Multiple primary neoplasms in blacks compared to whites. IV. Further cancers in patients with cancer of the digestive organs.

Second primary cancers found among whites and blacks with initial cancer of the digestive organs were reported based on data from the Charity Hospital Tumor Registry. Observed second primary cancers were compared to expected numbers to obtain a direct estimate of risk. Both white and black men had about a twofold risk of developing a second cancer. For white men, the excess was limited to a subsequent skin cancer, but this finding was probably an artifact of reporting and lacked biologic significance. Among women, both white and black, large excesses of invasive cancer of the cervix and ovary were found after an initial cancer of the large intestine and anorectum was discovered. No excess of breast cancer was found.

Macrophage-mediated destruction of human malignant cells in vivo.

Macrophages require a plasma component, designated "recognition factor" (RF), for the expression of optimal function. The RF activity was profoundly depleted in plasma from patients with malignant disease, and the degree of depletion and the severity of the malignant state seemed to be related. Since experiments demonstrated that an active RF significantly inhibited tumor growth, clinical studies were initiated to investigate the influence of intratumor administration of an active RF fraction. Glucan, a potent macrophage activator, was also employed alone or combined with RF. These studies were undertaken to enhance the recognition of malignant cells by macrophages and to mobilize and activate macrophages intralesionally. The initial 9 patients studied had malignant melanoma, adenosquamous carcinoma of the lung, or carcinoma of the breast. Control and experimental lesions were injected; subsequently biopsies were performed at varying intervals for histologic evaluation. Always when glucan or glucan and RF fraction were administered intralesionally, the size of the lesion was strikingly reduced in as short a period as 5 days. This reduction was associated with necrosis of the tumor and a monocytic infiltrate. In small lesions, resolution was complete, whereas in large lesions, resolution was partial. The amount of glucan injected and the quantity of residual tumor appeared to be related. The induced necrosis of the tumor nodule was associated with an increase in plasma levels of circulating RF activity.

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Changes in distribution of human malignant melanoma membrane antigens in the presence of human antibody by immunofluorescence.

Four viable human melanoma cell lines demonstrated full-surface fluorescence (FSF) after incubation at room temperature with antisera from three melanoma patients receiving autologous or homologous immunization with irradiated cultured melanoma cells and Bacillus Calmette-Guérin. By sequential immuno-fluorescent staining, it had been shown that FSF was followed by capping and extrusion of antigen-antibody complexes. One melanoma cell line was tested against its autologous antiserum. In the presence of excess antigen, FSF cells peaked to 25% of the total cell population at 30 min. Maximum capping (20%) was noted at 3 hr. When excess antibody was present, FSF cells were 30% at 2 min and capped cells peaked to 25% at 1.5 hr. Capping ceased at 4 degrees under both conditions. When the serum-treated cells were reincubated after fixation with methanol, 80 to 85% of the cells showed FSF at 2 min to 13.5 hr. Negative controls were preimmune sera and skin fibroblasts. These experimental data suggest the presence of embedded and protruding melanoma membrane antigens in the phospholipid layer. Methanol amy dissolve the lipid layer and expose the embedded antigens. The extrusion of melanoma antigen-human antibody complexes in vitro seems to be a possible mechanism of antigen shedding by melanoma cells in vivo.

Delayed hypersensitivity to 5-fluorouracil following topical chemotherapy of cutaneous cancers.

Skin tests to various common antigens, dinitrochlorobenzene, and 5-fluorouracil (5-FU) were performed on patients being treated for cutaneous neoplasms with topical 5-FU cream. Eleven of 15 patients tested both before and after therapy converted from skin test negative to positive with respect to 5-FU. This conversion correlated with positive dinitrochlorobenzene skin tests and therapeutic cure. The relation between the induction of delayed hypersensitivity reactions to 5-FU following treatment with topical 5-FU and the cure rate for cutaneous neoplasms showed a trend toward correlation.

Antibody-induced movement of common melanoma membrane antigens on the surface of unfixed human melanoma cells.

Antisera to common human melanoma antigens were obtained from melanoma patients receiving autologous immunization with their own irradiated cultured melanoma cells and Bacillus Calmette-Guérin. The antibody thus derived was used to detect common antigens on the plasma membrane of three different human melanoma cell lines by membrane immunofluorescence. The antigen-antibody complexes on the surface of melanoma cells would move to a pole (capping) and would subsequently be extruded into the extracellular milieu at room temperature. Approximately 25 to 30% of viable cells were positive by immunofluorescence. However, when the cells were fixed with methanol, 60 to 70% of cells demonstrated membrane binding. Capping was inhibited at 0 degrees or when the cells were pretreated with vinblastine sulfate. It can be concluded that common tumor antigens exist on the surface of viable human melanoma cells and that the redistribution of antigen-antibody complexes is an active process. The extrusion of antigen-antibody complexes in vitro may represent a mechanism of antigenic modulation in vivo and could indicate a basic method of tumor survival since presumably the antigen-denuded cell is viable and capable of replication but not of recognition by subsequent effector immune events.

Immunological heterogeneity in human melanoma: immunogenic alloantigen expression in autologous host.

A patient presented with a primary melanoma, Level IV, 2.5 mm thick; 30 excised lymph nodes were all negative for tumor. Four local recurrences followed in the ensuing 17 months. Tumor cells cultured at this time were epithelioid. Autoimmunization was followed by a disease-free interval of 15 months. Postimmunization, the patient's lymphocytes destroyed his melanoma cells in culture and were stimulated in mixed cell culture by his irradiated tumor cells. Cells grown from the relapsing tumor were spindle/dendritic with bizarre morphology and were not attacked by his lymphocytes in culture. Using a C' fixation technique, DR antigen profiles of the patient's B-cells and both tumor cell types showed that the immunizing tumor was positive for DR antigens 3, 5, and 8, none of which were present on his B-cells which had DR 2 and 4. Both B-cells and immunizing tumor cells were positive for DQ antigens. The relapsing tumor cells were positive for DR2 and negative for all other D region antigens tested. The evidence suggests that given a melanoma of heterogeneous cell population, autoimmunization against the predominant immunogenic cell inhibits tumor growth but allows the ascendance of a nonimmunogenic tumor cell type.

A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma.

Three hundred thirty-one women with metastatic breast cancer were randomized to receive combination chemotherapy with either cyclophosphamide, Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ), and fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and fluorouracil (CAF). Patients could not have had prior chemotherapy, although adjuvant chemotherapy was acceptable. Initial doses were 500 mg/m2 of cyclophosphamide and 500 mg/m2 of fluorouracil with either 10 mg/m2 of mitoxantrone or 50 mg/m2 of doxorubicin, administered intravenously (IV) on day 1 and repeated every 3 weeks. There were no statistically significant differences in pretreatment or prior therapy characteristics between the groups. For patients assigned to the CNF and CAF groups, respectively, 25 (18%) were premenopausal, 39 (40%) were estrogen receptor (ER) negative, 39 (38%) had a disease-free interval less than 1 year, and 24 (26%) had received prior adjuvant chemotherapy. All patients were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. None of these parameters were statistically significant favoring one regimen over the other. The response rate (complete [CR] and partial response [PR]) was 29% for the CNF group (95% confidence interval of 22% to 37%) and 37% for the CAF group (95% confidence interval of 29% to 45%). The median response duration and TTF were 171 days and 125 days for the CNF group and 254 days and 147 days for the CAF group, respectively. The median survival times for the CNF group and the CAF group were 377 and 385 days, respectively. The major dose-limiting toxicity for both regimens was leukopenia, manifested as granulocytopenia. The incidence of stomatitis/mucositis was 10% in the CNF group and 19% in the CAF group. Alopecia occurred in 49% of CNF patients (severely for 4%) and in 86% of CAF patients (severely for 39%). Nausea/vomiting occurred in 80% of CNF patients and in 81% of CAF patients; the degree of severity was also comparable. There was significantly less cardiotoxicity observed in the CNF group compared with the CAF group. Although CNF is somewhat less effective in overall response rate, survival curves are identical. CNF can be offered to patients who reject anthracycline-containing regimens because of fear of alopecia.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Plantar lentiginous melanoma: a distinctive variant of human cutaneous malignant melanoma.

The neoplastic system of human cutaneous melanoma includes three generaly recognized variants: lentigo maligna, superficial spreading melanoma, and nodular melanoma. Lentiginous melanomas other than lentigo maligna constitute a fourth group, of which plantar lentiginous melanoma qualifies as an anatomic subgroup. Histologically and clinically, plantar lentiginous melanoma (PLM) is characterized by a period of radial growth and often by one or more foci of regression. In 27 of 33 plantar melanomas, a characteristic lentiginous, radial component of melanocytic proliferation was noted. In the remaining six cases, histological material failed to document a radial component. Eighteen of the 27 patients with PLM were blacks, and 18 patients died of distant metastasis. Tumors invasive to level II did not metastasize, but at levels IV and V and in tumors with a high mitotic rate, the prognosis was poor. The presence of lymph node metastases at the time of initial therapy correlated with a poor prognosis group.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Breast cancer as analyzed by the human tumor stem cell assay.

Patients with primary and recurrent carcinomas of the breast were studied by the human tumor stem cell assay to determine if (1) colonies would form from breast cancer specimens, (2) growth in the culture would equate with aggressiveness of disease, (3) the assay would yield specific information on drug responsiveness, and (4) the assay would yield nonspecific information on drug responsiveness. Colony counts ranged from 0 to 363. There was no significant difference in median colony counts by pathologic stage of disease or site. Among stage IV patients presenting for treatment with primary disease, those with colony counts greater than 10 had a mortality rate of 4.7/1000 person-days; there were no deaths among those with colony counts less than or equal to 10 (P = 0.042). Stage IV patients presenting with recurrent disease showed no association between colony counts and survival (P = 0.53). No significant relationship between colony counts and disease-free intervals was observed among stages I, II, and III patients (P = 0.10). Drug sensitivity in vitro was found in 14% of the cultures with colony counts greater than or equal to 30. The only complete clinical responses in stage IV patients occurred in two patients with 0 colony counts. These data demonstrate that colonies grow from breast cancer specimens, that colony formation in vitro may be related to aggressiveness of growth in vivo in patients presenting with stage IV disease, that drug sensitivity is demonstrated in few cultures, and that patients with metastatic disease who have complete response to systemic therapy may be identified by lack of growth in the culture.

Transfer of in vitro cytotoxicity against osteogenic sarcoma cells.

Evidence of lymphocyte cytotoxicity against osteosarcoma, suggesting a degree of cell-mediated immunity, was found in the mother of a patient with osteogenic sarcoma. The mother was found to be HL-A identical to the patient and therefore was an ideal donor for whole lymphocytes. Lymphocytes were obtained from the mother by leukophoresis and were administered to the patient. Lymphocytotherapy transferred or re-established a delayed hypersensitivity response to mumps antigen and transferred the ability of killing osteogenic sarcoma cells in vitro. There was slight improvement in the patients' clinical condition coincident with the establishment of lymphocytoxicity in the patient. Loss of this capacity coincided with a rapid deterioration of the patient's condition.

Recurrence of neuroblastoma following prolonged remission.

A 6-year-old girl with unresectable and metastatic neuroblastoma had a complete remission with irradiation to the primary tumor and systemic administration of cyclophosphamide. The patient was disease-free for 16 years but had an explosive recurrence of tumor six weeks after a hysterectomy. Although no clear cause-and-effect relationship exists between the surgery and the recurrence, this case illustrates that a recurrence is possible after a long disease-free interval. Diagnostic and therapeutic procedures in such patients should be undertaken with caution.

Treatment of abdominal malignant neoplasms using regional chemotherapy with hemofiltration.

The regional delivery of high-dose chemotherapy for malignant neoplasms of the limb with the isolated regional perfusion technique was first described in the late 1950s. Recently, the use of concomitant hemofiltration for rapid systemic drug removal permits the use of higher regional drug levels in treating patients with advanced abdominal malignant neoplasms without complete vascular isolation. Twenty-five patients successfully underwent 42 treatments of high-dose intra-arterial chemotherapy with concomitant hemofiltration at Tulane University Medical Center Hospital, New Orleans, La, from 1989 through 1990. One patient (4%) achieved a complete response. Two patients (8%) had partial responses following high-dose intra-arterial chemotherapy with concomitant hemofiltration and their residual disease was resected for cure. Seven patients (28%) achieved a partial response, 11 (44%) had stable disease, and four (16%) had progression of disease.

Acral lentiginous melanoma.

Acral lentiginous melanoma represents a fourth variant of malignant melanoma in company with lentigo maligna melanoma, superficial spreading melanoma, and nodular melanoma. It is characterized by a lentiginous (radial) growth phase that evolves over months or years to a dermal (vertical) invasive stage. Clinical and pathologic features were reviewed in 35 cases of acral lentiginous melanoma of the palms and soles. This variant of melanoma probably represents the most common expression of melanoma in blacks; two thirds of the patients in our study were black. The average three-year survival rate was 11%.

Nevi, lentigines, and melanomas in blacks.

Two hundred fifty-one black patients were examined for the presence of melanocytic nevi. The average number detected was 8.3 per patient. Light-skinned blacks had a greater number of total body nevi, while dark-skinned blacks had more lesions on the palms and soles. The usual histologic pattern seen in plantar-palmar lesions was that of lentigo simplex. The differentiation of lentigines of the palms and soles from early expression of acral lentiginous melanomas may be difficult; however, most acral pigmented lesions do not require excision.

Multiple perfusions for melanoma.

From 1957 to 1992, 1139 patients had regional perfusion alone, or combined with excisional surgery for malignant melanoma. Of these, 158 patients had multiple perfusions for recurrent disease, including 155 for limb melanoma and three for head and neck melanoma. One-hundred-and-twenty patients were perfused twice, 28 treated three times, eight treated four times, and two treated five times. At first perfusion, 39 patients were classified as disease stages I and II, 98 at stage III, and 21 at stage IV. Melphalan was used in 70% of perfusions, either alone or in combination. Nitrogen mustard was used sparingly in only a few patients. Fifty-one patients with stage III disease had the greatest number of perfusions (127). Cumulative survival from date of first perfusion at 5 and 10 years were: stage 1,68 and 36%; stage IIIA, 25 and 16%; stage IIIB, 32 and 10%; stage IIIAB, 29 and 11% and stage IV, 14 and 0%. When compared with the entire series, the percent survival was decreased by 2 to 3 times, however, 21 patients remain alive and disease-free. For stages I and II, patients are alive and disease-free from 5 to 33 years. For stage IIIA, 6 patients were alive at the last follow-up, however, the status of two are currently unknown. For stage IIIB survival times range from 8 to 106 months with two patients alive without recurrence. For stage IIIAB, two patients are alive and disease-free at 15 and 26 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Adoptive immunotherapy of advanced renal cell cancer using PHA-stimulated autologous lymphocytes.

Patients with advanced renal cell carcinoma, previously failed maximal treatment with standard chemo-hormonal-radiation therapies, were treated with plant lectin phytohemagglutinin (PHA)-stimulated autologous peripheral blood lymphocytes in a 10-year study with a 16-year follow up period. In a phase I-II setting, 52 patients were given subcutaneously 40-80 x 10(6) PHA-stimulated lymphocytes weekly for 3 weeks and then escalated to a maximum number of 80 x 10(9) lymphocytes over the next 9 weeks at 3 week intervals. In vitro blastogenesis under study conditions (10 micrograms/ml PHA for 72 hr) measured by [3H]thymidine uptake was optimal with lymphocyte stimulating indexes approaching 300. Lymphocytes obtained from patients with breast cancer, melanoma and renal cell carcinoma responded to PHA similarly to those from normal volunteers. All patients that responded developed erythematous reactions at the sites of injection; malaise, joint paint and chill-fever for 24-48 hr. The patients that responded the best were those with at least 1 positive reaction out of 4 skin tests (tuberculosis, yeast, dermatophytin, mumps) prior to therapy. All toxicity was transient and did not exceed Grade I based on criteria of the Southwest Oncology Group. The majority of patients developed a lymphopenia in the first 24 hr followed by a lymphocytosis 48-72 hr later. For some patients the lymphocytosis was as much as 30% atypical lymphocytes. Of 41 evaluable patients, there were 5 complete responses, 8 partial responses, 3 stable diseases, and 25 progressive disease. The overall response rate was 32% and the median survival was 2.8 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary hyperparathyroidism in the seventies. A decade of change?

In an effort to identify new trends in the presentation and treatment of primary hyperparathyroidism, 66 patients treated since 1975 were compared with 100 patients diagnosed and treated from 1948 to 1970. Despite widespread use of multichannel analyzers, the late patients had an insignificant increase in diagnosis while asymptomatic (18 percent versus 9 percent in the early group). Hypertension was the most common presenting complaint in patients seen since 1975, compared with renal disease in patients seen before 1970. Findings of diffuse hyperplasia were more common in the late patients (17 percent versus 3 percent in the early patients). There were no differences in rates of operative complications or persistent postoperative hypercalcemia. In the late series of patients persistent hypercalcemia after surgery for hyperplasia was due to inadequate resection of parathyroid tissue. In the adenoma patients, failure to locate the abnormal parathyroid gland was the cause of operative failure.