Michael A. Bean

Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases.

In 100 consecutive cases of prostatic adenocarcinoma treated by pelvic lymphadenectomy and interstitial implantation of 125I the relationship of tumor stage, size and grade was analyzed relative to the incidence and site of metastases, and the response of the primary tumor to irradiation. High stage, large size and poor histological differentiation were associated with a significantly higher probability of pelvic node metastases. The response of the primary tumor to irradiation was significantly higher among patients with small stage B tumors and/or those with negative pelvic lymph nodes. Important determinants of metastases subsequent to 125I implantation were the large size of the primary tumor, poor histological differentiation, seminal vesicle invasion, large (more than 3 cc) volume of lymph node metastases and absence of local prostatic response to irradiation.

Prostatic involvement by transitional cell carcinoma: pathogenesis, patterns and prognosis.

Prostatic involvement by transitional cell carcinoma of the bladder includes a spectrum of histologic patterns. Ductal only or ductal and acinar involvement occurs with or without stromal invasion. Stromal invasion may exist without glandular involvement. Invasive prostatic patterns are most frequent in the setting of high stage invasive bladder tumors and 5-year survival rates for these patients are low. Non-invasive in situ prostatic patterns are usually associated with low stage bladder tumors and 5-year survival approaches that predicted from radical cystectomy for low stage bladder tumor alone. When an invasive pattern is associated with a low stage bladder tumor the 5-year survival rate is determined by the prostatic lesion and is low. Although the survival rate is severely jeopardized by stromal prostatic invasion the prognosis is not hopeless. Preoperative radiotherapy followed by cystoprostatourethrectomy can be expected to produce a 20 per cent 5-year survival rate.

Suppressed antidonor MLC responses in renal transplant candidates conditioned with donor-specific transfusions that carry the recipient's noninherited maternal HLA haplotype.

Forty-seven patients with end-stage renal disease were entered into a donor-specific transfusion protocol consisting of three infusions of whole blood every two weeks prior to transplantation. Fourteen of the patients became sensitized following transfusion and were not transplanted. Thirty-one patients received a transplant from the DST donor and have an estimated two-year graft survival of 97%, three-year survival of 88%, and four-year survival of 69%. Cells of eleven of the 36 recipients tested in one-way MLC before and two weeks after completion of DST exhibited a significantly decreased antidonor MLC response. Deletion of CD8+ positive lymphocytes from suppressed MLCs resulted in restoration of antidonor MLC reactivity in four of six patients. An analysis of the family HLA profile in patients exhibiting a decreased donor-directed MLC response revealed a significant (P less than 0.02) association between decreased MLC reactivity following DST and the expression of noninherited maternal HLA antigens by cells of the transfusion donor. These alterations in cellular immune responses noted in some patients following DST are consistent with the appearance of specific antidonor T suppressor cells as a result of donor-specific transfusion.

T-Cell Responses to Mitogens in Atomic Bomb Survivors: A Decreased Capacity to Produce Interleukin 2 Characterizes the T Cells of Heavily Irradiated Individuals

Abstract Kusunoki, Y., Hayashi, T., Morishita, Y., Yamaoka, M., Maki, M., Hakoda, M., Kodama, K., Bean, M. A. and Kyoizumi, S. T-Cell Responses to Mitogens in Atomic Bomb Survivors: A Decreased Capacity to Produce Interleukin 2 Characterizes the T Cells of Heavily Irradiated Individuals. Significant decreases in the fraction of lymphocytes that are CD4+ and increases in serum levels of some classes of immunoglobulin have been reported to occur in atomic bomb (A-bomb) survivors and in victims of the Chernobyl nuclear plant accident. To investigate the long-term effects of nuclear radiation on cellular immunity in more detail, we used limiting dilution assays with peripheral blood mononuclear cell preparations to analyze the T-cell responses of 251 A-bomb survivors exposed to less than 0.005 Gy and 159 survivors exposed to more than 1.5 Gy. The percentages of CD2-positive cells that were capable of proliferating in response to phytohemagglutinin (PHA) in the presence of exogenous interleukin 2 (IL2) did not differ substantially between distally exposed and more heavily exposed survivors. The heavily exposed survivors appeared to possess fewer T cells that were capable of proliferating in response to concanavalin A (Con A) or of producing interleukin 2. Assuming that CD4 T cells were the ones primarily responsible for producing IL2 in response to Con A, we were able to estimate how many cells in any given CD4 T-cell population were actually producing IL2. The results indicated that peripheral blood samples from heavily exposed survivors contained significantly fewer IL2-producing CD4 T cells than did similar samples from distally exposed survivors, indicating that significant exposure to A-bomb radiation may have a long-lasting negative effect on the capacity of CD4 T-cell populations to produce IL2.

Immune evaluation with skin testing. A study of testicular, prostatic, and bladder neoplasms.

Fifty patients with testicular carcinoma, 45 with prostatic neoplasm, 84 with bladder carcinoma, and 13 with benign bladder papilloma were evaluated for skin reactivity to DNCB and other intradermal antigens. Correlation between pathologic staging and skin‐test reactivity was sought. Reaction to DNCB among patients with testis tumors was more significantly depressed by chemotherapy than by the extent of retroperitoneal or distant metastatic disease indicating that skin testing as a means of following the course of disease or of predicting survival may be limited by alterations caused by chemotherapy. DNCB reactivity did not correlate with the prognosis for the different stages of disease, but follow‐up studies of individual patient survival are needed for substantiation. Depression of DNCB reactivity exists among patients with prostatic carcinoma whether the disease is localized or widely metastatic. Only lengthy follow‐up will determine if there is any correlation of reactivity with survival in individual patients. DNCB reactivity among patients with bladder tumors shows progressive reduction with increasing stage of disease and lends support to the evidence suggesting immune deficiency in patients with bladder neoplasm.

Prevention of transfusion-induced sensitization to minor histocompatibility antigens on DLA-identical canine marrow grafts by gamma irradiation of marrow donor blood

Dogs given total-body irradiation and marrow transplants from DLA-identical littermates exhibit prompt and sustained hematopoietic engraftment. However, animals given three preceding blood transfusions from the marrow donor before transplant become sensitized and reject the marrow graft. Rejection is due to exposure to polymorphic minor non-DLA histocompatibility antigens expressed on blood mononuclear cells. We sought to determine whether heat treatment would prevent blood from sensitizing recipients in this model since heating blood to 45°C for 45 min abrogates the ability of blood mononuclear cells to stimulate in mixed lymphocyte culture. Three of 4 evaluable dogs given heat-treated blood before transplant rejected their marrow grafts. To prevent possible reexpression/reacquisition of mononuclear cell functional activity in vivo after transfusion, subsequent dogs were given heated blood that was additionally exposed to 2000 cGy gamma irradiation. Eight of 10 evaluable dogs given blood treated in this fashion engrafted. Unexpectedly, 9 out of 10 evaluable dogs transfused with blood treated only with gamma irradiation also engrafted. These results demonstrate that treatment of blood with gamma irradiation alone or in combination with heat prevents transfusion-induced sensitization to minor histocompatibility antigens. Results from this canine model suggest that blood products be gamma irradiated before transfusion in patients who are transplant candidates in order to prevent sensitization to minor histocompatibility antigens and reduce the risk of marrow graft rejection.

Prognostic Significance of Regional Lymph Node Histology in Cancer of the Bladder

The regional lymph nodes from 47 patients with carcinoma of the bladder who had undergone radical cystectomy and bilateral pelvic lymphadenectomy were classified into 3 histologic patterns that correlated with immunologic function. Lymph nodes were designated as stimulated if they exhibited prominent germinal centers (B cell proliferation) and expansion of the deep cortex (T cell proliferation), depleted if they appeared markedly hypocellular and fibrotic, and unstimulated if they resembled a normal resting lymph node. Correlation of the histologic pattern with the extent of disease revealed that patients whose nodes appeared stimulated had fewer metastases (p less than 0.05) than those with either unstimulated or unstimulated combined with a depleted pattern. A markedly improved 5-year survival rate was seen in patients with a stimulated pattern (p less than 0.0001) compared to those patients who exhibited a depleted and/or unstimulated lymph node pattern. The survival advantage related to the stimulated pattern was observed primarily among patients with advanced disease. It is suggested that stimulated nodes reflect proliferation of T and B lymphocytes engaged in cell-mediated and humoral immune responses to the bladder tumor and that this favorably influenced survival in those patients. Patients whose lymph nodes showed a depleted pattern fared poorly despite the extent of the disease and those with an unstimulated pattern were intermediate in survival. A depleted pattern may represent a state of local immune paralysis, exhaustion of the draining lymph nodes as a result of exposure to excess tumor-derived products such as antigen or toxic substances or simply an atrophic node incapable of response. In the absence of a local immune response such patients might be expected to do poorly. These results suggest that morphologic evaluation of the lymph nodes regional to bladder cancer may provide a clue to their immunologic function and a more accurate guide to prognosis of patients with this neoplasm.

Cytological Characterization of Human Tumor Cells from Monolayer Cultures

Classically, when using the technique of monolayer tissue culture, an investigator describes the cytology of the tumor cells he is studying by referring either to a fixed and stained slide, to a coverslip preparation of the adherent cells or to the phase contrast appearance of these cells while living and attached to either a glass or plastic surface (see the listing of published human tumor cell lines, Chapter 5). The observer is then able to assign certain cytological characteristics to the cells such as epithelioid, spindle cell, fibroblastic, or pleomorphic. Because these cells are attached to glass and have been actively growing, a considerable amount of information can be gathered in terms of growth pattern, such as the degree of contact inhibition, piling up, colony formation, cohesiveness, and focus formation, all of which may be useful in distinguishing neoplastic from benign cells.