Biomedical subjects
Publications and source records attributed to J S Malpas.
This study shows that hitherto unexplained thrombocytopenia and neutropenia occurring after bone marrow allografting and autografting may have an immune basis. In the case of autografts, such antibodies are, by definition, auto-antibodies, and it is suggested that similar antibodies occurring after allografting are also auto-immune.
After bone marrow grafting, severe unexplained thrombocytopenia and granulocytopenia may complicate the post-graft recovery of the patient. The present study has shown the presence of antibodies to platelets and granulocytes of donor origin in recipients of both allogeneic and autologous bone marrow grafts. In the case of autografts, such antibodies are by definition autoantibodies, and similar antibodies after allografting may also have an autoimmune origin. It is likely that this is the result of transient immune system imbalance, common to both allo- and autografts, in the early post-graft period. The extent to which these antibodies affect the peripheral counts probably depends on the ability of the engrafted marrow to compensate for the rate of antibody-mediated cell destruction.
Eighty children aged less than 16 years with newly diagnosed Hodgkin's disease were treated between 1974 and 1982. Complete remission occurred in 95%, with actuarial five year overall survival of 94%, and relapse free survival of 82%: median follow up was 4.8 years. Sixty one children were staged clinically while 19 had staging laparotomies before treatment. Most received combined modality treatment with Ch1VPP chemotherapy (chlorambucil, vinblastine, procarbazine, and prednisolone) followed by irradiation of initial bulk disease. Nodular sclerosis predominated in both sexes, accounting for 60% of the total. Girls with stage IV disease, nodal sclerosis histology, and bulky mediastinal masses had a relatively poor prognosis. Ten children have relapsed, and three prolonged (6 to 7 years) second remissions have been observed. Four died of disease, and one from infection. Clinical staging, avoiding splenectomy, reduced the risk of serious infections. Our current policy is to treat stage IA disease with local irradiation and all other stages with chemotherapy, adding irradiation for bulky mediastinal disease.
Monoclonal antibodies to epithelial cells, antigenic determinants labelled with I123 and I125, were administered to 10 immunodeficient mice bearing subcutaneous xenografts of human ovarian cancer. Radio scans of the body taken with a gamma camera at various time intervals demonstrated the presence of the cancer in all the mice. The smallest detectable tumor was approximately 1 mm in diameter. In a subsequent clinical study using 123I-labelled monoclonal antibodies in 10 patients with ovarian cancer, tumor detection was achieved in 8 patients, with tumor uptake of labelled antibody ranging between 0.2-2.6%. As a complementary method to existing forms of diagnosis, the targeting of monoclonal antibodies to ovarian cancer cells in vivo raises the hope of achieving early diagnosis in otherwise undetectable ovarian cancer, and provides encouragement to the concept of selective therapy in oncology.
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Repeated administration of long acting analogues of gonadotrophin releasing hormone diminishes gonadal function and in men decreases testosterone concentrations; for this reason the effect of the analogue buserelin was studied in prostatic carcinoma. Twelve consecutive patients with newly diagnosed locally advanced or metastatic carcinoma of the prostate were treated. Each patient received intranasal buserelin in divided dosages of either 600 or 1000 micrograms daily. Suppression of the gonadotrophins and testosterone occurred in all patients. Objective and subjective signs of regression of disease were seen in nine patients. Buserelin offers an effective treatment of metastatic prostatic cancer without the side effects and cardiovascular risks associated with oestrogen treatment.
Panels of monoclonal antibodies offer a rapid and accurate adjunct to conventional techniques in the diagnosis of neuroblastoma, leukaemia, and lymphoblastic lymphoma. Heterogeneity of antigen expression is observed within a tumour type, and therefore a panel of reagents should be used for each malignancy investigated. Eight monoclonal antibodies which bind to neuroblastoma but not to normal bone marrow and five which bind to leukaemic and lymphoma cells but not to neuroblastoma have been selected for indirect-immunofluorescence testing of bone-marrow aspirates, frozen sections of tumours, and cells from malignant effusions. With this technique a confident diagnosis can be made within 2 h. Profiles of antibodies binding to tumour cells have been used to establish a definitive diagnosis in cases where conventional techniques have proved inadequate.
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Fourteen patients with acute myelogenous leukaemia, who had either failed to enter remission or had relapsed following conventional chemotherapy, received human lymphoblastoid interferon (Hu IFN-alpha N) at a dose of 100 X 10(6) units/m2 daily by continuous IV infusion for 7 days. Complete remission was not achieved in any of 10 patients evaluable for response, although a transient decrease in the degree of bone marrow infiltration was observed in two patients.
Seventy three children with rhabdomyosarcoma were treated by members of the Children's Solid Tumour Group during the period, 1974-1981. The extent of disease at diagnosis was found to be the major influence affecting outcome. Children with tumours confined to the tissue of origin with no evidence of nodal or metastatic spread, had a predicted actuarial 5-year survival rate of 86%. However children with 'unconfined' tumours, i.e. those with extension of disease outside the tissue of origin, had a much poorer prognosis with an actuarial 5-year survival rate of only 21%. Two other factors, histological type and site of primary tumour, appeared to affect prognosis but were not independent of the extent of disease at diagnosis. All children were treated according to protocol. Fifty-two patients showed a complete response to initial therapy and 4 of the 11 partial responders achieved a full remission after additional therapy. The overall complete response rate was therefore 77%. Nineteen children who achieved a complete response on initial treatment subsequently relapsed. Only 3 of these children were alive with no evidence of disease 3 years later, a salvage rate of 15%. "Late" relapses, defined as those occurring more than 2 years after diagnosis, were seen in only 5 children, 4 in boys with primary paratesticular tumours.
Fibreoptic bronchoscopy in previously untreated patients with malignant lymphoma provided diagnostic information in 8 of 25 cases with radiological evidence of intrathoracic involvement. There was a marked difference in the pattern of endobronchial involvement between Hodgkin's Disease (HD) and Non Hodgkin's Lymphoma (NHL) which specifically infiltrated the bronchus-associated lymphoid tissue. Bronchoalveolar lavage was abnormal in only one patient with Hodgkin's Disease in whom the presence of many Sternberg-Reed cells suggested occult dissemination of otherwise localised disease.
Twenty-two consecutive patients with newly diagnosed symptomatic, locally advanced or metastatic prostate cancer were treated with intranasal buserelin, a long-acting analogue of gonadotrophin releasing hormone, in divided dosages of between 600 and 1000 micrograms daily. Suppression of testosterone occurred in 1 of 5 patients treated with 600 micrograms daily and in all 17 patients receiving 1000 micrograms daily. Two of 5 patients treated with the 600 micrograms regimen and 16 of 17 patients receiving the 1000 micrograms regimen showed subjective and objective evidence of disease regression. Follow-up was from 1 to 16 months (mean 7.1 months); 6 patients have relapsed during this period. Buserelin offers an effective alternative medical treatment of carcinoma of the prostate and, apart from impotence, does not have the side effects of oestrogens.
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A retrospective comparison was made of the survival of patients with small-cell lung carcinoma treated by combination cytotoxic chemotherapy (CT), radiotherapy (RT) or symptomatic therapy alone (ST). Forty-three patients received CT and 42 patients of similar age and performance status each received RT or ST at the same group of hospitals. The median survival was 43 weeks with CT, 18 weeks with RT and 6 weeks with ST and 1 year survivals of 36%, 12% and 8% respectively were obtained. Despite the limitations of a retrospective study these results suggest that an improved survival with toxicity acceptable to most patients results from cytotoxic chemotherapy.
A long-term study of gonadal function was conducted in 46 men and 28 women in prolonged remission of advanced Hodgkin's disease after cyclical combination chemotherapy with nitrogen mustard, vinblastine, prednisolone, and procarbazine. The mean follow-up was 6.9 years. Azoospermia or profound oligospermia occurred in 36 of the men, but late recovery was occasionally observed. Testosterone secretion was preserved. Amenorrhoea and gonadal hormone deficiency developed in 22 of the women and never recovered. Partial or complete chemical sterilisation and gonadal hormone deficiency is currently a consequence of cure of advanced Hodgkin's disease in most patients.
Two tumour-associated monoclonal antibodies, HMFG1 and HMFG2, were labelled with iodine-123 and used to detect primary and metastatic ovarian, breast, and gastrointestinal neoplasms by external body scintigraphy in twenty patients with advanced disease. Tumours became visible 3 min to 18 h after injection of labelled antibody. The presence of antibody in the tumours was confirmed by autoradiography and immunoperoxidase staining of surgically removed tissues. The mean tumour uptake of radiolabel was 0.6% of the injected amount. These antibodies can therefore localise specifically to tumours and successful imaging can thus be achieved. This method can complement existing diagnostic techniques and also provide a basis for a selective therapeutic approach to malignant disease.
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Short-term treatment with doxorubicin, cytarabine, and 6-thioguanine was given to 91 consecutive adults with acute myelogenous leukaemia. Fifty patients received high doses (regimen I) and 41 very high doses (regimen II). Where possible, six treatment cycles were given (total dose of doxorubicin 450 mg/m2) regardless of the number of cycles required to achieve complete remission. No additional treatment was given. The remission rate was significantly higher with regimen I than with regimen II (34/50 compared with 15/41, p less than 0.01), the latter, more intensive regimen being associated with a greater incidence of fatal infection (13/41 compared with 5/50, p less than 0.01). Duration of remission was, however, significantly longer with regimen II (p less than 0.05); the median has not yet been reached after a minimum follow-up of two years. Intensive short-term treatment is a feasible strategy for the treatment of acute myelogenous leukaemia.