Biomedical subjects
Publications and source records attributed to D Cunningham.
Carcinoma of the stomach is increasingly treated with chemotherapy. We describe two cases of intra-abdominal panniculitis in patients after laparotomy and chemotherapy for stomach carcinoma. Intra-abdominal panniculitis can result in mass lesions in the mesentery and omentum. The diagnosis should be considered in patients who have undergone chemotherapy for stomach carcinoma and who develop abdominal masses.
Following a single intravenous dose given pre-chemotherapy, the efficacy and tolerability of oral ondansetron treatment given twice daily was compared with the established three times daily oral supplementary regimen in the prophylaxis of nausea and vomiting induced by cyclophosphamide (greater than or equal to 500 mg/m2) in combination with doxorubicin (greater than or equal to 40 mg/m2) or epirubicin (greater than or equal to 40 mg/m2). Oral ondansetron given twice daily or three times daily was equally effective in controlling nausea and emesis. The twice daily oral treatment prevented emesis in 73% of patients in the first 24 hours and in 65% of patients over 3 days. Both dose schedules were safe and were tolerated well. Twice daily oral ondansetron showed good efficacy for controlling emesis and nausea in oncology outpatients.
OBJECTIVE: To characterise electrical restitution in the intact human heart. PATIENTS AND METHODS: A series of monophasic action potential electrical restitution curves were constructed from a single right ventricular endocardial site in eight patients (three men) without structural heart disease aged 52-68 (mean 55 years). A combination pacing/monophasic action potential electrode was used to pace and record monophasic action potentials at drive cycle lengths of from 350 ms to 1500 ms. Ventricular extrastimuli were delivered at 20 cycle intervals and decreased from the longest coupling interval attainable without escape beats. RESULTS: Restitution curves shifted downward and towards the left; steady state action potential duration shifted from the restitution plateau and descended the curve, the amount of shift being linearly related to drive cycle length in two patients in whom the relation could be assessed; the amount of monophasic action potential shortening was a function of the degree of prematurity and that relation was unaffected by drive rate; the magnitude of restitution and the time constant of the restitution curve were not changed significantly by altered drive cycle length. CONCLUSION: In the intact heart in vivo, electrical restitution (of the monophasic action potential) has similar characteristics to those (of the transmembrane action potential) in cellular preparations in vitro. Thus the alteration of action potential plateau currents by instantaneous rate change or drug effects, which can be directly observed by techniques available to the cellular electrophysiologist, may be indirectly assessed in vivo by characterisation of the effect of these on electrical restitution.
Invasive cardiac electrophysiology studies began as diagnostic studies. The past decade has seen the introduction of several new treatments which have broadened the scope of invasive electrophysiology studies. In particular, the development of catheter ablation techniques increasingly allows curative treatment to be delivered in the catheter laboratory. The workload of electrophysiological procedures has steadily increased in our tertiary referral centre. Over 1000 patients have been treated in the past 20 years and it is projected that 219 new patients will be treated in 1991 and 342 procedures will be carried out. Over 25% of patients now receive either catheter or surgical ablation and almost 80% of these are cured permanently without the need for further drug treatment. The development of safer techniques for catheter ablation has led to its increased use and a decline in surgical ablations. Because catheter ablation is a much simpler and less traumatic procedure than surgical ablation there are great advantages both for the patient and in terms of cost-effectiveness. Antitachycardia pacing, relatively common in 1985, has now largely been supplanted by ablation and implantation of defibrillators. As the tendency to non-pharmacological treatment increases and evidence mounts that cost-effectiveness is greater for electrophysiological treatments, the implications for the funding of electrophysiology services grow. The initially high cost of curative treatment needs to be balanced against the longer term and potentially higher costs of palliative drug treatment. The potential to cure patients with catheter procedures may lead to a greater demand for this expertise and a need for an increase in training and facilities.
Magnetic resonance (MR) imaging examinations of the lumbar spine and clinical and laboratory findings in 32 patients with multiple myeloma were reviewed. On T1-weighted images, signal intensity (SI) of the vertebrae approximated that of muscle in 14 cases and was intermediate (between the SIs of muscle and fat) in 18. Definite foci of decreased SI were seen in eight cases (25%), and foci of increased SI, representing fatty infiltration, were seen in 12 (38%). On T2-weighted images, SI approximated that of muscle in 17 cases and was intermediate in 15. Definite foci of increased SI were seen in 17 (53%). Of 38 vertebral compression fractures (including 18 in nine additional patients), foci of abnormal SI consistent with tumor on either T1- or T2-weighted images were seen in 19 cases (50%). There was no correlation between MR imaging findings and laboratory or bone marrow findings. Foci of presumed tumor were better or exclusively shown on T2-weighted images in 11 of 17 patients (65%) with identifiable focal disease. Other suggestions of multiple myeloma on T1-weighted images may be the absence of fatty replacement or a generalized decrease in SI.
PURPOSE: To evaluate the use of high-dose busulfan (HDB) with autologous bone marrow transplantation (ABMT) in patients with myeloma. PATIENTS AND METHODS: Fifteen patients received HDB (16 mg/kg), eight of whom received high-dose melphalan (HDM) but had experienced a short remission or progression-free interval. Two patients had received HDM on two previous occasions, one had no response to low-dose melphalan, and four had impaired renal function (edathamil clearance < 40 mL/min). All patients received induction chemotherapy before HDB. RESULTS: Two patients were in complete remission (CR) after induction chemotherapy before HDB. Of the remaining 13 patients, four (31%) achieved CR and two (15%) achieved a partial remission for an overall response rate of 46%. There were three treatment-related deaths, but the toxicity was otherwise predictable and manageable. CONCLUSIONS: In heavily pretreated patients, HDB results in a relatively high response rate. It can also be used safely in patients with renal impairment who are not suitable for HDM.
Total body irradiation (TBI) is a highly emetogenic component of the majority of conditioning regimens in use for bone marrow transplantation. Conventional antiemetic therapy fails to control nausea and vomiting induced by single fraction TBI in as many as 50% of patients. In a double blind study of 20 patients undergoing marrow transplantation, a single 8 mg ondansetron dose was compared with placebo given immediately prior to TBI. Our routine premedication of phenobarbitone and corticosteroid was also administered to all patients. All patients had received high dose melphalan the previous evening. Only 1 of the 10 patients in the ondansetron group experienced an emetic event compared with 5 of the 10 in the comparison group (p = 0.029). No significant adverse events were observed. Ondansetron appears to have extremely useful antiemetic activity during single fraction low dose rate TBI.
A multicentre, randomised, double-blind, cross-over trial was done to compare the efficacy and safety of a serotonin receptor antagonist--ondansetron--and dexamethasone in the prophylaxis of acute and delayed emesis and nausea induced by moderately emetogenic non-platinum-containing chemotherapy regimens. Patients were treated as outpatients and received intravenous ondansetron 4 mg or dexamethasone 8 mg before chemotherapy and oral maintenance (ondansetron 4 mg every 6 h and dexamethasone reducing from 4 mg to 1 mg 6-hourly between days 1 and 5) for 5 days. 112 patients were treated (38 men, 73 women, 1 with no gender recorded; age range 30-73 years) and 100 were evaluable for cross-over analysis. Patients taking ondansetron or dexamethasone reported no significant difference in complete and major control of acute (83% vs 79%, p = 0.46) or delayed (82% vs 88%, p = 0.214) emesis (vomiting plus retches). Significantly more patients on dexamethasone (87%) than on ondansetron (72%) reported control of delayed nausea (days 2-5) (p = 0.003). Both drugs were well tolerated with no significant difference in the number of adverse events, and this is reflected by similar patient preference for ondansetron (40%) and dexamethasone (30%) (p = 0.244). Both drugs offer adequate out-patient control of chemotherapy-induced emesis; however, dexamethasone has an advantage in the control of delayed nausea, and also in terms of cost and resource allocation.
Fifteen patients with refractory B-cell lymphoma were treated in a Phase I dose escalation clinical trial with a highly potent immunotoxin consisting of the Fab' fragment of a monoclonal anti-CD22 antibody (RFB4) coupled to chemically deglycosylated ricin A chain. All patients had low, intermediate, or high grade non-Hodgkin's lymphoma. The immunotoxin was administered i.v. in two to six doses at 48-h intervals. The peak serum concentration and the t1/2 were not dose dependent among patients and averaged 1.3 micrograms/ml and 86 min, respectively. Three patients made antibody against A chain, and a fourth made antibody against both A chain and mouse immunoglobulin. Antibody responses were low (less than or equal to 85 micrograms/ml) in three patients and were not detected until 1 mo after treatment. The maximum tolerated dose of the immunotoxin was 75 mg/m2. Dose-related toxicities included vascular leak syndrome, fever, anorexia, and myalgia. Dose-limiting toxicities included pulmonary edema and/or effusion, expressive aphasia, and rhabdomyolysis (resulting in reversible kidney failure). There was no evidence of liver dysfunction. Partial responses were achieved in 38% of evaluable patients, and in those patients who had greater than 50% CD22+ tumor cells, 50% of the patients achieved a partial response. Clinical responses were not related to tumor grade and were generally transient, lasting between 1 and 4 mo.
Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder characterized by abnormally enhanced binding of von Willebrand factor (vWF) by patient platelets. Although the platelet glycoprotein (GP) Ib/IX complex is known to constitute the platelet's ristocetin-dependent receptor for vWF, a unique structural abnormality within this complex has not previously been identified in PT-vWD. Using the polymerase chain reaction to amplify genomic DNA coding for the alpha chain of GP Ib (GP Ib alpha) and then sequencing the amplified DNA following cloning into M13mp18 and M13mp19 phage vectors, we have found a single point mutation in the GP Ib alpha coding region of PT-vWD DNA resulting in the substitution of valine for glycine at residue 233. This substitution within the vWF-binding region of GP Ib alpha is likely to exert a significant influence on the conformation of the resulting protein. Competitive oligonucleotide primer assay for this mutation showed a homozygous wild-type pattern in genomic DNA from the 161 normal volunteers studied and from 6 phenotypically normal members of a PT-vWD family. All 7 affected members of this family studied were heterozygous for the mutant allele. Platelet GP Ib alpha mRNA reverse-transcribed and studied by competitive oligonucleotide primer assay showed similar expression of the mutant and wild-type alleles in the affected PT-vWD patients. Absence in the normal population, tight linkage with phenotypic expression of disease, and absence of any additional abnormality of GP Ib alpha in these patients identify the glycine-to-valine substitution as a point mutation underlying functional abnormality of the vWF receptor in PT-vWD.
Catheter ablation has become an accepted technique for creating complete heart block in patients with drug refractory supraventricular tachycardias. However, it remains experimental for other indications, such as ablation of accessory pathway or ventricular tachycardia. The use of high energy defibrillator discharges is associated with adverse effects which greatly contribute to the limitations of the technique. Advances in technology have led to newer methods, such as radiofrequency and low energy capacitive discharge, which hold significant advantages over the conventional high energy technique, to the extent that the use of defibrillator discharges should now be considered outmoded and potentially damaging. Radiofrequency is the technique of choice for accessory pathway ablation and modification of AV conduction, and low energy capacitive discharge is the preferred method for creation of complete heart block. There are currently no acceptably safe and efficacious catheter techniques for treating ventricular tachycardia, and more research needs to be done in this area. The potential for the success of these techniques depends to an extent on the creation of new standards of practice for catheter ablation. There has been no unbiased comparative assessment of the different techniques, and consequently no consensus exists on the preferred technique and technologies which should be used. Only within the framework of these standards can the technique achieve significant clinical utility.
Thrombin, a serine protease of the blood coagulation system, has additional effects on cells in vitro. It is mitogenic for fibroblasts and astrocytes and contributes to the regulation of neurite outgrowth and astrocyte stellation. Until now the expression of thrombin or its precursor prothrombin in tissues other than liver has not been demonstrated conclusively because of difficulty in avoiding serum contamination. Using sensitive mRNA detection methods, we show here that prothrombin is expressed not only in the liver, but also in the brain throughout development. Polymerase chain reaction, Northern, and in situ hybridization studies demonstrate the presence of prothrombin transcripts in the olfactory bulb, the cortex, the cerebellum, and other regions of the rat and human nervous system, as well as in neural cell lines. These results support an involvement of (pro)thrombin in the regulation of cellular events in the nervous system.
Thirty-four patients with progressive low grade non-Hodgkin's lymphoma were treated with 1 microgram oral alfacalcidol daily. Complete response was seen in four patients and a partial response in four patients with an overall response rate of 24%. Median duration of response was 14 months. Disease stabilised in ten other patients (29%) and 16 patients (47%) had tumour progression. In the sub-group of patients with follicular, small-cleaved cell-lymphoma the overall response to treatment was 29%. Apart from one patient who had a mild transitory elevation of serum calcium there was no recorded toxicity from alfacidol. These results indicate that alfacalcidol has significant antitumour activity in patients with low grade non-Hodgkin's lymphoma of the follicular, small-cleaved cell type.
Molecular monitoring by the polymerase chain reaction was used to detect and follow minimal disease in working formulation category B and C on non-Hodgkin's lymphoma. Rearrangement of the bcl-2 gene served as the target for gene amplification. Thirty patients were studied. Bone marrow histology was compared to PCR analysis of bone marrow aspirate and blood. PCR upstaged disease status in approximately 50% of patients. Results are shown from a patient whose disease was followed with PCR during chemotherapy from initial remission to relapse. We conclude that PCR of bone marrow and blood can be used to upstage disease status in low grade lymphoma and PCR of blood may be used to monitor response to treatment with obvious patient benefit. The general approach of molecular monitoring provides a means for appraising therapies in the setting of subclinical disease.
A 23-year-old man was resuscitated from ventricular fibrillation and subsequently shown to have the Wolff-Parkinson-White syndrome. Electrophysiological study demonstrated a posteroseptal accessory pathway, and coronary sinus angiography demonstrated that this was associated with a diverticulum of the coronary sinus. Catheter ablation was performed using a new low energy system. Five shocks were delivered within the coronary sinus diverticulum, with a cumulative energy of 39 joules (J). Accessory pathway conduction was blocked successfully, and there were no complications.
A 38 year old woman with a structurally normal heart presented with near syncope and had right ventricular outflow tract tachycardia. She was intolerant of antiarrhythmic medication and underwent low energy catheter ablation. Six non-arcing shocks of 25 J were delivered to the right ventricular outflow tract. No further ventricular tachycardia occurred during a follow up of seven months without antiarrhythmic treatment.
Sixteen patients presenting on 21 occasions with atrial flutter in association with complex congenital heart disease were treated by intracardiac stimulation techniques combined with activation mapping. Nineteen episodes of atrial flutter were successfully converted to sinus rhythm. In the remaining two episodes atrial fibrillation was induced with spontaneous conversion to sinus rhythm within 12 hours in one episode and immediate DC cardioversion to sinus rhythm in the other. Intracardiac stimulation techniques were highly successful in this group and allowed reliable conversion to sinus rhythm without general anaesthesia and high energy cardioversion. In patients with atrial flutter associated with congenital heart disease intracardiac stimulation techniques should be tried first.
Fifteen of 25 bone marrow aspirates from 23 patients who presented or had been treated for multiple myeloma at the Royal Marsden Hospital produced myeloma colonies (MY-CFUc) in vitro. There was no correlation between disease severity and the level of interleukin-6 (IL-6) in bone marrow plasma nor was there any evidence that the level of IL-6 was higher in bone marrow aspirates from patients whose tumour produced MY-CFUc in vitro compared with those who did not. The mean level of IL-6 in the whole group of patients was 0.41 ng/ml (range 0.1-0.66 ng/ml), a value similar to that found in plasma from normal donor bone marrow, 0.42 ng/ml (range 0.14-0.62 ng/ml). Separation of peripheral blood cells from serum 24 h after collection, compared with 2 h after collection, resulted in a substantial increase of IL-6 in the serum. The results suggest that levels of IL-6 in bone marrow plasma is not a monitor of disease severity in multiple myeloma (MM) and that the collection and separation of blood and/or bone marrow samples into the cellular and aqueous components should be performed using standardized conditions to minimize inter-sample variation resulting from the release of IL-6 from the cellular components.