Allelotype influence at glutathione S-transferase M1 locus on breast cancer susceptibility.

The influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1*A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects > or = 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19-3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23-0.77), P = 0.03].

Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration.

PURPOSE: To determine the long-term impact on disease-free survival (DFS) and overall survival (OS) of adjuvant anthracycline-based chemotherapy, when prospectively compared by random allocation with standard cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive (N+) breast cancer patients. PATIENTS AND METHODS: Two hundred forty-nine patients with N+ breast cancer, recruited from eight French cancer centers, were randomized to receive 12 monthly cycles of adjuvant chemotherapy, either CMF (n = 112) or doxorubicin, vincristine, cyclophosphamide, and fluorouracil (AVCF) (n = 136). All had a negative metastatic work-up before inclusion, which was stratified by accrual center, tumor stage (International Union Against Cancer [UICC]), and menopausal status. RESULTS: No severe adverse effect related to grade 4 (World Health Organization [WHO]) toxicity was observed. There was no difference in second primary tumor incidence between the two arms. The treatment given was 88% of planned for AVCF and 75% for CMF in both premenopausal and menopausal patients. With a median follow-up time of 16 years (range, 13 to 17), the OS and DFS rates are significantly longer in the AVCF arm (56% v 41% [P = .01] for OS, and 53% v 36% [P = .006] for DFS). These differences are significant, irrespective of tumor stage (T1 to T2 v T3 to T4), and remain positive in patients with or without postoperative locoregional radiotherapy (55% of cohort). When analyzed according to menopausal status, the differences remain significant only for premenopausal patients. CONCLUSION: This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.

[Well-differentiated papillary mesothelioma of the peritoneum: an attenuated malignant tumor. Review of the literature apropos of a case]. / Le mésothéliome péritonéal papillaire bien différencié: une tumeur à malignité atténuée. Revue de la littérature à propos d'un cas.

The authors present a new case of a well-differentiated papillary mesothelioma of the peritoneum. This is an uncommon tumor which have a slow evolution like a low malignant potential tumor. But, because of its tendency to recurrence, the designation of Well-Differentiated Tumor is better. The diagnosis with others peritoneal tumors is sometimes difficult, especially with the Peritoneal Serous Tumors. Tumor recurrence must be treated by curative surgery. Adjuvant therapy is discussed for the diffuse form.

Isolation of cDNA clones corresponding to genes differentially expressed in two colon-carcinoma cell lines differing by their tumorigenicity.

In an effort to isolate genes involved in the progression of colonic cells leading to a carcinoma, we used as a model 2 rat colon-carcinoma cell lines selected from the same tumor, differing by their tumorigenicity. When soluble, Triton-X-100 extracted, or cytoskeletal proteins from the progressive PROb cells and the regressive REGb cells were analyzed by SDS-PAGE, minor differences were seen. Furthermore, mRNA-cDNA hybridization analyses showed extensive homology between the 2 mRNA populations. Thus, the homology between the 2 clones is high at both the protein and the mRNA levels. A PROb cDNA library was hybridized with 32P-cDNA synthesized from PROb or REGb mRNA. The clones giving a stronger signal when hybridized with the homologous PROb probe were isolated. The specificity of each clone was confirmed by RNA blotting. Most of the positive clones showed a 2- to 3-fold higher expression in PROb cells when compared with REGb cells. One clone (J 13) corresponded to an mRNA 7- to 10-fold more abundant in PROb cells, and was further studied. No gene amplification was detected by Southern blot analysis, indicating that the difference in mRNA content was most likely due to an increased transcription of this gene in PROb cells. Sequencing of the cDNA showed high homology with the rat ferritin light sub-unit. Over-expression of ferritin in PROb cells as compared with REGb cells was confirmed at the protein level using specific antibodies.

Monoclonal antibodies specific immunotherapy of gastrointestinal tumors.

Monoclonal antibody 17-1A showing cytotoxic properties to GI tract adenocarcinoma cells in vitro and mediating tumor growth inhibition in nude mice, was used as immunotherapeutic agent in 95 patients with various metastatic gastrointestinal adenocarcinomas. Several clinical trials were performed in patients with metastatic disease unaccessible to more conventional therapy of proven efficacy. Results of the different trials are reported here. Tolerance to monoclonal antibody infusion was excellent with minor side effects, except when combinations of several monoclonal antibodies were used. Three complete responses, five partial responses inferior to 50% and 24 stable diseases were noticed. A randomized trial is presently performed in high risk cancer patients with B2 or C colorectal carcinomas with 17-1A as adjuvant immunotherapeutic agent after surgery.

Immunotherapy of gastrointestinal cancer with monoclonal antibodies.

Twenty patients with widespread metastatic colorectal carcinoma were infused with 500 mg of the cytotoxic IgG2a monoclonal antibody 17-1A preincubated with autologous peripheral blood leukocytes. Ten patients showed no benefit from such therapy and ten died, with a mean survival time of 7.6 +/- 4.5 months after treatment and a median survival of 6 months. In ten additional patients, the course of disease was modified by antibody therapy; disease in five of these patients stabilized, while tumor size in the other five patients decreased after therapy. Median actual survival in this group of ten patients is presently 24 months; four of these patients died of disease progression within a mean of 15 +/- 5 months. Duration of response was 10.5 +/- 6.7 months after antibody treatment. Treatment tolerance for these 20 patients was excellent in all but one patient, who experienced an anaphylactic reaction during a second infusion with 17-1A.

Adriamycin, vincristine, cyclophosphamide and 5-fluorouracil (AVCF) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in premenopausal breast carcinoma. Personal results.

Adjuvant treatment of breast cancer with AVCF gave significantly longer disease-free survival than CMF in the group of patients taken as a whole, in the subgroup with lymph node involvement and in the premenopausal subgroup. No significant difference was found regarding overall survival.

Enzyme-linked immunosorbent assay to monitor colorectal carcinoma patients treated with a monoclonal antibody (17-1A).

An enzyme-linked immunosorbent assay (ELISA) was compared to a radioimmunoassay (RIA) for the detection and quantification of mouse monoclonal antibody MoAb 17-1A and for measurement of the host response (i.e. anti-mouse immunoglobulin in sera from patients receiving immunotherapy with MoAb 17-1A. Comparable sensitivity and reproducibility were noted with RIA and ELISA but ELISA was more rapid to perform than RIA. Thus quantitative ELISA compared favorably with the RIA for MoAb detection.

Defect in lectin-induced interleukin 2 (IL-2) production by peripheral blood lymphocytes of patients with Hodgkin's disease.

Peripheral blood lymphocytes (PBL) of patients with Hodgkin's disease were studied for their capacity to produce interleukin 2 upon in vitro phytohemaglutinin stimulation in the presence or absence of either interleukin 1 or indomethacin (2 micrograms/ml); eight patients were studied at the discovery of their disease before receiving any therapy (onset HD; OHD). Seventeen patients were tested in long-term (greater than 3 yr) remission (remission HD; RHD); most RHD were treated with both chemotherapy and irradiation. Fourteen healthy individuals served as controls. PBL from OHD have a significant (P less than 0.01) defect in the production of PHA-induced IL-2. Indomethacin and IL-1 had no effect on IL-2 yield. PBL from RHD yield intermediate levels of IL-2, which are nevertheless significantly lower (P less than 0.02) than control values. RHD recover the capacity of normal PBL to increase their production of IL-2 in indomethacin-supplemented culture medium. Interestingly, PHA responsiveness was significantly decreased only in RHD, thus not explaining the low IL-2 yield obtained in supernatants. In addition, 4-day PHA-blasts from both HD patients and control individuals increase their thymidine incorporation in the presence of purified lectin-free IL-2 to a similar degree, suggesting that their IL-2 receptors are unimpaired. Finally, OHD sera significantly inhibit PHA-induced IL-2 yield of normal PBL, suggesting that a seric component(s) may play a role in some cases. We conclude that defective IL-2 production may play a role in the well-documented deficient cellular immunity seen in Hodgkin's disease.

Immunoscintigraphy of colon carcinoma.

Two I-131 labeled monoclonal antibodies that react specifically with human gastrointestinal cancers in cell cultures were administered to 90 cancer patients for the scintigraphic detection of cancer sites. Antibody 17-1A, or its F(ab')2 fragments, accumulated significantly in 27 of 46 (59%) colorectal cancer sites, but not in 21 nonepitheliomatous colon cancers and cancers at other sites. Antibody 19-9, or its F(ab')2 fragments, showed significant accumulation in 19 out of 29 (66%) colorectal cancer sites. In 17 patients, immunoscintigraphy with antibody 19-9 correlated with an immunoperoxidase study with the same antibody on resected tissue specimens. In 12 patients injected with two antibodies (17-1A + 19-9, or anti-CEA + 19-9), ten of 13 colorectal cancer sites were positive.

[Use of radio-labelled monoclonal antibodies for the scintigraphic detection of human colorectal cancers]. / Utilisation d'anticorps monoclonaux radio-marqués pour la détection scintigraphique des cancers colorectaux humains.

Two monoclonal antibodies, 17-1A and 19-9, which recognized human gastrointestinal cancers in cell cultures, were labeled with iodine 131 for immunoscintigraphic application. With the intact 131I-17-1A antibody, 21 out of 35 (60%) primary or secondary colorectal cancer sites were visualized, whereas all 21 nonepitheliomatous colic cancer sites or noncolic cancer sites were negative. With F(ab')2 fragments of the 19-9 antibody, 18 out of 27 (67%) colorectal cancer sites were positive. With both radioantibodies, the best contrasted tumor images were late, 4 to 5 days after injection. A study with paired-label technique, associating a specific iodine-131-labeled antibody with a nonspecific iodine-125-labeled immunoglobulin, demonstrated, that tumor uptake was indeed specific for the 17-1A or 19-9 antibody in tumor and normal colon fragments obtained during operations on 4 patients. A preliminary prospective study showed that only immunoscintigraphy was able to confirm and localize a recurrence of rectal cancer in one patient. A larger series will be necessary to validate the clinical benefit of the technique, as compared with the results of other diagnostic techniques, before immunoscintigraphy can be proposed for routine clinical use.

Ewing's sarcoma: 5-year survival under adjuvant chemotherapy.

The results at 5 years of an adjuvant chemotherapy trial in primary Ewing's sarcoma, started in 1973, are presented. Twenty-three eligible patients were treated with radiotherapy (60 Gy) to the tumor site and given polychemotherapy either using the E3 protocol (12 patients) or the E76 protocol (11 patients). Overall survival at 5 years was 37%, with 34% disease-free survival. There was no significant difference between the two chemotherapy groups. Only three local relapses and one major orthopedic failure were reported. Among the distal relapses, no metastases to the brain have been observed. These results are encouraging and show a clear improvement over the classical survival rate. However, further improvement is necessary and may be obtained by using new active drugs, as well as earlier and probably more aggressive cyclic chemotherapy. But primary surgical amputation and prophylactic CNS irradiation are not indicated for treatment of primary Ewing's sarcoma.

[Acute myeloblastic leukaemia following Ewing's sarcoma: iatrogenic complication? (author's transl)]. / Leucémie aiguë myéloblastique après sarcome d'Ewing: complication iatrogène?

A seven-year-old child treated for a Ewing's sarcoma of the pelvis with a combination of radiotherapy and sequential polychemotherapy (vincristine, cyclophosphamide, adriamycine and procarbazine), developed an acute myeloblastic leukaemia fourty-one months later. The leukaemia was preceded by a ten-month period of isolated moderate neutropenia. Several possible explanations of the aetiology of this association are discussed, with particular emphasis on current concepts of the histogenesis of Ewing's sarcoma, and more particularly the possible role of radiotherapy and cytotoxic treatment in the induction of acute leukaemia.

[Treatment of Ewing's sarcoma by radiotherapy and adjuvant chemotherapy : results at 3 and 5 years (author's transl)]. / Traitement du sarcome d'Ewing par radiothérapie et chimiothérapie adjuvante : résultats à 3 et 5 ans.

The local treatment of Ewing's sarcoma by radiotherapy is classically linked to a very poor prognosis : 10 to 15% of 5 years survival, 75 to 95% of distant metastasis in 2 years. The combination of local radiotherapy to a systemic adjuvant chemotherapy have been recently shown to give a real benefit to this prognosis. The therapeutic trial of the EORTC and GETO, presented here allows us to hope a disease free survival at 5 years for 50% of our patients and a complete survival at 5 years for 56% of them.

Modulation of antibody synthesis by an anti-tumour alga.

An unicellular alga, Chlorella pyrenoidosa, which had been reported to protect C3H mice against sarcoma BP8, is shown, when injected in Freund's incomplete adjuvant, to modulate the antibody synthesis induced by immunization with a hapten-carrier complex. C. pyrenoidosa appeared to be able to initiate an antigenic competition between hapten and carrier determinants of the antigen molecule during antibody synthesis, and thus it could be speculated that C. pyrenoidosa modulates the immune response at the macrophage level.