Analysis of treatment in childhood leukaemia. I. Predisposition to methotrexate-induced neutropenia after craniospinal irradiation. Report to the Medical Research Council of the Working Party on Leukaemia in Childhood.

The degree of drug-induced neutropenia resulting from a controlled trial (UKALL I) of treatment in acute lymphoblastic leukaemia was analysed. The main agent associated with severe neutropenia was methotrexate, and methotrexate-induced neutropenia was significantly greater in patients who had received craniospinal irradiation. The synergistic toxic effect of irradiation followed by methotrexate treatment seems to have contributed to three of the five deaths which occurred in complete remission in this trial; all deaths in remission occurred in patients who had received central nervous system prophylaxis. Analysis of patients who subsequently relapsed compared with those still in remission after 18 months of treatment indicated that the former, on average, had slightly lower neutrophil counts. This suggests that the children who relapsed did not receive any less aggressive treatment than those who remained in remission.     

Late marrow recurrences in childhood acute lymphoblastic leukaemia.

Thirty children with acute lymphoblastic leukemia had a recurrence in the bone marrow after treatment was stopped electively. A second haematological remission was achieved in 27 (90%), and the median duration of remission was shortest (six months) in those relapsing within six months of stopping treatment. Four of six children relapsing over one year after stopping treatment remained in second haematological remission. Leukaemic infiltration of the central nervous system developed in four patients remaining in marrow remission. It is concluded that conventional chemotherapy is unlikely to be effective in children with acute lymphoblastic leukaemia who relapse soon after stopping treatment, that "reprophylaxis" of the central nervous system probably with long-term intrathecal chemotherapy is essential, and that some patients relapsing after prolonged unmaintained remission may achieve long-term leukaemia-free survival.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Results of Treatment of Thyrotoxicosis following Relapse after Antithyroid Drug Therapy

One hundred and thirty patients who relapsed after a full course of treatment with antithyroid drugs have been reviewed. Of 22 patients receiving a second course of antithyroid drugs, 17 (77%) relapsed. In contrast, only 2 out of 44 patients treated by surgery relapsed and seven became hypothyroid. Nevertheless, local complications, in particular parathyroid insufficiency, were especially common in this group. Eighty patients received radioiodine, 11 (14%) requiring more than three doses before finally being rendered euthyroid. Postradiation hypothyroidism developed in 39 (49%) patients.     

Comparison of regimens of treatment with sodium stibogluconate in kala-azar.

One hundred and twenty six patients with kala-azar (visceral leishmaniasis) were allocated at random to one of two groups for treatment with sodium stibogluconate. One group was treated for 20 days; in the other group the patients were assessed after 20 days'' treatment and treatment was continued if necessary. Both groups were followed up for six months. There was no significant difference in symptomatic outcome between the two groups at 20 days. At six months eight of the patients in the group treated for 20 days had relapsed and 54 were cured. Of the group given more than 20 days'' treatment if necessary, 62 were cured and none had relapsed (12 required more than 20 days'' treatment). This difference between the two groups was significant. One patient in each group did not respond to sodium stibogluconate, but both were were cured with pentamidine. Altogether 104 patients were cured after 20 days'' treatment; 20, including the eight who relapsed, were cured after more than 20 days'' treatment. There was no significant difference between the two groups in the side effects of the drug, which were minor. The longer courses of treatment (50 days in one patient) were well tolerated. It is suggested that the traditional six day course of treatment with sodium stibogluconate for kala-azar is grossly inadequate and that a longer course is required to prevent relapse.     

Analysis of T cell subsets in Graves' disease: alterations associated with carbimazole.

Conflicting data on subpopulations of peripheral blood lymphocytes in patients with autoimmune disease largely reflect variations in methods of study. An investigation was therefore conducted aimed at avoiding this difficulty. Serial samples of peripheral blood mononuclear cells from 42 patients with hyperthyroid Graves'' disease were collected at monthly intervals before, during, and for 12 months after a six month course of carbimazole. Samples were stored in liquid nitrogen until completion of the study, when they were thawed and all samples from each patient analysed within the same assay using mouse monoclonal antibodies to human cell subsets and a fluorescence activated cell sorter. Proportions of cytotoxic/suppressor (OKT8) positive cells before treatment (mean 17.4 (SEM 0.8)%) were significantly lower (p less than 0.001) than those in normal controls (29.8 (1.9)%; n = 10) and returned to normal by the end of treatment. In contrast, the proportions of activated T cells (OKIa-OKM1) were significantly raised before treatment as compared with normal (14.4 (0.6)% versus 4.6 (0.8)%; p less than 0.001) and fell to normal by the end of treatment. Proportions of OKT3 and OKT4 positive T cells remained unchanged throughout treatment and in the succeeding 12 months. In patients who relapsed after treatment there was a rise in the proportion of activated T cells and a fall in OKT8 positive T cells, which returned towards normal with retreatment. The explanation for the alterations in numbers of circulating T cells remains to be determined but they may provide a means for predicting more accurately the outcome of Graves'' disease after treatment with carbimazole.     

Long-term Stability of Remission in Nephrotic Syndrome after Treatment with Cyclophosphamide

Fifty-eight children with minimal-change nephrotic lesions who relapsed repeatedly and showed toxic side effects from corticosteroids were treated with cyclophosphamide for an average of 12 weeks. The initial dose was 5 mg/kg/day. Four to seven years (mean 5·8 years) later 20 remained in remission, 34 were still relapsing, and 4 had died (two during relapses, one of measles after cyclophosphamide, and one of a brain-stem astrocytoma). The half time for the relapse-free period after treatment was 2·8 years. There was no relationship between the length of treatment with cyclophosphamide and the stability of remission within the limits studied.     

Thirty-five cases of transient hyperthyroidism.

Over a 7-year period transient hyperthyroidism was diagnosed in 35 patients seen in a consulting practice in a community hospital. The patients were followed up for an average of 15 months. Initially all of them had biochemical evidence of hyperthyroidism but a very low 24-hour uptake of radioiodine. The hyperthyroid phase was short, and there were no relapses. Seventeen patients subsequently became hypothyroid; this phase, too, was almost always transient. The clinical course of the disease in the 11 women who became hyperthyroid within 6 months after giving birth was similar to that experienced by the other patients, but of the 11 who had increased titres of antimicrosomal antibodies a significantly greater proportion (73%) showed at least transient evidence of hypothyroidism; 1 patient remained frankly hypothyroid for a year. Transient hyperthyroidism can be distinguished from Graves'' disease only if the uptake of radioiodine is measured. It is important to make this distinction, as transient hyperthyroidism can be managed safely and symptomatically with beta-blockers alone. The propensity of this disease for the postpartum period and the high proportion of patients with antithyroid antibodies suggest an autoimmune cause.     

MVPP chemotherapy regimen for advanced Hodgkin's disease

During January 1968 to December 1972, 133 patients with advanced Hodgkin''s disease (HD) were admitted to hospital for combination chemotherapy with mustine, vinblastine, procarbazine, and prednisolone (MVPP regimen). Remission rates were 76% among 49 untreated patients and 90% among 42 patients who had relapsed after radiotherapy. The corresponding five-year survival rates were 65% and 86% respectively. Provided the observed yearly mortality (6%) remains unchanged 75% of patients who had previously received no treatment or irradiation and achieved remission are expected to continue in first remission after five years. Forty-two patients had received prior chemotherapy. They had lower remission and five-year survival rates (40% and 33% respectively), and fewer than half of those achieving remission were still in first remission after five years. There were several reasons for the poor prognosis in this group, including advanced-stage disease (stage IVB), age over 40, and achievement of remission.Chemotherapy was administered on an outpatient basis. Haematological toxicity and immediate drug-related side effects were similar to those of other regimens but there was no appreciable neurotoxicity. Most deaths were due to either HD itself or complications of advanced disease. Five malignancies other than HD occurred in patients who had received both single-agent chemotherapy and radiotherapy before MVPP chemotherapy. Two patients developed osteonecrosis of the femoral heads.Combination chemotherapy has a profound effect on the prognosis of advanced HD. The MVPP regimen yields results comparable to those of other regimens but with perhaps less toxicity.     

Strategy for antithyroid drug therapy in Graves' disease

A critical review of the literature concerning the treatment of patients with Graves' disease discusses the multitude of protocols used. Prospective studies of patients treated with carbimazole alone for a predetermined duration reveal that the remission rate after 6 years' follow-up is between 40 and 50%. The incidence of treatment duration on remission rates is discussed: the authors think that long-term treatments give better results than short-term treatments. Nevertheless, no standard duration for treatment can be indicated and the most appropriate attitude is an adaptation to each individual case. Various criteria which could modify the prognosis are discussed: small goiter size and normalization of early iodine uptake improve the prognosis. While better results were obtained after high doses of carbimazole in a preliminary work, further study is necessary to clarify this point.     

Are pituitary and thyroid function tests useful for the monitoring of antithyroid drug treatment and the post therapeutic control of Graves' disease?

The control of Graves' disease patients treated with antithyroid drugs (ATD) involves monitoring the dose of ATD, the duration of therapy and the prediction of the long-term outcome of the disease. The sequential follow-up of free thyroid hormones and ultrasensitive TSH (USTSH) helps in monitoring of ATD therapy, except in patients complemented with thyroid hormones. The normalization of early thyroid uptake of radioiodine or pertechnetate, which seems to be closely related to circulating thyroid-stimulating immunoglobulins, confirms the remission that leads to stopping ATD therapy. The raise of plasma USTSH in a normal range within the six months following ATD withdrawal is another indicator of remission. However, the post therapeutic course of Graves' patients remains unpredictable: late relapses and hypothyroidism may occur despite the normalization of the pituitary-thyroid axis, leading to a yearly clinical control with USTSH evaluation.     

Optimization of 131I ablation in patients with differentiated thyroid carcinoma: comparison of early outcomes of treatment with 100 mCi versus 60 mCi

INTRODUCTION: The aim of this study was to compare the early outcomes between two groups of patients with differentiated thyroid carcinoma (DTC) who received 60 or 100 mCi of (131)I for remnant ablation. MATERIAL AND METHODS: 224 DTC patients with primary tumor > 1 cm of diameter or multifocal were randomised into prospective clinical trial. Patients with extrathyroideal extension of primary tumor and nodal metastases or M1 were not enrolled. 99 patients received 60 mCi, and 125--100 mCi of radioiodine as the first ablative dose. RESULTS: The effectiveness of thyroid ablation was evaluated after one year, during endogenous TSH (thyroid stimulating hormone) stimulation, and after two years during Lthyroxine therapy. Whole body scintigraphy (WBS) was performed under thyroxine withdrawal and thyroglobulin serum level was assessed. Distant micrometastases were detected in 9.8% of patients by post-therapy WBS, 11 patients in group A treated with 60 mCi and 11 in group B treated with 100 mCi. In other patients no symptoms of persistent disease were detected. At one year follow up full remission was diagnosed in 176 patients: 76 in group A and 100 in group B. The remaining ones, 13.3% and 11.2% respectively, received the second course of (131)I for remnant ablation. There were no statistically significant differences in Tg (thyroglobulin) serum level either 12 or 24 months after 131I treatment. CONCLUSIONS: Our evaluation of early efficacy of adjuvant radioiodine treatment in low risk DTC patients shows no differences between two radioiodine activities - 60 and 100 mCi in relation to thyroid ablation. Thus, the activity of 60 mCi is recommended.     

High dose busulfan/etoposide as a preparatory regimen for second bone marrow transplants in hematologic malignancies

Five patients with hematologic malignancies who had relapsed between seven months and eight years after their primary bone marrow transplants were prepared with high dose busulfan/etoposide for second marrow transplantations from the same donors who had provided the marrow for the primary transplants. The preparatory regimen was well tolerated. All patients engrafted and entered complete remission. Two patients are alive and in continued remission two and ten months after second transplant. One patient died with acute respiratory failure after two months and two patients relapsed again eight and 17 months after second marrow transplantation. The combination busulfan/etoposide may prove to be a suitable preparatory regimen for second bone marrow transplant attempts in selected patients.     

Treatment of Cushing's disease with low dose radiation therapy.

Nineteen patients with Cushing''s disease were treated with low dose external pituitary irradiation (20 Gy (2000 rad) in eight fractions over 10 days). While awaiting the effects of pituitary irradiation all patients were treated with metyrapone. Seven patients had a complete remission of their disease within six to 12 months of irradiation. They did not require any further treatment and were followed up for a mean of three and a half (range one to eight) years. Another patient had a complete remission after a second course of pituitary irradiation. A further two patients showed a significant biochemical improvement after irradiation, although they were not rendered eucorticoid. There were no complications after this dose of irradiation. These results compare favourably with those reported after pituitary irradiation at conventional doses (40-50 Gy (4000-5000 rad) over four or five weeks) but were not associated with any complications. It is therefore recommended that low dose external pituitary irradiation be used as definitive first line treatment for Cushing''s disease.     

Why Did I Stop? Barriers and Facilitators to Uptake and Adherence to ART in Option B+ HIV Care in Lilongwe,Malawi

Causes for loss-to-follow-up, including early refusals of and stopping antiretroviral therapy (ART), in Malawi’s Option B+ program are poorly understood. This study examines the main barriers and facilitators to uptake and adherence to ART under Option B+. In depth interviews were conducted with HIV-infected women who were pregnant or postpartum in Lilongwe, Malawi (N = 65). Study participants included women who refused ART initiation (N = 10), initiated ART and then stopped (N = 26), and those who initiated ART and remained on treatment (N = 29). The barriers to ART initiation were varied and included concerns about partner support, feeling healthy, and needing time to think. The main reasons for stopping ART included side effects and lack of partner support. A substantial number of women started ART after initially refusing or stopping ART. There were several facilitators for re-starting ART, including encouragement from community health workers, side effects subsiding, decline in health, change in partner, and fear of future sickness. Amongst those who remained on ART, desire to prevent transmission and improve health were the most influential facilitators. Reasons for refusing and stopping ART were varied. ART-related side effects and feeling healthy were common barriers to ART initiation and adherence. Providing consistent pre-ART counseling, early support for patients experiencing side effects, and targeted efforts to bring women who stop treatment back into care may improve long term health outcomes.     

Early mobilisation and outcome in acute sprains of the neck.

OBJECTIVE--To assess the long term effect of early mobilisation exercises in patients with acute sprains of the neck after road accidents. DESIGN--Single blind randomised prospective study of patients receiving physiotherapy, advice on mobilisation, or on an initial period of rest followed up after two years by postal questionnaire. SETTING--Accident and emergency department in urban hospital. PATIENTS--247 Consecutive patients (mean age at injury 30.6 years) presenting within 48 hours after injury with no pre-existing disease of the neck or serious skeletal injury. Of these, 167 patients responded to the questionnaire; 77 who responded but had not completed their treatment or review course were included in the analysis as a fourth group (non-attenders). MAIN OUTCOME MEASURE--Presence of symptoms after two years. RESULTS--Of the 167 patients (68%) responding, the percentage of patients still with symptoms was not significantly different in those receiving rest or physiotherapy (46%, 12/26 v 44%, 24/54), but that in those receiving advice on early mobilisation was significantly lower (23%, 11/48, p = 0.02). Of the 104 patients without symptoms, 94 (90%) recovered within six months and 62 (60%) within three months. Patients without symptoms who received advice or physiotherapy wore a collar for a significantly shorter time than those with persistent symptoms (mean duration 1.4 (SD 0.7) months v 2.8 (1.6) months, p = 0.005 and 1.6 (1.1) months v 1.8 (1.3) months, p = 0.006 respectively). CONCLUSIONS--Advice to mobilise in the early phase after neck injury reduces the number of patients with symptoms at two years and is superior to manipulative physiotherapy. Prolonged wearing of a collar is associated with persistence of symptoms.     

Long-Term Follow-Up of a Patient With Papillary Thyroid Carcinoma,Elevated Thyroglobulin Levels,and Negative Imaging Studies

ObjectiveTo describe a patient with papillary thyroid carcinoma who had measurable thyroglobulin (Tg) levels for 20 years without clinical or imaging evidence of a malignant lesion.MethodsWe reviewed the clinical course, pathologic findings, Tg measurements, and results of various imaging studies in our patient and reviewed the literature regarding Tg-positive, diagnostic total-body radioiodine scan-negative patients with thyroid cancer.ResultsFour months after a 3.5- by 3.5-cm follicular thyroid cancer was removed from the anterior neck area of a 5-year-old girl, a bilateral subtotal thyroidectomy was performed. At age 12 years, she presented with a 2-cm mass on the right side of the neck. After a completion thyroidectomy, recurrent mixed papillary-follicular thyroid cancer was found scattered throughout the remaining thyroid parenchyma. Although a postoperative diagnostic total-body radioiodine scan did not reveal uptake of ¹³¹I, the Tg level was 58 ng/mL. Despite Tg levels as high as 2,528 ng/mL, the patient had no clinical evidence of thyroid cancer during a 20-year period of follow-up. Moreover, numerous imaging studies, including total-body scanning after the administration of 150 mCi of ¹³¹I and [¹⁸F]fluorodeoxyglucose positron emission tomography, were negative. Review of pathologic specimens from both operations with use of updated diagnostic criteria indicated that the tumor was a papillary thyroid carcinoma.ConclusionOur observations and the observations of other investigators indicate that some thyroid cancers produce Tg so efficiently that high levels of Tg may be associated with tumors that remain too small to be detected by imaging studies. The Tg levels may remain stable, decline, or even disappear over time without treatment. (Endocr Pract. 2005;11:43-48)     

THE USE OF RADIOACTIVE IODINE IN THE TREATMENT OF GRAVES' DISEASE

Fifty patients with uncomplicated Graves'' disease were treated with radioactive iodine (I₁₃₁). Twenty-six patients who were followed for one year or longer are the basis of this report. Twenty-five are now euthyroid; only one is not completely well.The total dose of radioiodine administered varied from 0.5 to 10 millicuries. The average length of time necessary for return to a euthyroid state was from three to four months.Hypometabolism developed in three patients, and in one the signs and symptoms of myxedema developed. No other complications ensued. One patient who apparently relapsed had complete return to normal after further iodine administration.The determination of the uptake of radioactive iodine by the thyroid gland is a useful diagnostic procedure in differentiating conditions simulating hyperthyroidism.Following treatment with radioactive iodine, the thyroid gland becomes smaller, the uptake of iodine by the gland is reduced, and the level of organic iodine in the plasma becomes normal.In acute thyroiditis, in spite of a high basal metabolic rate, high content of organic iodine in the plasma and other evidences of “hyperthyroidism,” the uptake of I₁₃₁ has been very low.     

Cyclophosphamide Therapy in the Nephrotic Syndrome in Childhood

Forty-six children with the nephrotic syndrome whose renal biopsy specimens showed minimal changes and whose response to corticosteroid therapy was unsatisfactory were treated with cyclophosphamide. Three patients were completely steroid-resistant from the outset and the remainder were steroid-dependent. In several patients steroids controlled the condition less effectively with time. Most patients showed signs of steroid toxicity, and growth retardation was striking.A moderate leucopenia was induced with cyclophosphamide, and treatment was maintained for three to four months in the majority of cases. Thirty-eight children (83%) have remained in complete remission off all treatment for periods of 3 to 23 months, 33 after one course of cyclophosphamide and five after a second course. Two other patients who remitted but relapsed later are still on treatment. In only six patients was full remission not obtained, and three of these were steroid-resistant from the start. Two died from pneumonia and adrenal failure and four continued to have proteinuria, though in one an impressive reduction occurred.The results indicate that cyclophosphamide therapy is an effective alternative for nephrotic children with normal glomeruli on light microscopy who develop steroid dependence or resistance, and who exhibit toxic effects of steroid therapy.     

Predicting a relapse of Graves' hyperthyroidism in adults during the early phase of treatment with anti-thyroid drugs

INTRODUCTION: The long-term effectiveness of anti-thyroid drugs (ATD) in the treatment of Graves' hyperthyroidism (GH) is still unsatisfactory and difficult to predict. The aim of this study was to evaluate the usefulness of a determination of serum level of thyrotropin-binding inhibiting immunoglobulins (second generation TBII assay) in predicting the possibility of relapse in the early phase of pharmacological treatment. MATERIAL AND METHODS: We investigated 37 patients within the 20-60 age range with the first occurrence of GH. All patients were treated with thiamazole for 12 months. Clinical assessment, ultrasound estimation of thyroid volume and determination of serum thyrotropin, free thyroxine, free triiodothyronine, thyroid autoantibodies and TBII levels were carried out at the onset and after 1, 3, 6, 9 and 12 months of ATD treatment. RESULTS: The mean follow-up period after ATD withdrawal was 27.24 +/- 5.81 months. Of 37 patients 12 (32%) had a relapse of hyperthyroidism (mean time 8.17 +/- 6.91 months after drug withdrawal). The difference in TBII levels between the relapse and the remission group was found to be significant after the first month of therapy until the end of ATD treatment. We observed that patients with TBII above 14 IU/L after 3 months and above 8 IU/L after 6 months of therapy relapsed more frequently than patients with lower levels (sensitivity 50% and specificity 92 and 96%, respectively). CONCLUSIONS: The study confirmed that TBII estimation in the early phase of ATD could be useful in the proper planning of GH therapy and early qualification to more radical treatment (radioiodine or surgery).