Serum alkaline phosphatase in hypophosphatasia.

It is recognized that serum alkaline phosphatase may reflect enzyme contributions from bone, liver, and intestine. We have investigated serum alkaline phosphatases in two siblings with hypophosphatasia. After administration of long-chain triglycerides, the major alkaline phosphatase component of their sera was shown to be of intestinal origin on the basis of inhibition by l-phenylalanine. Starch block electrophoresis suggested that there were other regions of l-phenylalanine-sensitive alkaline phosphatase in addition to the major slow-moving intestinal band. Medium-chain triglycerides which are absorbed by the portal route did not cause a similar augmentation of intestinal alkaline phosphatase activity. These studies indicate that serum levels of intestinal alkaline phosphatase are increased normally after long-chain fat feeding in hypophosphatasia and may be the major component of total serum alkaline phosphatase activity.

Serum levels of N2, N2-dimethylguanosine and pseudouridine as determined by radioimmunoassay for patients with malignancy.

A sensitive, rapid, and specific radioimmunoassay procedure was used to determine levels of N2,N2-dimethylguanosine and pseudouridine in sera of patients with acute leukemia and breast cancer. Elevated levels of both nucleosides were above standard deviations of the normal mean for patients in both disease categories.

Elevation of histaminase and its concurrence with Regan isoenzyme in ovarian cancer.

Histaminase has been shown to be associated with several types of human cancer. In the present study, we examined the activity of histaminase and its relationship with Regan isoenzyme of alkaline phosphatase in ascitic fluids obtained from patients with ovarian and several other types of cancer. We have found that about 44% of the ovarian cancer patients had elevated levels of histaminase in the ascitic fluid, whereas a less frequent incidence was observed in fluids obtained from other types of cancer. There was concurrence in the elevation of histaminase activity with the appearance of Regan isoenzyme in most of the samples examined. Of the 10 patients who showed elevated histaminase, 9 had high Regan isoenzyme activity; whereas in 9 patients with normal levels of histaminase, all except 1 had low or moderate levels of Regan isoenzyme activity. These results, therefore, confirm the observation of an association of histaminase with human cancer and suggest the possibility for the utilization of histaminase, in conjunction with Regan isoenzyme and cancer-associated proteins, for cancer diagnosis and clinical evaluation of tumor progression and regression during therapy.

Problems in the clinical use of the microcytotoxicity assay for measuring cell-mediated immunity to tumor cells.

Lymphocytes from control donors and from cancer patients have been tested for antitumor, cell-mediated immunity against various melanoma and breast cancer target cell cultures with a microcytotoxicity assay. Control lymphocytes inhibited growth of target cells with high frequency, particularly with cell line, as opposed to short-term, cultures. Inhibition was not found for all target cells tested at a given time with a single preparation of lymphocytes. Sequential studies over a 2-year period with lymphocytes from the same control donors showed fluctuations of inhibition against the same target cells. With serial passage, the target cells also changed in their susceptibility to destruction by control lymphocytes. Lymphocytes from melanoma patients were more inhibitory than control lymphocytes for one melanoma target cell culture but not for two other melanoma cultures. Significant inhibition by lymphocytes from melanoma patients was not seen against two cultures derived from breast cancer patients. Lymphocytes from breast cancer patients were more inhibitory than control lymphocytes for 4 of 5 breast cancer cultures and they did not inhibit two melanoma cultures. Significantly specific inhibition was seen with short-term, but not cell line, breast cultures. The over-all data show specificity for target cells of the appropriate histological type. However, the high and inconstant reactivity of control lymphocytes in this assay suggests that nonspecific inhibition of tumor target cells by patient lymphocytes is found in many experiments. It is concluded that the microcytotoxicity assay is not suitable for clinical studies, since sequential data obtained in individual patients are difficult to interpret.

Markers for ovarian cancer: regan isoenzyme and other glycoproteins.

Since embryonic genes are not generally active in normal adult subjects and because certain of these genes are activated in cancer leading to ectopic synthesis, it is the difference between the ectopic level and the normal adult concentrations of embryonic gene products which we seek in developing "markers" for ovarian cancer. The carcinoplacental alkaline phosphatases corresponding to the term gestational phenotypes correlate positively with ovarian cancer as does hCG. Other fetal and placental glycoproteins whose presence is noted in ovarian cancer include CEA, alpha-FP, and Björklund's antigen. Antigens of mucinous cystadenocarcinoma have not yet been examined for their possible fetal or placental origins. The degree of concordance of expression of Regan isoenzyme and hCG is variable. Profiles of glycoproteins would appear to offer an opportunity to inquire more deeply into the nature of ovarian cancer and from this inquiry, one can expect to develop a system of markers which can be of clinical use.

A randomized comparison of cyclophosphamide-mitoxantrone-5-fluorouracil v cyclophosphamide-doxorubicin-5-fluorouracil in advanced breast cancer: preliminary observations.

Forty-four patients with measurable metastatic breast cancer have been entered in a randomized study comparing mitoxantrone to doxorubicin as a component of front-line combination chemotherapy. Patients were stratified according to whether or not they had previously received adjuvant chemotherapy. Initial doses of cyclophosphamide and 5-fluorouracil were 500 mg/m2 for both regimens, with either mitoxantrone, 10 mg/m2, or doxorubicin, 50 mg/m2. All drugs were given on day 1 only, with treatments repeated every 3 weeks. Doses were adjusted according to blood count nadirs. Responses have been observed in both of the treatment groups, though it is too early to determine the relative efficacy of the two regimens. Toxicity was comparable on the two treatment regimens except that far less alopecia and stomatitis were associated with the mitoxantrone therapy. No congestive heart failure has been seen. The combination of cyclophosphamide-mitoxantrone-5-fluorouracil is reasonably well tolerated, with myelosuppression being dose limiting. In both treatment groups of this study, reliance on the leucocyte count, rather than the granulocyte count, as a basis for dose alteration or treatment delay would lead to excessive dose reductions, many fewer dose escalations, and much more treatment delay.

Pretreatment radiographic evaluation of patients with malignant melanoma.

During a four year period, 53 patients with malignant melanoma underwent extensive pretreatment radiographic evaluation for detection of occult extranodal metastatic disease. This included chest x-ray with tomography, upper G.I. series with small bowel follow through, barium enama, intravenous pyelogram, and radio-nuclide scans of the brain, liver and bone. All occult metastatic disease in asymptomatic patients was discovered on routine chest x-ray examination. There were three false positive examinations, which necessitated further diagnostic tests but there was no change in the final treatment decision. There was no alteration in the management of the remainder of the patients on the basis of the pretreatment radiographic evaluation.

Influence of carbon chain length of dietary fat on intestinal alkaline phosphatase in chylous ascites.

The long-term effects of chain length of dietary fat on intestinal lymphatic transport of alkaline phosphatase were investigated in two patients with chylous ascites due to leakage of intestinal lymph into the peritoneal cavity. Substitution of a medium-chain triglyceride diet for long-chain triglyceride resulted in a parallel fall in triglyceride and the intestinal isoenzyme of alkaline phosphatase in chylous ascites. The concentrations of lymph triglyceride were linearly related to lymph intestinal alkaline phosphatase levels, suggesting a positive relation between absorption of long-chain triglycerides and transport of mucosal alkaline phosphatase into lymph.

Comparative evaluation of combined radiation-chlorambucil treatment of ovarian carcinomatosis.

In a study conducted by the Eastern Cooperative Oncology Group, 51 evaluable women with advanced ovarian carcinoma were randomized to either abdominal radiation therapy alone, chlorambucil alone, or to a combination of radiation therapy and chlorambucil by members of the Eastern Cooperative Oncology Group. Provision was made for crossover therapy for patients who were nonresponders to a single modality of treatment. Parameters followed included objective and subjective response rates and patient survival. The total response rate was 51%, with no significant difference among the three treatment regimens. Regarding survival, radiation therapy alone was significantly superior to the other regimens, with an average survival of 94.9 weeks. Best results were obtained in patients with normal performance status; for this group, radiation therapy alone offered the best chance for prolonged survival.

Estrogen receptor status and response to chemotherapy in advanced breast cancer: the Tufts-Shattuck-Pondville experience.

Eighty-eight patients with advanced breast cancer were retrospectively reviewed to compare estrogen receptor (ER) data with response to cytotoxic chemotherapy. All assays were done in a single laboratory. All patients were cared for at a single institution. Thirty-four patients were treated with chemotherapy, 30 of whom were evaluable for response by criteria of the Eastern Cooperative Oncology Group (ECOG). Of 16 ER-positive patients, 12 (75%) responded; of 14 ER-negative patients, six (43%) responded (P < 0.05). The two groups did not differ significantly in chemotherapy received, menopausal status, site of predominant disease, stage at diagnosis, or disease-free interval. Response to cytotoxic chemotherapy does not appear to correlate with ER status.

Treatment of renal carcinoma: a phase III randomized trial of oral medroxyprogesterone (Provera), hydroxyurea, and nafoxidine.

Seventy patients with metastatic renal carcinoma were randomized to receive hydroxyurea, nafoxidine, or medroxyprogesterone (Provera) orally. Sixty patients were considered evaluable, with a response rate of 5% for medroxyprogesterone (one complete remission) and hydroxyurea (one partial remission) and a response rate of 16% for nafoxidine (two complete remissions and one partial remission). Differences in response rates and duration of survival were not statistically significant. The major toxicity observed with hydroxyurea was hematologic, and the major toxic effect of nafoxidine was an ichthyosis-like skin rash. Toxicity for medroxyprogesterone was minimal.

Phase II trial of mitomycin, vindesine, and hexamethylmelamine in metastatic non-small cell bronchogenic carcinoma.

Mitomycin (10 mg/m2 iv on Day 1), vindesine (3 mg/m2 iv on Days 1 and 8), and hexamethylmelamine (100 mg/m2/day orally on Days 1-14) was administered to 32 patients with metastatic non-small cell bronchogenic carcinoma. No patient had been previously treated with chemotherapy and Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 in 21 of 32 patients. Eleven partial responses (34%) were observed, with a median duration of 9 weeks. No complete responses were observed in this group of patients, whose median survival duration was 22 weeks. Moderate leukopenia (median leukocyte count nadir, 2500/mm3) was the major toxic effect. Although this regimen is active and relatively nontoxic, it will not be utilized in future ECOG trials because it has not produced an apparent improvement in survival duration.