Adriamycin in the Treatment of Acute Leukaemia

In a preliminary study a new antitumour antibiotic, adriamycin, was found to be capable of inducing complete remission in 6 out of 17 patients with acute lymphoblastic leukaemia and in one out of four with lymphoblastic lymphosarcoma despite the fact that these patients had either failed to respond or had relapsed after chemotherapy with agents recognized to be potentially successful in each condition. In five cases of acute lymphoblastic leukaemia adriamycin was used in combination with cytosine arabinoside—three achieved complete remission and two good partial remissions. This combination seems to merit further study in patients who have relapsed on the more conventional chemotherapeutic regimens in acute lymphoblastic leukaemia.In 13 patients with acute myelogenous leukaemia previously treated with daunorubicin and cytosine arabinoside no remissions were obtained with the dose range used.     

Remission of diarrhoea due to cryptosporidiosis in an immunodeficient child treated with hyperimmune bovine colostrum.

A boy aged 6 months who presented with poor weight gain, diarrhoea, and infection with Pneumocystis carinii was found to have congenital hypogammaglobulinaemia, which did not improve despite monthly treatment with intravenous gammaglobulin. At the age of 3 years and 2 months he developed severe vomiting and diarrhoea due to cryptosporidiosis, which failed to respond to conventional treatment. Infusion of hyperimmune bovine colostrum produced against parasite antigen, given by nasogastric tube, was started after symptoms had persisted for three weeks. His vomiting and diarrhoea resolved within five days of treatment, and oocysts were no longer seen in the stools after eight days. Later, however, he developed a rare complication, and oocysts were found in the common bile duct. Hyperimmune bovine colostrum may be useful in the treatment of many patients with immunodeficiency disorders.     

Neurological effects of recombinant human interferon.

Ten women with advanced locally recurrent breast cancer who had failed to respond to radiation and hormonal and cytotoxic agents were given up to 12 weeks of recombinant leucocyte interferon 20 X 10(6) U/m2 daily or 50 X 10(6) U/m2 three times a week. Within one hour of administration influenza-like symptoms began, which one week later were superseded by lethargy, anorexia, and nausea, with a consequent loss of weight in most patients. Other side effects included profound somnolence, confusion, paraesthesia, and (in one patient) signs of an upper motor neurone lesion in the legs. All these effects together with increased slow wave activity in electroencephalograms from all patients during treatment disappeared when interferon was withdrawn and did not recur on reintroducing the drug at a lower dosage. Studies are continuing to determine the mechanisms of these effects.     

Obesity by choice: the powerful influence of nutrient availability on nutrient intake

The consumption of nutrients by rodents is markedly influenced by the number of containers of each nutrient provided. Most rats given a choice from separate sources of protein, carbohydrate, and fat thrived if given one cup of each but half failed to thrive if given one cup of each and three extra cups of carbohydrate or fat. Rats given five bottles of sucrose solution and one bottle of water became fatter than rats given five bottles of water and one of sucrose. These studies in rats may point to a model for human obesity, in which the availability of food can override physiological controls of ingestion.     

Controlled trial of methylprednisolone pulses and low dose oral prednisone for the minimal change nephrotic syndrome.

In a multicentre, randomised, prospective trial 89 patients (67 children and 22 adults) with the minimal change nephrotic syndrome were treated with three intravenous pulses of methylprednisolone followed by low dose oral prednisone for six months (group given methylprednisolone) or with high dose oral prednisone for four weeks followed by low dose oral prednisone for five months (control group). Five patients in the group given methylprednisolone and one in the control group did not respond initially. The time to response was shorter in children treated with methylprednisolone. No significant differences between the two groups were observed in the number of patients who relapsed or number of relapses per patient per year. Patients given methylprednisolone tended to relapse earlier than patients in the control group. Side effects related to treatment were significantly fewer in the group given methylprednisolone than in the control group. These data suggest that a short course of methylprednisolone pulses followed by low dose oral prednisone is only marginally less effective than a regimen of high dose oral steroids but can improve the ratio of risk to benefit associated with treatment of the minimal change nephrotic syndrome.     

Measurement of urinary steroid profile in patients with adrenal tumor as a screening method for carcinoma

Results of measurement of urinary steroid metabolite profile using gas chromatographic analysis in eight patients with adrenocortical tumors, i.e. 3 adenomas with Cushing's Syndrome, one adenoma with virilization, one adenoma without clinical manifestations, one carcinoma with Cushing's syndrome and virilization, one carcinoma with Cushing's syndrome and feminization, and one carcinoma without endocrinological symptoms, are reported. A unique pattern dominated by 5 beta and 11 beta-hydroxy steroid metabolites was confirmed in five patients with Cushing's syndrome consisting of three cases with adenomas and two with carcinomas. Excessive 3 alpha, 17 alpha, 21-trihydroxy-5 beta-pregnan-20-one (tetrahydro-11-deoxycortisol, THS) and delta 5-pregnene-3 beta, 11 alpha, 20 alpha-triol (delta 5-pregnenetriol) values were found in all three carcinomas including a nonfunctional carcinoma. These findings would strongly suggest the tumor to be a carcinoma, although excessive excretion of THS and delta 5-pregnenetriol was detected in one patient with a large adenoma associated with virilization. One patient with carcinoma was responsive to ACTH stimulation while the remainder show almost no response to exogenous ACTH. Urinary steroid profiling using gas chromatographic analysis, especially the values for THS and delta 5-pregnenetriol, appears to be a useful method to use in detecting these steroid metabolic characteristics in patients with adrenocortical carcinoma.     

Treatment of Chondromalacia Patellae by Transposition of the Tibial Tubercle

The first 20 patients treated by transposition of the tibial tubercle for chondromalacia of the patella are reported. The patients, usually adolescent girls, had failed to respond to conservative measures. Seventeen patients benefited from the operation and three did not.     

Comparison of a bacteriophage-delivered DNA vaccine and a commercially available recombinant protein vaccine against hepatitis B

A bacteriophage lambda DNA vaccine expressing the small surface antigen (HBsAg) of hepatitis B was compared with Engerix B, a commercially available vaccine based on the homologous recombinant protein (r-HBsAg). Rabbits (five per group) were vaccinated intramuscularly at weeks 0, 5 and 10. Antibody responses against r-HBsAg were measured by indirect enzyme-linked immunosorbent assay, by limiting dilutions and by subtyping. Specific lymphocyte proliferation in vitro was also measured. After one vaccination, three of the five phage-vaccinated rabbits showed a strong antibody response, whereas no r-HBsAg-vaccinated animals responded. Following two vaccinations, all phage-vaccinated animals responded and antibody levels remained high throughout the experiment (220 days total). By 2 weeks after the second vaccination, antibody responses were significantly higher (P<0.05) in the phage-vaccinated group in all tests. After three vaccinations, one out of five r-HBsAg-vaccinated rabbit still failed to respond. The recognized correlate of protection against hepatitis B infection is an antibody response against the HBsAg antigen. When combined with the fact that phage vaccines are potentially cheap to produce and stable at a range of temperatures, the results presented here suggest that further studies into the use of phage vaccination against hepatitis B are warranted.     

Highly selective vagotomy and duodenal ulcers that fail to respond to H2 receptor antagonists

A study was conducted to see whether patients with duodenal ulcers that failed to heal in response to H₂ receptor antagonists had a higher incidence of recurrent ulceration after highly selective vagotomy than patients whose ulcers healed with these drugs. Between 1977 and 1983, 157 patients had a highly selective vagotomy for uncomplicated duodenal ulcer; in 57 patients the ulcer had failed to heal despite treatment with H₂ receptor antagonists (refractory group), 19 patients had developed recurrent ulceration while receiving maintenance treatment, 67 patients had remained healed while taking H₂ receptor antagonists but suffered frequent relapses when treatment was stopped, and 14 patients had not been given these drugs before operation. The overall incidence of recurrent ulceration was 6% after two years and 11% after five years of follow up. In the refractory group, however, the incidence of recurrent ulceration was 18% at two years and 34% after five years, whereas the incidence of recurrence was only 1.5% at two years and 3% after five years in patients whose ulcers had healed with H₂ receptor antagonists. Resistance to H₂ receptor antagonists was not related to preoperative basal or peak acid output but was related to cigarette smoking. Factors associated with recurrent ulceration after highly selective vagotomy were basal acid outputs before and after operation, cigarette smoking, and the surgeon who performed the operation.Duodenal ulcers that fail to respond to H₂ receptor antagonists represent a more severe ulcer diathesis, for which highly selective vagotomy is less effective.     

Tamoxifen versus aminoglutethimide in advanced breast carcinoma: a randomized cross-over trial.

Altogether 117 patients with advanced breast cancer were treated with either tamoxifen 10 mg by mouth twice daily or aminoglutethimide 250 mg by mouth four times daily with hydrocortisone 20 mg twice daily in a randomised cross-over trial in which patients who failed to respond to the first treatment or relapsed while receiving it were switched to the other. Eighteen (30%) out of 60 patients initially treated with tamoxifen achieved an objective response and 11 (18%) showed stable disease. Seventeen (30%) out of 57 patients treated initially with aminoglutethimide achieved an objective response and 13 (23%) achieved stable disease. Objective responses in bone metastases were achieved more commonly with aminoglutethimide (11 patients (35%)) than with tamoxifen (five (17%)). The predicted median duration of response for tamoxifen was 15 months and for aminoglutethimide over 15 months (no significant difference). Five (15%) out of 34 patients who failed to respond to tamoxifen and four out of six patients who relapsed after responding to tamoxifen subsequently responded to aminoglutethimide. In contrast, only two (6%) out of 31 patients who failed to respond to aminoglutethimide and none out of four patients who relapsed while receiving aminoglutethimide subsequently responded to tamoxifen. The main side effects occurring in the 97 patients who received aminoglutethimide as first- or second-line treatment were lethargy and drowsiness (36 patients) and rash (29); seven patients had to stop treatment because of side effects. In contrast, side effects were rare and mild with tamoxifen and no patient had to stop treatment because of them. Both tamoxifen and aminoglutethimide appeared from this study to be equally effective in the medical endocrine treatment of advanced breast cancer.     

Differential sensitivity of subclasses of human colon carcinoma cell lines to the growth inhibitory effects of transforming growth factor-beta 1

In this study we have employed a model system comprising three groups of colon carcinoma cell lines to examine the growth-inhibitory effects of two molecular forms of transforming growth factor-beta (TGF-beta), TGF-beta 1 and TGF-beta 2. Aggressive, poorly differentiated colon carcinoma cells of group I did not respond to growth inhibitory effects of TGF-beta 1 or TGF-beta 2, while less aggressive, well-differentiated cells of group III displayed marked sensitivity to both TGF-beta 1 and TGF-beta 2 in monolayer culture as well as in soft agarose. One moderately well-differentiated cell line from group II which has intermediate growth characteristics failed to respond to TGF-beta 1 or TGF-beta 2, but the growth of two other cell lines in this group was inhibited. TGF-beta 1 and TGF-beta 2 were equally potent, 50% growth inhibition for responsive cell lines being observed at a concentration of 1 ng/ml (40 pM). Antiproliferative effects of TGF-beta 1 and TGF-beta 2 in responsive cell lines of groups II and III were associated with morphological alterations and enhanced, concentration-dependent secretion of carcinoembryonic antigen. Radiolabeled TGF-beta 1 bound to all three groups of colon carcinoma cells with high affinity (Kd between 42 and 64 pM). These data indicate for the first time a strong correlation between the degree of differentiation of colon carcinoma cell lines and sensitivity to the antiproliferative and differentiation-promoting effects of TGF-beta 1 and TGF-beta 2.     

The role of external irradiation in the treatment of transitional cell carcinoma of the bladder-a review of fifty cases

Of 100 patients with carcinoma of the bladder seen in the Section of Therapeutic Radiology, University of California, San Francisco, between 1957 and 1962, 59 were accepted for radiation treatment. Fifty had transitional cell carcinoma and were treated with supervolt therapy (1 mev or cobalt-60).TWO TYPES OF TUMORS WERE AGAIN FOUND SUITABLE FOR EXTERNAL IRRADIATION: Papillary carcinomas Grades II and III, as long as they have not, or at least have not massively, invaded muscle; and undifferentiated carcinomas, Grade IV, regardless of degree of extension through the pelvis. The former type, if single, is treated by irradiation for the first recurrence after one attempt with radical transurethral resection. In the presence of multiple lesions at the first examination, radiation therapy is given immediately. The latter type is treated by radiation therapy without any attempt at surgical removal.Of 37 patients, Stages A to C, treated more than three years ago, 14 (38 per cent) lived more than three years and eight (22 per cent) had no cystoscopic or clinical signs of active disease and had normal bladder function. Of 23 patients treated more than five years ago, eight were alive after five years (35 per cent) and four (17 per cent) remained controlled by radiation therapy alone, with normal bladder function.No major complications were observed. In particular, no fibrosis of the bladder occurred. Doses ranged from 5,000 r in five and a half weeks to 6,000 r in seven weeks.A close cooperation between urologic surgeons and radiotherapists during recent years permits long-range treatment planning from the time of diagnosis, which is essential in the effective therapy of carcinoma of the bladder.     

The Role of External Irradiation in the Treatment of Transitional Cell Carcinoma of the Bladder—A Review of Fifty Cases

Of 100 patients with carcinoma of the bladder seen in the Section of Therapeutic Radiology, University of California, San Francisco, between 1957 and 1962, 59 were accepted for radiation treatment. Fifty had transitional cell carcinoma and were treated with supervolt therapy (1 mev or cobalt-60).Two types of tumors were again found suitable for external irradiation: Papillary carcinomas Grades II and III, as long as they have not, or at least have not massively, invaded muscle; and undifferentiated carcinomas, Grade IV, regardless of degree of extension through the pelvis. The former type, if single, is treated by irradiation for the first recurrence after one attempt with radical transurethral resection. In the presence of multiple lesions at the first examination, radiation therapy is given immediately. The latter type is treated by radiation therapy without any attempt at surgical removal.Of 37 patients, Stages A to C, treated more than three years ago, 14 (38 per cent) lived more than three years and eight (22 per cent) had no cystoscopic or clinical signs of active disease and had normal bladder function. Of 23 patients treated more than five years ago, eight were alive after five years (35 per cent) and four (17 per cent) remained controlled by radiation therapy alone, with normal bladder function.No major complications were observed. In particular, no fibrosis of the bladder occurred. Doses ranged from 5,000 r in five and a half weeks to 6,000 r in seven weeks.A close cooperation between urologic surgeons and radiotherapists during recent years permits long-range treatment planning from the time of diagnosis, which is essential in the effective therapy of carcinoma of the bladder.     

Analysis of thyroglobulin antibody synthesis by cultured peripheral blood lymphocytes from patients with Hashimoto's thyroiditis using biotin-avidin solid phase enzyme immuno-assay

The influence of bovine thyroglobulin (Tg) and/or staphylococcus aureus cowan I (SAC) on Tg antibody synthesis has been studied using cultures of 8 Hashimoto's and 5 normal peripheral blood lymphocytes (PBL). The detection of Tg antibody in the culture supernatants was performed by sensitive biotin-avidin solid phase enzyme immunoassay. By using this technique, we were able to detect small amounts of Tg antibody synthesized by cultured Hashimoto's PBL responsive to bovine Tg and/or SAC; PBL from three out of eight patients produced increased levels of Tg antibody in the presence of 0.02 microgram/ml bovine Tg. On the other hand, PBL from two other cases among them which were unresponsive to bovine Tg alone became responsive to bovine Tg following simultaneous stimulation with SAC. PBL from the other three cases failed to respond to bovine Tg or simultaneous stimulation with bovine Tg and SAC. The former five patients had serum Tg tanned red cell hemagglutination (TGHA) titers greater than 1:409,600 except in one case and the latter had serum TGHA titers less than 1:12,800. These results indicated the presence of the different functional stages of B cells to produce Tg antibody in the circulation of Hashimoto's patients and suggested that sufficient number of lymphocytes responsive to bovine Tg are present in the circulation of Hashimoto's patients with high titers of serum TGHA.     

Does vinblastine add to the potency of alpha interferon in the treatment of renal cell carcinoma?

The combination of alpha interferon and vinblastine has been reported to yield a response rate of 30-40% in previously untreated patients with metastatic renal cell carcinoma. This combination was given to nine patients with advanced metastatic renal carcinoma after they failed or relapsed on alpha-interferon alone, to attempt to evaluate the role of vinblastine in this combination. Neither complete nor partial response was observed. Two patients had disease stabilization for two and seven months. Our preliminary results suggest that vinblastine did not add to the efficacy of interferon in this group of patients.     

Continuous opportunistic and systematic screening for hypertension with computer help: analysis of non-responders.

For two years an office computer was used to identify patients to prompt for opportunistic screening and call for systematic screening. After the two years 92% of patients on the list had had blood pressure readings recorded within the previous five years, of which 34% resulted from special prompts and 22% from screening letters. Those who failed to respond to letters were sent questionnaires, and their records were compared with those of screened patients. With the help of a microcomputer it is practicable to sustain a continuous screening rate of between 90% and 95%.     

Chronic Granulocytic Leukaemia: Multiple-drug Chemotherapy for Acute Transformation

The response to 60 trials of therapy in 50 patients with chronic granulocytic leukaemia (C.G.L.) in acute transformation is reported. None of the 13 patients who received single-agent chemotherapy had a satisfactory response. The use of two drugs in combination produced only one satisfactory response in 30 patients. Various types of multiple-drug treatments in eight patients achieved one good response which lasted four months. In contrast when nine patients with rapidly progressive acute transformation of C.G.L. received a regimen—TRAMPCO(L)—incorporating seven or eight drugs (thioguanine, daunorubicin, cytarabine, methotrexate, prednisolone, cyclophosphamide, and vincristine, with or without L-asparaginase colaspase) five improved significantly. Four patients had a good clinical and haematological response with survival for over three, eight, over 12, and 14 and a half months; and one patient had a partial response. Toxicity was not extreme and maintenance therapy with the same regimen was given on an outpatient basis. TRAMPCO(L) seems superior to previously reported regimens and should be considered for rapidly progressive transformation of C.G.L. especially when simpler treatments have failed.     

Lack of correlation between in vitro corticosteroid effect on hemopoietic colony formation and response to corticosteroid therapy in aplastic anemia

We performed hemopoietic colony culture assays in 15 patients with aplastic anemia (AA) in order to test the effect of hydrocortisone (HC) on late erythroid colony (CFU-e) formation of the patients' marrow and to correlate the in vitro culture results with the clinical response to corticosteroid therapy. HC enhanced CFU-e growth in four patients. All four patients failed to respond to corticosteroid, but three improved with with androgens. The addition of HC did not increase CFU-e colony formation in 11 patients. However, two of them responded to corticosteroid therapy. Among the nine patients showing no HC effect in vitro, two subsequently improved with androgens and one each with anti-thymocyte globulin and anti-lymphocyte globulin. The results suggest that the in vitro corticosteroid effect may not necessarily correlate with responsiveness to corticosteroid therapy.     

Critical Evaluation of the Tetracycline Fluorescence Test in the Diagnosis of Gastric Carcinoma

Exfoliative cytology is a useful tool in the differential diagnosis of gastric lesions. The simplified method developed by Klinger and Katz⁴ using tetracycline fluorescence was subjected to a critical evaluation. Five cases of gastric carcinoma, two of esophageal carcinoma, 21 of benign peptic ulcer, one case of carcinoma eroding into the bile duct, one case of carcinoma of the pancreas penetrating into the stomach, five normal controls on no medication and two normal controls taking vitamin B₂ were studied. The most apparent drawback of this technique is the number of false negatives encountered in cases of gastric carcinoma (three negative results in five cases of carcinoma). One false-positive test was recorded among 21 patients with benign ulcer. Vitamin B₂ if taken a half hour prior to the test will also produce a false-positive test. It is concluded, therefore, that the tetracycline fluorescence test is inferior to accurate studies of exfoliative cytology.     

Monilial and Trichomonal Vaginitis—Topical Treatment with Povidone-Iodine Preparations

A regimen of treatment for vaginitis combining the use of a povidone-iodine solution for swabbing, a povidone-iodine vaginal gel for application at night and a povidone-iodine douche for use in the morning, was evaluated in 93 courses of treatment in 87 patients with monilial or trichomonal vaginitis or a combination of both.In monilial vaginitis, symptoms were cleared and negative laboratory results obtained in one to three weeks in all 74 courses of treatment. These results were obtained within one week in 52 cases and within two weeks in another 17.In four of five patients with trichomonal vaginitis, symptoms were cleared within three weeks. In the fifth, negative laboratory results were obtained but a mild discharge persisted at the end of the fourth week.In 14 courses for combined infections, symptoms were cleared within three weeks in 13, and the pathogens were absent in those patients within four weeks. In one patient the disease did not respond.