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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.

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.

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.

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.

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.

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].

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.

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.

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].

SummaryLong-term administration of vindesine, included in a maintenance regimen for acute lymphoblastic leukemia (ALL) with poor prognosis, proved to be effective. There was no apparent long-term cumulative neurotoxicity.

Stages III and IV lymphosarcoma (LS) and reticulosarcoma (RS) are disseminated diseases that are typical indications for chemotherapy. Utilizing the drugs vincristine, cyclophosphamide, prednisone (12), adriamycin (6), bleomycin (4), nitrosoureas (5), VM 26 (20), and/or a few others (see [7] and [18]) and combinations of these drugs (8, 9, 10, 21, 22, 23, 24), chemotherapy has been shown to be able to induce a high rate of remission and to significantly but variably prolong survival due to several factors, the major factor being histologic classifications. One group [1] applied Lennert’s classification [11]. Most others used the classic Rappaport classification [25], including in the so-called “histiocytic” type several different types, some of which may have good prognosis, e.g., diffuse large cell prolymphocytic (centrofollicular) LS, some of which may have very severe prognosis, e.g., immunoblastic LS [15], and a few of which may have intermediate prognosis, e.g., RS, as discussed in this paper. The present work assesses the value of the WHO categorization [19] in which 1) tumors of the lymphocytic series are called LS and those of the fixed, so-called mononuclear phagocytes [32] (e.g., reticular cells, dendritic cells), which are not in fact macrophages [see 29, 30, 31], are called RS and 2) types of LS are distinguished according to the cell differentiation stages. Among the common varieties, the prolymphocytic (centrofollicular) nodular or diffuse type, the lymphoblastic type, and the immunoblastic type are recognized.