Dissociation of natural killer cell activity and antibody-dependent cell-mediated cytotoxicity in kidney allograft recipients receiving high-dose immunosuppressive therapy.

Peripheral blood lymphocytes (PBLs) of normal subjects and of kidney allograft recipients treated with immunosuppressive drugs (azathioprine and prednisone) were tested for natural killer (NK) cell activity against K562 cells, and for killer (K) cell activity against L-1210 cells in the presence of rabbit anti-L-1210 antiserum. It was found that the natural cell-mediated cytotoxicity (NCMC) was abolished in the immunosuppressed patients while the antibody-dependent cell-mediated cytotoxicity (ADCC) remained normal. Furthermore, no correlation was observed between both activities in the treated group, whereas a strong positive correlation did exist in the control population. Uremic routinely hemodialyzed patients tested for NK cell activity did not exhibit any significant difference with the control group. These data indicate that NCMC and ADCC are different functions, apparently correlated in normal population but discriminated by immunosuppressive medical treatment. The abrogation of NCMC in patients in whom the risk of malignancy is highly increased strengthens the concept of a crucial role of NK cells in the in vivo surveillance toward malignancies.

An alternating chemotherapy and radiotherapy combination for non-Hodgkin's lymphomas of unfavourable histologies: feasibility and preliminary results.

In 1980, on the basis of fundamental and clinical data, a protocol was developed at the Institut Gustave-Roussy, alternating eight monthly courses of chemotherapy (CHVP) and two or three radiotherapy sequences (15 Gy in 6 fractions of 10 days, each), to treat non-Hodgkin's lymphomas of unfavourable histologies, mainly stage II, presenting bulky tumours. Systemic, haematological and digestive tolerances were satisfactory. For 19 previously untreated stage II patients, overall survival and relapse-free survival after 30 months were 85 and 65%, respectively. Three of the relapses were observed in patients who did not receive the alternating schedule in an optimal way; this suggests that these results can be further improved.

Antitumor activity, pharmacology, and toxicity of ellipticines, ellipticinium, and 9-hydroxy derivatives: preliminary clinical trials of 2-methyl-9-hydroxy ellipticinium (NSC 264-137).

Ellipticine and some derivatives are highly cytotoxic substances which kill L1210 cells at concentrations ranging form 10(-8) to 10(-6)M. Some compounds in this series bind with high affinity to DNA (affinity constant between 10(7) M-1 and 10(5) M-1) by intercalation between base pairs. The antitumoral properties of these derivatives are thought to be related to their DNA-binding ability. Both 9-hydroxylation of ellipticine and quaternarization of 2-pyridinic nitrogen tend to increase DNA binding and antitumor activity. 2-Methyl-9-hydroxyellipticine (NSC 264-137) was selected for a phase I and later for a phase II trial in human cancer. This drug does not affect blood cell counts in animals or in man. It is not mutagenic in the Ames' test nor teratogenic in mice, but is endowed with anti-inflammatory properties and induces a marked decrease of motoricity in mice. Transient bradycardia and decrease of blood pressure are the most noticeable cardiovascular effects in dogs. This compound administered at 80-100 mg/m2/week in 1-h intravenous (IV) infusion induces objective remissions in about 25% of patients suffering from advanced breast cancer refractory to all other treatment. These remissions, which occurred after 3-4 weeks, lasted for 1-18 months. This drug seems particularly to improve the condition of patients suffering from oesteolytic breast cancer metastasis. Activity against anaplastic thyroid carcinoma and ovarian carcinoma has also been observed in some cases. Toxic side effects are nausea and vomiting (one-third of the patients), hypertension (less than 10% of the patients), muscular cramp (one-third of the patients), fatigue which can be very pronounced (in most patients after 3 months of treatment), mouth dryness, and mycosis of the tongue and esophagus (less than 20% of the patients).

Screening of human bladder carcinomas for the presence of Ha-ras codon 12 mutation.

Contradictory results were obtained from previous studies aiming at defining the frequency of Ha-ras codon 12 mutations in bladder tumors. Differences in the sensitivities of the methods used could account for this discrepancy. In this study, we reevaluated the frequency of Ha-ras codon 12 mutations in a series of 87 human bladder tumors using a combination of two different methods. The first was derived from the protocol of Ooi et al and consisted in a one-step allele-specific polymerase chain reaction using mismatched primers in two separate PCR. This method is very rapid and highly sensitive, detecting the presence of minor populations (less than 10%) of mutant alleles. The second strategy consisted in screening all tumors using natural restriction fragment length polymorphism (RFLP) analysis. The two methods were in complete concordance and enabled us to show that only one out of 87 primary bladder carcinomas (1%) exhibited the mutation, in accordance with previous studies. These results strongly suggest that, even if minor cell populations overexpress codon 12 Ha-ras mutation, the analysis of this mutation cannot be used to screen potentially invasive transitional cell tumors of the bladder.

Preliminary phase I clinical study and pharmacokinetics of (1,2-diaminocyclohexane) (isocitrato) platinum (II) or PHIC.

PHIC [NSC-350602; (1,2-diaminocyclohexane) (isocitrato) platinum (II)] is a new highly water-soluble platinum derivative. Preclinical studies showed antitumor activity on a wide range of tumors, no cross-resistance with cisplatin and little or no nephrotoxicity in mice and baboons. A phase I clinical trial was then initiated at doses of 300 mg/m2 infused intravenously over one hour without induced diuresis or hydration. Dosages were escalated up to 1500 mg/m2. A total of 29 patients received 52 courses of treatment. The most important side-effect is thrombocytopenia which is rapidly reversible. Nausea and/or vomiting were mild or moderate with onset 1 hr after the end of the infusion and seldom persisted beyond 24 hrs. Measurements of biological parameters did not reveal significant evidence of nephrotoxicity except in one patient who developed urinary tract infection and for whom hemodialysis became necessary. No change in the audiogram could be demonstrated. Peripheral neuropathy was documented in one patient, and in two other patients to whom morphine was given confusional episodes were observed. Although no antitumor effect was observed, there was apparent stabilization of disease. Pharmacokinetic parameters were calculated in twelve out of these 29 patients. Based upon total platinum plasma concentrations, the elimination half-life is 58.3 hrs and the plasma clearance is 21.2 ml/min with an apparent volume of distribution of 7.6 liters. However, considering both plasma concentrations and urinary excretion, we could estimate the half-life of free filterable species (60 min), the plasma clearance (125 ml/min) and the renal clearance (86 ml/min). Mean urinary excretion is 64.4% of the dose after 6 days and 53.1% at 24 hrs. Other administration protocols are suggested, based upon these pharmacokinetic parameters.

The roles of adoptive and active forms of immunotherapy in the cure of children suffering from acute lymphoid leukemia: a) underestimation of active immunotherapy benefit, b) its immunogenetic indications to select sensitive patients, hence prevent chemotherapy's late effects.

Children's acute lymphoid leukemia (ALL) chemotherapy started in 1948 with antimetabolites combined with steroids. It was enriched in 1959 with vincristine and cyclophosphamide and, in 1970, with daunomycin. It induced more and more apparently what were called complete remissions, and prolonged more and more the survivals without reducing however, until 1973, the (100%) mortality. It started to reduce it at the fifth year, to 20 and even 40% between 1973 and 1976, due to progressive and maximal intensification and duration of chemotherapy. It is in the same period that we proposed to apply in ALL remissions after relapses and in the first remissions of the most malignant type, allogeneic bone marrow grafts; we published the first success in human ALL in 1963, and clinically observed the same actions as those described experimentally: cytoablation of both leukemia and hematopoiesis, the latter being restored by the graft, whose reaction versus the residual neoplastic cells (called graft versus leukemia or GvL) appeared to be able to often eradicate them, at the cost however of a graft-versus-host reaction (both reactions sharing the same mechanism). One of us became a member of the Committee of the International Bone Marrow Transplant Registry, whose results showed the improvement in the prognosis of the aggressive form of ALL. The intensity and length established for chemotherapy for the most severe form of children's ALL have often been applied to the intermediary and to the least aggressive ones. The global 5-year survival increased to 60% between 1976 and 1984, and is around 80% today. But the registration of late debilitating or malignant effects of chemotherapy toxicities makes us wonder if some patients have not received an excessively intense and long application of cytostatics (often combined with ionizing radiations on CNS). In fact, the patients belonging to some HLA phenotypes (A33 and B17) have appeared to be especially often cured with active immunotherapy (killed leukemic cells and/or BCG), whose action was shown by specific cytotoxicity amplification, which was applied after short adjuvant chemotherapy, and hence is able to reduce the long chemotherapy incidence of debilitating or malignant late effects. Sakurai's group confirmed our absence of late relapses after ALL active immunotherapy, which contrasts with their risk after maintenance chemotherapy, whose minimal residual disease is a worrisome stumbling block to the cure.

The contribution of clinical trials to the treatment of patients with early stages of Hodgkin's disease.

An analysis of the results that have been obtained in several recent controlled clinical trials showed that the inclusion of combination chemotherapy in the initial treatment of Hodgkin's disease significantly improved relapse-free survival but did not improve survival. This is due to the high efficacy of salvage chemotherapy. Paradoxically, the advent of powerful combination chemotherapy makes initial treatment by radiotherapy alone possible in a large proportion of patients with early stages of Hodgkin's disease. Prognostic factors have been identified by a multivariate analysis of the results obtained in the three controlled clinical trials carried out by the EORTC. These factors can help to delineate the subsets of patients who can be treated initially by radiotherapy alone with an acceptable relapse rate and to adjust the size of the radiation fields. The two prominent prognostic factors are: a combination of systemic symptoms and erythrocyte sedimentation rate the number of lymphatic areas involved.

[Mendelian genetics and cancer (author's transl)]. / Génétique mendélienne et cancer.

Two hundred different mendelian genes can have a cancerogenic effect in man, but it is difficult to make out between the genetic and the environmental part. Acute lymphoblastic leukemia is an example that the actual cancerogenic factor can be environmental and not genetic. Genetically controlled tumors can result from two successive mutations, the first being in some cases prezygotic. The first genetic accident can be a birth defect or a chromosomic fragility syndrome. The histocompatibility major system can play a role in the frequence and in the evolutive type of some cancers. The most frequent hereditary syndromes which can be associated with cancers are quoted here.

[Salvage chemotherapy in resistant malignant lymphomas (author's transl)]. / Chimiothérapies de rattrapage dans les lymphomes malins résistants.

A salvage chemotherapy was used in advanced malignant lymphomas resistant to previous chemotherapy. The chemotherapy schedule consisted by the monthly administration of vindesine and continuous infusions of bleomycins, associated with cis-diammine-dichloro-platinum in Hodgkin's disease (patients resistant to MOPP and ABVD protocols) and with DTIC in non-Hodgkin lymphomas (patients resistant to CHOP or equivalent protocol). In 10 patients with advanced Hodgkin's disease (stages III and IV), one complete remission and four partial regressions were achieved. Five patients are still alive after 6 and 14 months. In 15 non-Hodgkin lymphoma patients, two complete remissions and seven partial regressions were achieved. Eight patients are still alive after 4 to 12 months. Severe toxicities related to the chemotherapy protocol have never been observed. These results demonstrate the efficiency of the described chemotherapy schedules in advanced malignant lymphomas resistant to visual therapy.

[2 N methyl 9 hydroxy-ellipticine in treatment of metastatic breast cancers (author's transl)]. / Intérêt de la 2 N-methy-9-hydroxy-ellipticine (NSC 264-137) dans le traitement des cancers du sein métastasés.

A phase II trial was conducted in 57 patients with advanced metastatic breast cancer given 2-N-methyl 9-hydroxy-ellipticine (NMHE) as 100 mg/m2 weekly. Evaluation of response, after at least 4 injections, was possible in 46 patients. Two complete regressions (of 3 and 12 months) and 7 regressions of over 50 p. cent were observed, a total regression rate of 19 p. cent. Regression was mainly observed in cutaneous or subcutaneous metastases. No objective regression was noted for pulmonary or hepatic metastases. Bone metastases were not taken in account when assessing response to treatment. Absence of haematological changes must be emphasized. The most frequent side effects were anorexia, nausea +/- vomiting and dryness of mouth. Major toxicity was intravascular haemolysis, observed in 6 of 175 patients receiving NMHE in the Institut Gustave-Roussy, always controlled by symptomatic treatment. This product, of acceptable efficacy in breast cancer treatment, will probably occupy an original place in anti-cancer chemotherapy because of its lack of myelotoxicity.

Current trend in the treatment of Hodgkin's disease.

The analysis of three subsequent randomized trials carried out within the frame of the European Organization for Research on Cancer (E.O.R.T.C.) enables to define a strategy for the staging and the treatment of early stages of Hodgkin's disease. Several prognostic factors were identified by multivariate analyses: 1) erythrocyte sedimentation rate, which has a greater impact on relapse-free survival than systemic symptoms but which can be combined with them; the combination of the two is a more powerful prognostic indicator than ESR alone; 2) the number of involved lymphatic areas: patients with one or two lymphatic areas involved (CS I and II2) have a better outcome than stage II patients with 3 or more areas involved (CS II3). Patients with favorable prognostic indicators are submitted to staging laparotomy because for them spleen involvement has a pejorative impact. For patients with unfavorable indicators, the spleen involvement has little prognostic significance and therefore those patients who need, anyway, an aggressive treatment do not undergo staging laparotomy. Patients with favorable prognostic indicators and negative staging laparotomy can be treated by radiotherapy alone, patients with positive laparotomy or patients with unfavorable prognostic indicators are treated by combination of multiple chemotherapy and radiotherapy.

[Chemotherapy in placental tumors]. / La chimiothérapie des tumeurs placentaires.

Chemotherapy is a useful element, but not the only element, for controlling placental tumours. In cases of simple mole routine chemotherapy does not seem to be justified and usually, in 9 cases out of 10, it is useless. It is certainly not always effective and sometimes it may even be dangerous because of the development of chemoresistance. Invasive mole and tumours where a histological diagnosis has not been made and where there is no particularly unfavourable prognosis, usually heal with twice weekly methotrexate carried on for two months after cure has been confirmed clinically, radiologically and biologically. Choriocarcinomata and cases where histology has not been carried out but which have poor prognosis (extra-pulmonary metastases, numerous or large pulmonary metastases, long delay in treatment and the excretion of high levels of HCG) justify chemotherapy in which vincristine is followed by methotrexate or vincristine is followed by actinomycine D. For cure in these bad cases secondary surgery to remove residual lesions, either in the uterus or the lungs, may be necessary.

PIP: The role of chemotherapy in the control of placental tumors is examined, both as a separate, single treatment, and as a conjuctive treatment. Its usefulness is most evident in the latter form of approach. In cases of the simple mole, its use is not really justified, and it does not appear to be effective in 9 out of 10 cases. In any therapeutic approach, it is not always effective and can be dangerous in the event of the development of chemoresistance. In cases of invasive mole and tumors where a histological diagnosis has not been made, and where a definite unfavorable prognosis is not evident, a twice weekly administration of methotrexate for a 2-month period after the cure has been clinically, radiologically, and biologically confirmed usually heals the formations. Choriocarcinomata and cases where a histology has not been carried out but where a negative prognosis is evident (extrapulmonary metastases, pulmonary metastases, delays in treatment, or the excretion of high levels of human chorionic gonadotropin), chemotherapy is considered justified with vincristine followed by methotrexate or actinomycin D. Surgical intervention to remove residual lesions may be necessary in these cases.

[Indications for hysterectomy in placental tumors]. / Les indications de l'hystérectomie dans les tumeurs placentaires.

Indications for hysterectomy in placental tumours are now most often to carry out hysterectomy as a second attack designed to deal with residual lesions of choriocarcinoma that prove resistant to chemotherapy. Of 80 patients treated, 24 were first seen for chemotherapy after hysterectomy and this is too great a number. On the remaining 56 patients we carried out hysterectomy in 8 cases of whom 7 were secondary to chemotherapy. Seven times we found a residual lesion. These patients are now apparently cured.

[Choriogonadotrophic hormone and placental tumors]. / L'hormone choriogonadotrophine et les tumeurs placentaires.

The radioimmunological dosage of choriogonadotrophic hormone is the actual basis for the choice of patients to be treated, to recognize the poor prognosis cases, to adjust the treatment in drugs, doses and durations, to detect the relapses. The clinicien must obey the biologist who is always right.

[Surgical treatment of trophoblastic diseases]. / Le traitement chirurgical des maladies du trophoblaste.

Early diagnosis of a developing hydatidiform mole gives an opportunity to evacuate this by intrauterine suction. This atraumatic procedure which is sure in its outcome has considerably lowered the indications for curettage, for hysterectomy and for hysterotomies. On the other hand, when trophoblastic disease persists chemotherapy is indicated so long as the indications are strictly grounded on biological criteria. The real indication for surgery is found when an isolated focus is resistant to medical treatment.

[The value of cis-diamminedichloroplatinum (cis-platinum) CDDP in the treatment of stage III and IV cancers of the ovary (author's transl)]. / Intérêt du cis-diamminedichloroplatinum (CDDP) dans le traitement des cancers de l'ovaire, stade III et IV.

Cis-diamminedichloroplatinum is remarkably useful in stage III and IV cancers of the ovary. It should therefore be added to the armamentarium of chemotherapeutic substances used up till now. This effectiveness adds extra indication to the use of chemotherapy as a first treatment for stage III cancers of the ovary after the lesions have been reduced as far as possible by surgery.

[Monoclonal antibodies directed against the beta hCG subunit and against a synthetic peptide analog of the carboxyl-terminal end. Clinical use in vivo and in vitro]. / Anticorps monoclonaux dirigés contre la sous-unité beta hCG et contre un peptide synthétique analogue de l'extrémité carboxyl-terminale: utilisation clinique in vivo et in vitro.

In order to detect specifically the beta-hCG, we have produced monoclonal antibodies (Mabs), using as immunogens hCG, beta hCG or a totally synthetic molecule (109-145 peptide) analogous to the beta-subunit carboxyl terminus. 34 fusion experiments were performed and led to 8 Mabs which presented a high reactivity to 125I beta hCG in the screening test. Mab D1E8 was directed to the 1-115 region of beta hCG and was cross reactive with hLH (greater than 60%). Mabs 702, 1032, and 1211 were directed against three different epitopes located in the 109-145 region and were specific for the beta hCG. The in vivo localization of tumors containing beta hCG ty tomoscintigraphy (SPECT) was evaluated in 5 patients by injecting 131I-Mab D1E8, selected for imaging because of its high affinity to beta hCG (Ka = 1.9 X 10(9)). SPECT was performed 48 h and 96 h after injection: 2 patients with proven tumor sites had positive "immunoscintigraphy" results. One patient, simultaneously injected with 125I non-specific IgG, had a tumor resection: the count ratio between normal and tumoral tissues revealed a low specific uptake. Two and three-site immunoradiometric assays (IRMA) were performed with monoclonal antibodies purified from nude mice ascitic fluids. IRMA were based upon two or three Mabs, with D1E8 on a solid phase and 125I Mab 702 or a mixing of 125I-702 and 125I-1032 as tracer. The specificity of IRMA was demonstrated by the absence of binding with increasing amount of hLH, hFSH and hTSH up to 5000 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

[Factors of severity in placental choriocarcinoma]. / Les éléments de gravité dans les choriocarcinomes placentaires.

A retrospective study has been carried out on the poor prognostic features of a group of 57 patients. These are: the existence of extra-pelvic and extra-pulmonary metastases and a level of serum HCG above 200000. The most favourable prognostic signs are absence of these two factors in pregnancy that is not normal and a delay between the onset of the first diagnostic elements and treatment of less than 6 months.

[Isolated hepatic metastases. Treatment by intra-arterial chemotherapy using a subcutaneous access chamber]. / Métastases hépatiques isolées. Traitement par chimiothérapie intra-artérielle par l'intermédiaire d'une chambre d'accès sous-cutanée.

Twenty eight patients with isolated liver metastases of colorectal origin have been treated with discontinuous intra-arterial chemotherapy. This treatment was performed weekly with a surgically implanted subcutaneous access chamber. In all the patients the metastases were non-resectable and involved less than 75% of the liver. The first six patients were investigated in a phase I study which demonstrated that the method was well tolerated and provided a normal life at a lower price than the totally implanted pump. A subsequent phase II study included 22 patients. After implantation, they received an 8-hour infusion of 5 Fu 1 g/m2 each day for 8 consecutive days and after discharge, a weekly 8-hour infusion of 5 Fu 1 g/m2 and mitomycin C 1.5 mg/m2 as out-patients. Twenty-one patients have now been followed up for more than 3 months and are assessable in terms of response: we observed 4/21 complete responses, 6/21 partial responses, 3/21 minor responses, 7/21 stable disease and 1/21 progression. The objective response rate was 48%. The complication rate was low (2 leukopenias and 2 duodenal ulcerations) and comfort excellent with normal life between courses. In conclusion, with discontinuous intra-arterial chemotherapy we obtained the same response rate as with the totally implanted pump, with good tolerance and quality of life and perhaps a lower rate of complication. The two methods should now be compared in a randomized trial.

[Initial chemotherapy in the treatment of inflammatory breast cancers. 230 cases]. / Chimiothérapie première dans le traitement des cancers du sein inflammatoires. 230 observations.

The results of 2 chemotherapeutic regimens used in 170 cases of inflammatory breast cancer were compared with those obtained in 60 historical controls treated with radiotherapy and hormonal therapy. Inflammatory breast cancers could be divided into evolutive phase 2 with limited signs of inflammation and evolutive phase 3 where inflammation involved the whole breast. The 60 controls had been treated between 1967 and 1974 with radiotherapy (45 Gy plus an extra dose of 20 or 30 Gy); premenopausal patients underwent ovarian irradiation. The 91 patients treated with regimen A between 1976 and 1980 received a DVM-type induction chemotherapy (doxorubicin 40 mg/m2 on day 1, vincristin 1 mg/m2 on day 2, and methotrexate 6 mg/m2 on days 3, 4, 5) every 3 or 4 weeks, and a VCF-type maintenance chemotherapy (vincristin 1 mg/m2 on day 1, cyclophosphamide 200 mg/m2 on days 2, 3, 4 and 5-fluorouracil 300 mg/m2 on days 2, 3, 4) every 4 weeks. Premenopausal patients had their ovaries irradiated; postmenopausal patients received tamoxifen. The therapeutic sequence was: 3 DVM - 45 Gy - DVM - 15 Gy - 4 DVM - 4-12 VCF. The 79 patients treated between 1980 and 1982 with regimen B received a DVCMF-type induction therapy (doxorubicin 50 mg/m2 on day 1, vincristin 0.6 mg/m2 on day 2, 5-fluorouracil 300 mg/m2 on days 3, 4, 5, cyclophosphamide 200 mg/m2 on days 3, 4, 5 and methotrexate 10 mg/m2 on days 3, 4, 5) every 4 weeks. Hormonal therapy was the same as with regimen A. The sequence was 3 DVCMF - 45 Gy - DVM - 20-25 Gy - 4 DVM - 4-12 VCF. The survival rate at 3 years was 42% in controls, 53% in regimen A patients and 74% in regimen B patients (P less than 0.05). The relapse-free survival rates in these three groups at 3 years were 15%, 32% and 54% respectively (P less than 0.0008). These results suggest that a multidisciplinary approach and initial chemotherapy are useful in this type of breast cancer. The value of prolonged maintenance treatment is discussed.