Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

The RAPID3 questionnaire as a screening tool to reduce the number of outpatient clinic visits: a retrospective cohort study

Clinical Rheumatology - Treat-to-target strategies require frequent on-site evaluations of disease activity in patients with rheumatoid arthritis (RA), burdening patients and caregivers. However,...     

Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay

The traditional coagulant assay for plasma factor XI suffers from a relatively high coefficient of variation, the need for rare congenitally deficient plasma, and a poor correlation between precision and sensitivity. We have developed a simple functional amidolytic assay for factor XI in plasma using the chromogenic substrate PyrGlu-Pro-Arg- p-nitroanilide (S-2366). After inactivation of alpha 1-antitrypsin, CI inhibitor, and other plasma protease inhibitors with CHCI3, plasma was incubated with kaolin, in the absence of added calcium, which limited the enzymes formed to those dependent on contact activation. Soybean trypsin inhibitor was used to minimize the action of kallikrein on the substrate. Once the reaction was complete, corn trypsin inhibitor was used to inactive factor XIIa, the enzyme generated by exposure of plasma to negatively charged surfaces, which had activated the factor XI. The assay is highly specific for factor XI, since plasma totally deficient in that zymogen yielded only 1%-3% of the enzymatic activity in normal plasma under identical conditions. The requirements for complete conversion of factor XI to XIa in plasma within 60 min were, respectively, factor XII, 0.6 U/ml, and high molecular weight kininogen, 0.2 U/ml. Prekallikrein was not an absolute requirement for complete activation but did accelerate the reaction. The intraassay coefficient of variation was 3.4%, and the mean of 35 normal plasmas was 1.00 U +/- 0.24 SD. In addition, a new rapid radioimmunoassay was devised using staphylococcal protein A as the precipitating agent for a complex of factor XI antigen with monospecific rabbit antibody. The mean was 1.01 U +/- 0.30 SD. The correlation coefficients for amidolytic versus coagulant and amidolytic versus radioimmunoassay were r = 0.95 for the former and 0.96 for the latter. Thus, a simple, accurate amidolytic assay and a radioimmunoassay have been devised for measuring factor XI in plasma that correlate well with the coagulant activity of factor XI, as determined in our laboratory.     

Hydrogen sulfide: physiological properties and therapeutic potential in ischaemia

Hydrogen sulfide (H₂S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H₂S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia.

Linked Articles

This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6     

The Consumer Quality Index in an accident and emergency department: internal consistency,validity and discriminative capacity

Background

Patients’ experiences are an indicator of health‐care performance in the accident and emergency department (A&E). The Consumer Quality Index for the Accident and Emergency department (CQI A&E), a questionnaire to assess the quality of care as experienced by patients, was investigated. The internal consistency, construct validity and discriminative capacity of the questionnaire were examined.

Methods

In the Netherlands, twenty‐one A&Es participated in a cross‐sectional survey, covering 4883 patients. The questionnaire consisted of 78 questions. Principal components analysis determined underlying domains. Internal consistency was determined by Cronbach''s alpha coefficients, construct validity by Pearson''s correlation coefficients and the discriminative capacity by intraclass correlation coefficients and reliability of A&E‐level mean scores (G‐coefficient).

Results

Seven quality domains emerged from the principal components analysis: information before treatment, timeliness, attitude of health‐care professionals, professionalism of received care, information during treatment, environment and facilities, and discharge management. Domains were internally consistent (range: 0.67–0.84). Five domains and the ‘global quality rating’ had the capacity to discriminate among A&Es (significant intraclass correlation coefficient). Four domains and the ‘global quality rating’ were close to or above the threshold for reliably demonstrating differences among A&Es. The patients’ experiences score on the domain timeliness showed the largest range between the worst‐ and best‐performing A&E.

Conclusions

The CQI A&E is a validated survey to measure health‐care performance in the A&E from patients’ perspective. Five domains regarding quality of care aspects and the ‘global quality rating’ had the capacity to discriminate among A&Es.     

Evaluation of three physiologically based pharmacokinetic (PBPK) modeling tools for emergency risk assessment after acute dichloromethane exposure

Introduction

Physiologically based pharmacokinetic (PBPK) models may be useful in emergency risk assessment, after acute exposure to chemicals, such as dichloromethane (DCM). We evaluated the applicability of three PBPK models for human risk assessment following a single exposure to DCM: one model is specifically developed for DCM (Bos) and the two others are semi-generic ones (Mumtaz and Jongeneelen).

Materials and methods

We assessed the accuracy of the models’ predictions by simulating exposure data from a previous healthy volunteer study, in which six subjects had been exposed to DCM for 1 h. The time-course of both the blood DCM concentration and percentage of carboxyhemoglobin (HbCO) were simulated.

Results

With all models, the shape of the simulated time course resembled the shape of the experimental data. For the end of the exposure, the predicted DCM blood concentration ranged between 1.52–4.19 mg/L with the Bos model, 1.42–4.04 mg/L with the Mumtaz model, and 1.81–4.31 mg/L with the Jongeneelen model compared to 0.27–5.44 mg/L in the experimental data. % HbCO could be predicted only with the Bos model. The maximum predicted % HbCO ranged between 3.1 and 4.2% compared to 0.4–2.3% in the experimental data. The % HbCO predictions were more in line with the experimental data after adjustment of the Bos model for the endogenous HbCO levels.

Conclusions

The Bos Mumtaz and Jongeneelen PBPK models were able to simulate experimental DCM blood concentrations reasonably well. The Bos model appears to be useful for calculating HbCO concentrations in emergency risk assessment.     

Transoesophageal echocardiographic evaluation of atrial morphology in children with congenital heart disease.

In a prospective study, atrial morphology was evaluated by both transoesophageal and precordial echocardiography in 86 unoperated children with congenital heart disease (age range = 0.2 to 14.8 years, mean = 3.8 years) to determine what advantages, if any, might be inherent in the transoesophageal approach. The information derived from both ultrasound approaches was correlated and compared to information obtained during subsequent cardiac catheterization (78 patients) and, or, surgical inspection (53 patients). Atrial appendage morphology and hence atrial situs was determined by transoesophageal echocardiography in every case (82 solitus, two right atrial isomerism, two left atrial isomerism). In addition, the transoesophageal approach indicated left juxtaposition in four patients, compared to only one by precordial examination. Probe patency of the foramen ovale was correctly predicted in 21 patients by transoesophageal imaging, but in only 10 by precordial imaging. In two children significant secundum defects, undetected by the precordial route, were identified. Multiple atrial septal defects were correctly defined in four patients by transoesophageal study but in only one by precordial study. Sinus venosus defects were documented in four by the transoesophageal approach, but in only one by the precordial. Primum defects were equally well documented (nine patients) by either technique, but the associated valve leaflet morphology was better documented by transoesophageal study in 5/9. A subtotal cor triatriatum was diagnosed in one child only by transoesophageal investigation. Transoesophageal echocardiography allows a much more detailed evaluation of atrial morphology than precordial imaging even in infants. It provides direct diagnosis of atrial situs, detection of juxtaposed atrial appendages and improved demonstration or definitive exclusion of atrial septal defects.