The FDA's perspective on the evaluation of tumor marker tests.

Cancer marker tests are often proposed for three intended uses: screening, diagnosis, and monitoring. For each intended use, performance characteristics need to be well defined. The utility of a marker in a given setting depends heavily on two predominant performance characteristics--sensitivity and specificity. These parameters must be established with respect to the intended clinical use of the marker. The value of the marker in a particular situation also depends on the effectiveness of therapy for the malignancy. In reviewing a cancer marker test, the US Food and Drug Administration focuses on both the proposed intended use statement and the clinical utility of the marker. The sponsor is expected to provide specific claims data in support of the safety and effectiveness of the device through well-designed and -executed clinical studies. Several cancer markers are already available. In the future, new markers are anticipated that may greatly expand the range of usefulness in cancer diagnosis screening and monitoring.

Appraisal and coping in the process of patient change during short-term psychotherapy.

The process of patient change during short-term dynamic therapy was followed in eight patients by repeatedly measuring their appraisal and coping with significant people and issues in their lives. Patients' ratings of their appraisal and their coping with each of these variables were compared to a line of optimal functioning, which describes the ideal appraisal/coping relationship. Two groups of patients were identified who must carry out different corrections on these measures during therapy in order to approximate the optimal functioning line. The appraisal/coping relationship measure appears promising as a way to reflect patient change during therapy.

Circulating IgA immune complexes in head and neck cancer, nasopharyngeal carcinoma, lung cancer, and colon cancer.

A double antibody enzyme-linked immunosorbent assay (ELISA) was developed to quantitate circulating immune complexed IgA (IgA IC) in human serum. The serum panel for this study consisted of normal blood donors, benign surgery (BS), head and neck cancer (HN), nasopharyngeal carcinoma (NPC), lung cancer (LC), and colon cancer (CC) patients. Immune complexes (IC) were isolated from these sera by precipitation with 3.5% polyethylene glycol (PEG), washed and then redissolved in 0.1 M phosphate-buffered saline pH 7.2. The amount of IgA IC present were then quantified using the double antibody IgA ELISA. This assay was found to be both sensitive (26.0 ng/ml) and reproducible (intra-assay coefficient of variation 4.0%). The mean IgA IC for each cancer group tested (HN = 11.38 +/- 12.54 micrograms/ml; NPC = 13.36 +/- 17.56 micrograms/ml; LC = 17.39 +/- 13.04 micrograms/ml; CC = 26.50 +/- 4.60 micrograms/ml) were significantly elevated (P = 0.001) over both the normals (5.12 +/- 4.09 micrograms/ml) and the benign surgery controls (5.92 +/- 5.04 micrograms/ml). In addition to providing a new tumor marker the presence of high levels of IgA IC in cancer patients could provide a source of tumor-specific antibody as well as antigen and provide reagents to study immune regulation in cancer patients.

Immune complexes, serum proteins, cell-mediated immunity, and immune regulation in patients with squamous cell carcinoma of the head and neck.

A collaborative study of the humoral and cellular immune status of patients with carcinoma of the Head and Neck (H&N) was conducted at the West Virginia University (WVU) hospital. In addition, blind-coded serum panels were supplied on H&N cancer patients being treated at the National Cancer Institute (NCI). Serum protein analysis of the WVU study groups revealed that at the pretreatment sampling, the alpha-1 acid glycoprotein (AGP), total complement, and IgA levels were significantly elevated. The AGP levels and total complement levels declined to normal levels in the post-treatment period, whereas the IgA levels remained elevated throughout the entire observation period. Levels of serum immune complexes (SIC) were measured in both the WVU and NCI H&N cancer populations using the polyethylene glycol (PEG) precipitation method. In both survey populations all cancer groups had significantly elevated levels of SIC when compared to any of the control populations. The SIC levels never returned to comparative normal values even in cases after successful treatment. A subpopulation of the WVU-H&N cancer study group underwent a short course of intravenous hyperalimentation prior to their treatment regimen. These patients demonstrated a transient decrease in their SIC levels as well as a concomitant increase in their in vitro cell-mediated immune (CMI) correlates. The analysis of in vitro CMI correlates of the WVU study group using both polyclonal mitogens and specific antigens demonstrated a significant depression in these parameters pretreatment and post-treatment. In addition, it was observed that the time course for elevation of selected serum proteins (i.e., IgA and SIC) correlated with concomitant drops in CMI activity. Investigations were also conducted into the effects of immune complex-rich serum fractions upon selected in vitro CMI correlates. Significant blockage of a normal donor leukocyte migration-inhibition assay was demonstrated. Also, a similar inhibition of the ability of normal human lymphocytes to form high affinity rosettes was accomplished with serum from H&N cancer patients.

Serum ferritin as a tumor marker in patients with squamous cell carcinoma of the head and neck.

A double antibody enzyme immunoassay was used to measure serum ferritin levels in several different control and tumor-bearing populations collected from two institutions. The control groups consisted of normal volunteers, smokers, and Latter Day Saints. No statistically significant differences were noted in ferritin levels between pairs of these groups. Differences were noted among the normal groups when separated on the basis of age and sex, with higher ferritin levels in individuals older than 32 years of age and in men. By one-way analysis of variance, most control groups and subgroups were shown to have significantly lower levels (P less than 0.05) than the head and neck cancer group, with the exception of male smokers, who had levels comparable to male head and neck cancer patients. Serum ferritin levels were higher in head and neck cancer patients than in controls; however, there was no difference when compared with patients with other types of solid malignancies or when considering the anatomic site of the head and neck lesion. Ferritin levels were significantly (P less than 0.05) higher in patients with advanced (Stages III and IV) cancer than in those individuals with Stage I or II cancer. In patients with no evidence of clinical disease 5 years after treatment, the ferritin level had essentially returned to normal. In a group of head and neck cancer patients followed longitudinally, a significant decline in ferritin levels (P less than 0.05) was seen by 5 months after the completion of successful treatment. Furthermore, ferritin levels showed a tendency to increase or remain at high levels in patients with a poor prognosis and to decrease in those patients with a favorable prognosis, giving support to the contention that ferritin may prove to be a valuable tumor marker in head and neck cancer.

Increased serum antibacterial activity after turpentine-induced acute inflammation.

An acute inflammatory response was induced in rabbits by an intramuscular injection of turpentine. After this injection serial serum samples were obtained and serum haptoglobin levels were monitored. In addition, increased antibacterial activity was measured using a viable plate and photometric growth assay. As early as 4 hrs after turpentine challenge an increase was noted in serum antibacterial activity towards Staphylococcus aureus. At 48 hrs pronounced killing activity was demonstrated against S. aureus and S. epidermidis but not against Escherichia coli or other gram negative bacilli. By five days another serum bactericidal activity was present against Bacillus subtilis. Enhanced serum antibacterial activity persisted for 2 weeks. Partial characterization of these factors indicates that they are probably beta lysins.

Soluble tumor-associated markers in lung cancer extracts.

Three lung tumor-associated markers (LTAM), previously identified as a Cohn Fraction IV alpha-globulin (LTAM-1), ferritin (LTAM-2) and lactoferrin (LTAM-3) were separated by a combination of ion exchange, dye-affinity and molecular sieve chromatography. They were further purified by polyacrylamide gel electrophoresis and antisera were raised. Analysis of human extracts by immunodiffusion showed that 80% of lung tumor extracts were positive for all three markers. Similarly, 70% of extracts from other tumors wre positive for LTAM 1, but only 10% of these extracts were positive for LTAM 2 and 3. Variation in concentration of LTAM 2 and 3 among several extracts was determined by a quantitative enzyme immunoassay. Analysis of a select group of extracts for carcinoembryonic antigen (CEA), alpha-fetoprotein and beta 2-microglobulin showed 50% of these extracts to have markedly elevated levels of CEA. The results suggest that ferritin, lactoferrin and CEA offer promise as markers for lung cancer.