Histamine and calcitonin release from medullary thyroid carcinoma

The secretagogue effect of histamine on calcitonin secretion has been studied in 15 patients with medullary thyroid carcinoma and compared with known stimuli: glucagon and calcium in combination with pentagastrin. The effect of concomitant histamine H2-receptor blockade on these responses has been studied in the same patients. Seven patients with undetectable basal plasma calcitonin concentrations had measurable responses to calcium/pentagastrin but not to histamine or glucagon. In the remaining eight subjects, significant responses were seen to all three test substances, calcium/pentagastrin proving to be the most potent secretagogue. Establishment of H2-receptor blockade with cimetidine had no effect on basal calcitonin concentrations and did not suppress responses to histamine, calcium or pentagastrin. The variable secretagogue effect of histamine could be mediated through H1-receptors, through nonspecific vascular dilation "washing out" preformed calcitonin, or through its destruction to varying degrees by histaminase, present in most medullary thyroid tumors. Histamine is unlikely to replace calcium/pentagastrin as the most discriminative, provocative diagnostic agent in medullary thyroid carcinoma, but correlation of secretory responses with tissue histaminase concentrations and attempted blockade with differing antihistamines will further our understanding of this tumor.     

A follow-up study of problem drinkers offered a goal choice option.

Patients (N = 100) who had been admitted to behaviorally oriented residential treatment for their drinking problems were followed up for 1 year. A treatment goal option of controlled drinking was explicitly catered for. Overall outcome, in which 27% of those available for follow-up were categorized as "successful," 35% as "equivocal" and 38% as "failure," does not appear to be markedly dissimilar to that reported from other agencies. The distribution of approximately equal abstinent and nonabstinent successful outcomes is similar to that found following treatment programs that promote a single goal. Sociodemographic variables were less influential in predicting outcome than were treatment variables--with frequency of aftercare attendance being particularly significant. Those who had received previous hospital treatment for their problem, those who habitually drank in company and those who had abnormal blood test results prior to entering treatment had poorer outcome.     

H1 and H2 receptor antagonists and hepatic oxygen supply-demand relationship in pigs

The hypothesis that histamine receptor (H1 and H2) blockade beneficially affects the hepatic oxygen supply-demand relationship was tested during experiments performed on 13 miniature pigs. Hepatic arterial and portal blood flows were measured with electromagnetic flowmeters. Cardiac output was determined by thermodilution. H1 and H2 receptor blockade was achieved with promethazine, 5 mg.kg-1 and cimetidine 30 mg.kg-1 IV, respectively. The study demonstrated no significant effect of H1 and H2 receptor blockade on hepatic oxygen uptake and no noticeable effects of cimetidine on hepatic circulation. However, promethazine decreased total hepatic blood flow, primarily by decreasing portal blood flow; this resulted in an increase in oxygen extraction as reflected in a decreased oxygen content in hepatic venous blood. The results reject the posed hypothesis: H1 receptor antagonist promethazine decreased, while H2 receptor antagonist cimetidine did not affect hepatic blood flow and oxygen supply; hepatic oxygen demand remained unaffected during H1 and H2 receptor blockade.     

Roux-Y Gastric Bypass: an effective anti-reflux procedure

Gastric limiting procedures have made an improvement in the lives of those patients in whom they have been successful. Not only have there been marked improvements in diabetes, hypertension, and arthritis, but there have been a number of other ‘spin-offs’, not the least of which is control of reflux esophagitis by totally eliminating the secretion of the parietal cell mass of the stomach from rising into the esophagus. We compared a group of 100 obese patients with reflux esophagitis who underwent Roux-Y gastric bypass (RYGBP) to a normalsized group of 23 patients on whom we had done Nissen fundoplications in the past. Visick gradings I-II of 100% vs 87%, respectively, may indicate a superiority of RYGBP over the Nissen procedure. Although the groups and time periods are too divergent to draw statistically significant conclusions, one can see that the RYGBP population was apparently better served considering their cure of ‘heartburn’ and other reflux symptoms as well as their achievement of sustained weight loss.     

Quantitation of motexafin lutetium in human plasma by liquid chromatography-tandem mass spectrometry and inductively coupled plasma-atomic emission spectroscopy

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected onto and LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 μg MLu mL⁻¹, with a signal-to-noise ratio of 15∶1. The response was linear from 0.05 to 5.0 μg MLu mL⁻¹. For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected onto the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 μg Lu mL⁻¹. The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples were ≤6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, and ≤8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred.     

Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices.

PURPOSE: This retrospective study was undertaken to assess practice patterns in adjuvant chemotherapy for early-stage breast cancer (ESBC) and to define the incidence and predictive factors of reduced relative dose-intensity (RDI). PATIENTS AND METHODS: A nationwide survey of 1,243 community oncology practices was conducted, with data extracted from records of 20,799 ESBC patients treated with adjuvant chemotherapy. Assessments included demographic and clinical characteristics, chemotherapy dose modifications, incidence of febrile neutropenia, and patterns of use of colony-stimulating factor (CSF). Dose-intensity was compared with published reference standard regimens. RESULTS: Dose reductions > or =15% occurred in 36.5% of patients, and there were treatment delays > or =7 days in 24.9% of patients, resulting in 55.5% of patients receiving RDI less than 85%. Nearly two thirds of patients received RDI less than 85% when adjusted for differences in regimen dose-intensity. Multivariate analysis identified several independent predictors for reduced RDI, including increased age; chemotherapy with cyclophosphamide, methotrexate, and fluorouracil, or cyclophosphamide, doxorubicin, and fluorouracil; a 28-day schedule; body-surface area greater than 2 m2; and no primary CSF prophylaxis. CSF was often initiated late in the chemotherapy cycle. CONCLUSION: Patients with ESBC are at substantial risk for reduced RDI when treated with adjuvant chemotherapy. Patients at greatest risk include older patients, overweight patients, and those receiving three-drug combinations or 28-day schedules. Predictive models based on such risk factors should enable the selective application of supportive measures in an effort to deliver full dose-intensity chemotherapy.     

Antineoplastic effects of partially HLA-matched irradiated blood mononuclear cells in patients with renal cell carcinoma.

PURPOSE: Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease. PATIENTS AND METHODS: Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives. RESULTS: There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients. CONCLUSION: Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.     

The validity of bioelectrical impedance models in clinical populations.

Bioelectrical impedance analysis (BIA) is the most commonly used body composition technique in published studies. Herein we review the theory and assumptions underlying the various BIA and bioelectrical impedance spectroscopy (BIS) models, because these assumptions may be invalidated in clinical populations. Single-frequency serial BIA and discrete multifrequency BIA may be of limited validity in populations other than healthy, young, euvolemic adults. Both models inaccurately predict total body water (TBW) and extracellular water (ECW) in populations with changes in trunk geometry or fluid compartmentalization, especially at the level of the individual. Single-frequency parallel BIA may predict body composition with greater accuracy than the serial model. Hand-to-hand and leg-to-leg BIA models do not accurately predict percent fat mass. BIS may predict ECW, but not TBW, more accurately than single-frequency BIA. Segmental BIS appears to be sensitive to fluid accumulation in the trunk. In general, bioelectrical impedance technology may be acceptable for determining body composition of groups and for monitoring changes in body composition within individuals over time. Use of the technology to make single measurements in individual patients, however, is not recommended. This has implications in clinical settings, in which measurement of individual patients is important.