Implications of kinetic heterogeneity in clinical oncology.
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Biomedical subjects
Publications and source records attributed to L Norton.
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The pharmacokinetics of vindesine was examined after the determination of serum drug levels by radioimmunoassay in patients who received the drug either as an i.v. bolus or a 24-hr infusion. After i.v. bolus, vindesine was eliminated from the serum by triphasic decay. The central compartment was approximately 6 times the serum volume. The peak serum level achieved by i.v. bolus was approximately 16 times that achieved by the 24-hr infusion. The post-24-hr-infusion serum decay followed biphasic decay. Pharmacokinetic modeling, assuming a prolonged infusion period, resulted in a triphasic decay curve, with an extremely short distribution phase which would not be clinically detectable. This was due to the incorporation of the distribution phase into the infusion period. This explains the experimental data of a biphasic decay curve observed after 24-hr infusion. Pharmacokinetic parameters for the two phases observed after 24-hr infusion were similar to values calculated from i.v. bolus data. The c X t for 24-hr infusion was identical to that after i.v. bolus; theoretically, the c X t appears constant regardless of infusion time. It is concluded that the rate of elimination and/or the c X t, rather than the peak serum level, played a role in the degree of hematological toxicity.
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Hemicorporectomy , or translumbar amputation, is a dramatically drastic surgical salvage procedure for patients with uncontrolled locally extensive pelvic-perineal malignancies. Several successful cases have been reported in the world literature [3-6] and careful perioperative management has been crucial. The case presented is that of a massive recurrent chondrosarcoma of the pelvis with special emphasis on close monitoring and finely tuned supportive care; unusual manifestations of neuroleptic malignant syndrome and of narcotic withdrawal are discussed.
Factors affecting nutritional adequacy of elderly persons in urban, suburban, and rural areas were assessed in an analysis of data from the first Health and Nutritional Examination Survey conducted by the National Center for Health Statistics. The specific purpose of this study was to determine whether there were residential differences among elderly adults in nutritional adequacy and to assess the predictive importance of any residential differences in relation to other predictive factors of nutritional adequacy. No significant differences in nutritional adequacy between rural and urban elderly adults were found; however, significant nutritional differences were found between the residents of suburban areas and the residents of either urban or rural areas. It was concluded that residential nutritional levels are most likely due to the educational and economic status of the individuals in an area and not to any causal effect of residential location.
Little information is available regarding the effectiveness of chemotherapeutic agents in malignant mesothelioma. Human malignant mesothelioma specimens from two patients were successfully transplanted and maintained in homozygous nude mice. Screening of chemotherapeutic agents revealed that cisplatin was the most active single agent in one line, and mitomycin C in the other. The combination of mitomycin C and cisplatin, however, was the most effective regimen for both lines of xenografted human mesothelioma. Based on these results in nude mice, a clinical trial of mitomycin C and cisplatin was undertaken. Four of 12 patients showed objective response (one complete and three partial). These clinical results support the usefulness of the nude mouse model for malignant mesothelioma.
Ocular involvement in Hodgkin's disease is relatively unusual. This report describes two cases of branch retinal artery occlusion in young patients with Hodgkin's disease. Both patients were thought to be in remission when the occlusions occurred. The possible etiology and relationship to drug therapy is discussed.
We assessed the roles of intrabacterial catalase and superoxide dismutase in the resistance of Escherichia coli to killing by neutrophils. E. coli in which the synthesis of superoxide dismutase and catalase were induced by paraquat 10-fold and 5-fold, respectively, did not resist killing by neutrophils. When bacteria were allowed to recover from the toxicity of paraquat for 1 h on ice and for 30 min at 37 degrees C, they still failed to resist killing by neutrophils. Induction of the synthesis of catalase 9-fold by growth in the presence of phenazine methosulfate did not render E. coli resistant to killing by either neutrophils or by H2O2 itself. The lack of protection by intrabacterial catalase from killing by neutrophils could not be attributed to an impermeable bacterial membrane; the evolution of O2 from H2O2 was no less rapid in suspensions of E. coli than in lysates. The failure of intrabacterial catalase or superoxide dismutase to protect bacteria from killing by neutrophils might indicate either that the flux of O-2 and H2O2 in the phagosome is too great for the intrabacterial enzymes to alter or that the site of injury is at the bacterial surface.
Twenty-two patients with newly diagnosed acute myelocytic leukemia (AML) and white cell counts (WBC) greater than 100,000/microliters received one, two, or three leukaphereses prior to induction chemotherapy with cytosine arabinoside (Ara-C) and daunorubicin (DNR). Fifteen of 22 (68%) achieved a complete remission. Greater than a 30% decrease in initial WBC was found to be an important predictor of response. Fifteen of 17 patients (88%) with greater than 30% reduction of initial WBC achieved remission, while none of 5 patients with less than a 30% reduction responded (P = 0.001).
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From 1974 to 1980, 69 patients with ith diffuse malignant mesothelioma were prospectively evaluated. The initial site of involvement was the pleura in 57 patients and the peritoneum in 12. Previous asbestos exposure was found in 53 patients (77%), with a shorter period of latency for peritoneal (mean, 28 years) than for ith pleural mesothelioma (mean, 35 years) than for pleural mesothelioma (mean, 35 years). Other associated exposure or diseases included talc, mica, familial Mediterranean fever, and diffuse lymphocytic lymphoma (one patient each). Thrombocytosis was common, as were thromboembolic episodes. Survival was significantly better for patients with an epithelial subtype, with pleural versus peritoneal mesothelioma, and for those under 65 years of age. Surgery was never curative, but its extent was correlated with survival and earlier diagnosis. Results of chemotherapy with doxorubicin and 5-azacytidine yielded a somewhat better survival rate than a combined program with doxorubicin and radiotherapy. Survival after chemotherapy was correlated with performance status, response to chemotherapy, and extent of previous surgery.
Cystic fibrosis (CF), a genetic disease characterized by abnormalities of exocrine gland and mucociliary function, has recently been shown to be associated with abnormal adrenergic and cholinergic physiologic responses in addition to decreased beta adrenergic-induced cyclic AMP generation in human leukocytes. In this study we have attempted to elucidate the nature of this hyporesponsiveness by assessing beta adrenergic receptor number and affinity (KD) in the intact neutrophil using the antagonist ligand [3H] dihydroalprenolol and cyclic AMP responses to isoproterenol in addition to histamine, and prostaglandin E1 in CF subjects, CF obligate heterozygotes (CFH), and normal control subjects. CF patients had significantly less (p less than 0.025) cyclic AMP stimulation above basals levels with isoproterenol (0.1 microM to 0.1 mM), compared with control values, but no consistent differences between groups were noted with histamine or PGE1. CF neutrophils had significantly fewer (p less than 0.005) beta adrenergic receptors per neutrophil (398.0 +/- 54.2 vs. 819.4 +/- 67.2) compared with control neutrophils, but the KD (0.740 +/- 0.11 vs. 0.630 +/- 0.05 nM) did not differ significantly (p greater than 0.05). There was no correlation between clinical severity and either cyclic AMP generation or dihydroalprenolol binding (r = 0.27 and 0.24, respectively, p greater than 0.05). The CFH group had approximately 50% of the cyclic AMP stimulation compared with controls, but the number (909.8 +/- 89.3) and KD (0.710 +/- 0.09 nM) of their beta adrenergic receptors were indistinguishable from control subjects. These findings suggest "down regulation" of the beta receptor in the CF patient. The cause of this remains unknown. Although the etiology of the decreased cyclic AMP responses in CFH was not due to decreased beta adrenergic receptors as assessed by antagonist ligand binding, further studies inthe CFH group to include agonist binding, receptor-adenylate cyclase coupling, intrinsic adenylate cyclase activity, and catecholamine metabolism may help determine the basic cause of beta adrenergic hyperesposiveness in both CFH and CF.
In 18 piglets, weighing 10-15 kg, third-degree burns or full-thickness skin excisions of 4 X 4 cm were inflicted. The effect of five dressing materials on adhesiveness to the wounds, appearance, conformability, wound contraction, bacterial count, and morphology of the wound was studied at the end of the seventh and fourteenth days without dressing changes. In 11 piglets with a burn wound, the most adherent dressing was collagen sponge(CS), followed by polyurethane sponge (PU), pigskin xenograph (PS), and xeroform. CS more effectively debrided the wound from coagulated necrotic tissue than the other dressings. Wound contraction was maximal with CS dressing (52%), followed by PU (44%), xeroform (32%), and PS (27%). In another seven piglets with full-thickness excised wounds, a velour dressing made of polytetrafluoroethylene (PTFE) or PU adhered significantly more than CS or PS. Wound contraction was greater with CS (37%) or PTFE (35%) than with PS (23%) or PU (18%). The bacterial counts were similar in wounds dressed with CS, PU, or PTFE. PS dressing showed significantly higher bacterial counts. The results of this study support those of a previous report on the effect of similar dressing materials on rabbit second-degree burns (8).
Nodular histiocytic lymphoma (NH) is uncommon, and its natural history is not well defined. Of 473 patients with non-Hodgkin's lymphoma, we found 16 (3.4%) with NH. Most patients (13/16) presented with pathologic stage (PS) III or IV disease, including 7 with liver involvement. One patient (PS III) was initially treated with cyclophosphamide alone, and 4 patients received only radiotherapy, and none were long-term survivors. Eleven patients received combination chemotherapy, and 8 achieved complete remission. Only one of these patients relapsed and died at 19 mo; the other 7 continue in complete remission without maintenance therapy with a minimum followup of 4.5 yr. The survival of the entire group of patients with NH is intermediate between that of the other nodular lymphomas and diffuse histiocytic lymphoma. Nine of 16 patients had either a repeat lymph node biopsy during the course of their disease or lymph node examination at autopsy. Lymph node histology in the majority converted to a diffuse, less differentiated subtype of lymphoma. NH has a natural history similar to that of diffuse histiocytic lymphoma and should be approached with the same therapeutic strategy.
Parameters of cell-mediated and humoral-mediated immunity were measured in ten infection-free, insulin-dependent, controlled diabetic patients and in ten similar but nondiabetic patients awaiting elective operations. Tests performed included total and differential leukocyte counts, neutrophil reduction of nitroblue tetrazolium, mitogen response of lymphocyte to phytohemagglutinin, ratio of thymus-derived to bone marrow-derived lymphocytes, serum immunoglobulins IgA, IgG, and IgM, macrophage inhibition factor, serum zinc, and reaction to skin test antigens. Diabetics had a significantly (P less than .05) decreased mean response response to phytoheagglutinin stimulation and a lowered ratio of thymus-derived to bone marrow-derived lymphocytes. These findings support the concept of depressed cell-mediated immunity in the controlled, adult diabetic and might explain the propensity of the uncontrolled diabetic to increased frequency and severity of bacterial infection.
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