Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) is an antineoplastic modality in which immune-activated cells are administered to a host with advanced cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested to have therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients with advanced malignant melanoma. Nineteen patients were entered in the trial. They received IL-2 at 3 x 10(6) U/m2 subcutaneously daily x 5 plus LEV 50 mg/ m2 orally three times daily (p.o. t.i.d.) x 5. Patients were reevaluated at four-week intervals. None of the patients achieved a partial or complete regression (PR, CR). The median time to treatment failure (refusal, progression, or off study due to toxicity) was 56 days. Grade IV toxicities included vomiting (3 patients), lethargy (1 patient), and musculoskellar pain (1 patient). This regimen is not recommended for further testing in patients with advanced malignant melanoma.     

Validation of the in vivo intravascular ultrasound measurement of in-stent neointimal hyperplasia volumes

OBJECTIVES: This study was undertaken to validate the in vivo intravascular ultrasound (IVUS) measurement of in-stent neointimal hyperplasia (IH) volumes. BACKGROUND: Because stents reduce restenosis compared to balloon angioplasty, stent use has increased significantly. As a result, in-stent restenosis is now an important clinical problem. Serial IVUS studies have shown that in-stent restenosis is secondary to intimal hyperplasia. To evaluate strategies to reduce in-stent restenosis, accurate measurement of in-stent neointimal tissue is important. METHODS: Using a porcine coronary artery model of in-stent restenosis, single Palmaz-Schatz stents were implanted into 16 animals with a stent:artery ratio of 1.3:1. Intravascular ultrasound imaging was performed at 1 month, immediately prior to animal sacrifice. In vivo IVUS and ex vivo histomorphometric measurements included stent, lumen and IH areas; IH volumes were calculated with Simpson's rule. RESULTS: Intravascular ultrasound measurements of IH (30.4+/-11.0 mm3) volumes correlated strongly with histomorphometric measurements (26.7+/-8.5 mm3, r=0.965, p < 0.0001). The difference between the IVUS and the histomorphometric measurements of IVUS volume was 4.1+/-2.7 mm3 or 15.8+/-11% (standard error of the estimate=0.7). Both histomorphometry and IVUS showed that IH was concentric and uniformly distributed over the length of the stent. Intravascular ultrasound detected neointimal thickening of < or =0.2 mm in 5 of 16 stents. Sample size calculations based on the IVUS measurement of IH volumes showed that 12 stented lesions/arm would be required to show a 50% reduction in IVUS-measured IH volume and 44 stented lesions/arm would be required to show a 25% reduction in IH volume. CONCLUSION: In vivo IVUS measurement of IH volumes correlated strongly with ex vivo histomorphometry. Using volumetric IVUS end points, small sample sizes should be necessary to demonstrate effectiveness of strategies to reduce in-stent restenosis.     

Effect of novel mixed ETA/ETB antagonists on responses to ET-1 in human small muscular pulmonary arteries

Selective ETA and ETB receptor antagonists do not fully inhibit responses to ET-1 in human small pulmonary arteries. Here, we have compared the influence of the novel mixed ETA/ETB antagonists SB/217242, SB/234551 and SB/209670 on ET-1-mediated vasoconstriction in these vessels. ET-1 was a potent vasoconstrictor (pEC50: 8.14+/-0.05, n=5) and the concentration-response curve to ET-1 was biphasic in nature. All three mixed antagonists (1 microM) inhibited the responses to ET-1, abolishing the biphasic form of the concentration response curve. The order of potency was SB 209670>SB 234551>/=SB 217242 with estimated pKb values of 8.0+/-0.20, 6.8+/-0.17 and 6. 6+/-0.11 respectively (n=3-5).     

Changes in folate status as determined by reduction in total plasma homocysteine levels during leucovorin modulation of 5-fluorouracil therapy in cancer patients

We measured plasma total homocysteine (tHcy) in 14 patients (13 patients with colorectal cancer and 1 patient with breast cancer) during their first treatment with 5-fluorouracil (5-FU) plus leucovorin [LV (5-FULV)]. Eight of these patients were investigated a second time after 3-10 cycles (median, 4 cycles) with 5-FULV. Each cycle consisted of two administrations of 5-FU (500 mg/m2) and LV (60 mg/m2) given 24 h apart. The first administration of 5-FULV on day 1 of the first cycle induced a rapid reduction of the tHcy level from 12.5 micromol/liter (10.4-15.1 micromol/liter; geometric mean with 95% confidence interval of the mean) to 9.1 micromol/liter (7.5-11.1 micromol/liter) in 24 h. tHcy remained stable at this level after the second administration of 5-FULV. In addition, the 5-FULV regimen caused a concurrent 4-fold increase in both serum and erythrocyte folate. The fifth cycle with 5-FULV had only marginal effects on the tHcy level. 5-FU without LV modulation had no effect on the plasma tHcy or folate status in eight breast cancer patients. Our data establish the reduction of tHcy as a responsive indicator of LV pharmacodynamics.     

Prevalence of voice problems in teachers

Teachers are frequently cited as experiencing a high rate of vocal dysfunction (1-7). Despite considerable research in the area of voice problems in teachers, the prevalence of voice disorders in this group is unknown. This study investigated the prevalence of self-reported voice problems in teachers using a mail survey of a simple random sample of 1168 state school teachers (preschool-Grade 12) in South Australia. As part of the survey, teachers were asked to report voice problems for the day of the survey, during the current teaching year, and during their careers. The response rate was 75%, with 16% of teachers reporting voice problems on the day of the survey, 20% reporting problems during the current teaching year, and 19% reporting problems at some time during their career. Females were twice as likely as males to report voice problems. These findings clearly indicate a need for further investigation of the causes of vocal dysfunction in teachers and for the development of educational programs aimed at preventing voice problems in this group of professional voice users.     

Red nucleus stimulation inhibits within the inferior olive

Red nucleus stimulation inhibits within the inferior olive. J. Neurophysiol. 80: 3127-3136, 1998. In the anesthetized cat, electrical stimulation of the magnocellular red nucleus (RNm) inhibits responses of rostral dorsal accessory olive (rDAO) neurons to cutaneous stimulation. We tested the hypothesis that RNm-mediated inhibition occurs within the inferior olive by using stimulation of the ventral funiculus (VF) of the spinal cord in place of cutaneous stimulation of the hindlimb. Fibers in the VF terminate on hindlimb rDAO neurons, so inhibition of this input would have to occur within the olive. rDAO responses elicited by VF stimulation were inhibited by prior stimulation of the RNm, indicating that inhibition occurs within the olive. In contrast, evoked potentials recorded from the VF or dorsal columns following hindlimb stimulation were not affected by prior stimulation of RNm, indicating that stimulation of the RNm does not inhibit olivary afferents at spinal levels. RNm stimulation that inhibited rDAO responses had little effect on evoked somatosensory responses in thalamus, indicating that inhibition generated by activity in RNm may be specific to rDAO. To test limb specificity of RNm-mediated inhibition, conditioning stimulation was applied to the dorsolateral funiculus at thoracic levels, which selectively activates RNm neurons projecting to the lumbar cord. Stimulation at thoracic levels inhibited evoked responses from hindlimb but not forelimb regions of rDAO, suggesting that inhibitory effects of RNm activity are limb specific. Several studies have reported that olivary neurons have reduced sensitivity to peripheral stimulation during movement; it is likely that RNm-mediated inhibition occurring within the olive contributes to this reduction of sensitivity. Inhibition of rDAO responses by descending motor pathways appears to be a salient feature of olivary function.     

Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms

We investigated the retrograde axonal transport of 125I-labeled neurotrophins (NGF, BDNF, NT-3, and NT-4) from the sciatic nerve to dorsal root ganglion (DRG) sensory neurons and spinal motor neurons in normal rats or after neuronal injury. DRG neurons showed increased transport of all neurotrophins following crush injury to the sciatic nerve. This was maximal 1 day after sciatic nerve crush and returned to control levels after 7 days. 125I-BDNF transport from sciatic nerve was elevated with injection either proximal to the lesion or directly into the crush site and after transection of the dorsal roots. All neurotrophin transport was receptor-mediated and consistent with neurotrophin binding to the low-affinity neurotrophin receptor (LNR) or Trk receptors. However, transport of 125I-labeled wheat germ agglutinin also increased 1 day after sciatic nerve crush, showing that increased uptake and transport is a generalized response to injury in DRG sensory neurons. Spinal cord motor neurons also showed increased neurotrophin transport following sciatic nerve injury, although this was maximal after 3 days. The transport of 125I-NGF depended on the expression of LNR by injured motor neurons, as demonstrated by competition experiments with unlabeled neurotrophins. The absence of TrkA in normal motor neurons or after axotomy was confirmed by immunostaining and in situ hybridization. Thus, increased transport of neurotrophic factors after neuronal injury is due to multiple receptor-mediated mechanisms including general increases in axonal transport capacity.