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.     

Combination Chemotherapy in Generalized Hodgkin's Disease

Fifty-two patients with generalized Hodgkin''s disease were treated with a combination of mustine hydrochloride, vinblastine, procarbazine, and prednisolone. Complete remissions were obtained initially in six out of seven patients (86%) who had previously received no treatment, in 15 out of 19 (79%) who had had only radiotherapy in the past, and in 9 out of 26 (35%) who had previously been given chemotherapy with or without radiotherapy. Of these 30 patients in whom a complete remission was obtained 22 have been free of any symptoms or signs of disease for periods ranging from 4 to 22 months. The response to treatment was rapid, and toxicity was not a major problem, except in those who had previously been treated with cytotoxic drugs used continuously and not in courses. A comparative trial of radiotherapy and combination therapy in the treatment of Stage III Hodgkin''s disease is strongly recommended.     

Possible Role of Hormones in Treatment of Metastatic Testicular Teratomas: Tumour Regression with Medroxyprogesterone Acetate

Three patients in a consecutive series of 16 cases of metastatic mallgnant teratoma testis have shown well-marked tumour regression during hormone treatment. In two cases multiple lung metastases had previously failed to respond to actinomycin D therapy, and following treatment with medroxyprogesterone acetate one patient had well-marked selective tumour regression for nine months while the other is alive, well, and free from disease at seven years. The third case was treated with a combination of actinomycin D and medroxyprogesterone acetate and is alive and disease-free at two years.Attention is drawn to this preliminary study in the hope of stimulating interest in the possible value of hormones, either alone or combined with chemotherapy and irradiation, in the treatment of metastatic testicular teratoma. Multicentre prospective clinical trials are now needed if knowledge is to be advanced in this field.     

Pregnancy in patients presenting with hyperprolactinaemia.

Ninety-two pregnancies occurred in 76 hyperprolactinaemic patients treated with bromocriptine. Half conceived within three months of attempted conception. There was no evidence of an increased rate of spontaneous abortion, fetal abnormality, or multiple pregnancy; the three twin pregnancies occurred in women who were additionally treated with clomiphene and human chorionic gonadotrophin. Thirty-one patients had radiological evidence of a pituitary tumour; 14 with major radiograph changes in the pituitary fossa or serum prolactin concentrations greater than 100 ng/ml received pituitary irradiation before conception. None of the latter showed evidence of enlargement of the tumour during pregnancy. In contrast two of the four patients with similar tumours but who were not irradiated developed visual field defects, one with gross destruction of the pituitary fossa. Prophylactic treatment to limit subsequent tumour expansion during pregnancy in patients with prolactinomas is indicated, and pituitary irradiation before conception appears to be a safe and effective method to achieve this goal.     

Second malignancies in Hodgkin's disease: a complication of certain forms of treatment.

A total of 764 patients with Hodgkin''s disease treated with radiotherapy (RT) or chemotherapy or both were reviewed 3-186 months (median 43 months) after initial treatment to assess the incidence of second malignancies. Incidence of solid tumours and acute non-lymphoblastic leukaemia (ANLL) were calculated by a life-table method and percentages of patients affected derived from life-table plots. Within 10 years after initial treatment the overall incidence of second solid tumours was 7.3%, and over a comparable period 2.4% of patients developed ANLL. Solid tumours occurred only in patients given RT with or without adjuvant chemotherapy, and ANLL occurred only after treatment with MOPP (mustine, vincristine, procarbazine, and prednisolone) or modified MOPP regimens. Neither solid tumours nor ANLL occurred in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The highest incidence of leukaemia (5.4%) occurred after treatment with extensive RT plus (5.4%) occurred after treatment with extensive RT plus MOPP; hence the benefits of this approach in Hodgkin''s disease must be weighed against its carcinogenic potential.     

Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.

Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.     

Bromocriptine in management of large pituitary tumours.

Bromocriptine has an accepted place in the management of small pituitary tumours that secrete either prolactin or growth hormone. The treatment of large tumours with extrasellar extensions is more difficult, however: though surgery is the standard treatment, it is often unsuccessful in returning excessive hormone secretion to normal and may cause hypopituitarism. A prospective trial was undertaken to assess the frequency with which changes in pituitary function and size of large tumours occurs. Nineteen patients were studied before and during treatment with bromocriptine (7.5 to 60 ml/day) for three to 22 months, using contrast radiology and a detailed assessment of pituitary function. Eighteen patients had hyperprolactinaemia and two of these also had raised concentrations of growth hormones; one patient had an apparently non-functioning tumour. In 12 patients (63%) tumour size decreased with bromocriptine and no tumour enlarged. Nine patients had visual-field defects, which improved in seven, becoming normal in five. Pituitary function improved in nine patients (47%) becoming entirely normal in three. Bromocriptine should be the treatment of choice in patients with large pituitary tumours with extrasellar extensions, provided close supervision is maintained.     

Effects of bromocriptine on pituitary tumour size.

In a prospective study designed to assess the influence of bromocriptine on pituitary tumour size 12 patients with pituitary tumours, eight of whom had suprasellar extensions, were treated for three months with 20 mg of bromocriptine daily after a gradual increase to this dose. The group comprised eight women and four men, five with prolactin-secreting adenomas, four with acromegaly, two with functionless adenomas, and one with Nelson''s syndrome. All five patients with prolactin-secreting adenomas showed a reduction in pituitary tumour size as assessed by computerised tomography and metrizamide cisternography accompanied by a fall in prolactin concentrations and clinical and biochemical improvement in their hypopituitarism. One patient in this group had a visual-field defect before treatment, and this resolved. There was no radiological evidence of reduction in tumour size in the remaining seven patients, though this might refect the fairly short duration of treatment, particularly in view of the ancillary evidence of clinical, biochemical, and visual-field improvement in some of the patients. These results emphasise the potential value of bromocriptine in treating patients with large prolactinomas or recurrences of such tumours after previous chiasmal decompression and conventional external megavoltage irradiation on the pituitary.     

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.     

Fertility after Unilateral Orchidectomy and Radiotherapy for Patients with Malignant Tumours of the Testis

The results of treatment for patients with seminoma of the testis by orchidectomy and irradiation are so satisfactory that retroperitoneal lymph node dissection is no longer practised. However, this operation is still used routinely in some centres for patients with testicular teratomas despite the lack of evidence that it gives better results than those obtained with irradiation followed by removal of lymphographically demonstrable residual tumour and in the face of the high incidence of ejaculatory impotence which follows. On grounds of preservation of sexual function and fertility there is a great advantage to be gained from the latter form of treatment. Thirty-four of our patients between the ages of 25 and 45 years treated by irradiation to the para-aortic and iliac nodes for testicular tumours fathered 52 children to term after their treatment.     

Comparison of Beclomethasone Dipropionate Aerosol and Prednisolone in Reversible Airways Obstruction

This paper describes a double-bond crossover trial of prednisolone and beclomethasone dipropionate aerosol in 38 steroid-dependent patients with reversible diffuse airways obstruction. Altogether there was no difference in the patient''s preference of the two treatment groups or in the number of times they used their bronchodilator aerosol, or in the forced expiratory volume in one second, vital capacity, or peak expiratory flow rate in the two treatment groups. The plasma cortisol levels when the patients were on the aerosol were much higher than when they were on prednisolone. The use of inhaled aerosol steroids seems to be preferable as it eliminates the usual complications of oral steroid therapy.     

Vasodepressor carotid sinus syncope.

There have been few reports of vasodepressor carotid sinus syncope, as opposed to the cardioinhibitory type, and no definitive treatment has been described. A 58 year old man developed episodes of syncope after surgery and radiotherapy for a laryngeal tumour. The episodes were characterised by hypotension, sharp pain in the right neck, dizziness, and bradycardia. A temporary pacemaker failed to prevent the symptoms, but ephedrine and fludrocortisone produced substantial improvement. Of the four types of treatment used in carotid sinus syncope, irradiation was ruled out because the patient had had irradiation before developing syncope, surgery was inappropriate because of the laryngeal tumour, and pacing failed. Combined drug treatment with a vasoconstrictor and plasma volume expander produced an improvement in symptoms but did not eliminate them.     

Two randomized controlled clinical trials to study the effectiveness of prednisolone treatment in preventing and restoring clinical nerve function loss in leprosy: the TENLEP study protocols

Background

Nerve damage in leprosy often causes disabilities and deformities. Prednisolone is used to treat nerve function impairment (NFI). However, optimal dose and duration of prednisolone treatment has not been established yet. Besides treating existing NFI it would be desirable to prevent NFI. Studies show that before NFI is clinically detectable, nerves often show subclinical damage. Within the ‘Treatment of Early Neuropathy in LEProsy’ (TENLEP) study two double blind randomized controlled trials (RCT) will be carried out: a trial to establish whether prednisolone treatment of 32 weeks duration is more effective than 20 weeks in restoring nerve function in leprosy patients with clinical NFI (Clinical trial) and a trial to determine whether prednisolone treatment of early sub-clinical NFI can prevent clinical NFI (Subclinical trial).

Methods

Two RCTs with a follow up of 18 months will be conducted in six centers in Asia. In the Clinical trial leprosy patients with recent (< 6 months) clinical NFI, as determined by Monofilament Test and Voluntary Muscle Test, are included. The primary outcomes are the proportion of patients with restored or improved nerve function. In the Subclinical trial leprosy patients with subclinical neuropathy, as determined by Nerve Conduction Studies (NCS) and/or Warm Detection Threshold (WDT), and without any clinical signs of NFI are randomly allocated to a placebo group or treatment group receiving 20 weeks prednisolone. The primary outcome is the proportion of patients developing clinical NFI. Reliability and normative studies are carried out before the start of the trial.

Discussion

This study is the first RCT testing a prednisolone regimen with a duration longer than 24 weeks. Also it is the first RCT assessing the effect of prednisolone in the prevention of clinical NFI in patients with established subclinical neuropathy. The TENLEP study will add to the current understanding of neuropathy due to leprosy and provide insight in the effectiveness of prednisolone on the prevention and recovery of NFI in leprosy patients. In this paper we present the research protocols for both Clinical and Subclinical trials and discuss the possible findings and implications.

Trial registration

Netherlands Trial Register: NTR2300Clinical Trial Registry India: CTRI/2011/09/002022

     

Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study.

OBJECTIVE--To examine the effect of bronchodilator treatment given continuously versus on demand on the progression of asthma and chronic bronchitis and to compare the long term effects of a beta 2 adrenergic drug (salbutamol) and an anticholinergic drug (ipratropium bromide). DESIGN--Two year randomised controlled prospective ''crossover'' study in which patients were assigned to one of two parallel treatment groups receiving continuous treatment or treatment on demand. SETTING--29 general practices in the catchment area of the University of Nijmegen. PATIENTS--223 patients aged greater than or equal to 30 with moderate airway obstruction due to asthma or chronic bronchitis, selected by their general practitioners. INTERVENTIONS--1600 micrograms salbutamol or 160 micrograms ipratropium bromide daily (113 patients) or salbutamol or ipratropium bromide only during exacerbations or periods of dyspnoea (110). No other pulmonary treatment was permitted. MAIN OUTCOME MEASURES--Decline in ventilatory function and change in bronchial responsiveness, respiratory symptoms, number of exacerbations, and quality of life. RESULTS--Among 144 patients completing the study, after correction for possible confounding factors the decline in forced expiratory volume in one second was -0.072 l/year in continuously treated patients and -0.020 l/year in those treated on demand (p less than 0.05), irrespective of the drug. The difference in the decline in patients with asthma was comparable with that in patients with chronic bronchitis (asthma: 0.092 v -0.025 l/year; chronic bronchitis: -0.082 v -0.031 l/year). Bronchial responsiveness increased slightly (0.4 doubling dose) with continuous treatment in chronic bronchitis, but exacerbations, symptoms, and quality of life were unchanged. Salbutamol and ipratropium bromide had comparable effects on all variables investigated. CONCLUSIONS--Continuous bronchodilator treatment without anti-inflammatory treatment accelerates decline in ventilatory function. Bronchodilators should be used only on demand, with additional corticosteroid treatment, if necessary.     

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating the effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non-irradiation group. These results suggest that forced running exercise offers a potentially effective treatment for radiation-induced cognitive deficits.     

Resolution after radiotherapy of severe pulmonary damage due to paraquat poisoning.

A 29 year old man was admitted 36 hours after ingesting about 5 g paraquat. His arterial oxygen pressure fell progressively to 3.4 kPa (34 mm Hg), and pulmonary damage induced by paraquat was diagnosed. His condition did not improve after treatment with prednisolone and cyclophosphamide, but after irradiation both lungs cleared and arterial oxygen pressure started to improve. Irradiation of the lungs should be considered in patients who, after surviving the acute phase of poisoning with paraquat, show progressive deterioration of respiratory function.     

Immunologic responses in patients with pulmonary carcinoma receiving immunotherapy

Summary This is a preliminary report on immune responses observed in vivo and in vitro in resectable patients treated with oral BCG, and in nonresectable patients treated with autologous tumour cells complexed with PPD and with BCG applied by scarification. In some cases, to shorten the period of sensitization, transfer factor was given additionally. Several of the in vitro methods used for assessing the immune competence of the patients are shown to be sufficiently informative to warrant their use before immunotherapy in order to assess the immunologic resources of the patient. During immunotherapy, they allow monitoring the effect of the treatment.     

Prednisone in MOPP chemotherapy for Hodgkin's disease.

High remission rates have been produced by MOPP (mustine, vincristine, procarbazine, and prednisone) chemotherapy in patients with advanced Hodgkin''s disease, but the prednisone component has caused adverse effects in patients who have undergone radiotherapy. The remission rates and length of remission were reviewed in 211 patients with Hodgkin''s disease who received chemotherapy either with or without prednisone. In contrast to the findings of a British study, there were no significant differences in remission rates or length of remission between patients who had received prednisone and patients who had not. There were differences between the British prospective study and this retrospective one, but it is difficult to know what accounted for the substantial differences in the findings.     

Randomised trial of two-drug and four-drug maintenance chemotherapy in advanced or recurrent Hodgkin's disease. Medical Research Council's working party on lymphomas.

Between 1970 and 1975, 108 patients who presented with advanced or recurrent Hodgkin''s disease and were free of disease after six courses of chemotherapy with mustine, vinblastine, procarbazine, and prednisone (MVPP) were allocated at random to one of two regiments of maintenance treatment: either intermittent treatment with vinblastine and procarbazine or intermittent treatment with MVPP. After a median follow-up period of nearly five years there was no significant difference between the two groups in either the rate of relapse or death rate. Six of the 55 patients given the two-drug regimen died compared with 10 of the 53 given the four-drug regimen. The four-drug required hospital attendance and was less agreeable than the two-drug regimen. The efficacy of maintenance chemotherapy with the two-drug regimen was no less than that with the four-drug regimen, but the two-drug regimen had several practical advantages.     

Implications of serum TNF-beta and IL-13 in the treatment response of childhood nephrotic syndrome

The cause of childhood nephrotic syndrome (NS) is unknown and whether it responds to steroid therapy remains unpredictable. In the present study, we measured the Th1/Th2 cytokines, serum tumor necrosis factor-beta (TNF-beta) and interleukin-13 (IL-13), levels in children with NS before and after prednisolone (60 mg/m(2)/day) treatment for 4 weeks, to evaluate their relationships with disease activity and treatment response. Patients with acute NS had higher serum TNF-beta and IL-13 levels than normal controls. After 4 weeks of prednisolone treatment, patients with steroid-resistant NS (SRNS) presented a higher serum TNF-beta level than that before treatment (p=0.008). In contrast, patients with steroid-sensitive NS (SSNS) presented a higher serum IL-13 level than that before treatment (p=0.027). This study demonstrates the significance of serum TNF-beta and IL-13 levels in relation to the disease activity and treatment response of childhood NS. Patients with SRNS appeared to have elevated TNF-beta after steroid therapy, while patients with SSNS tended to have elevated IL-13 after steroid therapy. Thus, an altered Th1/Th2 reaction as demonstrated by TNF-beta/IL-13 imbalance may play a pathophysiologic role in childhood NS.