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The Faculty of Dental Surgery of the University of Strasbourg would not be the great institute it is today if it were not for an admirable, or rather extraordinary, man: Robert Frank (May 21, 1924-August 7, 2020). He was the first dean of the Faculty of Dental Surgery at the University of Strasbourg, France. He was a dynamic and notorious leader. He brought forward amazing progress-in administration, dental research, and public health at both national and international levels. He was recognized for his top-quality innovative research and elected the 60th president of the International Association for Dental Research (1983-1984). Upon retirement, he continued his commitment to advancing humanity through painting his vision of the microscopic world and developing a "nanoart" vision. Keywords: dental education; electron microscopy; evidence-based dentistry/health care; public health; publishing; scanning electron microscopy.

Resume L’evolution rapide de la pratique de la chirurgie dentaire durant ces dernieres decennies doit amener les praticiens a se poser des questions quant a leur exercice, notamment eu egard aux normes et aux protocoles qui sont crees pour les rehabilitations esthetiques du sourire. En effet, les patients montrent un engouement reel pour l’esthetique dentaire, un enthousiasme permis par l’evolution des techniques attenantes a la dentisterie, et largement relayees par les medias. On observe ainsi une culture du sourire (comme une branche de la culture de l’image), et les chirurgiens-dentistes s’engagent dans la course a la standardisation du sourire en y repondant par l’etablissement de normes et de lignes-guides. Il est important de se demander jusqu’ou va cette normalisation, et si des limites permettraient d’y incorporer de la prudence. C’est d’autant plus necessaire que certaines pratiques ont – deja – cours dans certains pays, comme l’Afrique du Sud. La normalisation du sourire risque bien d’aller a l’encontre de l’ethique si ce n’est pas deja fait.

Objectifs : Trois regions de l’Est de la France ont dresse un bilan des pratiques en matiere de prescription et de consommation de fluor par voie systemique au regard des references de l’Agence francaise de securite sanitaire des produits de sante (AFSSAPS) et de l’Organisation mondiale de la sante (OMS) ainsi que de leur importance en termes de sante publique et d’enjeu medico-economique. En parallele, un etat des lieux de la sante bucco-dentaire de la population etudiee a ete realise.Methodes : Une etude des apports fluores d’un echantillon des enfants de zero a douze ans a ete realisee. Lors d’un examen, effectue par des praticiens-conseils, un outil specifiquement elabore pour cette etude a permis le calcul des apports fluores chez les quatre a douze ans de l’echantillon. Les donnees concernant les prescriptions fluorees et l’etat bucco-dentaire de ces enfants ont ete recueillis aupres des prescripteurs, des familles ou des enfants.Resultats : Les apports de fluor etaient en deca des doses preconisees par l’AFSSAPS/OMS pour 86 % des 0-3 ans, 33,6 % des 4-12 ans avec prescription et 56 % des 4-12 ans sans prescription. En outre, l’observance de la prescription n’etait pas respectee pour 42 % des enfants aux dires des familles. En 2004, pour ces trois regions 622 000 euros ont ete rembourses par le regime general pour dix medicaments fluores par voie systemique. De plus, a 12 ans seuls 45 % des enfants etaient indemnes de caries, plus de 20 % avaient quatre dents cariees, absentes ou obturees et en moyenne deux a trois faces etaient atteintes.Conclusion : La mise en œuvre d’une fluoroprophy-laxie optimale est complexe et insuffisamment maitrisee par les differents acteurs. Le manque d’information concernant le taux de fluor des eaux de reseau et embouteillees apparait comme une des explications.Prat Organ Soins 2008;39(4):297-309

The subcellular plurilocalization of some lectins (galectin-1, galectin-3, galectin-10, calreticulin, etc.) is an intriguing problem, implying different partners according to their localization, and involvement in a variety of cellular activities. For example, the well-known lectin, galectin-3, a lactose-binding protein, can act inside the nucleus in splicing events, and at the plasma membrane in adhesion, and it was demonstrated that galectin-3 interacts in the cytoplasm with Bcl-2, an antiapoptotic protein. Some years ago, our group isolated a nuclear lectin CBP70, capable of recognizing N-acetylglucosamine residues. This lectin, first isolated from the nucleus of HL60 cells, was also localized in the cytoplasm. It has been demonstrated that CBP70 is a glycosylated lectin, with different types of glycosylation, comparing cytoplasmic and nuclear forms. In this article, we have studied the localization of CBP70 in undifferentiated HL60 cells by electron microscopy, immunofluorescence analysis, and subcellular fractionation. The results obtained clearly demonstrated that CBP70 is a plurilocalized lectin that is found in the nucleus, at the endoplasmic reticulum, the Golgi apparatus, and mitochondria, but not at the plasma membrane. Because CBP70, a nuclear glycoprotein, was found to be associated also with the endoplasmic reticulum and the Golgi apparatus where the glycosylation take place, it raised the question: where does the glycosylation of nuclear proteins occur?

The aim of this study was to evaluate the toxicity and the activity of two non-cross-resistant platinum compounds: oxaliplatin (L-OHP) and cisplatin (CDDP) in platinum pretreated ovarian cancer patients. Chemotherapy consisted of L-OHP and CDDP given sequentially as 2 h infusions on day 1 at their standard recommended dose (130 mg/m2 for oxaliplatin, 100 mg/m2 for cisplatin) every 3 weeks. Dose reductions (20-35%) were planned according to baseline haematological and renal status, but the dose ratio between L-OHP and CDDP was always maintained at 1.3. Cycles were repeated until progression or treatment limiting toxicities. From September 1992 to November 1994, 25 patients with pretreated ovarian cancer entered this salvage programme. They had received a median number of three previous chemotherapy lines (1-7), one at least platinum based. Previously cisplatin had been given to 22 patients at a median total dose of 600 mg/m2 (170-1175), while 18 had received carboplatin to a median total dose of 1135 mg/m2 (200-2450). 9 patients had also received and were resistant to taxanes (paclitaxel, 6 patients, docetaxel, 3 patients), while the rest were considered ineligible for simultaneously ongoing single-agent taxane phase II trials. 13 and 12 patients, respectively, were considered to have platinum refractory and potentially sensitive disease, according to Markman's criteria. 77 cycles of L-OHP/CDDP were given, with a median of three cycles/patient (range 1-6) and were evaluable for toxicity. The limiting toxicity of the L-OHP/CDDP combination was a cumulative, sensory peripheral neuropathy, severe (> or = grade 3 CTC) after more than three cycles, but reversible within a few months of its discontinuation. Grade 3-4 (WHO scale) neutropenia and thrombopenia were seen in 35-40% of cycles, with one neutropenic treatment-related death (septic shock). 22 patients with measurable/evaluable disease were assessable for antitumoral activity. Two complete responses (CR) (8%) (one proven histologically at laparotomy (pCR)) and 8 partial responses (PR) (32%) for an overall objective response rate (ORR) of 40% (95% CI, 21-61%) (intent to treat). The median duration of response was 4 months. Seven responses were seen among 12 potentially platinum-sensitive tumours (58%, CI 95% 28-85%), while 3/13 platinum refractory patients (23%, CI 95% 5-54%) had an objective response. These encouraging results are the basis for new first- and second-line combination treatment programmes in ovarian carcinoma.

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.

This study was designed to identify and quantify the number and type of complications relating to the oral environment following piercing of tissue in the oral sphere.The epidemiological survey included patients attending the University of Strasbourg Dental Hospital, students frequenting the University of Strasbourg canteen, and members of the public attending piercing conferences in Strasbourg, France between the months of February and June 2005. No dental examination was performed as part of this survey. RESULTS; 201 people were interviewed in this study. The average subject age was 22.7 years and 73.6% were smokers. Women comprised 72.6% of the sample population. Post-piercing complications occurred in 23.4%, but frequency depended on piercing location in relation to the oral sphere. Gingival recession occurred in 8.5%, and chipped teeth in 6.9% of the group who were aware of complications. Titanium, stainless steel and Teflon were associated with recession in 52.9%, 23.5% and 9%, and chipped teeth in 35.7%, 42.9% and 14.3% of this group respectively.The occurrence of complications was high. There is a need for public education and a further study with a dental examination.

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.

Analysis and design of control process safety of a steam-boilers network simulator, by hybrid Petri nets (HPNs) are presented in this paper. It is shown that for digital control of continuous processes, the use of HPN is particularly adapted. Simulation results demonstrate the efficiency of this approach. >

Our aim was to evaluate the clinical impact of pathology review in an oncology center, in which review is not performed for every patient. This retrospective study involved 100 consecutive patients, whose slides were reviewed in our center. A standardized data sheet was filled out by oncologists for each patient. Pathology review was considered as responsible for a major (35%), moderate (40%), or mild or no (25%) modification of clinical practice. Modification concerned either initial investigations, treatment or medical follow up, and was independent of the reason for which review was performed. Eleven patients underwent a second biopsy. Whatever the possible discrepancies between initial and review diagnosis, our results show that pathological review has a major influence on clinical practice in patients with cancer.

The subcellular plurilocalization of some lectins (galectin-1, galectin-3, galectin-10, calreticulin, etc.) is an intriguing problem, implying different partners according to their localization, and involvement in a variety of cellular activities. For example, the well-known lectin, galectin-3, a lactose-binding protein, can act inside the nucleus in splicing events, and at the plasma membrane in adhesion, and it was demonstrated that galectin-3 interacts in the cytoplasm with Bcl-2, an antiapoptotic protein. Some years ago, our group isolated a nuclear lectin CBP70, capable of recognizing N-acetylglucosamine residues. This lectin, first isolated from the nucleus of HL60 cells, was also localized in the cytoplasm. It has been demonstrated that CBP70 is a glycosylated lectin, with different types of glycosylation, comparing cytoplasmic and nuclear forms. In this article, we have studied the localization of CBP70 in undifferentiated HL60 cells by electron microscopy, immunofluorescence analysis, and subcellular fractionation. The results obtained clearly demonstrated that CBP70 is a plurilocalized lectin that is found in the nucleus, at the endoplasmic reticulum, the Golgi apparatus, and mitochondria, but not at the plasma membrane. Because CBP70, a nuclear glycoprotein, was found to be associated also with the endoplasmic reticulum and the Golgi apparatus where the glycosylation take place, it raised the question: where does the glycosylation of nuclear proteins occur?

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 myelodysplastic syndrome (MDPS) provides an opportunity for identifying host factors (genetic, endocrine, immune) involved in initiation and progression of preleukemia into frank acute myeloid leukemia. The aim of this study was to identify bone marrow (BM) cellular and humoral dysfunctions central to the development of MDPS and useful in therapeutic follow-up studies. Our preclinical studies have shown that (1) the characteristic stromal cell composition of the normal BM microenvironment was impaired in MDPS and in AML in 67 and 86% of the cases, respectively; (2) the 1 alpha,25(OH)2D3 concentration in BM plasma was abnormal in 50% of MDPS and 30% of AML; and (3) an inverse correlation existed in MDPS between the 1 alpha,25(OH)2D3 concentration and the frequency of F-CFU, (r = 0.41, p0.02), suggestive of a regulatory interaction between this secosteroid hormone and BM stromal cells. The analysis of clonal extinction of BM blast cells in response to all trans retinoic acid (RA), 1 alpha,25(OH)2D3, and colony stimulating factors (PHA-LCM), either alone or in various combinations, revealed individual patterns of responses in the cases of MDPS or AML. The results indicate the necessity for preclinical studies to select patients for combined differentiation therapy. Our ongoing clinical trials suggest that RA (Roaccutan, 20 mg/day continuously) as induction therapy, followed at weeks 6 to 8 by prednisone (40 mg/day for 15 days) and 1 alpha,25(OH)2D3 (Rocaltrol, 3 x 0.25 micrograms/day for 3 months) may induce a long-lasting hematological remission in MDPS.

One hundred and eleven patients presenting a breast cancer were treated with intensive and prolonged chemotherapy from 1980 to 1990. Medium age is 50, 2 patients have less than 20 and 5 more than 70. All fulfill selection criteria: no countra-indication to chemotherapy with anthracyclines, cancer diagnosis made with cytology, unmetastasied breast tumor, tumor diameter larger than 2 cm or associated with clinical lymphnode extent. All diagnoses are made with cytology, with cytoprognosis grading and hormonal receptor dosage. If possible, lymphnode punction is performed.

1,2 diamino cychlohexane (trans-I) oxalatoplatinum II was isolated by Kidani among isomeric mixture of DACH derivatives of Platinum as yielding the highest survival increment on L1210 leukemia.

The activity/safety profile of TXT in heavily pretreated MB pts is of interest to the practicing oncologist. Pts char From Aug 1994 to Feb 1995, 29 women with heavily pretreated MBC, have received TXT: 24 pts with 100 mg/and 5 pts with 70 mg/sqm q 3 weeks given with steroids premedication: median age 53 years [42–75]; PS (WHO) 0–1: 16 pts (55%), 2: 9 pts (31%), 3: 4 pts (14%), median time diagnosis first relapse: 28 months (m) [1–216]; median time first relapse/TXT: 40 m [1–164]; Metastatic Sites: liver: 17 pts (58%), bone: 16 pts (55%), lung: 14 pts (48%), skin: 12 pts (41%), lymph nodes: 2 pts (6%), CNS: 4 pts (14%), miscellaneous: 1 (3%). Number of sites/pt: 1: 6 pts (20%), 2: 13 pts (45%), ≥ 3: 9 pts (31%); CA 15-3 was increased in 20 pts (68%). Median nb previous chemotherapy (CT) Unes: 4 [2-11], with anthracyclines 27 pts (93%); 16pts (55%) had also Mitoxantrone; previous hormonotherapy in 25 pts (86%). Toxicity 123 cycles (cy); median (cy) nb/pt: 4 [1–10]; 84 (cy) and 28 (pts) evaluable for hematol Tox, 13 cy (23%) grade III and 44 cy (52%) grade IV neutropenia, 5 cy (6%) grade III–IV thrombocytopenia; 106 cy and 28 pts evaluable for non hematol Tox: asthenia (100%); 5 episodes of mucositis grade III, other Tox: edema: 15 pts (53%) (1 severe); nail changes: 12 pts (42%). Activity 22 pts evaluable (2 early death and 5 too early): 4 PR (6+, 7+, 7+, 8), 11 Minor Response, 7 PD. Median TIP (all pts) 3 months (1–8). Encouraging results and acceptable toxicity in a multitreated cohort confirm the value of TXT and its interest as second or first line treatment in MBC.

We treated 101 patients with advanced (stage III and IV) lymphosarcoma and reticulosarcoma at first presentation of the disease or in relapse according to a protocol combining initial chemotherapy, complementary radiotherapy on icebergs, supplementary chemotherapy, and, finally, active immunotherapy. The overall complete remission rate was about 79% for lymphosarcoma and 73% for reticulosarcoma. About 50% of the patients were still in remission in each of the two diseases at 2 years; 60% of lymphosarcoma and 44% of reticulosarcoma patients achieved 2-year survival. This study shows the prognostic value of the WHO classification for lymphosarcoma and reticulosarcoma: the prognosis of prolymphocytic (centrofollicular) lymphosarcoma is far better than that of the lymphoblastic type, which is in turn better than that of the very poor prognosis of the immunoblastic type. The prognosis of reticulosarcoma is intermediate between that of the best-prognosis and that of the poorest-prognosis type of lymphosarcoma.

Vindesine (VDS) has been submitted to a phase-II trial, the results of which were assessed in terms of regression induction. VDS was given weekly IV in doses of 2 mg/m2 on two consecutive days to 59 patients, 55 of whom were evaluable. A high proportion of complete (36%) and over 50% partial regressions were obtained in acute lymphoid leukemias (ALL) (overall response 63%) whatever the perceptible phase, in blastic crisis of chronic myeloid luekemia (55%), and some responses were recorded in lymphosarcoma (40%). No effect has so far been seen in acute myeloid keukemia or in Hodgkin's disease. Malignant neoplasms of the immunoblastic type seem to be particularly sensitive to VDS. Continuous 48 h IV infusion can induce a remission where an IV push administration of the same dose has failed. One remarkable characteristic of VDS is the apparent absence of cross-resistance with VCR: in acute leukemic forms, 55% of patients who failed to obtain remission induction after three weekly injections of VCR (used in combination chemotherapy) achieved a complete or partial remission with VDS. The toxicity was mainly neurologic (paralytic ileus, constipation, paresthesias, loss of reflexes) and hematologic (leukopenia and thrombopenia), and was not more significant than with the other agents: four patients died of infection or hemorrhage.

To improve influenza vaccine efficacy in hospitalized elderly, we compared the evolution of antibody level after vaccination in three patient groups. A sample of apparently primo vaccinated elderly were randomized to receive either Imuthiol® (Na diethyldithiocarbamate: group I) or a placebo (group P). They were compared to patients who had been vaccinated annually for several years (group C). All patients were immunized in the same week. Antibody responses increase within 15 days to reach a plateau in group P and C, while they continue to increase in the Imuthiol treated group, reaching higher antibody levels 30 days after vaccination. This higher antibody rise in group I is essentially due to higher antibody responses in patients with initially low antibody levels and who exhibited at least a four-fold antibody rise. This effect of Imuthiol on influenza antibody responses was observed in spite of a lower nutritional status in this group, a condition that induces lower antibody responses. The higher antibody responses observed in the Imuthiol treated group allow longer protection against influenza.

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.

The effect of purified diethyldithiocarbamate, DTC (Imuthiol®) on human T-cell dependent functions has been investigated. The mitogenic response of PHA-stimulated peripheral blood lymphocytes (PBL) was significantly enhanced by Imuthiol at low drug concentration (10 −7 mg/ml). The same dose of Imuthiol also stimulated IL2 production by human PBL. This enhancement depended on the presence of adherent cells. These results could, in part, explained the immunostimulant activity of Imuthiol.

Vindesine is a derivative of vinblastine and of vincristine. A high proportion of remissions were obtained in acute lymphoid leukaemia (6 complete and 1 incomplete remissions in 15 patients), in blastic crisis of chronic myeloid leukaemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. Permanent 48 h i.v. infusion may include a remission where i.v. pusch of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukaemia.

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 at different stages was carried out. Proliferating mammary cells in bone marrow were detected using a double-staining method with monoclonal antibodies. Mammary cells were visualized with antibodies raised against human breast tissue or carcinoma. DNA-synthetising cells (S-phase) were detected on the same slide, using the monoclonal antibody antibromodeoxyuridine (BrdU), after cell incubation with BrdU. Mammary cells could be detected in the bone marrow of 60% of the studied cases. In 50% of the samples with such 'micrometastasis', a high labelling index of the carcinoma cells was found. The correlation between the presence of micrometastasis and the general prognosis at the stage of residual disease is discussed.

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 1962, we started a controlled study (the principle of which was based on our experimental data) [19] to compare active systemic immunotherapy (AI) with no treatment for patients with acute lymphoid leukemia (ALL) after stopping their rerhission chemotherapy. The difference in remission duration and survival in favor of AI became significant so rapidly [21] that, for obvious ethical and juridical reasons, we were not authorized to introduce more patients than the 30 already in the trial, nor to perform another trial with controls left without treatment. We recently published two critical discussions of this trial [20, 22].

42 patients suffering from terminal leukaemic lymphosarcoma were treated as acute lymphoid leukaemia patients. 26 entered apparently complete remission (CR). They were submitted to complementary cell reducing treatment comprising systemic and intrathecal chemotherapy and radiotherapy on the CNS and on the lymphosarcomatous masses that had been detected at the beginning of leukaemic conversion. Eight relapsed during this treatment and 18 were still in CR at the end of it: nine were submitted to active immunotherapy (BCG + C. granulosum + irradiated allogeneic leukaemic lymphosarcoma cells): five out of the nine have remained free of disease for between 13 to 66 months. Nine served as controls: all except two, who are still at the beginning of the trial, have already died from leukaemic manifestations.

18 acute myeloid leukemia patients were submitted to a Phase II active immunotherapy trial. The median duration of complete remission (CRD) (60 weeks) and of survival after remission (SAR) (104 weeks) were longer than those for our historical control groups. However, the CRD and SAR curves were not broken to form a "cure expectancy" plateau, as was the case for acute lymphoid leukemia.

Vindesine (VDS) is an analogue of the vinca alkaloids. Its spectrum of antitumoral activity is similar to that of vincristine (VCR), but with milder experimental neurotoxicity, and it inhibits the polymerization of tubulin. Its terminal half-life is 24 h and its plasma clearance is intermediate between those of vinblastine (VLB) and VCR. The maximal tolerated dose is 4–5 mg/m2/week, the dose-limiting toxicity being myelosuppression (nadir by days 7–8 and recovery by days 11–13). It has already been demonstrated as efficient in childhood acute lymphoid leukemia (ALL), non-Hodgkin’s lymphoma, blastic crisis of chronic myeloid leukemia, and esophageal carcinoma. It has also shown activity in Hodgkin’s disease, breast and germ cell carcinomas, and melanoma. Intolerance is mainly neurologic, with paresthesias, without motor impairment, or hematologic, with leukopenia, and sometimes alopecia, asthenia, and muscle pains. The results are better if the patients have not been treated previously; continuous infusion could be of interest and there appears to be no cross-resistance with its parent VCR, as documented in ALL.

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.

Fifty-seven patients with digestive tract tumors or metastatic tumors of unknown origin were treated in a phase II trial with RFCNU [chloro-2-ethyl-1-ribofuranosyl-(isopropylidine-2′-3′-paranitrobenzoate-5′)3-nitrosourea] administered on a two-day schedule. Doses were based on the results of a phase I trial, and ranged from 300 to 350 mg / m 2 . When hematological tolerance was excellent, the dose was escalated to 570 mg / m 2 . In cases of documented bone-marrow intolerance, we decreased the total dose to below 300 mg and even gave only 150 mg / m 2 to one patient. Courses were repeated every month. Three complete remissions (CR) and five partial regressions (PR) were achieved among 57 patients available for assessment of response. The overall rate of major responses (CR + PR) (PR being regressions superior to 50%) was 14%, with a median duration of 9 months . These major responses included 4 cases of liver metastases (including 2 CR) and 3 lung metastases of colorectal carcinoma (one CR). The responses were obtained at doses in excess of 275 mg / m 2 . We also obtained 30% CR + PR in the case of a metastasis of unknown origin. This above evaluation is severe because it only reports major responses according to the WHO-EORTC-NCI recommendation. We also mention in complement 12% responses inferior to 50% in colorectal cancers, one in a stomach carcinoma, one in a hepatoma and 15% more in metastasis of unknown site primary tumors. The hematological toxicity was mild. It consisted of thrombocytopenia 18%, which was only dose-limiting in 3 patients (6%) previously treated with other nitrosoureas. Leukopenia with white cell counts of 1500/ mm 3 was rarely observed. In 32 previously untreated patients, no correlation was found between hematologic toxicity and the number of cycles administered. Nausea and vomiting were noticed in 14% of patients. These results indicate that the efficacy of RFCNU for digestive tract tumors is at least comparable and probably slightly superior to that of other nitrosoureas. Adverse reactions, and mainly with hematological toxicity, were less marked that those observed with BCNU, CCNU or MeCCNU and do not appear to be cumulative.

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.

The authors would remind us that the classification of the hemato-sarcomas is at present being reorganized and that, lymphosarcomas are appearing more and more in the form of disseminated diseases sensitive to chemotherapy as well as radiotherapy. It is highly recommended that first a pre-therapeutic check be carried out in order to classify the disease into one of the five stages before deciding on the therapy. The authors report on the association of radiotherapy and chemotherapy and the role of each as used in their treatment of the disease, at present.

We previously reported the prognostic factors that can be identified at the onset of acute lymphoid leukemia (ALL) [8]. The factors defining the prognosis are, according to our experience: the WHO Reference Center cytologic types (the “prolympho- blastic” type being always poor, the “microlymphoblastic” type good, and the “macrolymphoblastic” and the “prolymphocyte” intermediate [8]); the T-type is always poor, the null, as they were only characterized in our preceding protocols, intermediate [1]; and, in the cases of those above “intermediate” prognosis types, the volume (V) of the neoplasia plays a prognostic role, i.e., V+ (³ 104leukemic cells/mm3) and/or significant clinical masses suggest a poor prognosis [8].

RFCNU or (chloro-2-ethyl)-l-(ribofuranosyl-isopropylidene-2', 3' paranitrobenzoate-5')-3 nitrosourea, a new synthetic nitrosourea derivative, which has been shown to have, in mice, among all nitrosourea derivatives tested, the longest maximallly efficient dose interval (MEDI) and which is not immunosuppressive at the smallest dose of MEDI, gave in a phase II trial on digestive tract tumours (at the dose of 400 mg/m2 per month determined by the phase I trial), 30% objective remissions among which 13% were greater than 50%.

Vindesine, an analog of vinblastine and vincristine, has been submitted to a phase II trial, the results of which are judged in terms of remission induction. A high proportion of remissions were obtained in acute lymphoid leukemia and blastic crisis of chronic myeloid leukemia, and a few responses have been registered in lymphosarcoma and Hodgkin's disease. A continuous 48-hour iv infusion may induce a remission where an iv push of the same dose has failed. The most remarkable characteristic of vindesine is the absence of cross-resistance with vincristine as documented in acute lymphoid leukemia.