Discordant lymphoma versus single-histology lymphomas.
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Humans↗
Biomedical subjects
J M Connors
Publications and source records attributed to J M Connors.
MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin's disease.
Seventy patients with advanced Hodgkin's disease, 54 with new disease, and 16 in first relapse after initial radiotherapy, have been treated with a seven-drug, 8-month program: MOPP (nitrogen mustard, vincristine, procarbazine, prednisone)/ABV (Adriamycin [Adria Laboratories of Canada, Mississauga, Ontario], bleomycin, vinblastine) hybrid. A single involved field of radiotherapy was given to selected partial responders after 6 months of chemotherapy. Forty-six of the 52 (88%) evaluable new-disease patients and 14 of the 16 (87%) evaluable patients with relapsing disease reached a complete response. The actuarial overall survival at 49 months for the patients with new disease was 90% (median follow-up from diagnosis was 27 months). For the patients with relapsing disease, the actuarial survival at 54 months was 79% (median follow-up from diagnosis was 27 months). The actuarial relapse-free survival at 41 months for complete responders was 93% for patients with new disease (median follow-up after treatment was 20 months) and 80% for those with relapsing disease (median follow-up after treatment was 27 months). Toxicity was moderate, with two treatment-related deaths and eight episodes of serious infection. These results compare favorably with the best results reported in the literature. Furthermore, they were achieved with a moderate level of toxicity, high drug delivery rates, and a relatively short duration of treatment. The efficacy and toxicity data of the MOPP/ABV hybrid program will now be evaluated in a prospectively randomized multicenter study.
Actuarial Analysis↗
Effects of food deprivation on the feedback regulation of the hypothalamic-pituitary-thyroid axis of the rat.
We have studied the effects of food deprivation on the plasma concentrations of T4, T3, and TSH, the TSH MCR, the pituitary TSH content, and the pituitary TSH response to TRH in female rats. Two days before the beginning of the experiment all rats were prepared with chronic intraatrial catheters through which TRH (100 ng/100 g BW) or [125I]iodo-TSH was administered, and sequential blood samples were obtained. The plasma concentrations of T4 and T3 in food-deprived rats were significantly (P less than 0.05) reduced compared to those in control rats 6, but not 2, days after food removal. Despite the fall in plasma concentrations of T4 and T3, no compensatory rise in the plasma TSH concentration was observed in the food-deprived rats. Plasma TSH concentrations did not differ between groups at any time. The change in the plasma TSH concentration (delta plasma TSH) was significantly greater 15, 30, and 45 min after iv bolus injection of TRH in food-deprived rats than in control rats. To further evaluate the basal TSH secretion rate (MCR X plasma TSH concentration) and the amount of TSH secreted in response to TRH (MCR X area under delta plasma TSH curve), the MCR of TSH was determined in control and food-deprived rats from the plasma disappearance curves of injected [125I]iodo-TSH. No differences were found in the TSH MCR or the calculated basal plasma TSH secretion rate (micrograms per day/100 g BW) of control or 6-day food-deprived rats. However, the change in the amount of TSH secreted in response to TRH was significantly greater in food-deprived rats than in control rats (17.7 +/- 2.1 vs. 11.0 +/- 1.0 micrograms/100 g BW; P less than 0.05). In addition, pituitary weight was significantly decreased in food-deprived rats (8.3 +/- 0.3 vs. 10.8 +/- 0.5 mg; P less than 0.05), but the pituitary TSH concentration (micrograms per mg tissue) was unchanged. These results are consistent with the development of tertiary hypothyroidism (i.e. decreased TSH stimulatory input to the pituitary by TRH or some other agent) during food deprivation in the rat.
Animals↗
MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma.
Between April 1981 and May 1984, 61 patients with advanced diffuse large-cell lymphoma completed treatment with MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), an innovative pilot chemotherapy program emphasizing weekly treatment, antibiotic prophylaxis, daily corticosteroid treatments, and brief duration (12 weeks). Fifty-one patients (84%) achieved a complete response and 10 patients (16%) had a partial response. Over a median follow-up after treatment of 23 months, the actuarial overall survival for the entire group has been 76%; for complete responders the relapse-free survival has been 90%. Toxicity was modest with one treatment-related death and seven episodes of serious infection. The most frequent toxicity was mucositis. Thus, MACOP-B is an effective treatment for large-cell lymphoma that can be delivered in 12 weeks with an acceptable incidence of toxicity. This regimen can achieve results similar and possibly superior to those of other presently used regimens of longer duration.
Actuarial Analysis↗
Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor.
Tyrosine-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by three chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, beta-phorbol 12,13-dibutyrate, and beta-phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A), and polyacetates ( aplysiatoxin and debromoaplysiatoxin ) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (beta-phorbol, alpha-phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of 125I-labeled EGF to A431 cells. Scatchard analysis, however, revealed two apparent EGF receptors in this cell type. The dose-responses for tumor-promoter inhibition of EGF receptor tyrosine phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of tyrosine by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.
Amino Acids↗
Is it an E lesion or stage IV? An unsettled issue in Hodgkin's disease staging.
To determine whether recognized experts in the area of Hodgkin's disease would agree on the determination of stage when various types of extranodal disease are present, we asked senior investigators at 15 major centers to assign a stage to four different patients. In general, these experts agreed in cases representing the extremes of difference between localized and distant extranodal disease. However, when presented with patients with nearby but not contiguous extranodal disease of lung or bone, one half of the experts classified this as an E lesion and one half as stage IV. This disagreement in stage assignment has implications not only for individual patient treatment, but also for reporting of clinical trials. Over-assignment of stage IV has the practical result of "improving" the results of treatment of both low stage (by removing higher risk patients) and advanced stage patients (by including better risk patients). Papers reporting the results of treatment of Hodgkin's disease should include information concerning how patients with extranodal disease were separated into those with E lesions and those with stage IV disease.
Hodgkin Disease↗
The effects of the duration of severe hypothyroidism and aging on the metabolic clearance rate of thyrotropin (TSH) and the pituitary TSH response to TSH-releasing hormone.
We have studied the effects of the duration of severe hypothyroidism (thyroidectomy) and aging on the pituitary TSH response to exogenous TRH and the TSH MCR in female rats. Rats were thyroidectomized (THYREX) or sham operated (SHAM) 4, 14, or 68 days before experimentation. All rats were prepared with chronic intraatrial catheters through which TRH (0, 250, or 1000 ng/100 g BW) or [125I]TSH was administered, and sequential blood samples were obtained. The MCR of TSH was determined in each group from the plasma disappearance curves of injected [125I]iodo-TSH and were found to be decreased in 4-day-THYREX [0.23 +/- 0.01 (+/- SE) vs. 0.27 +/- 0.01 ml/min X 100 g; P less than 0.05], but not in 14-day-THYREX or 68-day-THYREX rats compared with age-matched SHAM controls. In addition, the TSH MCR was found to be decreased in 68-day-SHAM compared to 4- or 14-day-SHAM rats (0.15 +/- 0.01 vs. 0.27 +/- 0.01 ml/min X 100 g; P less than 0.05). The amount of TSH secreted (MCR X area under delta plasma TSH curve X BW) in response to each dose of TRH was calculated and was found to be decreased in 4-day-THYREX rats (4.5 +/- 1.5 vs. 30.0 +/- 4.5 micrograms; P less than 0.05), but not different in 14-day- or 68-day-THYREX rats compared with age-matched SHAM controls. The amount of TSH secreted in response to TRH was also reduced in 68-day-SHAM compared with 4- or 14-day-SHAM rats (16.0 +/- 1.0 vs. 30.0 +/- 4.5 micrograms; P less than 0.05). These results indicate that 1) the MCR of TSH is decreased by aging, but not by severe hypothyroidism in the rat; 2) the pituitary TSH response of the rat to exogenous TRH is decreased by aging, and 3) during severe hypothyroidism, the pituitary TSH response of the rat to a midrange or maximal dose of TRH is decreased (4-day-THYREX) or not different (14- and 68-day-THYREX) compared with that of age-matched euthyroid rats.
Aging↗
Phase I study of weekly high-dose human lymphoblastoid interferon.
Interferon has been shown to have antineoplastic activity but an optimal dose schedule has not been defined. In this phase I study 12 patients with advanced cancer were treated with weekly high-dose human lymphoblastoid interferon given by 3-hour iv infusion to assess toxicity. The median maximum tolerated dose was 55 X 10(6) units/m2 and the dose-limiting toxicity was a complex of fever, fatigue, myalgias, anorexia, and weakness. Neither myelosuppression nor hepatotoxicity was encountered. One patient with metastatic melanoma achieved complete remission, which has been maintained for 2 years. Weekly high-dose iv infusion of interferon has antineoplastic activity, did not cause myelosuppression or hepatotoxicity, and was well-tolerated up to doses of 40-50 X 10(6) units/m2. Future trials should start at 30 X 10(6) units/m2 and should escalate by 10 X 10(6) units/m2/week to patient tolerance.
Adult↗
Effect of lymphoblastoid interferon on lymphocyte subsets in cancer patients.
The effect of interferon dose on lymphocyte subsets is unclear for humans, especially with prolonged intermittent administration. Enumeration of T4 and T8 cells and natural killer (NK) cell activity against K562 cells were examined as part of our ongoing randomized clinical study comparing low- and high-dose treatment strategies. Fifty-four patients have been entered into study, of which 46 are now evaluable. High-dose patients showed no significant changes during actual interferon infusion. However, over the entire period on study, there was a significant increase in NK cell activity (p = 0.001), a concurrent decrease in T8 (p = 0.004), and an increase in T4/T8 (p = 0.02). By contrast, for low-dose patients there was a trend of increasing NK activity during interferon administration, but no change during the total time on study, with a concurrent trend of decreasing T4/T8 and a significant increase in T8 (p = 0.01). Although there is as yet no significant response difference between high- and low-dose treatments, a favourable response was associated with an overall increase in NK activity (p = 0.005), a decrease in T8 (p = 0.02), and an increase in T4/T8 (p = 0.03). In a preliminary study of immune complexes in selected patients, an inverse relationship between NK cell activity and immune complex concentration was suggested. This was supported by in vitro addition of autologous immune complex-containing sera during NK cell assay.
Breast Neoplasms↗
Cure of Ommaya reservoir associated Staphylococcus epidermidis ventriculitis with a simple regimen of vancomycin and rifampin without reservoir removal.
Staphylococcus epidermidis ventriculitis developed in a patient undergoing treatment for meningeal lymphoblastic lymphoma via Ommaya subcutaneous reservoir. Treatment with a regimen of intravenous and intraventricular vancomycin and oral rifampin resulted in prompt cure of the infection without removal of the reservoir. The antibiotic therapy, guided by CSF bacteriocidal levels, was convenient to administer, nontoxic, and well tolerated. No interruption of lymphoma treatment was necessary.
Adult↗
The cured lymphoma patient: guidelines for long-term follow-up.
Successful treatment of lymphoma represents a major achievement of modern medicine. At diagnosis, the major emphasis is placed properly on achieving durable remission. Once treatment has been successful, however, the emphasis must shift to helping the patient resume a normal and productive life. The primary care physician will probably be responsible for the long-term care of these patients. He or she should be alert to the possible disease- and therapy-induced problems such patients face (even years after treatment), especially those common problems in which informed intervention is most effective. The approach summarized here can be readily integrated with normal health surveillance measures but should be modified to suit the individual patient and supplemented as new information appears. Use of these guidelines may help the cured lymphoma patient realize maximum benefit from difficult but lifesaving therapy.
Female↗
Altitude-induced changes in plasma thyroxine, 3,5,3'-triiodothyronine, and thyrotropin in rats.
We have studied the thyroid function of high-altitude-acclimated (6,900 m for 5 wk) and nonaltitude-acclimated control (198 m) rats. After 5 wk of high-altitude exposure the plasma concentrations of both thyroxine (T4) and triiodothyronine (T3) were lower than those in control rats (4.7 +/- 0.3 vs. 3.3 +/- 0.2 microgram/dl and 96 +/- 5 vs. 74 +/- 6 ng/dl, respectively). The plasma thyrotropin (TSH) concentration was elevated in the high-altitude-acclimated rats compared with controls (52 +/- 4 vs. 29 +/- 3 micrograms/dl, respectively). Gross anatomical (thyroid wt/body wt) and histological observations of thyroid tissue were consistent with elevated plasma TSH concentrations. These results suggest that the fall in the plasma concentrations of T4 and T3 during acclimation to severe hypoxia is due to a primary block of thyroid secretion and not to a fall in plasma TSH levels.
Altitude↗
Feedback regulation of thyrotropin by thyroxine under physiological conditions.
We have studied the contribution of thyroxine (T4) itself to the feedback regulation of thyrotropin (TSH) secretion. Thyroidectomized rats received T4 replacement by one of two methods: 1) 5 or 10 micrograms T4 . 100 g-1 . day-1 in drinking water or 2) continuous subcutaneous infusion of 0.5, 1.0, or 2.0 micrograms T4 . 100 g-1 . day-1. Replacement of 5 micrograms T4 . 100 g-1 . day-1 resulted in elevated plasma T4 and TSH while triiodothyronine (T3) was decreased. Replacement of 10 micrograms T4 . 100 g-1 . day-1 resulted in greater elevation of plasma T4, a transient decrease in T3, and no change in plasma TSH. Continuous replacement of T4 resulted in a dose-dependent elevation of plasma T4, little plasma T3 generation, and inhibition of the postthyroidectomy rise in plasma TSH. The pituitary responsiveness to thyrotropin-releasing hormone (TRH) was increased in groups receiving 1.0 or 2.0 micrograms T4 . 100 g-1 . day-1. It was concluded that 1) the plasma T4 exerts a negative feedback on basal TSH secretion in addition to that due to plasma T3 and 2) small amounts of T4 replacement enhance the TSH response to exogenous TRH in short-term hypothyroid rats.
Animals↗
Dynamics and regulation of TSH secretion by superfused anterior pituitary cells.
Superfused dispersed cells respond rapidly to 2- to 10-min pulses of TRH (10(-10) to 10(-7) M) in a dose-dependent manner. The effects of decreasing the stimulus duration can be overcome by a proportional increase in concentration of TRH. A TRH stimulus of 10 min or greater duration results in a sharp peak in TSH secretion followed by a lower plateau. Somatostatin (10(-8) M inhibits the response to TRH (t X 10(-9) M). T3 (2.0 microgram/dl) inhibits TRH-induced TSH secretion by superfused pituitary fragments, but not by dispersed cells. Corticosterone (50 microgram/dl), however, inhibits crude CRF-induced ACTH secretion by such cells.
Adrenal Glands↗
Effect of continuous thyroxine administration on thyrotropin secretion in thyroidectomized rats.
We have studied the effect of T4 itself (i.e. without extrapituitary conversion to T3) on the feedback regulation of pituitary TSH secretion in thyroidectomized rats receiving continuous T4 or T3 replacement. Continuous sc infusion of 1.0 or 2.0 microgram T4/100 g . day in 0.01 N NaOH, 20% 1,2-propanediol vehicle failed to maintain the plasma T4 concentration in thyroidectomized rats for more than 48 h, despite the verification of T4 delivery. Continuous sc infusion of 1.0 or 2.0 microgram T4/100 g . day in 0.01 N NaOH, 5% rat serum resulted in a dose-dependent elevation in the plasma T4 concentration and inhibition of the postthyroidectomy rise in plasma TSH, in the presence of low plasma T3 concentrations. Mimicking the low plasma T3 concentrations that resulted from T4 infusion by continuous replacement of 280 ng T3/100 g . day failed to inhibit the postthyroidectomy rise in plasma TSH. The pituitary responsiveness to TRH (250 ng/100 g, iv) after 96 h of thyroid hormone infusion was significantly (P less than 0.05) inhibited only in the group receiving 2.0 microgram T4/100 g . day. These results indicate that the plasma T4, concentration in addition to that of plasma T3, conveys feedback information to the pituitary. With regard to pituitary TSH secretion, T4 acts as both a prohormone giving rise to a protion of the plasma T3 by peripheral monodeiodination and as a hormone conveying feedback information via the blood to the pituitary.
Animals↗
Feedback effectiveness of periodic versus constant triiodothyronine replacement.
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Animals↗
Insulin therapy in diabetic ketoacidosis.
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Diabetic Ketoacidosis↗