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Biomedical subjects

A Barrett

Publications and source records attributed to A Barrett.

At least 73 records · Page 4Linked to original sources
PubMed1992

Outcome of children with resistant and relapsed Hodgkin's disease.

During the period 1974-89, 169 children with Hodgkin's disease were treated in the Paediatric Oncology Units of the Royal Marsden and St Bartholomew's Hospitals. The overall actuarial survival for the whole group was 81% at 10 years. Thirty-five of the 169 children either did not achieve a complete remission or subsequently relapsed. The estimated actuarial survival from initial relapse or failure of primary treatment was 60% at 5 years and 45% at 10 years. Over half of the patients requiring salvage therapy had declared themselves within 2 years and only 3 relapses occurred more than 3 years from diagnosis. Very few patients remain disease free long term after failure of primary and initial salvage therapy. Patients relapsing within a year of diagnosis or not achieving a complete response to primary therapy and those with disseminated relapse had a poor response to salvage therapy. A significant subgroup of patients had prolonged survival despite multiple relapses. Neither initial histology nor stage affected survival from relapse although numbers in each subgroup were small.

Actuarial Analysis↗
PubMed1992

Effect of radiation dose on the development of mixed haemopoietic chimerism following T cell-depleted allogeneic bone marrow transplantation.

The presence of mixed haemopoietic chimerism (MXC) was evaluated by cytogenetic and molecular analysis in 48 patients undergoing T cell-depleted BMT. The dose of total body irradiation (TBI) prescribed to all patients (14.4 Gy) was calculated to compensate for the absence of T cells in the graft. The actual midline dose of TBI received, however, differed significantly depending on the method of TBI administration. Thus, 35 adult patients received an average midline dose of 14.3 Gy, while 13 children received a lower dose of 13 Gy. The incidence of MXC in the adult group, who had received very close to 14.4 Gy to the midline, was 34% (12/35), which is lower than in most reported T cell-depleted series. During follow-up, chimerism remained relatively stable with time but varied between haemopoietic lineages. There was no relationship with relapse. MXC in the 13 children who had received a lower midline TBI dose was significantly higher at 69% (9/13) (p < 0.05) and increased to 90% (9/10) if patients who received additional chemotherapy in their conditioning were excluded (p = 0.001). This suggests that, in terms of marrow ablation, relatively small changes in the dose of TBI may be biologically significant, at least at this dose range. Again, in the lower TBI group MXC was not predictive of relapse.

Adolescent↗
PubMed1992

Alternative models for early onset of childhood leukaemia.

This paper considers theoretical models for early-onset childhood leukaemia. The major focus of attention is the two-hit mutational model. A simple mathematical representation is used to explore mechanisms which might lead to onset of leukaemia at an unusually early age. Two such mechanisms are considered. The first of these, a germinal or very early embryonic first mutation is shown to imply that multiple independent leukaemic clones are likely to arise sequentially in very young patients. Clonal multiplicity could underlie the poor prognosis which has been associated with early onset childhood acute lymphoblastic leukaemia. It implies that curative therapy might require intensive treatment followed by bone marrow rescue to ensure eradication of all single-hit predisposed target cells. The prediction of multiple leukaemic clones might be tested in female patients by means of X-linked restriction fragment length polymorphisms and in patients with B-lineage neoplasms by determination of immunoglobin gene rearrangements. A second mechanism for early onset leukaemogenesis is the occurrence of a high cellular mutation rate in some patients. This is shown to result in leukaemia at significantly earlier age if the mutation rate is sufficiently high to influence target cell loss rate. This mechanism would enable more rapid clonal evolution of leukaemic cells and the early emergence of drug resistant variants. The prediction might be tested experimentally by sequential observation of genetic markers (e.g. Karyotypes, DNA fingerprint patterns) and the rate of emergence of drug resistant phenotypes. Other models, considered more briefly, include one-hit mutational 'dominants' in the developing embryo and faster growth kinetics in neoplasms of younger patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1992

Immune responses to chronic myeloid leukaemia.

The negative impact of donor marrow T lymphocyte depletion on relapse of chronic myeloid leukaemia (CML) following bone marrow transplantation strongly suggests that the leukaemia is particularly susceptible to immune regulation. The immune response to CML may be mediated by major histocompatibility (MHC) locus unrestricted natural killer and lymphokine activated killer cells, or by MHC-restricted CD4 and CD8 lymphocytes. Interaction with the leukaemia is both by direct cell-contact cytotoxicity, and indirectly via cytokines and growth factors. T4 and T8 lymphocytes recognize a spectrum of minor histocompatibility antigens on the leukaemia cell which may be non-specific, leading to graft-versus-leukaemia and graft-versus-host reactions, or present only on myeloid cells leading to a tissue restricted response. The possibility that the P210 protein derived from the BCR/ABL fusion gene on chromosome 22 leads to the presentation via MHC molecules of leukaemia-specific peptide antigens is currently under investigation. Developments in understanding the immune response to CML open up the possibility of developing leukaemia-specific immunotherapy strategies.

Antibody Formation↗
PubMed1991

Intracellular localization of metaiodobenzyl guanidine in human neuroblastoma cells by electron spectroscopic imaging.

The targeted radiotherapy of neuroblastoma with 131l-labelled metaiodobenzyl guanidine (mIBG) is now the subject of several clinical studies. The precise intracellular localization of mIBG, necessary for nuclear microdosimetry, has not previously been described. We report the use of electron-energy-loss spectroscopy and electron spectroscopic imaging to establish the intracellular distribution of mIBG in cells from the human neuroblastoma line NBI-G which had been incubated with the drug by mapping iodine in ultra-thin sections of tumours. Most of the iodine is found within the mitochondria, with lesser amounts in the vesicles and on the nuclear membrane. The use of alternative radionuclides with different physical characteristics has been suggested to optimize the efficacy of this therapeutic strategy. The lack of penetration of mIBG into the nucleoplasm means that ultra-short-range Auger electron emitters such as 125I are not likely to prove more cytotoxic than 131I.

3-Iodobenzylguanidine↗
PubMed1991

The effect of scheduling in children undergoing prophylactic cranial irradiation for acute lymphoblastic leukaemia.

Control of central nervous system (CNS) disease and overall survival have been analysed in a group of 829 children with leukaemia entered into the UKALL VIII trial to determine whether scheduling of the cranial irradiation is of prognostic significance. We show that short gaps in treatment do not influence prognosis and that current radiotherapy practice need not be modified.

Age Factors↗
PubMed1991

The curability of tumours of differing size by targeted radiotherapy using 131I or 90Y.

A mathematical model has been used to investigate the relationship of curability to tumour size and cell number for spherical tumours treated with targeted 131I or 90Y, assuming uniform uptake of radionuclide throughout the tumour. The analysis shows that, for any given cumulated activity per unit mass of tumour, cure probability is greatest for tumours whose diameter is close to an optimum value which depends on the path length of the emitted beta-particle. Smaller tumours are less curable because of inefficient absorption of radiation energy, and larger tumours are less curable because of greater clonogenic cell number. The lesser curability of very small tumours is a feature of targeted radiotherapy using long-range beta-emitters which does not occur with external beam irradiation. The predicted inefficiency of sterilisation of microscopic tumours poses a problem for targeted radiotherapy which is analogous to "geographic miss" in conventional radiotherapy. The implication is that small micro-metastases could escape sterilisation by radionuclides administered at activity levels sufficient to eradicate larger tumours. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated malignancy when multiple tumours of differing size, including micrometastases, may be present. The analysis implies that an advantage might result from the use of a panel of several radionuclides (including short-range emitters) or from combining targeted radiotherapy using long-range beta-emitters with external beam irradiation or some other modality to which microscopic tumours are preferentially vulnerable.

Beta Particles↗
PubMed1991

Intravaginal iridium-192 in the management of embryonal rhabdomyosarcoma.

Three patients with vaginal rhabdomyosarcoma and residual vaginal disease following surgery and chemotherapy have been treated using high dose irradiation with vaginal moulds loaded with iridium-192. These patients remain well and disease-free seven years, 30 months and 18 months after their initial presentations. This paper describes a technique for local vaginal irradiation with individualized vaginal moulds made using a rapid-setting silastic foam impression and loaded with a single plane of iridium wires. Details of the dosimetry are also included.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Rapid VAC high dose melphalan regimen, a novel chemotherapy approach in childhood soft tissue sarcomas.

Forty-three children with malignant soft tissue sarcomas (IRS Groups II-IV) were treated with rapid dose delivery chemotherapy protocol comprising six courses of vincristine, adriamycin and cyclophosphamide, given in most cases within 8 weeks (Rapid VAC). This was followed in 36 patients by high dose melphalan with autologous bone marrow rescue. Twenty-six patients also received irradiation to the site of primary tumour. The Rapid VAC regimen was well tolerated and largely administered as an out-patient. There was one toxic death which occurred 2 months after high dose melphalan due to a combination of infection and possible anthracycline cardiomyopathy. Stages were, (Intergroup Rhabdomyosarcoma Study (IRS) system) Group, Group II--four patients. Group III--27 patients and Group IV--12 patients; International Society of Paediatric Oncology (SIOP) staging, Stage I--11, Stage II--13, Stage III--7, Stage IV--12. Actuarial survival at 5 years for all stages is 57% and event free survival 44%. For patients with non-metastatic diseases, 62% and 53% respectively. This treatment strategy utilises the philosophy of rapid drug delivery with high dose consolidation and enables all chemotherapy to be finished within a 4 month period. In general, a conservative approach was applied to both radiation and surgery to minimise late sequelae related to these treatment modalities. Although the small number of high risk patients in this study limits conclusions regarding efficacy in these subgroups the overall results with this regimen appear to be comparable to that with other approaches.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Implications of the uptake of 131I-radiolabelled meta-iodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma.

Selective uptake of radiolabelled meta-iodobenzylguanidine (mIBG) in neuroblastoma provides a possible approach to biologically targeted radiotherapy of this disease. A mathematical model was used to predict absorbed doses to tumours of varying size from therapeutic 131I-mIBG, based on measurements of 125I-mIBG uptake in surgically excised tumours from six patients. Two size categories of tumour target were considered: bulk tumour and microscopic disease. The predicted absorbed doses were compared with doses calculated to achieve a 50% probability of tumour cure. The analysis shows that the probability of tumour cure depends strongly on mIBG uptake, effective half-life of mIBG in tumour and tumour diameter. Small microtumours may be relatively resistant to mIBG treatment owing to the limited absorption of 131I beta-energy. The product of patient mass and percentage uptake per unit mass of tumour may be a useful indicator of therapeutic outcome when targeted radiotherapy is used for the treatment of paediatric tumours.

3-Iodobenzylguanidine↗
PubMed1990

Treatment of clinical stage I Hodgkin's disease by local radiation therapy alone. A United Kingdom Childrens Cancer Study Group study.

The UKCCSG study of the treatment of Hodgkin's disease between January 1982 and January 1988 accrued 209 patients. Of these, 59 had clinical Stage I disease. These 59 patients were treated with radiation therapy alone to sites of initial involvement. In case of relapse, combination chemotherapy was used. With a median follow-up of 3 years, 50 patients are alive with no evidence of disease after radiation therapy alone. Nine patients have relapsed between 5 and 55 months (median time to relapse, 18 months). Eight patients have been successfully treated with combination chemotherapy and are alive with no evidence of disease (one of these patients having had two relapses). One patient has died after widespread relapse. Of the 59 Stage I disease patients, 85% are relapse free after single-modality treatment. Overall survival is 98%. Long-term complications are minimal at this stage but long-term follow-up is essential.

Adolescent↗
PubMed1990

Dosimetric model for antibody targeted radionuclide therapy of tumor cells in cerebrospinal fluid.

Although encouraging results have been obtained using systemic radioimmunotherapy in the treatment of cancer, it is likely that regional applications may prove more effective. One such strategy is the treatment of central nervous system leukemia in children by intrathecal instillation of targeting or nontargeting beta particle emitting radionuclide carriers. The beta particle dosimetry of the spine is assessed, assuming that the spinal cord and the cerebrospinal fluid compartment can be adequately represented by a cylindrical annulus. The radionuclides investigated were 90Y, 131I, 67Cu, and 199Au. It is shown that the radiation dose to the cord can be significantly reduced using short range beta particle emitters and that there is little advantage in using targeting carriers with these radionuclides. 199Au and 67Cu also have the advantage of having a suitable gamma emission for imaging, permitting pretherapy imaging and dosimetric calculations to be undertaken prior to therapy. If these methods prove successful, it may be possible to replace the external beam component used in the treatment of central nervous system leukemia in children by intrathecal radionuclide therapy, thus reducing or avoiding side effects such as growth and intellectual impairment.

Antibodies, Monoclonal↗
PubMed1990

The UK Children's Cancer Study Group: testicular malignant germ cell tumours 1979-1988.

The United Kingdom Children's Cancer Study Group (UKCCSG) malignant germ cell tumour (MGCT) studies were undertaken to establish standard protocols of investigation, staging, and treatment. The efficacy of new drug combinations and the value of serial measurements of serum alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG) were evaluated. Following the initial surgery, staging of the tumour was performed using a variety of investigative approaches. In stage 1 testicular tumours, orchidectomy was performed. In more advanced tumours, and in stage 1 tumours that failed to show the expected decline in AFP or recurred, chemotherapy was used after appropriate surgery. Seventy-three boys, under 14 years of age, with testicular MGCTs have been entered into the UKCCSG studies since 1979. Serum AFP was measured preoperatively, or within 2 weeks of operation, in 70 boys. It was unequivocally elevated in 69. Monitoring by serial AFP measurement proved valuable in assessing response and in early detection of recurrence. HCG was measured in 46 boys, and was raised in three. Sixty-seven (91%) of the tumours were yolk sac (Teilum) tumours, four were immature teratoma, and two were mixed MGCTs. The only non-AFP producing tumour was an immature polydermal teratoma in a 1-year-old boy. Serum HCG was raised in three boys with yolk sac tumours, one with a mixed teratoma, and one 14-year-old boy who had a mixed MGCT. The results of treatment were assessed on April 1, 1989 (median time from diagnosis, 3 years 4 months). Seventy-one boys were alive, 48 of whom had been cured by orchidectomy alone. The remaining 25 patients received chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

A comparison between oral ciprofloxacin and intra-peritoneal vancomycin and gentamicin in the treatment of CAPD peritonitis.

Fifty-one patients were included in a prospective, randomized comparison of oral ciprofloxacin and intraperitoneal vancomycin/gentamicin in the treatment of CAPD peritonitis. Staphylococcal species accounted for 40% of the isolates with an equal incidence of Staphylococcus aureus and coagulase negative staphylococci. Although, overall, there was no significant difference between the regimens in outcome, ciprofloxacin was significantly less effective when peritonitis was due to coagulase negative staphylococci.

Administration, Oral↗
PubMed1990

Radiobiological rationale for compensation for gaps in radiotherapy regimens by post-gap acceleration of fractionation.

It is now recognized that clonogenic tumour cells may repopulate vigorously during radiotherapy. Gaps in treatment schedules which lead to prolongation of overall treatment time may therefore cause sparing of tumour. Acute-responding normal tissues will also be spared if repopulation by surviving stem cells takes place. However, it is unlikely that stem cells in late-responding normal tissues repopulate significantly over the time-scale of a conventional treatment regime; these tissues will therefore experience little or no sparing as a result of a gap. This poses a dilemma since tumour cell repopulation implies that an increased therapeutic effect in the post-gap phase of treatment may be necessary to compensate for any prolongation of treatment time, but it is difficult to achieve increased tumour effect without also increasing damage to late-responding normal tissues. Neither increased total dose nor increased fraction size is able to achieve this. A possible solution is provided if total treatment time can be held constant, with unchanged total dose and fraction size, by use of twice-daily conventionally sized dose fractions administered after the gap. Provided the twice-daily fractions are sufficiently spaced (not less than 6-8 h apart), the result will be to offset repopulation in tumour and acute-responding normal tissues without additional impairment of late-responding normal tissues. The feasibility of the approach depends on being able to complete treatment by the time originally intended; it is therefore more readily applicable to gaps occurring early rather than late in a treatment schedule. The strategy should be especially advantageous for tumours with rapid repopulative potential in sites where risk of damage to late-responding normal tissues imposes limitation of dose.

Humans↗