Biochemotherapy of advanced metastatic renal-cell carcinoma: results of the combination of interleukin-2, alpha-interferon, 5-fluorouracil,vinblastine, and 13-cis-retinoic acid

Summary We conducted a phase I/II clinical trial evaluating the sequential outpatient combination of S.C. recombinant human interleukin-2 (rIL-2; given at 10 MIU/m² b.i.d. on days 3–5 of weeks 1 and 4 and at 5 MIU/m² on days 1, 3, and 5 of weeks 2 and 3), s.c. recombinant human alpha-interferon (rIFN-; given at 6 MIU/m² on day 1 of weeks 1 and 4 and on days 1, 3, and 5 of weeks 2 and 3 and at 9 MIU/m² on days 1, 3, and 5 of weeks 5–8), i.v. bolus 5-fluorouracil (5-FU; given at 1,000 mg/m² once weekly during weeks 5–8), and i.v. bolus vinblastine (given at 6 mg/m² once weekly during weeks 5 and 8) in conjunction with p.o. 13-cis-retinoic acid (13-C-RA; given at 35 mg/m² daily during weeks 1–8). Therapy was always given in the outpatient setting. Grade 3 constitutional symptoms (malaise, chills, fevers, anorexia) were observed in 4%–8% of treatment cycles and required a 50% reduction in the doses of rIL-2 and rIFN-. None of the patients experienced major 5-FU-related toxicities such as severe diarrhea and/or stomatitis; up to 20% of patients developed vinblastine-associated peripheral polyneuropathy, which was reversible after the cessation of therapy. 13-cis-Retinoic acid produced no significant side effect; no toxic death occurred. Among 24 patients with progressive metastatic disease, there were 4 complete remissions (lung, lymph nodes) and 6 partial remissions (lung, pleura, liver, lymph nodes, and peritoneal carcinosis), for an overall objective response rate of 42% (95% confidence interval, 22%–63%). An additional 13 patients achieved disease stabilization (54%). The median time to response was 3–4 months (range, up to 6 months); all responses are continuous. In summary, although the potential synergy of biochemotherapy plus 13-cis-retinoic acid requires further preclinical investigation, the current outpatient combination regimen (rIL-2, rIFN-a, 5-FU, vinblastine, and 13-C-RA) proved to be both safe and highly effective in patients with advanced metastatic renal-cell carcinoma. A current multiinstitutional prospectively randomized trial is comparing biochemotherapy with and without concomitant 13-C-RA against rIFN- plus vinblastine.     

Differential parental communication with adolescents who are disabled and their healthy siblings

Purpose: To examine the levels of parental communication and differential conversational styles with adolescents who are disabled and their healthy siblings, to better understand why the adolescent who is disabled has a higher risk of psychosocial problems during the transition into adulthood.

Methods: Families who had a disabled adolescent and at least one other adolescent who was not disabled were videorecorded during dinner at home. Twenty adolescents (12 girls and 8 boys) and their families participated. Analyses were conducted on the 392 interactions.

Results: Not only did the healthy adolescents participate in family interactions at higher frequencies than the adolescents who were disabled F(1, 383) = 14.00, p < .001, but the interactions were also more meaningful with healthy adolescents, F(2, 383) = 5.25, p < .01. Furthermore, healthy siblings had significantly greater conversational control than did their siblings with disabilities, χ² [1] = 14.36, p < .001. Parents responded more negatively when adolescents who were disabled initiated a topic in comparison with their response to the healthy siblings, F(2, 69) = 5.44, p < .01. Finally, adolescents with disabilities were ignored more often than their healthy siblings, z = −3.75, p < .001, and they did not monopolize the conversation as often as did their healthy siblings, z = −3.91, p < .001.

Conclusion: These results suggest that adolescents who are disabled may be at a disadvantage when engaged in family interactions in contrast with their healthy siblings.     

Toward an ecosocial view of health.

The changing patterns of health in the United States justify both celebration and dismay. We can celebrate declining mortality rates, increased life expectancy, and improvements in diagnostic and therapeutic technologies. But public health was caught by surprise by the return of infectious disease; the gap in health outcomes between rich and poor and between whites and blacks increases; there is a growing discrepancy between what is technically possible and the actual health status; and despite its greater expenditures on health, the United States lags behind the other developed countries in health outcomes. The authors examine four reasons for this: we do not buy more health care, only pay more for it; we receive more health care, but much of it inappropriate, ineffective, or harmful; only some of us get more health care; and we have created a way of life that makes us sick, then spend more to repair the damage. Major failures arise when problems are understood too narrowly. An ecosocial perspective attempts to look at the whole. It rejects as false the dichotomies social/biological, physical/psychological, genetic/environmental, lifestyle/environment, examining their interrelations rather than assigning them relative weights. In addition to looking at average differences among populations, the authors examine patterns of variability in health outcomes.     

Free radicals: important cause of pathologies refer to ageing

Free radical are highly reactive chemical species with an unpaired electron in an atomic or molecular orbital. In biological systems, the most important free radicals are superoxide anion and hydrogen peroxide; in the presence of transition metals such as iron, copper and manganese both these free radicals produce hydroxyl radicals. Free radicals attack proteins, nuclei acids and membranes containing large quantities of polyunsaturated fatty acids. Because of their toxicity, the organism has developed ways to deactivate them. The superoxide dismutase enzyme (SOD) catalyzes dismutation of the superoxide radical into hydrogen peroxide and oxygen hydrogen peroxide is in turn reduced to water and oxygen by peroxidase glutathione and catalase enzymes. The production of radicals in the brain is due to catecholamine metabolism such as dopamine and norepinephrine and is increased by the presence of transition metals and by a deficiency of antioxidant agents such as vitamin E. Two main groups of dementia exist in older age: the multi-infarctual dementias, caused by cerebrovascular disorders and the primary degenerative disorders such as Alzheimer, where no vascular disease is evident. Free radicals play an important role in Parkinson's disease, in Alzheimer's disease and in stroke. The value of SOD and CAT activity following the above mentioned degenerative diseases differ among the various studies carried out. In Alzheimer's disease, the value of SOD activity probably increases in the neuropathologically involved areas. In stroke, the SOD value does not vary either in the ischemic area or in the peri-infarctual one during the first 24 hrs after lesion, while the CAT value decreases.     

Synchronized approximately 15.0-35.0 Hz oscillatory response to spatially modulated visual patterns in man

When suitably stimulated, neurons in the striate visual cortex of cats fire in bursts at 20-60 Hz and the membrane potential oscillates rhythmically in the same frequency range and in phase. These oscillations reflect intrinsic properties of mammalian neurons, occur in coherent spatial patterns that depend on the segregation and stimulus selectivity of stimulated cells, and mediate in long-range synchronization across columns and over large cortical areas of cells responding to the same stimulus property/properties. The pool of activated neurons may be adequate in size to drive cellular oscillations into local fields and mass responses. Accordingly, stimulus-dependent oscillatory activity in the same frequency range was described in man after contrast stimulation. Our results describe oscillatory potentials at approximately 15.0-35.0 Hz that in man are (partly) independent from, and anticipate the occurrence of, the conventional low-frequency visual response evoked by transient, foveal stimulation with spatially-modulated patterns.     

Macrophage Fcgamma receptors expression is altered by treatment with dopaminergic drugs

Macrophage Fcgamma receptors have an important role in host defense and the pathophysiology of immune mediated disorders. Alteration of splenic macrophage Fcgamma receptors expression predisposes to severe infection. Inhibition or blockade of splenic macrophage Fcgamma receptors is one of the mechanisms by which immune cytopenias improve. Dopaminergic drugs have clinically significant regulatory functions on the immune response. Using an experimental model in the guinea pig we assessed the effect of commonly used dopaminergic drugs on the expression of macrophage Fcgamma receptors. Three dopa-antagonists, bromocryptine, leuprolide, and pergolide, and seven dopa-antagonists, chlorpromazine, SCH 23390, metochlopramide, sulpiride, veralipride, alizapride, and cisapride, were studied. Following guinea pig treatment with dopaminergic drugs, the clearance of IgG-sensitized RBCs in vivo, the in vitro binding of IgG-sensitized RBCs by isolated splenic macrophages and flow cytometry with monoclonal antibodies were performed. Treatment with dopa-agonists enhanced the clearance of IgG-sensitized RBCs, the in vitro binding of IgG-sensitized RBCs by isolated splenic macrophages, and the cell surface expression of both macrophage Fcgamma receptors, and vice versa, dopa-antagonists impaired macrophage Fcgamma receptors expression. Macrophage FcgammaR1,2 was more sensitive than FcgammaR2 to such dopaminergic effect. These alterations of macrophage Fcgamma receptors expression are mediated by both D1 and D2 dopamine receptors, with a major participation of D2 receptors. Dopaminergic drugs alter the clearance of IgG-coated cells by an effect at the expression of splenic macrophage Fcgamma receptors.     

Metastasis of hepatocellular carcinoma to the right colon manifested by gastrointestinal bleeding

An 82-year-old black woman with a history of hepatocellular carcinoma presented with gastrointestinal bleeding. Barium enema and fibrocolonoscopy revealed a 4-cm polypoid mass at the level of the ascending colon with evidence of active bleeding. Biopsies of the lesion proved it to be metastatic hepatocellular carcinoma. Exploratory laparotomy revealed no further dissemination of the tumor, and the patient underwent an ileocolectomy. The serosal side of the colonic lesion was free from tumor, and there was no peritoneal implantation, direct extension, or lymph node involvement. This case represents an extremely rare presentation of metastatic hepatocellular carcinoma.     

Effects of tourniquet compression on neuromuscular function

Neuromuscular function in New Zealand White rabbits was evaluated after thigh tourniquet compression in the directly compressed quadriceps muscles and the distal tibialis anterior by measuring isometric contractile function after supramaximal stimulation of the motor nerve. Tourniquet compression resulted in markedly decreased force production beneath and distal to the tourniquet. Two days after compression, maximal quadriceps force production was decreased to 46% of control values with 125 mm Hg compression and 21% of control values after 350 mm Hg compression. Maximum tibialis anterior force production declined to 70% of control values after 125 mm Hg thigh compression and 24% of control values after 350 mm Hg thigh compression. Functional deficits were greater in the directly compressed quadriceps muscles, but the quadriceps and tibialis anterior had significantly increased impairment when the tourniquet inflation pressure was increased from 125 mm Hg to 350 mm Hg. Three weeks after compression, quadriceps function had returned to 94% of control value after 125 mm Hg compression and 83% after 350 mm Hg. Tibialis anterior function returned to 88% of control values after 125 mm Hg thigh compression and 83% after 350 mm Hg. Clinically, the use of lower inflation pressures may minimize the complications of tourniquet use and enhance postoperative recovery.     

Activation of plasminogen activator inhibitor-1 synthesis by phorbol esters in human promyelocyte HL-60--roles of PCKbeta and MAPK p42

HL-60 cells treated by PMA develop the monocyte adherent phenotype and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCbeta gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCbeta gene expression or transfected with PKCbeta cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCbeta. In conclusion, we propose that the pathway PKCbeta-MEK-MAPK p42 is a potential linear route for PAI-1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells.     

Perirhinal cortex input to the hippocampus in the rat: evidence for parallel pathways, both direct and indirect. A combined physiological and anatomical study

The possibility of a direct projection from the perirhinal cortex (PER) to areas CA1 and subiculum (SUB) in the hippocampus has been suggested on the basis of tracer studies, but this projection has not unequivocally been supported by physiological studies. The demonstration of such a functional pathway might be important to understand the functioning of the hippocampal memory system. Here we present physiological and further anatomical evidence for such a connection between PER and the hippocampus. Electrical stimulation of PER in vivo evoked field potentials (EFPs) at the border area of CA1/SUB, consisting of a short latency and a longer latency component. Current source density analysis revealed that the sink of the short latency component was situated in the molecular layer of area CA1/SUB, while the longer latency component had its sink in the outer molecular layer of the dentate gyrus (DG). Anterograde tracer injections in PER showed labelled fibres in the border area of CA1/SUB, but anatomical evidence for a projection of PER to DG was not found. When synaptic transmission in the entorhinal cortex was partly blocked, the amplitude of the longer latency component of the recorded EFPs in the hippocampus was decreased while the short latency component was not affected, which suggests that the indirect pathway originating in PER is mediated through a synaptic relay in the entorhinal cortex. From the present results we conclude that information originating in PER reaches area CA1/SUB by parallel, direct and indirect, routes. The existence of this parallel organization appears to form an essential feature for the proper function of the medial temporal lobe memory system.