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The heterogeneity of therapeutic modalities and eligibility criteria and the lack of long-term follow-up in most reports of neoadjuvant chemotherapy for breast cancer preclude us from drawing conclusions about its value in clinically relevant patient subgroups. The present study aims to identify predictive and prognostic factors in 107 non-inflammatory stage II/III breast cancer patients treated between November 1980 and October 1991 with an anthracycline-based induction regimen before locoregional surgery. Preoperative chemotherapy comprised 3-6 cycles of doxorubicin (pirarubicin after 1986), vindesine, cyclophosphamide and 5-fluorouracil. Type of subsequent surgery and adjuvant treatment were decided individually. In analysis of outcome, univariate comparisons of end points were made using the log-rank test, and significant (P < or = 0.05) pre- and post-therapeutic factors were incorporated in a Cox multivariate analysis. With a median follow-up of 81 months (range 32-164+ months), the median disease-free survival (DFS) is 90.5 months while median overall survival has not yet been reached. Cytoprognostic grade and histopathological response in both the primary and lymph nodes were independent covariates associated with locoregional relapse with or without DFS and overall survival. Eleven patients with pathological complete response remain free of disease with a 68-month median follow-up, while the 18 with residual microscopic disease on the specimen showed a 60% cumulative incidence of locoregional recurrence. Despite encouraging response rates based on clinical or radiological evaluation (87% or 70%), neither method showed any significant correlation with pathological response and failed to contribute prognostic information on patients' outcome. Pathological evaluation of antitumoral activity of primary chemotherapy remains a major source of prognostic information and might be used to select patients in need of additional adjuvant treatment.

Myelodysplastic preleukemic syndromes (MDPS) and acute promyelocytic leukemia (APL) share a surprising in vivo sensitivity to the hormonally acting 13 cis or all trans retinoic acids (transRA). Here we show that transRA as a monotherapeutic agent induced a stable remission in APL at the third relapse. In MDPS, treatment with prednisone and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25D3) 13 cis RA induced a long-lasting hematological remission. Initially both patients had an impaired BM microenvironment which regenerated on retinoid therapy as judged by reappearance of the Hematon fraction in the BM aspirates. Our preclinical experiments using long-term liquid BM cultures (LTBMC) indicated that several individual patterns of growth and differentiation responses can be induced by combinations of transRA, 1 alpha,25D3 and hemopoietic growth factors (HGFs). The biological responses may vary from complete clonal extinction to a significant growth stimulation of the leukemic blast cell populations. These results further support the importance of preclinical studies in selecting "good" responders for, and excluding "poor" responders from protocols using differentiation therapy.

Summary Background: Many patients with advanced NHL ultimately relapse and require salvage treatment. Oxaliplatin, a diaminocyclohexane (DACH) platinum, has shown a differential spectrum of cytotoxicity with cisplatin, with activity in primary or secondary cisplatin-resistant solid tumors (colon and ovarian cancer). We report the tolerance/activity of this platinum derivate in previously-treated NHL patients. Patients and methods: From July 1988 to February 1994, 22 patients (11 men, 11 women) with recurrent NHL received single-agent oxaliplatin (100-130 mg /m 2 i.v. over two hours with antiemetic premedication, q three weeks). All had been previously treated (median number of prior chemotherapy regimens 2, range 1-7) ^ 1 alkylating agent: 22 patients, anthracyclines: 18 patients, cisplatin: four patients, and radiation: 11 patients. Fourteen patients (63%) had progessive disease as best response to their last chemotherapy, and were considered treatment-refractory. All histologies were centrally reviewed in accord with the R.E.A.L. Classification; they were: eight follicular, five MCL, three diffuse large cell, two MALT, one lymphoplasmocytoid, and three other. Results: A total of 144 cycles were administered for a median number of 6 (range 1-30) per patient. The objective response rate was 40% (95% CI: 21-64), including one CR (MCL) and eight PRs (four follicular, two MCL, two MALT). The median response duration was 27 months (range 5-44). Treatment-related toxicity was limited to grade 1-2 nausea/ vomiting and reversible grade 1-2 peripheral neuropathy in most of the patients. Conclusion: Oxaliplatin is an active agent in relapsed/ refractory NHL, including the MCL type. Its safety profile makes this agent a good candidate for the development of combined salvage regimens. Further phase II studies are needed to confirm these preliminary results.

Adult T-cell leukemia/lymphoma is a monoclonal T-cell neoplasm associated with human T-cell lymphotropic virus-1 (HTLV-1) that occurs almost exclusively in adults. This report concerns a Romanian girl who had recurrent skin eruptions since infancy, subcutaneous tumors in childhood, and peripheral blood lymphocytosis, which initially developed at the age of 12 years. The circulating lymphocytes were of helper T-cell immunophenotype. Serologic studies demonstrated a number of HTLV-1 antigens in the child and her mother, and molecular analyses revealed monoclonal T-cell-receptor gamma gene rearrangement and detectable HTLV-1 proviral DNA. Conventional cytogenetic studies revealed a t(3;6)(q23;q27) chromosome translocation in most of the neoplastic cells. The patient initially responded well to interferon alfa therapy and showed regression of skin lesions and diminished lymphocytosis, but 4 years later, she developed massive lymphadenopathy and leukemic infiltration of the breast. At last clinical follow-up, at the age of 17 years, the patient had stable low-level peripheral lymphocytosis and subcutaneous tumors while being continuously treated with interferon alfa. Our review of the literature revealed six additional children with HTLV-1-associated T-cell leukemia/lymphoma, including one case with a similar clinical presentation and ethnic background. To our knowledge, the t(3;6)(q23;q27) translocation identified in this patient's neoplasm has not been previously reported in adult T-cell leukemia/lymphoma cases and may explain the early onset of disease. Although adult T-cell leukemia/lymphoma is rare in Romania, the identification of healthy carriers and vertical transmission raise the possibility that Romania might be an endemic region for HTLV-1 infection.

The lipid-associated sialic acid (LASA) level in serum was increased in 663 out of 794 patients (83.5%) of which 55.1% were CEA negative. There were 16.5% LASA (possibly false) negative, CEA positive patients. There were 24.1% false positives in 116 patients without malignant tumors. In manifest prostatic carcinoma 94.2% of the LASA values but only 36.5% of the prostatic acid phosphatase values were increased. Similarly, in breast and pulmonary carcinoma, LASA was more sensitive than CEA. In 499 patients with minimal residual disease, 203 (41.5%) were LASA-negative, of which 180 were CEA-negative. Out of 180 LASA positive patients, 70 have relapsed, as have 70 out of 219 patients with increases in both LASA and CEA. The sensitivity of LASA (87%) in lymphoma was higher than that of the erythrocyte sedimentation rate (53.3%), of C-reactive protein (51.2%), serum copper (64.7%) and of six other markers.

Scintigraphic imaging due to its sensitivity is in many cases one of the most powerful techniques for demonstrating metastases. Severe limitations still exist in cancer when it is necessary to detect the presence of a few tumour cells in the residual minimal disease. In preliminary experiments it had been observed that an immunomodulator isolated from Nocardia bacteria (Nocardia Soluble Peptidoglycan Derivative: NSPD) electively bound to a model of activated macrophages. An hypothesis has been put forward that the enhanced detection of macrophages that are usually present in the vicinity or inside tumours should represent a polyspecific test for scintigraphy of a variety of metastases. NSPD radiolabelled with 99mTechnetium is not usable when injected intravenously due to its physiochemical properties. It has therefore been encapsulated into liposomes then administered via the respiratory tract as an aerosol. Amphiphilic properties, as well as its low molecular weight allow a rapid diffusion of NSPD in blood. Scintigraphy of metastases was possible from 1.5 to 6 hours after inhalation. The first stage of the study was carried out on 5 patients bearing known metastases (skin, lymph nodes, bone) from malignant melanoma that all were imaged with 99mTc-NSPD. The test was then applied to patients with a high risk of recurrent cancers (melanoma: 6, breast tumour: 7) based on the detection in their plasmas of high Lipid Associated Sialic Acid (LASA) concentrations. The association of these two sensitive techniques has resulted in the detection of very small metastases that were not seen using conventional scintigraphy; they were then confirmed histologically.

A study of 200 patients with breast cancer carcinoma at different stages of the disease, was carried out for detecting in their bone marrow, mammary cells and their proliferative condition using a double labelling method with two types of monoclonal antibodies. The mammary cells were visualised with monoclonal antibodies raised against human breast epithelium and/or carcinoma. DNA synthetising cells (in S phase) were detected on the same slide, using a monoclonal antibody directed against an antigen associated with bromodeoxyuridine (BrdU) after cell incubation with BrdU. Mammary cells could be detected in the bone marrow of 13 out of 20 cases presenting macroscopically visible metastasis, 12 out of 20 patients at diagnosis of their disease, 90 out of 160 patients in apparent disease free condition. The labelling index was 6/13, 6/12 and 45/90 in those respective three groups of patients. The similarity of these three groups for both parameters suggests that the fate of breast carcinoma patients and their prognosis in three types (++, +-, --) is carried from the beginning of the disease. We have, with Eriguchi shown that the mammary (and other) cancer patients survival exponential curves do not express homogeneous populations but are in fact composed of three segments, the first with a rapid slope represents the acute type patients, at high risk of early relapse, the second, with a slow slope, represents the chronic type patients at risk of late relapse and the third, the slope of which is parallel to the general population life expectancy, represents the so called "cured patient".(ABSTRACT TRUNCATED AT 250 WORDS)

The present AML protocol which only applies one anthracycline associated with arabinosyl-cytosine gives a first remission plateau of 65% and a 75% survival plateau at five years. Contrary to other teams, we do not apply the allogenic bone marrow graft at the first remission but at the second one. The new protocol comprises application of two anthracyclines, adriamycin and aclacinomycin, a possible autologous bone marrow graft at first remission upon reinforcement, a combination of methotrexate and thioguanine as maintenance chemotherapy and immunotherapy with bestatine. The two protocols respectively applied to the ALL good prognosis and reserved prognosis, give 85% global survival. The autologous bone marrow graft is added at first remission to B or T forms or voluminous CALLA + types. The advantage of CNS radiotherapy is compared with its disadvantages. Bestatine is employed in immunotherapy. The immunoprevention protocol applied to CML blastic crisis (vaccination with a pool of CB blasts) from the second year has prolonged survival of patients suffering from this affection and also treated by splenectomy and hydroxyurea. Allogeneic or autologous bone marrow graft is added to the protocol. The same protocol is applied to not very aggressive LLC and LNH (lymphocytic and centrofollicular with small cleaved nucleus cells) and includes maximum remission induced by chemotherapy followed by immunotherapy (by thymuline and then, if immunity disorders are not corrected, by zinc, then bestatine and finally tuftsin). A similar sequence was applied to the myeloma, comprising MLP-PDN-CPM chemotherapy to induce remission, combination of MLP-PDN and CPM and, if there is resistance, CLB, 6-TG, PDN and TNP. Interferon is appropriate with certain cytopenic forms. A protocol comprising VCR, ADM, PDN, CPM and TNP is applied to centrofollicular NHL with small non cleaved nucleus cells or large cells. As Hoerni and Jones have obtained significant benefits with BCG, its terminal application is compared with that of bestatine. Finally a less mutagenic protocol than MOPP and/or ABVD is proposed for Hodgkin's disease. In this protocol, two cycles alternate, and they combine: a) firstly VCR, PDN, THP-ADM and VPS, and b) secondly VLB, DXM, ACM and TNP with alternatively BLM and PPM between the cycles. This chemotherapy is followed by the same immunorestoration protocol as that applied to LLC and myeloma.

Oxalato-platinum in a new platinum derivative which was found to be active in experimental tumors and devoid of nephrotoxicity. A phase I study was conducted in cancer patients according to a new design following the recommendations of our Institution's ethical committee to avoid the major drawback of classical phase I studies in which many patients receive the experimental drug at doses far under the potentially active dose extrapolated from experimental studies. The potentially active dose of l-OHP was determined from the Maximally Efficient Dose Range (MEDR) to be between 45 mg/m2 (subcurative dose) and 67 mg/m2 (subtoxic dose). The patients in this study received with increasing intervals 1/100, 1/10, 1/5, 1/3, 1/2, 2/3, 3/4, 1, of the low dose of the MEDR, this dose being reached after 90 to 120 days on study. 23 evaluable patients have entered the trial of which 19 reached the low dose of MEDR (45 mg/m2). Gastro-intestinal toxicity, nausea and vomiting, similar to those with CDDP occurred in all patients at or above the dose of 30 mg/m2. Renal toxicity was monitored with creatinine level and did not occur in any patient at any dose nor did significant hematologic toxicity occur. Thus nausea and vomiting appear to be the limiting toxicity of the drug. Responses were observed in this phase I study in lung cancer (1), breast cancer (1), melanoma (1) and perhaps hepatoma (major decrease in alpha FP levels) (1). The proposed starting dose for phase II studies is 45 mg/m2 but we plan to continue dose escalation during the phase II according to the design of Jones and Holland. This new study design allows each patient entering a phase I study to be treated with a potentially active dose of the drug studied.

Thirty-four patients with cancer (30) or ARC (4) with severe T cell defect or imbalance persisting a long time after completion of any cytostatic treatment were treated by bestatin 30 mg/day 3 days per week during three weeks. The drug has no toxicity of any kind. Reassessment of T cell subsets after completion of bestatin therapy showed a significant improvement of the absolute number of CD4 cells in peripheral blood. CD8 subsets wether initially increased or decreased were modified towards normalisation but the modification reached statistical significance only in the subgroup with initial absolute defect of CD8 cells. CD4/CD8 ratio was significantly increased whether considering all cycles of therapy, or all those given to patients with initially high or normal CD8 subsets. Bestatin appears to have immunomodulating properties which might be useful in cancer patients.

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

Zinc is an trace metal necessary for T cell differentiation and maturation. Forty-two patients, with Aids Related Complex or malignancy in remission and with severe and stable CD4 lymphoid cells cytopenia were submitted to zinc gluconate, 125 mg twice daily orally for three weeks. Reevaluation of T cell subsets one week after the end of zinc intake showed non significant modification of total lymphocyte counts nor of CD4 subsets. CD8 cells however were significantly increased in absolute number in those patients with initially low counts of the cells while they were significantly reduced in those patients with initially normal or high CD8 cells counts. Zinc gluconate in short courses appear to act as a regulator of CD8 lymphoid cells subsets.

(1867). On the spontaneous movements of the leaves of Colocasia esculenta (Schott), and on the ejection of water from them in a continuous jet. Annals and Magazine of Natural History: Vol. 20, No. 119, pp. 384-385.