin fibroblasts and leukocytes from patients with xeroderma pigmentosum.