A phase I trial of an HLA-A1 restricted MAGE-3 epitope peptide with incomplete Freund's adjuvant in patients with resected high-risk melanoma.

Cytolytic and helper T cells recognize small peptide fragments of protein antigens that are intracellularly processed and delivered to the cell surface in conjunction with HLA molecules. In mice, peptide vaccines can protect against lethal virus infections and tumor challenges. To test whether epitope peptides derived from a human tumor antigen can induce immune responses in patients, a vaccine was prepared consisting of an HLA-A1-restricted epitope of the antigen MAGE-3 mixed with a pan-class II epitope peptide PADRE and emulsified with incomplete Freund's adjuvant. Eighteen patients with resected stages III and IV melanoma at high risk for relapse were vaccinated subcutaneously with increasing doses of the MAGE-3 vaccine ranging from 100 to 2,000 micrograms per injection four times, each 4 weeks apart. The purpose of the phase I trial was to assess the toxicity, tolerability, and immune responses to the vaccine. The vaccine was not toxic, with only one case of grade III lethargy, and most patients complaining of grade I or II local pain, swelling, and tenderness at the injection sites. Peripheral blood mononuclear cells (PBMC) were collected from most patients prior to and after vaccination and used for assessment of global levels of immunity prevaccination, and to measure immune responses to the MAGE-3 and PADRE peptides prior to and after vaccination. Significant defects in global immunity shown by anergy to DTH skin testing in 7 of 16 patients and decreased proliferation to PHA (phytohemagglutinin) and CASTA, a Candida albicans protein extract, were observed. Seven of nine patients showed an increased response to PADRE after restimulation in vitro. Five of 14 patients at doses from 100 to 2,000 micrograms demonstrated an immune response to MAGE-3 by cytolysis of MAGE-3-specific target cells. Release of gamma interferon by T cells from 8 patients at the 100, 1,000, or 2,000 micrograms dose was measured after vaccination, and only two of eight patients showed an increase indicating augmented antigen-specific immunity. These data suggest that immune responses can be detected against PADRE and MAGE-3 in vaccinated melanoma patients, albeit with a low frequency of effector cells.

Phase I trial of a MART-1 peptide vaccine with incomplete Freund's adjuvant for resected high-risk melanoma.

Twenty-five patients with high-risk resected stages IIB, III, and IV melanoma were immunized with a vaccine consisting of the minimal epitope, immunodominant 9-amino acid peptide derived from the MART-1 tumor antigen (AAGIGILTV) complexed with incomplete Freund's adjuvant. The last three patients received the MART-1(27-35) peptide with incomplete Freund's adjuvant mixed with CRL 1005, a block copolymer adjuvant. Patients were immunized with increasing doses of the MART-1(27-35) peptide in a Phase I trial to evaluate the toxicity, tolerability, and immune responses to the vaccine. Immunizations were administered every 3 weeks for a total of four injections, preceded by leukapheresis to obtain peripheral blood mononuclear cells for immune analyses, followed by a post-vaccine leukapheresis 3 weeks after the fourth vaccination. Skin testing with peptide and standard delayed-type hypersensitivity skin test reagents was also performed before and after vaccinations. Local pain and granuloma formation were observed in the majority of patients, as were fevers or lethargy of grade 1 or 2. No vaccine-related grade III/IV toxicity was observed. The vaccine was felt to be well tolerated. Twelve of 25 patients were anergic to skin testing at the initiation of the trial, and 13 of 25 developed a positive skin test response to the MART-1(27-35) peptide. Immune responses were measured by release of IFN-gamma in an ELISA assay by effector cells after multiple restimulations of peripheral blood mononuclear cells in the presence of MART-1(27-35) peptide-pulsed antigen-presenting cells. An ELISPOT assay was also developed to measure more quantitatively the change in numbers of peptide-specific effector cells after vaccination. Ten of 22 patients demonstrated an immune response to peptide-pulsed targets or tumor cells by ELISA assay after vaccination, as did 12 of 20 patients by ELISPOT. Nine of 25 patients have relapsed with a median of 16 months of follow-up, and 3 patients in this high-risk group have died. Immune response by ELISA correlated with prolonged relapse-free survival. These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and support further development of peptide vaccines for melanoma.

A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu.

A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of the study were to define the maximal tolerated dose (MTD) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics of MDX-H210 when administered with G-CSF, and to determine the toxicity, biological effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the FcgammaR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The beta-elimination half-life varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor alpha was observed after administration of bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.

Active specific immunotherapy of metastatic melanoma with an antiidiotype vaccine: a phase I/II trial of I-Mel-2 plus SAF-m.

PURPOSE: To determine the toxicity and immunologic activity of an antiidiotype melanoma vaccine that consists of monoclonal antibody I-Mel-2 (MELIMMUNE-2, IDEC Pharmaceuticals, La Jolla, CA) and an immunologic adjuvant SAF-m. PATIENTS AND METHODS: Twenty-six patients with metastatic melanoma, 17 of whom had previously received chemotherapy, were given 2 mg of I-Mel-2 and either 100 micrograms (n = 6) or 250 micrograms (n = 20) of SAF-m. Antiidiotype vaccine was given intramuscularly (IM) biweekly for 4 weeks, and then bimonthly until disease progression. Human antimurine antibodies (HAMA), anti-I-Mel-2 antibodies, and specific antibody (Ab)3 against the melanoma epitope mimicked by the vaccine were titrated before treatment, biweekly from weeks 4 to 12, and every 4 to 8 weeks thereafter. Computed tomographic (CT) scans of the chest, abdomen, and pelvis and magnetic resonance imaging (MRI) of the brain were obtained before and bimonthly during treatment to evaluate responses. RESULTS: Elevated titers of human antimouse antibodies and anti-I-Mel-2 antibodies were associated with clinical antitumor effect (P = .02 and P = .05, respectively). Ab3 was absent in most patients, but was found in the best clinical responder. Fever, myalgias/arthralgias, fatigue, nausea, and headaches were the most common toxicities. Grade III myalgias/arthralgias and headaches required dose reduction of SAF-m in eight patients at the 250-microgram dose. No treatment-related death occurred. Six patients had an antitumor effect: one complete response in liver and lung, two minor responses, and three stable disease. The patient with a complete response has survived nearly 5 years. CONCLUSION: I-Mel-2 antiidiotype vaccine was safe, tolerated best at the 100-microgram dose of SAF-m, and had immunologic and clinical activity.

Writing business communications. Are nurse managers prepared?

Based on interviews, this study indicates that writing business communications is a key task for nurse managers, affecting their professional success and power. However, most of the nurse managers interviewed felt they needed more education in business communications. Several ways of bringing this training to nursing students and practicing managers are suggested.

Fatigue in patients with cancer receiving interferon alpha.

Fatigue is the most frequently reported symptom of patients with cancer. The purpose of this study was to describe the experience of fatigue over time in patients with cancer receiving treatment with interferon alpha. Piper's Integrated Fatigue Model guided this study. A descriptive repeated-measures design was used. A convenience sample of 30 patients with malignant melanoma was drawn from a comprehensive cancer center in Southern California. Two instruments were used in data collection, the Symptom Distress Scale and the Piper Fatigue Scale. Study findings revealed descriptive data on patients' perceptions of the causes and remedies for fatigue while receiving active treatment for cancer. The pattern of fatigue was consistent over the five points of time during treatment, with the most extreme fatigue scores in the affective domain, followed by the sensory, temporal, total fatigue, and fatigue severity scores. The patterns and dimensions of fatigue provide implications for care of patients receiving interferon alpha, and for further investigation in the area of fatigue as a critical aspect of quality of life.

Sustained regression of a primary choroidal melanoma under the influence of a therapeutic melanoma vaccine.

PURPOSE: To determine whether active specific immunotherapy with lysates of cutaneous melanoma cells, administered with immunologic adjuvant DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT), is effective in shrinking a primary choroidal melanoma, in an elderly patient already blind in the nontumorous eye. An 81-year-old man was referred with a primary choroidal melanoma of the left eye, with virtual blindness of the right eye due to macular degeneration. He was begun on active specific immunotherapy with an experimental melanoma vaccine (melanoma theraccine) and DETOX on weeks 1, 2, 3, 4, and 6, respected after a hiatus of 2 weeks. After a response was noted, monthly injections were given. RESULTS: The patient had a significant shrinkage of his choroidal melanoma from a height of 4.2 mm to 2.4 mm within 2 months. This was sustained by continual treatment for 21 months until September 1991. After the patient failed to return for 9 months while recuperating from a stroke, the lesion regrew to a height of 3.7 mm and developed an additional lobe. On resumption of monthly treatments, the lesion shrank to 3.4 mm within 3 months, lost the additional lobe, and has since remained stable. No metastases have been found over a period of nearly 4 years on quarterly computed tomographic (CT) scanning of the chest and abdomen, and magnetic resonance imaging of the head. CONCLUSION: Active specific immunotherapy with cutaneous melanoma lysates has caused a clinically useful protracted regression of a primary choroidal melanoma in an elderly patient in whom surgery and radiation therapy were contraindicated. This may represent the first case of a primary choroidal melanoma, and perhaps the only primary tumor, successfully treated with systemic immunotherapy alone. A formal trial of active specific immunotherapy for primary choroidal melanoma in selected patients may be warranted.

The lateral hypothalamus: a primary site mediating excitatory amino acid-elicited eating.

Lateral hypothalamic (LH) injections of the excitatory neurotransmitter glutamate, or its excitatory amino acid (EAA) agonists, kainic acid (KA), D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA), or N-methyl-D-aspartic acid (NMDA), can rapidly elicit an intense feeding response in satiated rats. To determine whether the LH is the actual locus of this effect, we compared these compounds' ability to stimulate feeding when injected into the LH, versus when injected into sites bracketing this region. Food intake in groups of adult male rats was measured 1 h after injection of glutamate (30-900 nmol), KA (0.1-1.0 nmol), AMPA (0.33-3.3 nmol), NMDA (0.33-33.3 nmol) or vehicle, through chronically implanted guide cannulas, into one of seven brain sites. These sites were: the LH, the anterior and posterior tips of the LH, the thalamus immediately dorsal to the LH, the amygdala just lateral to the LH, or the paraventricular and perifornical areas medial to the LH. The results show that across doses and agonists the eating-stimulatory effects were largest with injections into the LH. In the LH, glutamate between 300 and 900 nmol elicited a dose-dependent eating response of up to 5 g within 1 h (P < 0.01). Each of the other agonists at doses of 3.3 nmol or less elicited eating responses of at least 10 g with injections into this site. Injections into the other brain sites produced either no eating, or occasionally smaller and less consistent eating responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Lateral hypothalamic injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats.

A convergence of evidence suggests that stimulation of lateral hypothalamic (LH) neurons can elicit eating, but the neurotransmitters that mediate this effect are unknown. To determine whether glutamate might be involved, it was injected through chronic guide cannulas directly into the LH of satiated adult male rats and consequent food intake was measured. Glutamate produced a dose-dependent eating response (mean intakes of 3.7 g at 300 nmol and 5.2 g at 900 nmol) only within the first hour after injection. As a first step in determining the receptor types mediating this response, agonists for specific excitatory amino acid (EAA) receptors were similarly tested. Kainic acid (KA), D,L-alpha-amino-3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) or N-methyl-D-aspartic acid (NMDA) injected into the LH each elicited eating in a dose-dependent fashion beginning at 0.33 to 1.0 nmol. At maximally effective doses (1.0-33 nmol), each agonist elicited food intakes of approximately nine grams within 1 h. Finally, analysis of meal and behavioral patterns produced by LH injection of glutamate (600 nmol) and KA (1.0 nmol) revealed that the elicited eating usually began 2-3 min postinjection and consisted of a single normal to large size meal. There were no other behavioral effects during this initial postinjection period and no effects on other oral behaviors, like drinking or gnawing, at any time. Collectively, these findings suggest that glutamate may act through several subtypes of its receptors on some LH neurons to elicit eating.

Legal issues in the treatment of adolescent psychiatric inpatients.

When planning a specialized adolescent treatment unit for a regional state mental hospital in North Carolina, staff of the child psychiatry training program explored several critical legal issues surrounding the admission, treatment, and discharge of minors, as well as issues of confidentiality. Through a question-and-answer format they conclude that, to help avoid conditions that could result in successful litigation against the hospital, parents, adolescents, and staff must have a documented, mutual agreement to and understanding of the techniques, procedures, and limitations of the treatment program. Such documentation could be provided through a signed treatment contract.