Biomedical subjects
Publications and source records attributed to C Wiseman.
Clinicians, units and hospitals in the UK should develop written policies for thromboembolic prophylaxis. Deep-vein thrombosis is both life-threatening and costly. The use of prophylaxis should be included in clinical audit and plans for patient care. The implementation of research-based and agreed guidelines can reduce the incidence of postoperative deep-vein thrombosis.
In-vivo fluorine-19 nuclear magnetic resonance spectroscopy (NMRS) allows non-invasive, real-time, chemical identification of specific fluorinated compounds inside human tumours after administration of fluorouracil (5-fluorouracil). Kinetic measures of the administered drug and metabolites allow estimation of the tumoral half-life of fluorouracil. We studied 57 patients by 19F NMRS immediately after they had received 600 mg/m2 fluorouracil intravenously. Serial spectra were acquired with the surface coil positioned on the skin above the tumour. We defined an intratumoral half-life of fluorouracil of 20 min or more as indicating trapping of the drug, based on the blood half-life of 8-12 min. 19 patients had intratumoral half-lives indicating trapping of fluorouracil, 27 had half-lives less than 20 min, and 11 had no detectable fluorouracil in their tumours. 8 of 9 evaluable patients whose tumours showed trapping had partial responses to chemotherapy that included fluorouracil compared with only 2 of 25 patients whose tumours did not trap the drug (p = 0.000021). 19F NMRS can identify patients likely to respond to chemotherapy with fluorouracil and could be used clinically to tailor optimum treatment.
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In a phase II study, 18 patients with advanced gastric carcinoma were treated with intravenous 6-thioguanine. A 30-minute infusion of 55 mg/m2 (starting dose) was administered once a day for 5 consecutive days, the courses being repeated every 5 weeks. A median of 2 courses (range, 1-4) was administered. Among the 18 patients, 17 having measurable cancer and optimum follow-up were fully assessable for response. None of the patients achieved a complete or partial response. One patient achieved a transient minor response (15 weeks) of the primary gastric carcinoma but the metastatic carcinoma was unchanged. One patient had no change in his measurable carcinoma, and the other 15 patients had progressive disease while receiving intravenous-6-thioguanine. Myelosuppression, although frequent, was mild to moderate at these doses and did not result in significant morbidity. Nonhematologic toxicities were also mild. Our data suggest that intravenous 6-thioguanine given at this schedule is ineffective in previously untreated patients with advanced gastric carcinoma.
We have initiated a clinical trial in 7 patients using low-dose OKT-3 monoclonal antibody, 50 mcg, followed 24 hours later by low-dose cyclophosphamide, 300 mg/m2. Complete data in 5 patients indicate a significant up-regulation of the number of peripheral blood lymphocytes. Before treatment, the mean (+/- standard deviation) total lymphocyte count was 524 (+/- 364)/mm3. After 4 weeks the value rose 64% to 860 (+/- 243)/mm3, (P less than .025, Student's t test). Similar changes were observed for the CD3+, CD4+, CD8+, and CD16+ (NK) lymphocyte subsets. The mean CD3+ population rose from 372 (+/- 325)/mm3 to 593 (+/- 300)/mm3 (P less than .025), the mean CD4+ group rose from 209 (+/- 142)/mm3 to 321 (+/- 104)/mm3 (P less than .05), the CD8+ cells rose from 218 (+/- 205)/mm3 to 341 (+/- 197)/mm3 (P less than .05), and the CD16+ (NK cells) rose from 80 (+/- 37)/mm3 to 157 (+/- 63)/mm3 (P less than .025). Statistically significant up-regulation occurred for all patients. The fraction of each lymphocyte subset and the T4/T8 ratio did not change. OKT-3/cyclophosphamide appears to modulate the number of circulating lymphocytes in human cancer patients.
Kaposi sarcoma and malignant lymphoma were successfully imaged with high purity liposomes containing indium-111 in two patients with AIDS. Gamma camera images of the patient with Kaposi sarcoma showed four discrete lesions along the left foot and calf with no foci along the right foot, and no uptake into clinically enlarged but non-neoplastic lymph nodes. The spread of the Kaposi sarcoma was proximal along the leg. The neoplastic cervical lymph nodes in the second patient who had large-cell diffuse intermediate grade lymphoma were also imaged successfully. Since Kaposi sarcoma and lymphoma frequently involve occult sites, liposome imaging may prove useful in the diagnosis and management of these diseases.
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We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.
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Based on previous results demonstrating that coumarin and cimetidine render objective tumor regressions in renal cell carcinoma, we conducted a pilot study to determine whether these drugs possess activity against malignant melanoma. A total of 22 patients with advanced melanoma received 100 mg coumarin p.o. daily for 14 days; on day 15, cimetidine was added at an oral dose of 300 mg four times daily. Both drugs were continued until progression of disease. In all, 12 patients had previously been treated, but all patients had a favorable performance status. No response was observed in 19 patients. Two patients with a low tumor burden achieved a partial response and a third showed a minor response. There was no toxicity from this regimen. Although coumarin and cimetidine at this dose and schedule did not display significant activity in this study population, further studies are warranted to explore higher doses and focus on patients with relatively low tumor burdens.
Twenty-four patients with proven primary and/or metastatic cancer received single intravenous injections of phospholipid vesicles containing 0.5 mCi of Indium-111. Gamma camera scintigraphy 1 to 72 hours later visualized tumors in 22 patients (92%), including carcinomas of breast, lung, colon, prostate, kidney, cervix, thyroid, and soft tissue sarcoma, lymphoma, and melanoma. Tumor sites that were identified included soft tissues, bone, lung, liver, lymph node, and spinal cord. There were only two false-positive images in metastatic sites and four false-negative images in metastatic sites. Overall sensitivity for tumors in 97 individual sites was 85%, whereas specificity was 96%. Unsuspected areas of malignancy were seen in the lumbar subdural space, pleura, liver, thyroid, and lung. Besides tumor accumulations, homogeneous uptake was observed in normal liver and spleen. Radiation doses to these two organs were 2.2 and 2.9 cGy/0.5 mCi In-111, respectively. Whole body radiation dose was 0.3 cGy/0.5 mCi. The use of Indium-111-labeled vesicles permits a wide variety of human tumors in primary and metastatic sites to be imaged without toxicity and with radiation doses comparable to other radionuclide scanning techniques.
A patient with multiple infections whose serum had antibodies to a human immunodeficiency virus (HIV) developed a T-cell lymphoblastic lymphoma (T11+, Leu-1+, Leu-3a+, TdT+, B1-, common ALL-). Antibodies to human T-lymphotropic virus-I (HTLV-I) were absent. T-cell leukemia-lymphoma may be associated with HIV infection.
Forty-five patients with metastatic renal cell carcinoma were treated with coumarin (1,2-benzopyrone) and cimetidine. Patients received coumarin, 100 mg orally daily; cimetidine administration, 300 mg orally four times daily, was initiated on day 15 of therapy, and treatment with both drugs was continued until progression of disease. Three patients are too early to evaluate (on study less than or equal to 2 months with no change in tumor status). Objective responses (greater than or equal to 50% reduction in measurable disease) occurred in 14 of 42 evaluable patients (33.3%) (the 95% confidence interval based on this rate is +/- 14.3%), with three complete responses and 11 partial responses (PR). Complete responses lasted 9.5, 4+, and 9.5+ months. The median duration of response for the PR group was 5 months (range, 4 to 21+ months). Twelve patients experienced stabilization of disease ranging from 4 to 16.5+ months. No response was seen in 16 patients. There was no symptomatic, hematologic, or chemical (organ dysfunction) toxicity among the 45 patients treated. Coumarin and cimetidine appear to be safe and active agents in the treatment of metastatic renal carcinoma. Further studies are required to determine the optimal dose and scheduling of these agents.
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A pilot study of the use of verapamil and adriamycin in patients with advanced malignancy was conducted to determine if the two drugs could be safely combined and to explore whether antitumor responses were frequent. The dosage of adriamycin was 50 mg/M2 every 3 weeks. Eight doses of verapamil were given orally every 6 hours, with adriamycin being administered after the fourth dose. In five patients 240 mg of verapamil taken every 6 hours produced unacceptable nausea, vomiting, hypotension, and arrhythmia. In eight patients, 120 mg of verapamil taken every 6 hours was tolerated moderately well. In four adriamycin-resistant patients, the combination of adriamycin and verapamil produced one partial response and two minor regressions. Further studies using this combination are warranted.
Sixteen malignant cancer patients (seven melanoma, three colon, three lung, and three other) who received tumor vaccine therapy--14 autologous and two allogeneic--were studied for T-cell phenotyping changes. Blood samples were obtained prior to therapy, and also at various time intervals following the therapy. A consistent and reproducible elevation of T3 and T4 subsets, as tested on day 21 after the therapy, was observed in 12 patients. The mean percentages of T3 and T4 fractions before and after (21 days) the treatment were 63.8 versus 75.9% (p less than 0.002) and 44.4 versus 57.4% (p less than 0.001), respectively. Kinetic studies of absolute values of three melanoma patients also showed augmentation of T3 and T4 cells following each tumor vaccine. The lymphatic infusion of tumor vaccine did not cause any toxicity, particularly lymphadenopathy. We believe this is the first report demonstrating augmentation of T4 (helper/inducer) cells with tumor cell vaccine therapy.
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