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Biomedical subjects

A McIndoe

Publications and source records attributed to A McIndoe.

At least 19 recordsLinked to original sources
PubMed2004

A phase I trial of idiotypic vaccination with HMFG1 in ovarian cancer.

INTRODUCTION: An extended phase I trial was conducted in a total of 26 patients with ovarian cancer. The objectives were to assess the safety and tolerability of idiotypic vaccination using the murine monoclonal antibody HMFG1 (anti-MUC1), and to develop robust assays to monitor humoral immune responses generated against either the antibody or MUC1. MATERIAL AND METHODS: All patients had undergone standard debulking surgery (where appropriate) and at least one regimen of platinum-based chemotherapy. Eligibility criteria included: (a) residual disease at the end of chemotherapy, (b) relapsed disease, and (c) pathologically confirmed second complete remission following salvage chemotherapy. Patients received a priming dose of 25 mg of HMFG1 either intravenously or intraperitoneally, followed by up to six intradermal doses of HMFG1 in 10% Alhydrogel at intervals of 1 month. The three dose levels were 0.5 mg, 1 mg and 5 mg. We devised modifications of published protocols for the measurement of anti-idiotypic and anti-MUC1 antibody responses and also extended the use of the IAsys resonant mirror biosensor to measure the kinetics of the idiotypic network response in these patients. RESULTS: There were no serious adverse events at any dose level. The trial confirmed that all doses could be administered safely with minimal toxicity. No clinical responses were seen in patients with evaluable disease. ELISA for anti-idiotypic antibodies (Ab2) showed significant levels in patients who completed the protocol. There were no significant differences in the levels of Ab2 generated by the different doses of antibody. These results were confirmed by biosensor assays for Ab2, which also showed affinity maturation of the Ab2 response as patients progressed through the vaccination protocol. Biosensor assays also demonstrated no difference in the affinity of Ab2 generated by different booster doses of HMFG1. ELISA for anti-MUC1 antibodies showed less consistent results, with very small but statistically significant rises in anti-MUC1 signals seen in 38% of patients who completed the vaccination regimen. DISCUSSION: The clinical endpoints of safety and tolerability were met. The assays developed for this project have shown reproducibility and may provide surrogate endpoints to assess vaccination for future trials. The use of similar biosensors may be of particular relevance for monitoring of humoral immune responses in other vaccine trials. The low levels of anti-MUC1 antibodies generated may correspond with the lack of clinical efficacy in the few patients with evaluable disease.

Antibodies, Anti-Idiotypic↗
PubMed2000

Standards for the management of cervical and vulval carcinoma.

OBJECTIVE: To examine the feasibility of achieving designated target standards for the management of women with cervical and vulval cancer. DESIGN: Retrospective casenote review. SETTING: The Gynaecological Oncology Centre at Hammersmith Hospital, London. POPULATION: Sixty-one women with cervical and vulval cancer presenting to the gynaecological oncology clinic at the Hammersmith Hospital during 1996 and 1997. Various aspects of the management of those women were compared with standards suggested by a multidisciplinary panel of local experts. Targets included the referral and treatment process, the accuracy of staging, and measures of surgical performance. RESULT: The target interval of seven days between receipt of the referral and the first visit at the cancer centre was achieved in 93% of women. Surgical treatment was administered to 92% of the women within the target of 20 working days from the first clinic appointment. Tumour close to or involving the margins of the specimen was noted in 13% of cervical and 9% of vulval cancers. The node count fell below the target standards in 13% of pelvic and 10% of groin dissections. Appropriate imaging investigations for staging were not undertaken in 15 of 39 cases (38%) of cervical cancer and in 5 out of 22 (23%) of vulval cancers. CONCLUSION: The suggested targets of process and surgical performance are reasonable and achievable. These standards would be appropriate for national use. The area most clearly identified where these targets were not achieved was the requesting of complementary staging investigations. This could be addressed by the use of a simple investigation protocol to be included in each patient's notes and available at specialist clinics and gynaecology wards.

Benchmarking↗
PubMed1998

Co-incidental diagnosis of an extradural abscess while siting an extradural catheter for postoperative analgesia.

Extradural abscess is a rare but serious complication of the extradural route of administration of analgesic drugs. We report a case of spontaneous extradural abscess diagnosed during placement of an extradural catheter for analgesia after a negative diagnostic laparotomy. Magnetic resonance imaging is the usual diagnostic tool of choice. This, and subsequent surgery, confirmed the diagnosis suspected after drainage of pus through the Tuohy needle.

Abscess↗
PubMed1996

Priming in vivo and quantification in vitro of class I MHC-restricted cytotoxic T cells to human papilloma virus type 11 early proteins (E6 and E7) using immunostimulating complexes (ISCOMs).

Immunostimulating complexes (ISCOMs) efficiently deliver soluble antigen into both the cytosolic (endogenous) and endosomal (exogenous) pathways of antigen processing. Cytosolic delivery to antigen-presenting cells (APCs) may therefore be useful for the stimulation and assay of class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) in vitro. In this study, mice were immunized with ISCOMs containing fusion proteins of the E6 or E7 early proteins of human papilloma virus type 11 (HPV 11) to elicit CTL. These CTL were then restimulated in vitro using APCs pulsed with the same ISCOMs, prior to cytotoxicity assay using syngeneic target cells infected with recombinant vaccinia viruses. In this way, antigen-specific, MHC-restricted lysis by CD8+ cells was detected. However, this was dependent on the use of low density splenocytes as APCs for restimulation in vitro. Limiting dilution analyses showed a direct correlation between the CTL responder frequency and the number of times the animals were immunized in vivo. We conclude that in lieu of infectious virus, the use of ISCOMs to mediate antigen delivery to APCs in vitro can be used to quantitate CTL activity. This may have applications in monitoring vaccine efficacy, particularly to viruses such as HPV, which cannot be presently obtained as infectious virus in sufficient quantity for CTL propagation and assay.

Animals↗
PubMed1994

Human cytotoxic T lymphocytes stimulated by endogenously processed human papillomavirus type 11 E7 recognize a peptide containing a HLA-A2 (A*0201) motif.

Cytotoxic T lymphocytes (CTL) may play an important role in the control of human papillomavirus (HPV)-induced anogenital neoplasias, but have been difficult to study owing to the difficulty in obtaining sufficient quantities of infectious virus. To address this we have stimulated human HPV-specific CTL in vitro using low-density cells (LDC) from peripheral blood mononuclear cells (PBMC). Low-density cells were used to present synthetic peptides, or endogenously processed peptides expressed from recombinant vaccinia viruses, to high-density PBMC (predominantly lymphocytes) for 6 days. Cytotoxic T lymphocytes stimulated with endogenously processed HPV 11 E7 recognized the synthetic HLA-A2 (A*0201) motif-containing nonamer, 4-12. In reciprocal experiments, CTL stimulated with this peptide in vitro recognized targets expressing endogenously processed E7. The responses in each case were A2 restricted and peptide specific. Two additional A2 motif-containing nonamers from HPV 6b E7 (21-30 and 47-55) also elicited peptide-specific, A2-restricted CTL. The data illustrate the potential that in vitro stimulation with LDC has in understanding CTL responses to experimentally problematic viral systems such as HPV, and may offer a route to specific immunotherapy of HPV-associated lesions.

Amino Acid Sequence↗
PubMed1991

The induction of cytotoxic T-lymphocyte precursor cells by recombinant vaccinia virus expressing human papillomavirus type 16 L1.

Expression of the major coat protein L1 of human papillomavirus type 16 by recombinant vaccinia viruses using a vaccinia late promoter and their use in generating antibodies have already been reported (Zhou et al., 1990). We have now constructed recombinant vaccinia viruses (VVs) which express the L1 protein from an early promoter with the intention of inducing cell-mediated immunity. This necessitated the removal of sequence motifs (TTTTTNT) from the L1 gene which would otherwise have caused transcription termination when expressed from a vaccinia virus early promoter. The nucleotide sequence was mutated to retain the correct amino acid sequence of the L1 protein. Full-length mRNA and L1 protein were generated in cells infected with the recombinant virus containing the mutant sequence, whereas the wild-type sequence generated only truncated mRNA and no detectable protein. Mice were immunized with VV expressing L1 from the mutant sequence and from the wild-type sequence in constructs with either early or late vaccinia virus promoters. Only the early promoter constructs were effective in priming cytotoxic T lymphocytes (CTL). Moreover the mutant sequence was significantly more effective than the wild-type sequence. The same L1 sequences, expressed from a vaccinia virus late promoter or coexpressed with MHC Class I molecules also expressed from a late promoter, produced high levels of L1 protein in both cases but nevertheless failed to elicit CTL activity. This is the first report of an HPV-specific CTL response and we have reaffirmed the importance of choosing the correct promoter and sequence expressed when using recombinant vaccinia viruses to induce cytotoxic T lymphocytes. These data are relevant for the design of vaccines to generate cell-mediated immunity against human papillomavirus infection.

Animals↗
PubMed1990

Antigen presentation by keratinocytes induces tolerance in human T cells.

Antigen recognition by interleukin 2 (IL 2)-producing T lymphocytes can lead to two distinct outcomes, depending on the nature of the antigen-presenting cell. Recognition of antigen presented by specialized antigen-presenting cells leads to T cell activation; in contrast, antigen presentation by cells which lack "accessory function" can lead to a state of specific nonresponsiveness, which is characterized by a failure to produce IL 2. We have shown in this study that co-culture of an HLA-DR1/4-restricted, influenza hemagglutinin-specific T cell clone with a specific peptide presented by interferon-gamma-induced DR4-expressing keratinocytes causes tolerance induction. This effect was DR restricted, in that it required pre-incubation of the T cell clone with keratinocytes expressing an appropriate DR type (DR4Dw14). The induction of T cell tolerance was also antigen specific; no inhibition resulted from pre-incubation of the clone with an irrelevant peptide. Furthermore cell to cell contact appeared to be necessary, and the addition of supernatant from interferon-gamma-induced keratinocytes did not cause any inhibition. This phenomenon may have relevance to the immunogenicity of transplanted cultured keratinocytes and to the effects of major histocompatibility complex class II induction on non-bone marrow-derived cells. Presentation of tissue-specific autoantigens by cells such as keratinocytes may provide a mechanism of avoiding, rather than stimulating, autoimmune reactions in the context of a local inflammatory response.

Antigen-Presenting Cells↗
PubMed1987

The hematologic effects of latamoxef sodium when used as a prophylaxis during surgical treatment.

Latamoxef sodium, a third generation cephalosporin antibiotic, has been shown to provide good prophylaxis against postoperative infection. It has, however, been implicated as causing disturbances of hemostasis particularly when used in treatment. We have studied 40 patients who required antibiotic prophylaxis prior to surgical treatment randomizing and stratifying them according to age and type of operation, to receive either latamoxef or piperacillin. Five hematologic parameters were studied, prothrombin time, activated partial thromboplastin time, plasma factor II concentration, plasma factor VII concentration and platelet count. Minor differences were noted with latamoxef producing mild persistant elevation of prothrombin time (0.7 second) associated with depression of factor II and factor VII. In our study, we found that, when used as three dose, single agent prophylaxis, there was no difference between latamoxef and piperacillin in producing clinical disturbances of hemostasis. However, attention is drawn to the importance of recognizing that hemostatic disturbances can occur after the use of broad spectrum antibiotics as prophylaxis for surgical treatment Mechanisms of hemostatic disorders are reviewed and alternative hypotheses are suggested.

Cholecystectomy↗
PubMed1982

The use of ultrasonography in determining the amount of extraocular muscle surgery in strabismus.

In twenty strabismus patients using ultrasonography a measurement was taken from the apex of the orbit through the centre of rotation of the eye to the front of the eye along the oculomotor axis which is at an angle of approximately 10 degrees to the anteroposterior axis of the eye. From this and from the diameter of the eye average values were derived for the distance from the equator of the medial rectus insertion of 6.27 mm (range 3.96-8. 92 mm) the lateral rectus insertion 8.77 mm, the length of the medial rectus 35.32 mm (range 32. 40-40. 25 mm) and the lateral rectus 37.82 mm (range 34. 79-42. 75 mm). There are sources of error in these measurements but they are probably not great, though corneal diameter and muscle position should be checked at operation. In addition a recession/muscle length ratio may be calculated and it is probably wise not to exceed a ratio of of 0.20 for the medial rectus and 0.25 for the lateral rectus with similar resection muscle length ratios suggested. The variability of the distance of the muscle insertions from the equator is greater than the muscle lengths and it seems important not to recess beyond the equator while alteration of muscle length may be less important. This suggests maximal recession of the medial rectus may vary from 4 up to almost 9 mm and from 6.5 to almost 11.5 mm for the lateral rectus. The value of making these measurements pre-operatively seems obvious and the considerable variation is the amount of squint surgery is stressed, particularly for muscle recessions.

Humans↗
PubMed1981

Measurement of strabismus eyes with a scan ultrasonography.

A series of 25 patients with strabismus, of whom 16 had eso and 9 exo deviation were examined by A scan to determine the antero-posterior diameter of the eye. This seemed smaller than the accepted normal being 22.13 mm and with a greater range than normal --17.95 mm to 25.27 mm. In particular there were more small eyes. The fallacy of planning squint operation on the basis of the measurements of a standard eye is stressed --a 5 mm recession may be excessive in a small eye but inadequate in a large one. Two major variables in deciding on squint surgery are the diameter of the globe and the length of the muscles.

Adult↗