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Biomedical subjects

J M Thomas

Publications and source records attributed to J M Thomas.

At least 109 records · Page 6Linked to original sources
PubMed2000

Coronary artery bypass graft outcome: the Trinidad and Tobago experience.

The study is retrospective review of the demographic, clinical, angiographic, and operative data of the first 205 consecutive CABG operations performed by Caribbean Heart Care at the Eric Williams Medical Sciences Complex (EWMSC), Trinidad and Tobago, between November 1993 and December 1997. The aim of the study was to determine the in-hospital and intermediate-term follow-up results. The mean age of patients was 59 +/- 10 years and 78% were male. Sixty-four per cent were of East Indian descent, whereas 16% were of African descent. Forty-eight per cent of the patients were hypertensive, 46% were diabetic, 33% had hyperlipidaemia, 20% had a recent history of cigarette smoking and 16% were obese. Sixty-five per cent had a positive family history of ischaemic heart disease. The average time interval between angiography and surgery was 2.3 months. At the time of angiography, 63.5% of patients had Canadian Cardiac Society (CCS) class 3 or 4 angina. The mean ejection fraction was 61 +/- 15%. Wall motion abnormalities were seen in 67% of patients. Significant stenoses of the left anterior descending artery, right circumflex artery, circumflex and ramus coronary arteries were present in 91%, 78%, 54% and 5%, respectively. Many patients (67%) had severe diffuse disease on angiography. The mean intensive care stay was 2.2 +/- 0.8 days. In-hospital mortality was 3.9% (8/205). The most frequent post-operative complication was haemorrhage (2.6%). Acute renal failure occurred in 2.1%; pulmonary collapse, 1.6%; stroke, 1% and cardiac arrest, 1%. Both sternal wound infections and systemic sepsis occurred in 0.5%. Intermediate-term follow-up data were obtained for 92% (189/205). The duration of follow-up ranged from 1 to 5 years (mean 3.7 years). During the follow-up period, 7 patients (3.4%) died. Angina severity was reduced from a mean CCS score of 2.61 +/- 0.95 before CABG to 1.22 +/- 0.55 at the time of follow-up (p < 0.0001). Overall 4-year mortality compared favourably with data from international studies. Among survivors, quality of life improved as evidenced by the reduction in the mean angina score.

Angina Pectoris↗
PubMed1999

Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin.

BACKGROUND: Day of transplant T cell depletion with anti-CD3 immunotoxin or F(Ab)2 immunotoxin induces stable tolerance to renal allografts in rhesus monkeys given 15-deoxyspergualin (DSG), a NF-kappaB inhibitor that suppresses proinflammatory cytokine (PC) production. Because PC and NF-kappaB are involved in dendritic cell (DC) maturation, we asked if impaired DC maturation and Th2-type cytokine deviation might be related to the synergistic effect of DSG in this novel model. METHODS: Immunosuppression was initiated 4 hr before transplanting a major histocompatibility complex mismatched renal allograft. Some groups received a supplemental 5-day course of cyclosporine A or DSG or a 15-day course of DSG. Peripheral lymph nodes were sequentially examined for presence of mature DC. In vitro effects of DSG on PC-induced maturation of DC were also examined. RESULTS: Allografts survived without rejection in 87% of recipients given immunotoxin or F(Ab)2 immunotoxin with DSG x 15 days, in 50% with DSG x 5 days, and 0% with cyclosporine A. The longest DSG survivors are >1000 days with normal graft function and tolerance validated, including acceptance of challenge second donor kidneys without treatment. DSG-treated recipients were unique in developing polarized Th2-type plasma cytokines. In DSG recipients, mature DC were significantly reduced in day +5 lymph node biopsies, with complete repopulation by 30 days. In vitro studies verified an inhibitory effect of DSG on DC maturation. CONCLUSIONS: The study suggests DSG arrests DC maturation. The unusual synergy of immunotoxin and DSG apparently involves coincidental reduction in lymph node T cell mass and mature DC, a transient circumstance favoring development of stable tolerance.

Animals↗
PubMed1999

Tolerability and side effects of anti-CD3-immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients.

INTRODUCTION: Anti-CD3-immunotoxin (alpha-CD3-IT) promotes allograft tolerance in nonhuman primates owing to efficient depletion of sessile and circulating T cells. Common side effects of vascular leak syndrome, hepatotoxicity, and nephrotoxicity have limited tolerability of other immunotoxins. We report on preclinical studies of alpha-CD3-IT-related side effects. METHODS: Normal rhesus monkeys received a kidney transplant and alpha-CD3-IT alone (on day -to +2) or in combination with brief peritransplant adjunctive immunosuppressive therapy. Some received donor CD34+ cells. Blood chemistries, complete blood count, weight, liver, and kidney biopsies were examined for immunotoxin-related changes. Five spontaneously diabetic primates also received alpha-CD3-IT, three of whom had a pancreas islet transplant. RESULTS: The main side effect of alpha-CD3-IT, vascular leak syndrome, was entirely prevented by adjunctive immunosuppressive therapy. Renal and liver function tests and biopsies revealed a lack of nephrotoxicity and hepatotoxicity. All had transient weight loss (14+/-5%). Without infusion of donor CD34+ cells, 97% had full weight recovery. Of those given donor CD34+ cells, 50% were euthanized for wasting. CONCLUSIONS: Side effects of alpha-CD3-IT are manageable and should not prevent therapeutic application.

Animals↗
PubMed1999

Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma.

We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.

Adult↗
PubMed1999

Genetic modification of liver grafts with an adenoviral vector encoding the Bcl-2 gene improves organ preservation.

BACKGROUND: Liver function after transplantation is determined by the quality of the donor organ and the influences of preservation, flush, and reperfusion injury. In this regard, cell death (apoptosis) plays an important role in organ preservation and rejection. Therefore, we examined the possibility of genetic modification of the liver graft with a recombinant adenovirus vector encoding the Bcl-2 gene to reduce apoptosis during the preservation time. METHODS: Liver grafts from C57B1/6 mice were procured and preserved using standard techniques. A replication defective adenovirus vector (deltaE1) containing the human Bcl-2 gene (AdCMVhBcl-2) was developed in our laboratory. An adenovirus vector encoding an irrelevant gene (Escherichia coli beta-galactosidase) was used as a control. Each mouse received 1 x 10(9) plaque forming units administered i.v. 48 hr before the liver procurement. Analyses of liver enzyme activities were determined in the preservation solution. Apoptosis in liver biopsies was determined by DNA fragmentation with an in situ histochemical assay. RESULTS: Immunohistochemical analysis and RT-PCR confirmed the expression of hBcl-2 in the grafts. Grafts from livers expressing hBcl-2 showed significant reduction of the aspartame amino transferase (AST) and lactate dehydrogenase (LDH) release compared with grafts from the control groups. After rewarming, significant cytoprotection was also observed in grafts from animals treated with AdCMVhBcl-2. Histological analysis correlated with the hepatocellular injury determined with transaminases and LDH in the preservation solution. Significant reduction in the number of apoptotic cells was observed in grafts expressing hBcl-2. CONCLUSIONS: We have demonstrated a novel approach to reducing the preservation injury to liver grafts with the human Bcl-2 gene. This approach may allow a longer preservation time, potentially reduce the incidence of primary nonfunction, decrease the immunogenicity of the cold injured organ, and increase the safer use of "marginal" liver grafts.

Adenoviridae↗
PubMed1999

Reversal of naturally occuring diabetes in primates by unmodified islet xenografts without chronic immunosuppression.

BACKGROUND: Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx. MATERIALS AND METHODS: Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136+/-3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion. RESULTS: All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment. CONCLUSIONS: These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.

Animals↗
PubMed1999

Immunoregulatory role of CD8alpha in the veto effect.

BACKGROUND: Allogeneic bone marrow cell (allo-BMC) infusion induces tolerance to incompatible renal allografts in rhesus macaques after depletion of peripheral T lymphocytes with cytolytic anti-T cell antibodies. The tolerogenic effect of allo-BMC, ascribed to a veto mechanism, associates with specific functional deletion of antidonor cytotoxic T lymphocyte precursor (CTLp), and is dependent on a CD8+ donor BMC subset. In previous studies, the CD8 molecule was implicated by loss of suppression after blocking interaction between CD8 on allo-BMC and major histocompatibility complex class Ialpha3 domain on CTLp. CD8 cross-linking on BMC induced secretion of active transforming growth factor-beta1 (TGF-beta1), suggesting a regulatory mechanism(s) operating via a CD8-mediated signaling pathway. METHODS: CD8 on rhesus cells was cross-linked using IgG-conjugated beads, and TGF-beta1 mRNA and protein were quantified. CD8+ cells were tested for veto activity by mixed lymphocyte reaction (MLR)-induced cell-mediated lymphocytotoxicity (CML) assay. Activated rhesus T cells exposed to TGF-beta1 were examined for apoptosis by TdT-mediated end-labeling and annexin staining. RESULTS: CD8 cross-linking induces accumulation of TGF-beta1 mRNA and protein. Both CD3- CD8+CD16+ and CD3+ CD8+CD16- subsets of allo-BMC up-regulate TGF-beta1 mRNA after CD8 cross-linking, and exhibit veto activity. The CD3-CD8+CD16+ subset expresses more TGF-beta1 mRNA and increased veto activity at low BMC/CTLp ratios. Exposure of activated T cells to TGF-beta1 induces apoptosis. CONCLUSIONS: CD8+ allo-BMC are enriched for veto activity and activation via CD8 induces TGF-beta1 mRNA and protein accumulation. These results agree with the hypothesis that paracrine TGF-beta1 may be involved in peripheral deletion of alloreactive CTLp by CD8+ allo-BMC. We suggest that TGF-beta1 overexpression by donor lymphohematopoietic cells may enhance tolerance induction.

Animals↗
PubMed1999

The molecular mechanisms of veto mediated regulation of alloresponsiveness.

Transplantation tolerance, as defined by the specific acceptance of allogeneic tissue without chronic immunosuppression, can be induced in adults by a variety of methods. One method that is close to clinical implementation involves transient peritransplant depletion of host T cells followed by intravenous administration of a low dose of donor bone marrow cells (BMC). Current evidence suggests that BMC play an active role in tolerance induction by establishing residence in the host and effecting deletion of graft reactive T cells. This activity, in which the BMC inactivate T cells that recognize them, has been called the "veto effect," and cells that mediate such activity have been called "veto cells." The specificity of veto activity is conferred by the T cell receptor of the donor reactive T cells that are to be deleted. Other molecules that have been directly implicated in the mechanism of deletion of graft reactive T cells by BMC include the CD8 accessory molecule, major histocompatibility class I gene products, CD95/CD95 ligand (Fas/Fas ligand), and transforming growth factor-beta. These molecules react with their respective ligands by distinct, non-exclusive pathways among which the relative contribution to the deletion of graft reactive T cells may depend on the relative abundance of different cellular subpopulations capable of mediating veto activity.

Animals↗
PubMed1999

Relative risks of radiation-associated cancer: comparison of second cancer in therapeutically irradiated populations with the Japanese atomic bomb survivors.

In this paper the radiation-associated relative risks of second primary cancer incidence in groups treated for first primary cancer by radiotherapy are compared with radiation-associated relative risk estimates in the Japanese atomic bomb survivor cancer incidence data. For four cancer sites, namely lung cancer, bone cancer, ovarian cancer and leukaemia, the relative risks in the comparable (age at exposure, time since exposure, sex matched) subsets of the Japanese data are significantly greater than those in the majority of second cancer studies. Even when the differences between the relative risks in the Japanese atomic bomb survivors and the medical series do not approach conventional levels of statistical significance, relative risks tend to be higher in the Japanese data than in the second cancer studies. At least for leukaemia, the discrepancy between the Japanese and second cancer risks can be largely explained by cell-sterilisation effects. There are few indications of modification of radiation-associated second cancer relative risk among those treated with adjuvant chemotherapy, nor are there strong indications of modification of radiation-associated relative risk by heritable genetic factors. If anything, there is evidence that second cancer relative excess risks are lower among those patients with cancer-prone disorders than among non-susceptible patients. However, the higher underlying cancer risk in some of these medically exposed populations should also be considered, in particular for those with cancer-prone conditions, so that the absolute excess risk is sometimes higher than in the Japanese data.

Female↗
PubMed1999

Myxoid liposarcoma--the frequency and the natural history of nonpulmonary soft tissue metastases.

BACKGROUND: Myxoid liposarcomas (ML) make up the major subset of liposarcomas, which in most series represent the second or third most common type of soft tissue sarcoma. The tendency for ML to metastasize to other soft tissues (STM) in preference to lung parenchyma has been previously described; however, the natural history of this tumor's behavior is poorly documented. Our intent was to analyze the natural history of ML and further quantify the incidence of STM, concentrating on their significance in terms of survival. METHODS: We reviewed the experience at the Royal Marsden Hospital over a 10-year period, documenting the clinicopathological behavior of ML, including the frequency of STM. RESULTS: There were 50 patients, with a median follow-up of 43 months. The actuarial 5-year soft tissue metastasis rate was 31%, and the most common sites of STM were the retroperitoneum, abdominal wall, and abdominal cavity. In those 12 patients who had STM there was a median interval of 23 months after original diagnosis to the time the first metastasis became apparent (range, 0-142 months). Median survival following first metastasis was 35 months; 6 of the 12 patients died between 6 and 50 months. Four patients who had STM remain disease free at 15 to 59 months after their first STM. Any round cell component of the ML was associated with a significantly greater chance of metastatic disease (P = .02). In this series, the overall 5-year and 7-year survival rates were 85% and 68%. Patients with STM had an 11 times greater chance of dying than those who did not. CONCLUSIONS: ML usually is an indolent disease, but there is a subset of patients who develop STM and have a significantly worse prognosis. STM can occur years after the initial diagnosis and can be associated with medium-long-term survival after they occur. STM should be managed aggressively because of this.

Abdominal Neoplasms↗
PubMed1999

EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.

Analysis of Variance↗
PubMed1999

Combined inguinal and pelvic lymph node dissection for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing in the UK and a significant number of patients are still presenting with primary lesions of poor prognosis. As a consequence there is likely to be an increasing number of patients with lymph node metastases for whom the appropriate extent of groin dissection remains controversial. This review summarizes the evidence to enable surgeons to make an informed decision about the management of patients with melanoma metastases to the groin lymph nodes. METHODS: A Medline search was performed to identify all English language articles about melanoma containing the words lymphadenectomy, lymph nodes, inguinal or lymphoedema. Eighty-seven relevant articles were selected from 3904 abstracts retrieved; 34 were related directly to the aim of this review. RESULTS: There are no randomized controlled trials comparing the outcome of combined inguinal and pelvic lymph node dissection (CLND) and superficial inguinal lymph node dissection (SLND). Excision of pelvic lymph node metastases is reported to yield a 5-year survival rate of 0-35 per cent. Recurrence within the pelvis occurs in 9-18 per cent of patients after SLND and in less than 5 per cent after CLND. Morbidity following either CLND or SLND is poorly reported. Major long-term lymphoedema limiting patient activity affects 6-20 per cent of patients after groin dissection. Cloquet's node was demonstrated in one study to be a useful predictor of pelvic lymph node involvement. Patients may be selected for pelvic node dissection on the basis of clinical findings, the results of pelvic computed tomography and the status of Cloquet's node. CONCLUSION: The controversy surrounding the appropriate management of cytologically positive inguinal nodes in melanoma can be resolved only by a prospective randomized trial comparing CLND with SLND. Morbidity and local disease control must be measured as outcomes in addition to disease-free and overall survival.

Humans↗
PubMed1999

Malignant peripheral nerve sheath tumours associated with von Recklinghausen's neurofibromatosis.

AIMS: A retrospective study was conducted of patients with von Recklinghausen's neurofibromatosis who developed malignant peripheral nerve sheath tumours to determine their clinical characteristics, treatment outcome and prognostic factors. METHODS: During the period 1987-1995, 29 patients with von Recklinghausen's neurofibromatosis (VRN) were seen at the Royal Marsden Hospital, of whom 23 had malignant peripheral nerve sheath tumours (MPNSTs). RESULTS: The median age of the patients with MPNSTs was 30 years and the sex distribution was equal. The commonest site was the lower extremity, with a tendency for tumours to occur in the proximal parts. A nerve of origin was identified in 59% of the tumours and heterologous differentiation was present in 26%. Multiple primary MPNSTs occurred in four patients (17%) and other malignant tumours developed in three (13%). The overall 5-year survival was 35% with a median survival of 36 months. The incidence of local recurrence was 38% and 75% of them occurred within 2 years. CONCLUSIONS: MPNSTs which develop in association with VRN occur in a younger age group, tend to be of a higher histological grade and are associated with a very poor prognosis. Tumour size > or = 10 cm (P=0.003) and high tumour grade (P=0.003) were adverse independent prognostic factors for overall survival.

Diagnosis, Differential↗
PubMed1999

Surgical aspects of iliopsoas compartment tumours.

AIM: To demonstrate the pathological variety and highlight the surgical principles involved in the management of tumours of the iliopsoas compartment (IPC). METHODS: Review of four clinical cases. RESULTS: Adequate surgical resection or palliation was achieved in each case. CONCLUSION: Resection of IPC tumours is feasible but access to the most superior part of the muscle may be impossible. An extraperitoneal approach is advocated.

Abdominal Neoplasms↗
PubMed1999

Desmoid tumours of the anterior abdominal wall.

AIMS: To review the surgical management and outcomes for large desmoid tumours of the abdominal wall. METHODS: Seven patients with large desmoid tumours of the anterior abdominal wall were treated by wide local excision and reconstruction with two layers of Marlex V mesh (Bard, Galway, Ireland). RESULTS: No patient having initial surgery at this hospital has either a significant residual functional deficit or developed a recurrence. CONCLUSIONS: Large desmoid tumours of the abdominal wall are safely and adequately managed with abdominal wall resection followed by mesh reconstruction.

Abdominal Muscles↗