Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer.

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1-2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.

Killer cell receptors: keeping pace with MHC class I evolution.

NK cells express receptors that bind to polymorphic determinants of MHC class I heavy chains. MHC ligands vary greatly between mammalian species, and the use of distinct molecular families of NK cell receptors by humans and mice suggests that the receptors too can be evolving rapidly. The KIR (killer cell inhibitory receptor) family of receptors are found in primates and recognize class I epitopes that are of relatively recent origin in primate evolution. Therefore, KIR molecules have probably evolved class I receptor function more recently than C-type lectins, which are represented in both humans and mice. Individual humans express NK cell receptors for which they have no class I ligand, demonstrating a looseness in the coupling of expression between the receptors and their ligands. However, study of a single donor suggests that every NK cell expresses at least one inhibitory receptor for a self-HLA class I allotype, consistent with the missing self hypothesis. Thus the NK-cell receptor-class I interaction appears to control the NK-cell repertoire during ontogeny of the individual and has the potential to be a selective factor influencing both MHC class I and NK cell receptor diversity in the evolution of populations and species.

Lack of evidence of neurotoxicity following 8 weeks of treatment with tripotassium dicitrato bismuthate.

OBJECTIVE: To search for evidence of subclinical neurotoxicity in patients treated with tripotassium dicitrato bismuthate. DESIGN: Prospective, controlled, triplicate study using urinary bismuth concentration, magnetic resonance imaging (MRI), nerve conduction studies, visual evoked response and a battery of 10 neuropsychological screening tests. SETTING: Out-patient clinics, Walsgrave Hospital, Coventry, UK. SUBJECTS: Fourteen dyspeptic patients; 8 (treatment group) treated with tripotassium dicitrato bismuthate one tablet q.d.s and 6 (control group) treated with ranitidine 150 mg b.d. for 8 weeks. MAIN OUTCOME MEASURES: Changes in urinary bismuth, MRI, nerve conduction studies, visual evoked response, and neuropsychological tests performed before, immediately after and 8 weeks after the cessation of treatment. RESULTS: In the treatment group the median (range) urinary bismuth concentration was 1 (1-12) ng/ml before treatment, increased to 560 (140-1300) immediately after treatment (P < 0.01, Wilcoxon Rank Sum test) and was still significantly elevated (23 (7-53) ng/ml) 8 weeks after the cessation of treatment. In the patient who recorded the highest urinary bismuth, a high intensity signal appeared in the globus pallidus immediately after treatment and was still present (though diminished in intensity) 8 weeks after the cessation of treatment. This isolated MRI finding was not associated with evidence of subclinical neurotoxicity. No changes in the MRI, nerve conduction studies, visual evoked response and neuropsychological tests were observed among the other patients studied. CONCLUSIONS: Bismuth accumulation occurs in patients receiving a conventional course of treatment with tripotassium dicitrato bismuthate but this is not associated with significant changes in the nervous system.

Lactulose in the treatment of symptomatic diverticular disease: a comparative study with high-fibre diet.

OBJECTIVE: To compare the efficacy and tolerance of lactulose (Duphalac) and high-fibre diet in the treatment of symptomatic diverticular disease. DESIGN: Prospectively randomised, parallel groups study over 12 weeks. Patients were seen by their clinician for an initial assessment and then at weeks 4, 8 and 12. SETTING: Hospital out-patients in the United Kingdom. PATIENTS: Forty-three patients with a confirmed diagnosis of diverticular disease were entered into the study. INTERVENTION: Patients were prospectively randomised to receive lactulose (15 ml bd) or high-fibre diet (30-40 g daily) for 12 weeks. MEASUREMENTS AND RESULTS: Data were collected using diary cards and physicians' assessments. Bowel frequency and stool consistency improved similarly with both treatments. Pain on bowel movement improved with both treatments in respect of frequency (lactulose: P = 0.017, fibre: P = 0.084) and severity (lactulose: P = 0.028, fibre: P = 0.043). Abdominal pain also improved with both treatments in respect of frequency (lactulose: P = 0.0015, fibre: P = 0.022) and severity (lactulose: P = 0.009, fibre: P = 0.028). Nine patients on lactulose and 12 on fibre reported treatment-emergent symptoms, of which none was serious. CONCLUSIONS: Lactulose and high-fibre diet were both shown to be effective in the treatment of diverticular disease, with some differences in favour of lactulose.

Carcinoid tumour secreting dopa.

A middle aged woman referred for an abdominal mass was found to have large amounts of dopa (3-4-dihydroxyphenylalanine) metabolites in her urine. At operation a tumour affecting almost the entire left lobe of the liver was removed. Histologically the tumour was a metastatic carcinoid. After operation the excretion of dopa metabolites fell substantially, confirming that the tumour was the source. Apparently, owing to an enzyme defect the tumour had been unable to decarboxylate dopa. These findings are further evidence of a neural origin for the endocrine system of the gut.

Tyrosine turnover and protein synthesis during parenteral nutrition.

Three patients receiving total parenteral nutrition and one healthy subject receiving 5% glucose were infused for 10 hours with L-(U14C)tyrosine (1.5 microCi/hr). Two alternative assumptions were made regarding the fate of labeled carbon. Total and oxidative fluxes of tyrosine were calculated and these were used to determine rates of protein synthesis and breakdown. Patients showed positive net protein synthesis and oxidation of infused phenylalanine via tyrosine was shown not to be excessive.

Leukocyte amino acid concentrations and their relationship to changes in plasma amino acids.

The leukocyte was selected as an accessible example of an actively metabolizing cell. Plasma and leukocyte amino acids (AA) were studied in a reference group and a group of 12 patients receiving total parenteral nutrition. Differences in the plasma AA were variable; some were higher and others lower in concentration in the infused group. Leukocyte AA concentrations were almost all higher in the infused group and the AA pattern was less altered than in plasma. An explanation of the changes is proposed which helps to clarify the relationship of plasma to cellular AA changes.

Plasma amino acid relationships during parenteral nutrition.

The plasma amino acidfs of 17 patients were studied before and during total parenteral nutrition (TPN). The amino acid (AA) pattern changed similarly for all patients. The AA concentration changes relative to preinfusion (PAER) were the most informative index of change. Two groups of AA were defined, the "branched chain" group (five amino acids) and the "hepatic" group (four amino acids) based on the correlation of PAER values. Comparison of PAER values with the ratio of AA intake to requirement indicated that the requirements of the sick patients were more similar to those of children than those of healthy adults.

Pancreatic scanning as a diagnostic tool in the district general hospital.

The results of 200 radioisotope pancreatic scans in a general hospital show that 32 scans were recorded as "false positives," though these included 13 patients with diabetes mellitus and nine who had had truncal vagotomy. There were no "false negatives." Scanning is a useful diagnostic tool and a distinct advance on other tests more usually available for testing pancreatic function.