Daily subcutaneous injection of low-dose interleukin 2 expands natural killer cells in vivo without significant toxicity

We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2. Adult cancer patients received a single daily s.c. injection of IL-2 as outpatients for 90 consecutive days. Cohorts of four to nine patients were treated at escalating IL-2 dose levels until the maximum tolerated dose (MTD) was defined. Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated. Thirty-eight patients were treated at seven IL-2 dose levels ranging from 0.4 to 1.75 million International Units (mIU)/m2 daily. The MTD was 1.25 mIU/m2, with constitutional side effects, vomiting, and hyperglycemia dose limiting. Severe toxicity did not occur at or below the MTD, although mild local skin reaction and mild constitutional side effects were common. Objective tumor regressions were not observed during this Phase I trial. Low-dose IL-2 resulted in natural killer (NK) cell (CD3(-) CD56(+)) expansion at all dose levels. This effect was dose dependent (P < 0.01), ranging from a 154 to 530% increase over baseline. Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks of therapy. As predicted by in vitro studies of IL-2 receptor structure-activity relationships, the subset of NK cells that constitutively express high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more profound dose-dependent expansion, with increases ranging from 368 to 2763% (P = 0.015). NK expansion occurred at peak IL-2 levels <10 pM (2.3 IU/ml). Three patients developed nonneutralizing anti-IL-2 antibodies. Thus, we concluded that selective expansion of NK cells may be achieved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.     

Patients' experiences of patient-controlled analgesia

We examined patients' experiences of patient-controlled analgesia by the use of semistructured interviews in 26 patients shortly after discontinuation of the device. The options expressed by the patients were examined qualitatively to identify recurring themes in their experience of patient-controlled analgesia. The areas of interest were analgesia, factors influencing whether the patient pressed the button or not, whether they felt in control and side effects. Negative as well as the expected positive evaluations were found. The negative evaluations reflected problems with nausea and vomiting and inadequate analgesia. No clear strategy for pressing, or not pressing, the button emerged and the principle of control by the patient over their pain relief was not considered important.     

5-[125I]iodo-2'-deoxyuridine in the radiotherapy of brain tumors in rats

Glial neoplasms of the human central nervous system have defied treatment, in part because of the limited selectivity of available cytotoxic agents. The thymidine analog 5-iodo-2'-deoxyuridine radiolabeled with the Auger electron emitter 125I (125IUdR) is highly toxic to dividing cells when it is deoxyribonucleic acid incorporated, but it is relatively innocuous when located outside the nucleus. Previous studies have shown that 125IUdR has significant antineoplastic potential against mammalian cells in vitro and direct administration of 125IUdR is effective therapy for ovarian ascites tumors in mice and neoplastic meningitis in rats. Studies using external gamma imaging and autoradiography have also shown that direct intratumoral administration of 123IUdR/125IUdR into intracerebral 9L gliosarcomas in rats results in selective uptake of the radionuclide into tumor cells. Based on these encouraging results, we have evaluated the therapeutic potential of 125IUdR in rats bearing intracerebral 9L gliosarcomas. METHODS: Iodine-125-IUdR was infused intracerebrally over a 2-day period into rats bearing 1-day-old 9L tumors and over a 6-day period into animals with 9-day-old 9L tumors; equimolar concentrations of 127IUdR were infused into control animals. Tumor growth was monitored by contrast-enhanced 1H MRI and animal survival was followed over time. RESULTS: Intracerebral tumors (3-7 mm) were readily detected by MRI. Tumor-bearing rats treated with 127IUdR succumbed within 17-24 days, whereas tumor-bearing animals treated with 125IUdR survived significantly longer, and 10%-20% of the animals were cured of tumors. CONCLUSION: These data substantiate the antineoplastic potential of 5-[125I]iodo-2'-deoxyuridine and indicate that it may be a useful agent for the therapy of solid tumors that are accessible to direct radiopharmaceutical administration.     

Quality of life after acoustic neuroma surgery

OBJECTIVE: To assess how surgery affected the quality of life of patients with acoustic neuromas and to investigate possible predictors of the functional outcome following surgery. STUDY DESIGN: A questionnaire based on the Glasgow Benefit Inventory was completed by patients randomly selected following acoustic neuroma surgery. SETTING: Skull base surgery unit of a university teaching hospital (tertiary referral center). PATIENTS: Fifty-three patients with acoustic tumors (follow-up, 1 to 3 y). RESULTS: With regard to overall quality of life, nine patients (17.4%) reported that it became better, 28 patients (53.8%) worse, and 15 patients (28.8%) that it remained the same. Four patients (7.8%) became better off financially, 15 patients (29.4%) worse, and 32 (62.8%) remained unchanged. Forty-one patients (78.8%) did not change their occupation, and 11 (21.2%) had to change their occupation, mainly because of the adverse effects of the operation. With regard to the age at operation, older patients were found to have better overall quality of life. Moreover, younger patients had worse postoperative financial status and they were more likely to change their occupation after the operation. The tumor size did not significantly affect the overall postoperative quality, but it did affect the postoperative financial status (patients with larger tumors were more likely to have worse postoperative financial status). CONCLUSION: Acoustic neuroma surgery has a significant impact on patients' overall quality of life. Surgeons proposing to operate on small tumors should not assume that the impact on patients' life will be necessarily less than that following the removal of larger tumors. All patients, especially in the younger age group, should be prepared and thoroughly informed about the consequences of the operation on their quality of life.     

Cerebrospinal fluid levels of oxytocin in Prader-Willi syndrome: a preliminary report

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder characterized by mental retardation, appetite dysregulation, and a high risk for obsessive-compulsive disorder (OCD). Microscopic abnormalities of the hypothalamus have been described in PWS, and oxytocin has been implicated in both appetite regulation and OCD. METHODS: Oxytocin and arginine vasopressin (AVP) were measured in the cerebrospinal fluid of 5 subjects with PWS (2 male, 3 female) and in 6 normal control subjects (all female). RESULTS: CSF oxytocin was elevated in PWS (9.2 +/- 3.9 pmol/L) as compared to normal control subjects (5.1 +/- 0.9 pmol/L, p = 0.045), a finding that was more significant when excluding male subjects from analysis (p = 0.02). AVP was not significantly different between the groups as a whole. CONCLUSIONS: These data provide further evidence for hypothalamic and oxytocinergic dysfunction in PWS. The associations between oxytocin, appetite regulation, and obsessive compulsive symptomatology in PWS warrant further investigation.     

Immunogenicity of Plasmodium falciparum circumsporozoite protein multiple antigen peptide vaccine formulated with different adjuvants

Only low antibody levels were obtained from vaccinating human volunteers with single-chain peptide from the Plasmodium falciparum circumsporozoite protein (PfCSP). This resulted in modest protection against sporozoite challenge. In addition, HLA restriction limits the probability of synthesis of a vaccine effective for a diverse population. We report immunization studies with a multiple antigen peptide (MAP) system consisting of multiple copies of a B-cell epitope from the central repeat region of the PfCSP in combination with a universal T-cell epitope, the P2P30 portion of tetanus toxin. This MAP4(NANP)6P2P30 vaccine was highly immunogenic in four different strains of mice when used with various safe and nontoxic adjuvants. When this MAP vaccine was encapsulated in liposomes with lipid A and adsorbed to aluminium hydroxide and given three times at 4-week intervals, the resultant antibody prevented 100% of sporozoites from invading and developing into liver stage infection. This high degree of immunogenicity of MAP4(NANP)6P2P30 vaccine formulated in liposomes, lipid A and aluminum hydroxide provides the foundation for consideration of human trials with this formulation.     

Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development

The leukocyte-specific adapter molecule SLP-76 (Src homology 2 domain-containing leukocyte protein of 76 kilodaltons) is rapidly phosphorylated on tyrosine residues after receptor ligation in several hematopoietically derived cell types. Mice made deficient for SLP-76 expression contained no peripheral T cells as a result of an early block in thymopoiesis. Macrophage and natural killer cell compartments were intact in SLP-76-deficient mice, despite SLP-76 expression in these lineages in wild-type mice. Thus, the SLP-76 adapter protein is required for normal thymocyte development and plays a crucial role in translating signals mediated by pre-T cell receptors into distal biochemical events.     

Inhibition of rat lung mixed-function oxidase activity following repeated low-level toluene inhalation: possible role of toluene metabolites

Toluene is a commonly used solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration. The purpose of this study was to determine whether similar changes occurred following repeated, low-level inhalation exposure, and to investigate the role of toluene metabolites in these alterations. Exposure to 375 ppm toluene, 6 h/d for up to 5 d, resulted in significant inhibition of the activity of pulmonary arylhydrocarbon hydroxylase (AHH), cytochrome P-4502B1 (CYP2B1), and CYP4B1, but not CYP1A1. After exposure to lower toluene levels (125 ppm, 6 h/d, 3 d), the activities of lung AHH, CYP2B1, and CYP4B1 were also significantly decreased, but in a dose-related manner. MFO activity was not consistently altered in liver. Control pulmonary or liver microsomes were incubated with various concentrations (0.01-10 mM) of toluene or its metabolites and CYP2B1, CYP1A1, and/or CYP4B1 activities were subsequently determined. Benzaldehyde produced a significant dose-related inhibition in the activity of all three lung P-450s examined (IC50 10(-3) M). Toluene was found to be a more potent inhibitor of lung CYP2B1 and CYP1A1 (IC50, 10(-4) M) than benzaldehyde, but neither toluene nor benzyl alcohol was an effective inhibitor of lung CYP4B1. Toluene and its metabolites were weaker inhibitors of CYP1A1 than of CYP2B1. For CYP2B1 and CYP1A1, the order of inhibitory potency was toluene > benzaldehyde > benzyl alcohol and suggests that both the parent molecule and its metabolites may act in concert to inhibit catalytic activity of these cytochromes. The MFO inhibition seen after repeated low-level toluene inhalation exposure could result in altered metabolic profiles of other xenobiotics in an organ-specific fashion.