Renal hemodynamic and tubular effects of S 10036 (fotemustine) in man.
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Biomedical subjects
Publications and source records attributed to C Jacquillat.
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Thirty-three patients with disseminated malignant melanoma were entered in a phase II study of the new nitrosourea S 10036 using a 100-mg/m2 weekly induction schedule for 3-4 consecutive weeks. Patients who responded to this treatment were followed with a maintenance therapy every 3 weeks. Toxic effects were mainly hematological and consisted of delayed thrombocytopenia and leukopenia. Among 30 patients who could be evaluated, eight partial responses were observed (response rate, 26.67%); among seven patients with cerebral metastasis, two partial responses were observed. This multicentric study is currently being continued to confirm this interim report.
A series of 185 squamous cell carcinomas of the head and neck was retrospectively analyzed. Induction chemotherapy was systematically administered. The overall tumour response rate was 38 per cent, and 39 tumours (22.4 per cent) became resectable after chemotherapy. The survival of complete responders was statistically higher than that of non or partial responders. Complete responders treated either by radiation therapy or surgery had similar survivals. Surgery improved the prognosis and reduced the rate of local and regional failures in non responders, including poor responders (less than 50 per cent).
Ninety-eight patients with locally advanced breast cancer (Stage IIIA-IIIB) were entered into a pilot study combining intensive induction (neoadjuvant) chemotherapy (VTMFAP) with or without hormonochemotherapy, external and interstitial radiotherapy, and consolidation chemotherapy with or without hormonochemotherapy. Tumor regression over 50% was observed in 91% patients after chemotherapy, and complete clinical remission occurred in 100% patients after irradiation. The rate of local relapse is 13%. The 3-year disease-free survival is 62% and 3-year global survival is 77%. Initial chemotherapeutic tumor regression greater than 75% is the main predictive factor for disease-free survival.
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Cancer immunotherapy still appears very unsatisfactory in humans. However, it has been shown recently that Interleukin 2 (IL2) could be used to generate, in vitro as well as in vivo, a new anti-tumoral activity directed against fresh tumor cells, allogenic as well as autologous, both of leukemic and solid tumor origin. This activity is not connected with the NK activity, but with a lymphocyte sub-population termed 'Lymphokine Activated Killer (LAK) Cells'. The exact nature of these LAK cell precursors is still a matter of controversy: 'nul' lymphocyte, T or NK markers bearing lymphocytes, or different precursors according to the system of activation that has been used. However, after being activation, these LAK cells always express T cell-markers. The activation has a very short lifespan, explaining the need for a prolonged contact of the cells with IL2, and therefore the necessity to continue injecting the lymphokine in vivo. The clinical results that have been reported so far are still very preliminary. The most common treatment protocol consists of 5 days of IL2 injections followed by 5 days of leukapheresis and in vitro activation of the collected cells, and then auto-transfusion of the activated cells and IL2 during the next 5 days. The clinical toxicity encountered is impressive in terms of frequency as well as severity. Clinical activity seems to be relatively weak. Nevertheless, the concept still appears to be very promising.
A metastasis from a breast carcinoma developed in the cervical cord. The localisation and nature of the lesion were easily diagnosed by a contrast MRI study with Gadolinium DTPA.
Diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido]ethylphosphonate (S 10036) is a new nitrosourea that has been evaluated in a clinical trial because of its activity in the National Cancer Institute panel screen and its rational chemical approach. A Phase I study was conducted in 22 evaluable patients with advanced cancers. The drug was given as a slow i.v. infusion over a period of 60 min on days 1, 8, 15, and 22 followed by a 4-week rest period. The dose levels ranged from 25 to 200 mg/m2/week for 4 consecutive weeks using a modified Fibonacci scheme. Thrombocytopenia was the only acute dose-limiting toxicity and started at a dose of 100 mg/m2/week and above. Hematological toxicity was delayed, cumulative, and dose related. Nausea and vomiting were moderate to severe and dose related. Three responses (one complete and two partials) have been noted. Phase II studies of S 10036 are planned at a dose of 100 mg/m2/week for 4 consecutive weeks ("induction therapy") for patients without prior therapy and 100 mg/m2/week for 3 consecutive weeks for those with prior chemotherapy or radiotherapy. Because of the cumulative toxicity, the recommended dose for the second cycle of S 10036 chemotherapy ("maintenance therapy") is 100 mg/m2/week every 3 weeks.
We have developed a simple, rapid, and sensitive enzyme-linked immunoadsorbent assay (ELISA) to measure soluble cell-free human Fc gamma receptor (Fc gamma R) in serum. This assay is based on the use of two monoclonal antibodies directed against different epitopes expressed on the same low avidity human Fc gamma R (CD16), which is present on polymorphonuclear leukocytes, macrophages and NK cells. This sandwich ELISA, which can measure 2 nM concentration of Fc gamma R, has enabled us to demonstrate the presence and to measure the level of soluble cell-free human Fc gamma R (CfH-Fc gamma R) in normal human serum.
Twenty-two patients with metastatic malignant melanoma received either 36 X 10(6) U (15 patients) or 18 X 10(6) U (7 patients) of human recombinant interferon alpha-2-A daily for 3 months by the intramuscular route, with progressive increase of dosage. This was followed in responders by a maintenance treatment consisting of 3 intramuscular injections per week in the same doses as those received at the end of the induction treatment. Out of 18 patients assessable for effectiveness, 1 had complete remission (7 months +) and 3 had partial response (52,61 and 82 days respectively), an overall improvement rate of 22%. The main side-effects observed were: pseudoinfluenza syndrome (100%), fatigue (100%), somnolence (95%), anorexia (90%) and haematological disorders. Dosage reduction was necessary in 13 of the 15 patients receiving 36 MU. This study shows that human recombinant interferon alpha-2-A has antitumoral activity in metastatic malignant melanoma. Other studies, notably with therapeutic combinations, are needed to determine the optimal dosage regimen of the drug and to increase its effectiveness.
Immunomodulatory effect of Isoprinosine are presented in melanoma and HTLV-III/LAV infected patients. Isoprinosine (50 mg/kg) was used as a pulse immunotherapy according to two different schedules: A) 5 days every 15 days and B) 5 days every 15 days for 2 months, then 5 days every 2 months. The patients' immunological profiles were tested before and during the treatment in terms of T-cell subsets, cell number requirement for PHA-induced proliferation, and delayed hypersensitivity reaction to recall antigens. Primary malignant melanoma patients are randomized between surgery alone or associated to isotherapy (schedule A or B). Schedule A, after an initial improvement of surgery-induced immune deficiency, is responsible for an immunodepression, whereas schedule B determines a prolonged restoration in immune responses in melanoma and AIDS related complex or Kaposi sarcoma patients as well. In vitro effects of Isoprinosine on HTLV-III/LAV infection are presented. These data exhibit 1) the need of an immunological follow-up during isotherapy and 2) the immunological benefit of a pulse immunotherapy during acquired immunodeficiencies related to cancer surgery or to HTLV-III/LAV infection in man.
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We have recently demonstrated the occurrence of functional circulating soluble cell-free Fc gamma 2b/gamma 1 receptor in normal mouse serum by means of the 2.4G2 rat monoclonal antibody. With the solid phase radioimmunoassay described previously, we report here a dramatic increase in the level of circulating soluble cell-free Fc gamma 2b/gamma 1R in Schistosoma mansoni-infected mice individually tested before and on days 22, 41, 62, and 82 after infection. This increase was statistically highly significant when the five measurements from each mouse were compared, and also when the entire group of infected mice was compared with the stable level of Cf-Fc gamma 2b/gamma 1R measured in strain-, sex-, and age-matched control mice individually tested on the same days. This increase was commensurate with a rise in the amount of IgG detected in the sera of the S. mansoni-infected mice. Thus, infection seems to be one of the factors that modulate the expression of such soluble Cf-Fc gamma 2b/gamma 1R in mouse serum. Furthermore, the experimental device reported here for the production of high levels of Cf-Fc gamma 2b/gamma 1R by infection (in this case by parasitic infection) could serve as a model for obtaining large quantities of serum Cf-Fc gamma 2b/gamma 1R for further purification. Lastly, we point out that, by establishing a functional relationship with circulating IgG, such soluble Cf-Fc gamma 2b/gamma 1R may modulate some of the functions in which the Fc portion of immunoglobulins is involved.
The effect of chronic uremia on the development of subcutaneously injected malignant tumoral cells was evaluated in 213 male Wistar AG rats made chronically uremic by simultaneous right nephrectomy and partial ligation of the left renal artery. The tumoral cells injected were stemming from a parental rhabdomyosarcoma (9-4/0) induced by intramuscular injection of 20 mg of colloidal nickel suspended in oil to a male Wistar rat. 54 sham-operated rats and 43 nonoperated animals served as control-groups. Renal function and tumoral growth were checked weekly up to the 60th postoperative day, at which time the surviving rats were sacrificed and submitted to autopsy. At day 15 after cell grafting, a tumoral lump could be felt by finger touch in 68% of the uremic rats, but in only 11% of the sham-operated and 14% of the nonoperated controls (p less than 0.0001). Throughout the study, the tumoral lumps which developed in the uremic animals were of significantly larger size than in the nonuremic controls. Pulmonary tumoral metastases were evidenced at autopsy in 95% of the uremic rats, but in only 50% of the sham-operated and in 54% of the nonoperated controls (p less than 0.005). These results indicate an apparently accelerating and amplifying effect of uremia on the development of a malignant tumor in the rat, for which a decrease in cell-mediated immunity associated with the uremic state still remains a questionable hypothesis.
The frequency of hematogenously propagated hepatic metastases occurring from ocular melanoma led us to treat 20 patients with adjuvant chemotherapy, 19 patients starting chemotherapy during the month following enucleation and 1 patient, a year after enucleation. With a median follow-up of 6 years, 17 patients (80%) are disease-free. Three patients developed hepatic metastases at 24, 24 and 30 months, respectively. The results suggest that adjuvant chemotherapy is effective in preventing metastases from ocular melanoma.
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A series of 344 patients with squamous cell carcinoma (oropharynx, larynx, hypopharynx, or buccal cavity) were treated between November 1982 and January 1985 by chemotherapy. This involved either cisplatinum (C) on day 1 followed by continuous infusion of 5-fluorouracil (F) and bleomycin (B) from day 1 to day 4 or C combined with F as continuous infusion from day 1 to day 4. Tumoral response was 61% and nodal response 61%. Among the 234 patients operated upon, 31 (13%) were free from tumoral cells in the specimen and 25 (48%) with residual tumor. Toxicity of cancer chemotherapy was markedly minimized with the second regimen involving continuous administration of Cisplatin over 24 hours for a period of 4 days. Tolerance was improved mainly in the digestive and renal spheres: cardiovascular complications related to essential hyperhydration during administration of single-dose Cisplatin on day 1 were non-existent with this new continuous mode of administration. This new procedure should optimize results and improve the comfort of patients.