Serum TA90 antigen-antibody complex as a surrogate marker for the efficacy of a polyvalent allogeneic whole-cell vaccine (CancerVax) in melanoma.

INTRODUCTION: TA90 is a tumor-associated 90-kD glycoprotein antigen expressed on most melanoma cells, including those of CancerVax, a polyvalent allogeneic whole-cell vaccine. Previous studies have shown that a TA90 antigen-antibody immune complex (IC) in the serum of patients with melanoma is a marker of subclinical tumor burden and a strong prognostic factor. We hypothesized that the induction of TA90-IC during postoperative adjuvant CancerVax therapy might indicate vaccine-mediated immune destruction of subclinical melanoma cells with release of TA90, and thereby serve as a surrogate marker of vaccine efficacy. METHODS: From 1993 to 1997, 219 melanoma patients were enrolled in a prospective phase II trial of CancerVax plus bacille Calmette-Guerin (BCG) after complete tumor resection. Coded serum samples were prospectively collected and analyzed for TA90-IC before and 2, 4, 8, 12, and 16 weeks after initiation of CancerVax therapy. TA90-IC seroconverters were those patients whose negative TA90-IC values (< .410) became positive (> or = .410) after initiation of CancerVax treatment. RESULTS: Before CancerVax therapy, 51 patients had positive TA90-IC values and 168 patients had negative TA90-IC values. During CancerVax treatment, all 51 positive patients remained positive, 79 (47%) negative patients seroconverted to positive, and 89 (53%) negative patients remained negative. Seroconverters had higher 2-year rates of disease-free survival (59% vs. 32%; P < .006) and overall survival (78% vs. 63%; P < .02) than did patients whose TA90-IC values remained positive. CONCLUSIONS: CancerVax induces TA90-IC in melanoma patients with subclinical disease. TA90-IC seroconverted patients have significantly improved disease-free and overall survival compared with TA90-IC positive patients. TA90-IC is an important prognostic factor that can serve as a surrogate marker for the clinical efficacy of CancerVax.

Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade.

OBJECTIVE: To describe the incidence, time to onset and extent of anaemia occurring in patients with prostate cancer receiving combined hormone blockade (CHB) and the timing and extent of recovery from anaemia in those patients where CHB was discontinued. PATIENTS AND METHODS: Patients with prostate cancer were evaluated prospectively by physical examination and laboratory tests at baseline and at routine intervals while receiving CHB. Of 142 patients who received CHB, 133 were evaluable for the assessment of anaemia; CHB was discontinued in 76 patients, of whom 64 were assessable for recovery from their anaemia. RESULTS: Haemoglobin levels declined significantly in all patients from a mean baseline of 149 g/L to means of 139 g/L, 132 g/L and 131 g/L at 1, 2 and 3 months, respectively. Haemoglobin levels continued to decline during CHB to a mean nadir of 123 g/L at a mean of 5.6 months of CHB, representing a mean absolute haemoglobin decline at nadir of 25.4 g/L. In 120 of the 133 (90%) patients, the relative decline in haemoglobin at nadir was > or = 10% and was > or = 25% in 17 (13%) others, representing a mean absolute haemoglobin decline in this subset of 42.7 g/L. Significant symptoms related to anaemia occurred in 17 patients (13%). Anaemia and symptoms in these patients were easily corrected with the subcutaneous administration of recombinant human erythropoietin. CONCLUSIONS: The anaemia associated with androgen deprivation is significant and occurs routinely in men receiving CHB. It is normochromic, normocytic, temporally-related to the initiation of androgen blockade and usually resolves after CHB is discontinued. We suggest that patients receiving CHB undergo haematological testing at baseline, 1-2 months after initiating CHB and periodically thereafter. Patients developing anaemia should be questioned about symptoms reflecting physiological compromise (e.g. angina, dyspnoea on exertion). In the absence of other causes, CHB should be suspected in the development of anaemia in patients receiving this treatment.

Measurement of red blood cell-vitamin B12: a study of the correlation between intracellular B12 content and concentrations of plasma holotranscobalamin II.

We have recently reported a new and rapid assay to measure plasma holotranscobalamin II (holo TC II) as a means of exploring vitamin B12 status. In order to further evaluate the significance of plasma holoTC II in determining tissue cobalamin, we have chosen the red blood cell-vitamin B12 (RBC-B12) assay as a measure of tissue vitamin B12 content and studied the relationship between RBC-B12 and plasma holoTC II levels. Plasma holoTC II and RBC-B12 concentrations were concomitantly assayed in 20 hematologically normal controls and cancer patients. In our groups of controls, the mean value of RBC-B12 was determined as 241 +/- 51 pg/ml of packed erythrocytes (PE) with a range varying from 180 to 355 pg/ml PE. Preliminary results obtained in 32 cancer patients revealed lower holoTC II and RBC-B12 levels than the control group and a required threshold value of 70 pg/ml of holoTC II in order to maintain a normal RBC-B12 greater than 180 pg/ml PE.

New assay for the rapid determination of plasma holotranscobalamin II levels: preliminary evaluation in cancer patients.

We describe a new and rapid assay for the measurement of plasma B12 bound to transcobalamin II (holotranscobalamin II) using the property of adsorption of the polypeptides of apotranscobalamin II and holotranscobalamin II to the hydrophobic surface of microfine glass particles. Acid-washed microfine glass was used to separate vitamin B12 bound to the glycoproteins transcobalamin I and transcobalamin III (haptocorrin or R binder) from that bound to transcobalamin II. Sephadex gel filtration separation of 57Co-labelled vitamin B12 binders confirmed that > 90% of holotranscobalamin II can be removed from plasma holohaptocorrin by adsorption to microfine glass particles. Since only holotranscobalamin II is capable of delivering vitamin B12 to metabolizing cells, plasma holotranscobalamin II content reflects the availability of B12 to cells. Use of this test in cancer patients undergoing either chemotherapy or radiation therapy revealed evidence of early negative B12 balance that in some instances was induced by the treatment itself.

Effectiveness of intermediate-dose methotrexate and high-dose 5-fluorouracil as sequential combination chemotherapy in refractory breast cancer and as primary therapy in metastatic adenocarcinoma of the colon.

Many studies reported the pretreatment with methotrexate followed by 5-FU resulted in the greatest tumor cell killing. Our preliminary laboratory studies confirmed the possibility of drug synergism in the L1210 cell line, but not in human bone marrow cells. Thirteen patients with metastatic adenocarcinoma of the breast and seven patients with metastatic adenocarcinoma of the colon were treated with an innovative approach in which methotrexate preceded 5-FU administration in an attempt to cause drug synergism and prevent drug antagonism. All patients with breast cancer and two patients with colon cancer had been extensively pretreated with multiple drugs. Of the cancer patients so treated, three (23%) with breast cancer and two (28%) with colon cancer demonstrated objective tumor response. In addition to these patients, six (46%) with breast cancer and three (43%) with colon cancer demonstrated subjective improvement as manifested by total pain relief and reduction in CEA titer. The preliminary results reported in this study suggest that sequential utilization of intermediate doses of methotrexate, followed by high doses of 5-FU, is an effective combination chemotherapy for patients with breast and colon malignancies.

Modulation of in vitro lymphocyte stimulation by subpopulations of transforming lymphocytes.

The finding of less-than-expected lymphocyte transformation by both PHA-P and PWM acting together supports the possibility that subpopulations of lymphocytes may interact to suppress their transformation and thereby help regulate the immune response.

In vitro myelosuppression and immunosuppression by ethanol.

Concentrations of ethanol similar to those in the blood of intoxicated patients suppressed phytohemagglutinin- or streptolysin O-induced lymphocyte transformation, and inhibited bone marrow granulocyte colony growth in soft agar. Inhibition of lymphocyte transformation and granulocyte colony growth occurred despite the presence of large concentrations of folate and other vitamins. These in vitro findings may relate to in vivo effects of ethanol on myeloid and lymphoid tissue.