In vivo induction of lymphokine-activated killer cells by interleukin-2 splenic artery perfusion in advanced malignancy.

In an effort to stimulate in vivo LAK cell activity at relatively nontoxic doses, 20 patients with advanced metastatic malignancy (13 renal cell carcinoma, 6 melanoma, 1 lymphoma) were treated with recombinant human interleukin-2 (IL-2) by continuous 5-day splenic artery perfusion using the femoral approach. Two treatment cycles were administered 3 weeks apart; IL-2 doses ranged from 1.5-4 x 10(4) Cetus units/kg/day. Peripheral blood lymphocyte cytotoxicity in a 4-h 51Cr release assay was measured using as tumor cell targets K562 for natural killer (NK) activity, Daudi for LAK, and Daudi plus in vitro IL-2 for inducible LAK (I-LAK). For the 20 patients, an increase in mean peak percent cytotoxicity from pretreatment levels was seen for NK (36% to 53%), LAK (8% to 37%) and I-LAK (20% to 53%) activity, all significant at P = 0.001. On day 43, 16 days after completing the second cycle of treatment, NK activity remained elevated at 47% and I-LAK at 40% (P = 0.008 and 0.01, respectively). Lymphocyte phenotype analysis by flow cytometry demonstrated increases from pretreatment levels in Leu 11+ (13 to 23%), Leu 19+ (10 to 21%), Leu 11+ 19+ (7 to 17%), IL-2r+ (4 to 17%), and HLA-DR+ (12 to 25%) subsets, all significant at P less than or equal to 0.01. Dose effect was studied at 3 dose levels: 1.5, 3, and 4 x 10(4) Cetus units/kg/day. At the higher doses mean peak NK (57%) and I-LAK (57%) activity were greater than at the low dose (42 and 31%, respectively), both significant at P less than 0.05. A trend to positive dose effect was seen in LAK activity (P = 0.08). Splenic artery perfusion with IL-2 can result in significant in vivo peripheral LAK cell generation as well as enhancement of I-LAK and NK activity that persists at least 16 days after the cessation of treatment. Such sustained activity would not be expected with conventional high dose i.v. therapy.

Relative operating characteristic analysis and group modeling for tumor markers: comparison of CA 15.3, carcinoembryonic antigen, and mucin-like carcinoma-associated antigen in breast carcinoma.

Relative operating characteristic (ROC) analysis was used to examine the clinical applicability of 3 breast carcinoma tumor markers, CA 15.3, carcinoembryonic antigen, and mucin-like carcinoma-associated antigen. Each tumor marker was quantitated in single serum samples collected from 100 normal blood donors, 60 patients with nonmalignant diseases, 33 women at high risk for breast carcinoma, 30 patients with malignancies other than breast carcinoma, and 158 breast carcinoma patients including 67 with no evidence of disease following surgery, 46 with a tumor burden less than 5 g, and 45 with a tumor burden greater than 5 g. These were used to construct models for early diagnosis among those at high risk for breast carcinoma, the influence of nonmalignant disease on early diagnosis, discrimination of breast carcinoma from other adenocarcinomas, detection of early recurrence, and assessment of change in tumor burden. For each model ROC data permitted the unbiased selection of the most appropriate critical values based on the interaction of sensitivity and specificity. ROC analysis indicated that in practice the assays were remarkably similar. While CA 15.3 generally performed best, there was significant variation among models. Optimal marker selection can thus depend on specific clinical application. In some cases ROC identified a combination of markers as superior to any single assay, but this was not statistically significant.

Isolation and immunochemical characterization of antibodies from the sera of cancer patients which are reactive against human melanoma cell membranes by affinity chromatography.

Immunoglobulins were isolated by affinity chromatography from sera of two patients with melanoma, one with sarcoma, and one with carcinoma. The affinity columns were prepared by covalently linking the membrane-rich fraction of biopsied melanoma cells to cyanogen bromide-activated agarose beads. The membrane-rich fractions were prepared by two methods: (a) hypotonic cell lysis, and (b) homogenization and differential centrifugation. Melanoma sera were autologous to melanoma membrane preparations. The isolated immunoglobulins showed immunoreactivity against antigens prepared from melanoma, sarcoma, and carcinoma cells by complement fixation but not against antigens prepared from normal human liver and lung tissues. Absorption of the isolated immunoglobulins with rabbit anti-human immunoglobulin immunobeads resulted in complete elimination of the complement-fixing antibody titer in one instance, whereas reduction occurred in other samples. Similar absorption with rabbit anti-human immunoglobulin M immunobeads resulted in reduction, but not complete elimination, of the antibody titers against target tumor cell preparations. These results suggest the presence of immunoreactive immunoglobulin G in all immunoglobulins and immunoglobulin M in some. Absorption of the isolated immunoglobulins with cultured sarcoma cells reduced but did not completely abolish antibody activity against autologous or allogeneic melanoma target antigen, whereas it did completely abolish activity against sarcoma target antigen. However, absorption with cultured allogeneic melanoma cells abolished the antibody activity against melanoma as well as sarcoma target antigens. The antibody titers of the isolated immunoglobulins were not affected by absorption with cultured lymphoblastoid cells. Since cultured melanoma and sarcoma cells were known to contain oncofetal antigen(s), these results suggest that the isolated immunoglobulins from cancer sera by melanoma membrane affinity chromatography were of at least two specificities: (a) antioncofetal; and (b) antitumor associated. The former group may be comprised of antibody to cross-reactive antigens associated with different histological types of tumors. However, it was apparent that a portion of the antibody activity was against common tumor-associated antigen(s). These results provide further evidence for the presence of common antigen(s) associated with biopsy specimens of human malignant melanoma.

The detection of alpha 1-fetoprotein in patients with viral hepatitis.

PIP: Alpha fetoprotein (AFP) was detected in sera (351 samples) of 128 patients with viral hepatitis by radioimmunoassay. 77 positive tests for AFP were obtained. These positive results were demonstrated on 1 or more samples taken from 40 (31%) of the 128 patients studied; the highest value obtained was 4400 ng/ml. Hepatitis B antigen (HBAg) was positive in 26/40 (65%) of patients in whom AFP was detected during the disease process. However, 58/88 (66%) who were seronegative for AFP also demonstrated HBAg in their sera. Chi-square analysis revealed no significant difference in occurrence of detectable AFP between HBAg seropositive and seronegative patients. Individuals seropositive for AFP had no statistically different concentration of the protein than patients seropositive or seronegative for HBAg. 24 patients' sera were tested serially over a 2-week period. Both the peak glutamic-pyruvic transaminase (GPT) and peak total bilirubin levels were in a higher range in those 10/24 patients seropositive (P .001) for AFP than in the 14/24 who were seronegative. Appearance of AFP was related to the severity of liver tissue destruction, as reflected by serum GPT. However, peak AFP levels were attained 5-16 days after peak serum GPT appeared in the circulation.^ieng

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: We designed and conducted a randomized, double-blind, placebo-controlled trial to compare the response rates and survival of patients with metastatic melanoma who received carmustine (BCNU), dacarbazine (DTIC), and cisplatin with tamoxifen, or the same chemotherapy with placebo. PATIENTS AND METHODS: Eligible patients with metastatic melanoma received either BCNU 150 mg/m2 intravenously (i.v.) on day 1, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24, and cisplatin 25 mg/m2 i.v. daily on days 1 to 3 and on days 22 to 24 with placebo every 6 weeks, or the same chemotherapy with tamoxifen 160 mg orally daily for 7 days before chemotherapy and 40 mg orally daily throughout the remainder of the treatment cycle. Patients were treated on protocol for up to three cycles depending on the type of response. Assuming that a minimum increase in response rate of 20% would be necessary to conclude that tamoxifen conferred a clinically important benefit, we designed the study with an 80% chance of detecting that difference at the 5% level (two-sided). RESULTS: Between February 1992 and January 1995, 211 patients were accrued, 199 of whom were considered assessable for response and toxicity. The overall response rate was 21% in the placebo group and 30% in the tamoxifen group (P = .187). Complete and partial responses were 3% and 27%, respectively, for the tamoxifen group and 6% and 14%, respectively, for the placebo group. Poor performance status and liver involvement were associated with a reduced likelihood to respond to treatment. Major toxicities were similar in both groups with no statistically significant difference in the rates of deep vein thrombosis, pulmonary thromboembolus, grade 4 neutropenia, or grade 4 thrombocytopenia. CONCLUSION: These results demonstrate that the addition of high doses of tamoxifen to this chemotherapy regimen does not increase the response rate compared with chemotherapy alone in unselected patients with metastatic melanoma.

The school nurse practitioner: providing improved health care to children.

School nurse practitioners have the competence to participate in providing a broad range of direct primary health care and services to the school-age child. Greater utilization of these specially prepared and highly qualified nurse practitioners as providers of health care in the school is a practical and effective method of adding to the quality, availability, and continuity of health care for the school-age child.

Assessment and evaluation of child health associates.

More than 20 studies have been carried out of child health associates to assess their knowledge, training, and practice; their ability to interpret and integrate data; their cognitive knowledge and psychomotor and interpersonal skills; and their competence and effectiveness as a primary health care providers. The results of the assessment and evaluation studies of child health associates indicate that they can determine the health status and manage the health care of patients in ambulatory settings and in the newborn nursery with a degree of skill and competence approaching that of pediatricians. Child health associates can provide comprehensive primary health care for more than 90% of children seen in these settings. The high degree of acceptance of child health associates by families and their demonstrated proficiency and cost-effectiveness document that they can be an important source of primary health care for most children.

Immunology and adjuvant chemoimmunotherapy of breast cancer.

Antibody against a breast carcinoma antigen was present in patients with breast carcinoma and other cancer more often (P less than .05) than in normal women. The incidence of antibody in women with breast carcinoma correlated with the presence or absence of gross tumor, and the titer of antibody paralleled the clinical course. These results suggest importance of a host-immune response to breast carcinoma. Fifty-seven patients with stage II carcinoma of the breast were entered into a prospective randomized adjuvant chemoimmunotherapy program of cyclophosphamide, methotrexate, and fluorouracil, and BCG vaccine +/- an irradiated allogeneic tumor cell vaccine. After 24 months of study, metastases occurred in two patients (3.5%) and a new primary carcinoma developed in the contralateral breast in two others, for an overall treatment failure rate of 7%. Adjuvant chemoimmunotherapy can delay early recurrence. Long-term follow-up is needed to assess the significance of these results.

Suntan, sunburn, and pigmentation factors and the frequency of acquired melanocytic nevi in children. Similarities to melanoma: the Vancouver Mole Study.

The association between prevalence of benign melanocytic nevi and a number of skin cancer risk factors was examined among 913 white Vancouver (Canada) school children aged 6 to 18 years. Subjects with light skin, with a propensity to burn rather than tan in the sun, and with numerous or severe sunburns in the previous 5 years had significantly higher nevus counts than individuals without these characteristics. Subjects who acquired deeper tans tended to have fewer nevi than those who did not tan. Finally, children who freckled had higher nevus counts than those who did not freckle. These findings in children are similar to those seen in studies of malignant melanoma among adults and suggest that strategies to reduce melanoma incidence should begin with young children.

Anatomic distribution of acquired melanocytic nevi in white children. A comparison with melanoma: the Vancouver Mole Study.

The presence of acquired benign nevi is a risk factor for cutaneous melanoma, yet relatively little is known about the etiology of nevi. We have conducted a study of the prevalence of melanocytic nevi among 1146 white Vancouver (Canada) schoolchildren aged 6 to 18 years. Numbers of nevi per square meter of body surface area increase with age in children of both sexes. Male adolescents have more nevi than female adolescents on the head and neck as well as on the trunk, while prevalence in females is higher on the upper and lower limbs. This distribution parallels that of cutaneous melanoma in British Columbia adults. Nevi are more common in children on intermittently exposed body sites than on constantly or minimally sun-exposed sites. This suggests that exposure to strong intermittent sunlight in childhood (a risk factor for cutaneous melanoma) may also be important in the etiology of acquired benign nevi.

Immune complexes and human neoplasia.

The vast data pertaining to circulating immune complexes (CIC) detection and their possible clinical significance in human neoplasia have been reviewed. The clinical relevance of CIC occurrence in cancer patients' sera provide important non-diagnostic information on staging, evaluation of prognosis, detection of early recurrence, and quantitation of tumor response to treatment. A variable prevalence of CIC in cancer patients is now well established. The several reasons which made no available test entirely satisfactory for clinical use, have been discussed indicating the importance of molecular size and composition heterogeneity of CIC detected in cancer patients. Although the evaluation of CIC by current assays represents the antithesis of pre-diagnostic patients management, there are solid reports to suggest its possible clinical application. Those studies noting the relevance of CIC fluctuation to the evaluation of prognosis, monitoring of therapy and assessment of tumor burden were best attained when an effort to quantitate residual disease was undertaken. In addition, attempts to remove CIC from cancer patients circulation by plasma exchange alone or with extracorporeal immunoadsorption have resulted in a better understanding of a frequently observed immunomodulation. This modality provided a challenging and provocative new approach to cancer therapy which deserved prompt corroboration.

Utilization of gyniatricians as primary health care providers for women.

The role, functions, activities, educational preparation and relationship with other health professionals of a new type of primary health care provider is described. The name gyniatrician has been applied to this kind of physician, who will be qualified to provide overall primary health care for women from the onset of puberty through adult life.

PIP: The role, functions, activities, educational preparation and relationship with other health professionals of a new type of primary health care provider for women -- a gyniatrician -- is described. The term gyniatrician is applied to this kind of physician who will be qualified to provide overall primary health care for women from the onset of puberty through adult life. Gyniatricians will have a wide range of functions and activities. They will assume responsibility for the provision, coordination, integration and management of the full range of women's health care and services. The care provided by gyniatricians will be based on a firm foundation of integrated knowledge from the medical, biologic, social, psychologic and behavioral sciences. The gyniatricians will be responsible for recognizing and evaluating their patients' total health needs and for teaching women how to enter the health care system. The gyniatrician's specialized education and training will be 5 years in duration, will begin during the 1st year in medical school, and will include a 1-year residence spent primarily in ambulatory settings. All 5 years of gyniatric training will include intensive study of all aspects of primary health care and services for women. Students desiring to become gyniatricians will be selected from those candidates for admission to medical school who have demonstrated special motivation and interest in primary health care for women. A table of the functions and activities of the gyniatrician is included along with a curriculum guide. Gyniatricians will work with obstetrician-gynecologists in giving the improved total health care that women are requesting. As a result of women's increasing awareness that the health care system is failing to provide what they need and want, women are requesting more pertinent, comprehensive, accessible and competent professional health care.

Ocular pharmacokinetics of dacarbazine following subconjunctival versus intravenous administration in the rabbit.

The authors assessed the ocular toxicity and pharmacokinetics of subconjunctivally and intravenously administered dacarbazine in New Zealand white rabbits. Nine rabbits received a subconjunctival injection of 5 mg (three animals), 10 mg (three animals) or 25 mg (three animals) of dacarbazine in 0.5 mL of sterile water; 10 mg was found to be a well-tolerated dose. This dose was given as a bolus to 42 other rabbits either subconjunctivally (21 animals) or intravenously (21 animals). In both groups the dacarbazine concentrations in the ocular humours, serum and urine were measured by means of high-pressure liquid chromatography at 0.5, 1, 2, 4, 8, 12 and 24 hours, three animals being assessed at each interval. The peak serum levels of the drug were similar with the two routes of administration. The mean peak dacarbazine levels in the aqueous humour and vitreous humour after subconjunctival administration were 250 to 380 times those achieved after intravenous administration. The bioavailability of the drug over 24 hours was 107 micrograms/h.mL in the aqueous and 34 micrograms/h.mL in the vitreous after subconjunctival administration, compared with 0.65 and 0.14 micrograms/h.mL respectively after intravenous administration. Our results provide a solid pharmacokinetic basis for considering subconjunctivally administered dacarbazine in the treatment of human ocular melanoma.