Biomedical subjects
Publications and source records attributed to T Dorval.
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Eighteen patients with malignant gammapathies (16 with myeloma and 2 with Waldenström's disease) for a short time because in a phase II-I trial were treated with human (IF beta) given i. v. 6 X 10(6) units weekly (7 patients) or 3 X 10(6) units twice weekly (11 patients) during at least 3 months if tolerated. Treatment was discontinued because of side-effects in three patients. Reduction of the M component of at least 25% from the initial value was obtained in 3 patients. In one case, was also observed in disappearance of the urinary Bence-Jones protein, in 4 cases a significant reduction of bone marrow infiltration by plasma cells and, in 5 cases, major alleviation or disappearance of bone pain. Length of treatment seems an important factor for activity. Immune monitoring with currently available tests, mainly NK cell activity, yielded no correlation with therapeutic effect in these patients. This very preliminary study demonstrates the effect of fibroblastic interferon in myeloma, but further studies are mandatory to determine the population of patients likely to benefit from treatment, the best modalities, possible special indication, dose schedule and duration of treatment. Interferon, however, already appears in this population of patients as giving results similar to those of single agent chemotherapy. As it is not myelosuppressive, it could be indicated in that frequent situation of advanced myeloma with bone marrow failure contra-indicating combination chemotherapy.
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Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon alpha (IF alpha). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with a rising dose in the same patient from cycle to cycle, if tolerance permits, from 1.5 to 6 X 10(6) units daily. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who had previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10(6) units daily. Tumor mass reduction was seen in only three patients, but significant decrease in peripheral lymphocytosis was seen in 7 patients sustained in the continuous treatment group with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed, in this population of patients, a very good correlation between NK cell activity and clinical response. Further studies are warranted to determine the best modalities of treatment as well as the population of patients likely to benefit from it, and the possible special respective indications of IF, and of the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.
Vitamin A and its derivatives, so-called retinoids, can prevent squamous metaplasia induced not only by vitamin A deficiency but also by carcinogenic hydrocarbons. An aromatic retinoid, such as ET1, has been shown to prevent chemically induced papillomas in mice and to amplify certain immunologic reactions. Heavy smokers, 106 volunteers, were submitted to fibrobronchoscopy with bronchial biopsies. An index of metaplasia (IM) was calculated on the basis of microscopical examination of a total of 9,633 sections of 1,010 biopsies. Despite the subjectivity of the estimates of cigarette consumption, this was significantly (P less than 0.02) and positively correlated to the IM. Eighty-five percent of the women had a low IM as compared to only 42% of the men (P less than 0.01), although there was no significant difference in the reported cigarette consumption. Fifty-two subjects had an IM greater than 15% and were given 25 mg ET1 orally daily for 6 months. The bronchoscopy was repeated in 30 patients following completion of the 6-month treatment. The IM was significantly (P less than 0.01) reduced after treatment.
On the basis of compelling preclinical data in cats and dogs, we initiated a clinical gene therapy study in nine patients with advanced solid tumors using xenogeneic fibroblasts secreting human interleukin (IL)-2 (Vero-IL-2 cells). Cohorts of three successive patients with tumors accessible to computed tomography- or ultrasound-guided injection were treated repeatedly with 5 x 10(5), 5 x 10(6), or 5 x 10(7) Vero-IL-2 cells. The endpoints of the study were feasibility, toxicity, and the clinical and biological effects of this novel approach to immunotherapy of cancer. Histopathological, immunological, and molecular analyses were performed on biopsy specimens of tumors and blood samples before, during, and after treatment. Treatment was well tolerated, and toxicity consisted of transient fever in one patient and short-lived, mild itching and erythema in two others. One patient with soft-tissue sarcoma showed a reduction of >90% and >50% of the volume of two distant, noninjected metastases, lasting for 29+ and 26 months, respectively. Four other patients showed stabilization of their disease for 3-9 months; of these patients, one with melanoma developed marked vitiligo. We conclude that repeated injections of < or =5 x 10(7) Vero-IL-2 cells are feasible and safe in heavily pretreated patients with advanced solid tumors. An additional evaluation of an intratumoral application of Vero-IL-2 seems warranted.
Anthracyclin-based chemotherapy is the most efficient chemotherapy for advanced or metastatic soft tissue sarcoma (STS). Development of anthracyclin chemoresistance has been widely documented. In a previous clinical trial, we evaluated a possible reversal of anthracyclin chemoresistance after exposure to subcutaneous IL-2. The current phase II clinical study entered 17 proven metastatic STS patients, refractory to anthracyclin chemotherapy, who received IL-2, and subsequent anthracyclin-based chemotherapy. Subcutaneous IL-2 was administered at 18 million Units/day, 5 days a week for two consecutive weeks. Treatment was administered safely at the full dose for 16 out of 17 patients, and toxicity was mild. One patient had treatment stopped because of rapidly progressive disease. As soon as patients met biological and clinical criteria, chemotherapy was administered. The median delay was 12 days (2-23) from the end of IL-2 administration. Only 13 patients received anthracyclin chemotherapy after IL-2. The other 4 patients did not receive chemotherapy for progressive disease. One partial response was observed out of 13 evaluable patients (7.7% overall response, 95% confidence interval: 0.2 to 36). The overall response rate was 5.9% (95% CI: 0.15 to 29), so the study was stopped due to lack of efficacy. In previous and current studies, a few patients have developed restored anthracyclin chemosensitivity following exposure to IL-2. No conclusive evidence of IL-2 chemoresistance reversal was obtained from this study. Further investigations need to be performed with perhaps a larger group of more carefully selected patients using a different schedule and sequence of combined cytokines and chemotherapy.
We are using Cobalt 60 plaques at Curie Institute since 1968 for the treatment of malignant choroidal melanoma. We reviewed a series of 79 patients treated between 1982 and 1984 with a minimal follow up of 5 years. Tumors thickness varies between 2 and 11 mm with a mean thickness of 5.7 mm. All the tumors received at least 70 grays at the apex. 7 patients died from other cause, 7 patients presented metastasis 65 patients are alive and well, 49 of them have kept their eye and 16 have been enucleated. 18 patients have a visual acuity below 20/200 because of severe maculopathy, 29 patients have a visual acuity between 20/200 and 20/25. The most severe functional visual loss was due to maculopathy. It consisted of obliteration of the capillaries, exsudation and cystoid macular oedema. If we compare these results to other authors we see that maculopathy is a frequent problem with cobalt 60. For these reasons, we intend in the future to use iodine 125 plaques and prothontherapie that should give us better functional results.
In a serie of 759 patients treated for metastasized cancer of the breast, presence of an hepatic focus was observed in 29 percent of cases. Isolated hepatic metastases were found in 4 percent of cases while in 25 percent they were associated with other tissues. At the time of initial clinical staging, the difference between the hepatic metastases group and the other group stems from the much greater frequency of severity indices in the former group indicating a general and biological transformation of the metastatic tumor(s). At therapeutic staging, the slight effectiveness of medical therapies can be accounted for by the slight tolerance among patients with a secondary hepatic tumor(s). Lastly, it is interesting to note that progesterone receptor presence does not modify the prognosis in hepatic metastases cases.
18 patients with malignant gammapathies (16 with myeloma and 2 with Waldenström's disease) were treated with human fibroblastic Interferon (beta IF). This was administered i.v. 6 X 10(6) units weekly (7 patients) or 3 X 10(6) units twice weekly (11 patients). during at least 3 months if tolerated. Treatment was discontinued because of side effects in three patients. Reduction of the M component, by at least 25% from the initial value, was obtained in 3 patients. In one case the disappearance of a urinary Bence Jones protein was observed. In 4 cases, there was a significant reduction of bone marrow infiltration by plasma cells. In 5 cases, major alleviation or disappearance of bone pain was observed. Duration of treatment seemed to be an important factor for activity. Immune monitoring with currently available tests, mainly natural cytoxicity, yielded no correlation with therapeutic effect in these patients. This preliminary study demonstrates the effect of fibroblastic Interferon in myeloma. However, further studies are necessary to determine the population of patients most likely to benefit from treatment, the best modalities, possible special indications, dose schedules and duration of treatment. As it is not myelosuppressive it could be indicated in the frequent situation of advanced myeloma with bone marrow failure, contra-indicating combination chemotherapy.
Nine patients with chronic lymphoid leukemia (CLL) were treated with subcutaneous human (leukocyte) interferon a (IF a). In the first part of the study, 7 patients received intermittent 10 day courses, with free intervals of 10 to 15 days and with dose escalation in the same patient from cycle to cycle from 1.5 to 6 X 10(6) units daily, if tolerated. As we observed a decrease of peripheral lymphocytosis with low doses, and as high doses gave more side-effect in the second part of the study, 4 patients (including two who has previously received intermittent courses) were treated for three months or more at a dose of 1.5 X 10 units daily. Tumor mass reduction was seen in only three patients. However, a significant decrease in peripheral lymphocytosis was seen in 7 patients who were sustained in the continuous treatment group; with relapse at treatment discontinuation in one patient and despite continuation in another. Immune monitoring with currently available T, B, NK and macrophage tests, showed a good correlation between NK cell activity and clinical response, in this group of patients. Further studies are warranted to determine the best modalities of treatment, the population of patients likely to benefit from such treatment, the possible special respective indications of IF, and also the other treatments of CLL. One can already consider as a reasonable indication CLL presentations with myeloid insufficiency as IF is not myelotoxic, contrary to chemotherapy.
Thirty-nine evaluable patients with squamous cell lung carcinoma were treated with combination chemotherapy consisting of doxorubicin, oncovin, bleomycin, cytembena and cis-platin. Objective responses were seen in 46 per cent of the patients. Patients with limited disease had a response rate of 56 per cent. Two of the four complete responses were endoscopically and histologically verified. The median survival time was 37.6 and 26.3 weeks for patients with limited and extensive disease, respectively (p less than 0.05), and 29.9 weeks for the whole group. Hematologic and gastrointestinal toxicities were moderate. There was one drug-related death due to septicemia and 2 reversible acute renal failures. The chemotherapeutic combination appears to be relatively effective. It causes some tumor regression and may extend the survival of responding patients with acceptable quality of life. Maintenance chemotherapy with CCNU, cyclophosphamide, methotrexate, procarbazine alternating with vinblastine, nitrogen-mustard, methotrexate, procarbazine, frequently had to be discontinued because of severe toxicity.
In the system of long-term bone-marrow culture described by Dexter et al., the differentiation of hematopoietic stem cells into erythropoietic cells is not observed. In this system, bone marrow are grown in a medium supplemented with horse serum. We describe here the induction of erythrocytic maturation in the bone-marrow culture by the addition of 5% fetal calf serum, one or two weeks after seeding the bone-marrow cells. We obtained the persistance up to 5 weeks of erythrocytic production. This phenomenon does not depend on the presence of erythropoietin in fetal calf serum.