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J M Thomas

Publications and source records attributed to J M Thomas.

At least 91 records · Page 5Linked to original sources
PubMed2000

Durable donor-specific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin: absence of chronic allograft nephropathy.

Tolerance induction can prevent acute kidney allograft rejection without chronic immunosuppression. It is uncertain whether specific tolerance can prevent chronic allograft nephropathy (CAN), which involves both nonimmune and immune injury. This report provides evidence that immunologically tolerant macaques, induced with immunotoxin and deoxyspergualin, developed neither acute rejection nor CAN. Long survivors, bearing MHC-mismatched grafts without chronic immunosuppression for 0.8 to 3.4 years, exhibited general immune competence with donor-specific T and B cell tolerance and no functional or histological evidence of CAN. Stringent criteria for tolerance were satisfied by specific prolongation of donor skin grafts with rapid rejection of third-party skin, followed by indefinite acceptance of a second donor kidney graft and establishment of microchimerism. Primate tolerance with documented absence of CAN may give impetus to the clinical application of tolerance.

Animals↗
PubMed2000

Enhanced allograft survival induced by posttransplant donor spleen cell infusion occurs via a mechanism that is distinct from the mechanism of enhancement by donor bone marrow.

BACKGROUND: Our previous studies have shown that the ability of donor bone marrow to augment skin graft survival in antithymocyte serum (ATS)-treated recipients is dependent on the presence of functional CD95-ligand (Fas-ligand) molecules on donor cells. Because donor spleen cells can augment graft survival to a similar degree in the same model, we investigated whether the donor spleen cell effect was also dependent on the presence of CD95-ligand on donor cells and CD95 on recipient cells. METHODS: Mutant mice bearing defects in the expression of CD95 (lpr mutation) and CD95-ligand (gld mutation) were used as recipients and cell donors, respectively. Recipients were injected with rabbit ATS on days -1 and +2, and then were injected with 5x10(7) spleen cells on day +7. Skin graft survival was compared and correlated with the use of mutant mice as recipients and cell donors. RESULTS: The combination of ATS and infusions of wild-type [median survival (MST)=44 days, P=0.0004] and gld (mutant CD95-ligand, MST=37 days, P=0.02) donor spleen cells enhanced C3H graft survival, compared with (C57BL/6 x A)F1 recipients treated with ATS alone (MST=27 days). Furthermore, C57BL/6 lpr (CD95-deficient) strain recipients treated with ATS and donor spleen cells demonstrated enhanced B10.D2(R107) strain skin graft survival (MST=44 days, P=0.003), compared with C57BL/6 lpr recipients treated with ATS alone (MST=31 days). Wild-type C57BL/6 recipients treated in the same manner also exhibited an extension of graft survival (MST=64 days) versus controls treated with ATS alone (MST=31 days). CONCLUSION: The data demonstrate that the ability of donor spleen cells to augment allograft survival is not dependent on the CD95/CD95-ligand pathway; therefore the deletion of allospecific cells by donor spleen cells may be induced via a pathway other than deletion by donor bone marrow cells.

Animals↗
PubMed2000

Long-term functional islet mass and metabolic function after xenoislet transplantation in primates.

BACKGROUND: Pancreatic islet transplantation (PIT) is an attractive alternative for patients with type I diabetes mellitus. PIT is not yet an effective clinical reality due in part to the high incidence of rejection and early loss of functional islet mass. In addition, current immunosuppressive drugs have toxic effects on islets and increase the risk of morbidity and mortality. In the present study, the effects of PIT on glycemic parameters were assessed in spontaneously diabetic primates. METHODS: Five insulinopenic nonhuman primates (three Macacca fascicularis, one Ceropithecus aethiops, and one Macacca mulatta) were studied. All required twice-daily treatment with 4-10 U of insulin. For immunosuppression, the animals received anti-CD3-immunotoxin (100 microg/kg(initially infused 2 hr before transplantation and again on day +1), cyclosporine (CsA) (20 mg/kg(i.v./2 hr before transplantation), cyclosporine microemulsion (Neoral) 60 mg/kg/b.i.d. on days +1 to +3 with dose adjusted by blood levels, and methylprednisolone (15 mg/kg day 0 to +3). Three recipients were given islets from a single donor (M mulatta). The islets were prepared by a semiautomated technique using Liberase. A mean of 13,136 islet equivalents/kg was infused into the portal vein. Two animals (M fascicularis and M mulatta) were used as a diabetic, nontransplanted control. Several metabolic parameters were evaluated. RESULTS: All monkeys that underwent transplantation experienced reversal of diabetes mellitus with normalization of all diabetic glycemic parameters. In the nontransplanted primates given the same immunosuppression but no PIT, diabetic metabolic parameters were unchanged after 9 months of follow-up. In contrast, all three PIT recipients established fasting and nonfasting euglycemia within 1-2 weeks, and none required exogenous insulin after day 10. Normal intravenous glucose tolerance tests were observed at day 15, and no significant differences in the glucose disappearance rate (Kg) were observed at days 15, 45, 190, and 365 days after transplantation. The acute insulin response to glucose indicated no significant reduction of functional islet mass. CONCLUSIONS: PIT in severely insulinopenic type I diabetes mellitus primates resulted in restoration of normal glycemic parameters and durable islet mass. Operational tolerance was achieved with only 4 days of drug administration, sparing the animals from chronic exposure to potentially diabetogenic immunosuppressive drugs. These results offer an exciting new potential for type I diabetes mellitus treatment.

Animals↗
PubMed2000

Immunological tolerance as an adjunct to allogeneic tissue grafting.

Since its clinical inception, our group has worked in clinical and experimental transplantation. The exciting early results of composite tissue allografts (CTA) attracted our attention during the 1980s, when some of the first experimental CTA literature appeared. The recent extraordinary results of clinical CTA grafts, primarily the Louisville and Lyon results, have been highlighted at this meeting. Interestingly, this success followed not long after the first International meeting in Louisville in 1997. This is clearly an exciting new application of transplant techniques to one of the newest and most unique types of transplants. Previous studies used immunosuppression for skin allografting. Early results seem quite exciting and we expect to see a rapid growth of interest and activity in this area. We believe that the entire field would benefit from the novel, highly effective and minimally toxic immune tolerance induction using CD3-immunotoxin (CD3-IT) and deoxyspergualin (DSG).

Animals↗
PubMed2000

Epithelioid sarcoma: the clinicopathological complexities of this rare soft tissue sarcoma.

BACKGROUND: Epithelioid sarcoma is a rare high grade soft tissue sarcoma with a known propensity for locoregional recurrence. The literature is limited on other characteristics such as frequency of multifocal disease at presentation, the relationship of presenting size of the primary lesion to prognosis, and the ability of current staging systems to predict prognosis. METHODS: Review of the Royal Marsden National Health Service Trust (RMH) experience of 37 cases over 21 years. RESULTS: The mean age was 29 years, with male predominance (2.7:1), and distal limb locations were most common (56%). Five patients presented with multifocal local disease. Median follow-up was 88 months in the 19 patients still alive. The 5- and 10-year actuarial overall survival was 70% and 42%, respectively. Tumors deep to the investing fascia had a worse prognosis than superficial tumors. Regional metastasis events were also associated with significantly worse overall survival. Local recurrence, size of 5 cm or larger, and regional metastasis events were predictive of worse distant metastasis-free survival. Tumor size (<5 cm vs. > or =5 cm), local recurrence events, sex, and site were not significant predictors of survival. The American Joint Committee on Cancer/International Union Against Cancer staging systems and the recently proposed RMH staging system of the Royal Marsden National Health Service Trust provided poor differentiation of prognosis in epithelioid sarcoma. The 5-year actuarial local recurrence rate was 35%. The 5-year actuarial regional nodal metastasis rate was 23%. The actuarial 5-year distant metastasis rate was 40%, with pleuropulmonary metastases the most common site of metastatic disease, and 35% of pleuropulmonary metastases presented with pleural effusion. Median post-distant metastasis survival was 8 months. CONCLUSIONS: Epithelioid sarcoma has unusual clinical behavior compared with other high grade soft tissue sarcoma. It has a propensity for multifocal disease at presentation, local recurrence, regional metastasis, and particularly poor prognosis after regional or distant metastatic disease. Size and stage according to the American Joint Committee on Cancer/International Union Against Cancer are unreliable predictors of prognosis.

Adolescent↗
PubMed2000

Six mamu-A locus alleles defined by a polymerase chain reaction sequence specific primer method.

Rhesus monkeys are relevant models for human diseases and transplantation. In each case, a complete understanding of these models requires knowledge of macaque MHC. Due to high polymorphism and multiple genes per haplotype, it has been difficult to develop a rapid typing method for rhesus monkey MHC class I. We developed a simple and rapid PCR-SSP strategy for rhesus monkey Mamu-A locus typing. Fifty-two rhesus monkeys were included in the study. Six rhesus monkey allel-specific primer pairs were designed based on published Mamu-A locus gene sequences. Allele-specific PCR products ranged in size from 346 to 788 bp; 5' and 3' Mamu-A locus allele specific primers were located in the second and third exons, respectively. Specific PCR product gel purification was followed by direct sequencing, without subcloning, in both directions. Our data showed variability in the number of Mamu-A alleles ranging from 1 to 4 per genotype. The highest frequencies were observed for Mamu-A*02, -A*04, and -A*03 alleles. Thus, we report here the first PCR-SSP typing method for Mamu-A*02, -03, -04, -05, -06, and -07 array of class I alleles. This technique appears to be a highly reproducible and discriminatory method for detecting this subset of class I A locus genes in rhesus monkeys.

Alleles↗
PubMed2000

Myocardial infarction as a complication of injury.

BACKGROUND: MI is a rare complication of trauma. We anticipate that the aging of the population and the concomitant rise in geriatric trauma will result in an increase in acute illnesses of the elderly (such as MI) complicating recovery from injury. The purpose of this article is to define the presentation of MI in the immediate postinjury period. STUDY DESIGN: Medical records of all trauma patients in whom MI developed during their hospitalizations at a single Level I trauma center, the Barnes Hospital/Washington University Medical Center, between 1990 and 1999 were screened through the trauma registry. Nineteen patients with possible postinjury MI were identified. Of these, five had bona fide cases of postinjury MI, five had ambiguity about whether MI preceded or followed trauma, one had an MI resulting in trauma, and eight were excluded because they did not meet strict diagnostic criteria for MI. RESULTS: The five patients with posttraumatic MI were older than the general trauma population with ages ranging from 51 to 81 years (mean +/- SD = 72 +/- 14 years). Each had preexisting medical illnesses, some of which are recognized to predispose to coronary artery disease. There were no identifiable precipitants other than the recent injury. Importantly, only one of the five patients had chest pain as a presenting symptom and each of the five cases was complicated by acute congestive heart failure. CONCLUSIONS: MI remains a rare but important complication of injury and may increase owing to the changing demographics of trauma victims. Methods for thorough history-gathering to identify preexisting conditions, for early hemodynamic monitoring and anticoagulation for MI in the setting of trauma, and for identifying preexisting conditions should be defined. The presentation of MI in the setting of injury is atypical and complications are frequent.

Age Factors↗
PubMed2000

GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma.

BACKGROUND: Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy. PATIENTS AND METHODS: Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days. RESULTS: Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha. CONCLUSIONS: The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.

Adult↗
PubMed2000

Specificity of preformed alloantibodies causing B cell positive flow crossmatch in renal transplantation.

The specificity of alloantibodies (alloAb) and their clinical significance in association with T-/B+ flow cytometry crossmatch (FCXM) in kidney transplantation are not clearly defined. This study was undertaken to examine the HLA specificity and clinical relevance of Ab causing B+ FCXM in pre-transplant (final XM) recipients' serum samples. Final FCXM serum samples were analyzed from 457 renal transplant patients followed for 10 months post-transplantation. Two hundred and sixty patients had T-/B+ final FCXM. The control group included 197 recipients with T-/B- FCXM at time of transplantation. Class I/class II PRA and specificity of anti-HLA class I and class II Ab in final FCXM serum samples were analyzed by FlowPRA Class I Screening Test and FlowPRA Class II Screening Test. We found no correlation between graft outcome and pre-transplant T-/B- and T-/B+ FCXM status. Additionally, we observed no clinical relevance of B+ FCXM in retransplant patients. However, MCS > or =200 in B+ FCXM retransplant recipients was associated with anti-class II Ab to previous mismatches in regrafted patients (n = 46). This finding was confirmed by specificity analysis of anti-DR/DQ Ab in patients with high ( > or =15%) class II PRA. In 63% (12 of 19) of retransplants having T-/B+ FCXM, we defined the specificity of alloAb to first graft mismatched class II antigens. In contrast, anti-class II Ab was detected in only 5.7% (2 of 35) of single-graft recipients with different PRA values. Significantly greater MCS (240 +/- 61 vs. 163 +/- 48; p = 0.022) was observed in retransplant patients having short ( < or =5 m) previous graft survival time (PGST) than in those with long PGST ( > or =5 m). Only 2% of retransplant recipients with B + FCXM had non-HLA Ab. In contrast, the overwhelming majority of primary recipients had no detectable alloAbs. No significant difference in class I PRA was found between B- and B+ FCXM recipients. However, class II PRA was significantly higher in patients having B + FCXM (p = 0.028). Collectively, these data show that MCS intensity is not always a reliable criterion for anti-HLA Ab detection because of the presence of non-HLA Ab. These results can be explained by low titers of anti-class II Ab, at which concentration these Ab cannot produce a deleterious effect. FlowPRA and Flow screen beads appeared to be reliable and sensitive methods for detection and specificity analysis of anti-class II alloAb.

Antibody Specificity↗
PubMed2000

Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model.

To develop a cellular vehicle able to reach systemically disseminated areas of angiogenesis, we sought to exploit the natural tropism of circulating endothelial progenitor cells (EPCs). Primate CD34+ EPCs were genetically modified with high efficiency and minimal toxicity using a non-replicative herpes virus vector. These EPCs localized in a skin autograft model of angiogenesis in rhesus monkeys, and sustained the expression of a reporter gene for several weeks while circulating in the blood. In animals infused with autologous CD34+ EPCs transduced with a thymidine kinase-encoding herpes virus, skin autografts and subcutaneous Matrigel pellets impregnated with vascular growth factors underwent necrosis or accelerated regression after administration of ganciclovir. Importantly, the whole intervention was perfectly well tolerated. The accessibility, easy manipulation, lack of immunogenicity of the autologous CD34+ cell vehicles, and tropism for areas of angiogenesis render autologous CD34+ circulating endothelial progenitors as ideal candidates for exploration of their use as cellular vehicles when systemic gene delivery to those areas is required. Gene Therapy (2000) 7, 43-52.

Angiogenesis Inhibitors↗
PubMed2000

Prognosis and surgical management of patients with palpable inguinal lymph node metastases from melanoma.

BACKGROUND: The appropriate management of melanoma metastatic to inguinal lymph nodes remains controversial. The aim of this study was to identify disease- and treatment-related factors that influence the outcome of patients undergoing therapeutic groin dissection for clinically detectable melanoma lymph node metastases. METHODS: A retrospective analysis was performed on data collected from the case records of patients who had a therapeutic inguinal lymph node dissection performed between 1984 and 1998. RESULTS: Some 132 patients were suitable for inclusion. Sixty patients had superficial inguinal lymph node dissection (SLND) and 72 had combined superficial inguinal and pelvic lymph node dissection (CLND). There was no difference in postoperative morbidity or major lymphoedema between SLND and CLND. The overall survival rate was 34 per cent at 5 years. On univariate analysis, age (P = 0.003), the number of involved superficial lymph nodes (P = 0.001) and the presence of extracapsular spread (P = 0.003) were found to have a significant impact on survival. The presence or absence of pelvic lymph node metastases in patients who had CLND was a significant prognostic factor for survival (5-year survival 19 versus 47 per cent; P = 0.015). CONCLUSION: The prognosis of patients with clinically detectable melanoma metastases to the groin is variable and related to the biological characteristics of each case. CLND provided additional prognostic information and optimal regional control with no increased morbidity compared with SLND.

Adult↗
PubMed2000

Computed tomography 21 days after chemotherapy, three-dimensional estimates of metastatic volume and the need for surgery in patients with germ cell cancer.

OBJECTIVE: To assess whether the response visible on computed tomography (CT) 21 days after the first course of chemotherapy in patients with nonseminomatous germ cell tumour predicts the need for surgery and whether three-dimensional (3D) reconstruction adds to the diagnostic accuracy. PATIENTS AND METHODS: CT scans from 52 patients treated with cisplatin-based chemotherapy were assessed for tumour shrinkage by measuring the changes of a one-dimensional (1D) measurement of the maximum transverse diameter, and comparing CT scans before, 21 days after the first course and at the end of chemotherapy (1D method). In a subset of patients, using a special formula, the 1D-derived 2D and 3D shrinkage (2Dder and 3Dder) were compared with four other computed or calculated methods (1D, 2D, 3Dcalc, 3Dcomp). RESULTS: At day 21, in 32 of 52 patients (62%) there was < 50% tumour shrinkage using the 1D assessment; 21 of them (66%) needed surgery, compared with none of the 20 patients with > 50% tumour shrinkage by day 21 (chi2 = 22.83, P < 0.001). The 1D method showed significantly less shrinkage than all the other methods but when this was used to derive a 3D shrinkage, assuming the mass to be spherical (3Dder), it was not statistically different from that of 3Dcomp. CONCLUSIONS: The assessment of the response from 1D CT scan estimates 21 days after initiating chemotherapy identifies a subgroup of patients who have a high probability of needing surgery. Although expected to be more accurate, the 3Dcomp estimate of tumour shrinkage was no better than the 3Dder estimate.

Adult↗
PubMed2000

Sarcoma metastases due to iatrogenic implantation.

AIM: To demonstrate the ability of extremity soft tissue sarcomas (STSs) to implant into tissues exposed during surgery. METHODS: We use two cases to illustrate that wounds created during surgery for STSs, including donor sites for skin grafts, pedicled and free flaps and blood vessels used in reconstruction, should be regarded as potential sites of quasi-local recurrence. CONCLUSIONS: This report reinforces the need for meticulous surgical technique and planning of procedures to avoid contamination of clean areas that might not be included in adjuvant radiotherapy fields. The cases also highlight the pivotal importance of the correct initial management of these uncommon tumours.

Adolescent↗
PubMed2000

Outcome of treatment for limb and limb girdle sarcomas at the Royal Marsden Hospital.

AIMS: In this study we aimed to determine local recurrence, mortality an d amputation rates in patients presenting with limb and limb girdle soft tissue sarcomas. METHOD: A review of all 439 patients presenting with p rimary or recurrent soft tissue sarcomas of limb and limb girdle to the Royal Marsden Hospital between 1989 and 1995 was carried out. RESULTS: The local recurrence rate was 15.5% and the mortality rate was 30%, with a median follow up of 3.2 years and an overall amputation rate of 4.8%. CONCLUSION: The outcome of limb and limb girdle sarcomas in this study i s comparable to those reported elsewhere.

Amputation, Surgical↗
PubMed2000

Peterhouse, the Royal Society and molecular biology.

The term molecular biology was coined by Warren Weaver, a mathematician who was head of the natural sciences section of the Rockefeller Foundation, in his report to the president of the Foundation in 1938. The origins of the subject may be located in various places or periods, but Sir Peter Medawar used to argue that it was Sir William Bragg and W.T. Astbury at the Davy Faraday Laboratory in London who began it, when they investigated the structures of materials such as silk, wool and hair by X-ray diffraction. Others say that J.D. Bernal was the progenitor. Peterhouse, a Cambridge college, was a hothouse of the subject.

History, 20th Century↗
PubMed2000

Gynaecological presentation of retroperitoneal tumours.

OBJECTIVE: To illustrate the problems associated with mistaken pre-operative diagnosis following gynaecological presentation of patients with retroperitoneal tumours. DESIGN: A case series of five referrals. RESULTS: Non-gynaecological tumours were not suspected in each case and hence there was a failure to undertake further pre-operative investigation and referral to a specialised soft tissue sarcoma service. This resulted in four of the patients having an unnecessary laparotomy with an inappropriate transperitoneal biopsy undertaken when the retroperitoneal tumour was discovered. The mistaken diagnosis of ovarian malignancy lead to increased morbidity, compromise of potential for a long disease free interval and/or possibly lessened the chance of cure in each case. CONCLUSIONS: Misinterpretation of clinical signs and an over-reliance on ultrasound diagnosis were the commonest causes of inappropriate management of these patients. Gynaecologists should consider more frequently the other, less common differential diagnoses of a pelvic mass. This is especially true in circumstances with a predominantly solid tumour, where there are clinical signs of vascular or rectal displacement, or where there is ultrasound evidence of ureteric obstruction. The more frequent utilisation of a computerised tomography scan with intravenous and oral contrast with referral before inappropriate transperitoneal biopsy are recommended as complete en bloc surgical excision at the first laparotomy is the treatment of choice in virtually all primary retroperitoneal tumours.

Adult↗