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International audience; Le but de l'étude est de caractériser et de modéliser le comportement mécanique cyclique à l'ambiante du magnésium pur extrudé, en particulier sous chargement cyclique. Des essais de traction, compression et des essais cycliques, ont été réalisés (avec de petites déformations, respectivement Δεp/2 = 0,1 % et 0,4 % dans les essais cycliques). Les modes de déformation (glissement, maclage) ont été observés par Microscopie Electronique à Transmission, ce qui a permis de déterminer les cissions résolues critiques. Un modèle de plasticité cristalline s'appuyant sur ces observations a été développé. L'asymétrie de comportement entre traction et compression provient de l'activation de systèmes de glissement (pyramidal et prismatique ⟨a⟩ et pyramidal ⟨c + a⟩) en traction, et de l'activation du maclage en compression. Dans tous les cas, le glissement basal est très facile à activer, même pour de faibles facteurs de Schmid. La simulation numérique montre qu'il faut prendre en compte le démaclage lorsqu'une traction suit un passage en compression afin de modéliser la forme en S des courbes d'hystérésis. Les observations au MET montrent également d'intenses glissements secondaires dans les zones maclées sous chargement cyclique, si bien que tant le maclage en compression que le glissement des dislocations en traction sont impactés par le maclage. Les simulations numériques sont en très bon accord avec l'expérience, pour ce qui concerne les réponses macroscopiques contrainte-déformation, mais également pour la fraction maclée.

A thermal fatigue test (INTHERPOL) was developed by EDF in order to study the initiation of cracks. These tests are carried out on tubular specimens under various thermal loadings and surface finish qualities in order to give an account of these parameters on crack initiation. The main topic of this study is to test the sensitivity of different fatigue criteria to surface conditions using a micro/macro modelling approach. Therefore a 304L polycrystalline aggregate, used for cyclic plasticity based FE modelling, have been considered as a Representative Volume Element located at the surface and subsurface of the test tube. This aggregate has been cyclically strained according to the results issued from FE simulation of INTHERPOL thermal fatigue experiment. Different surface parameters have been numerically simulated: effects of local microstructure and of grains orientation, effects of machining: metallurgical prehardening, residual stress gradient, and surface roughness. Three different fatigue criteria (Manson Coffin, Fatemi Socie and dissipated energy types), previously fitted at a macroscale for thermal fatigue of 304L, have been computed at a meso scale, in order to show the surface “hot spots” features and test the sensitivity of these three criteria to different surface conditions. Results show that grain orientation and neighbouring play an important role on the location of hot spots, and also that the positive effect of prestraining and the negative effect of roughness on fatigue life are not all similarly predicted by these different fatigue criteria.

The low-cycle fatigue behaviour of a nickel-based superalloy has been investigated with regard to its surface damage features. This alloy endures localized plastic deformation confined in slip bands emerging as extrusions. The correlations between damage, grain orientation, the Schmid factor of slip systems and the height of extrusions have been questioned. It is proved here that reaching a critical height value is not a sufficient condition for an extrusion to induce the apparition of a transgranular crack.

Critical comparison of transmission electron microscopy and atomic force microscopy techniques was provided concerning size measurements of γ' precipitates in a nickel-base superalloy. The divergence between results is explained in terms of the resolution limit for atomic force microscopy, linked both to the tip dimension and the diameter of the investigated particles.

Atomic force microscopy was used to study the evolution of surface deformation during cyclic loading in a nickel-base superalloy. Cyclic slip irreversibility has been investigated using quantitative evaluation of extrusion heights and inter-band spacing. This approach is applied to formulate a microscopic crack initiation law, compared to a classical Manson–Coffin relationship.

The prognostic significance of six urinary modified nucleosides, 5-methylcytidine (5-MeCyd), 4-acetylcytidine (4-AcCyd), 1-methylinosine (1-MeIno), 1-methyladenosine (1-MeAdo), 7-methylguanosine (7-MeGua) and pseudouridine (psi-Urd) was evaluated in 68 breast cancer patients of the specialized cancer hospital of Lyon (France). Excretions of 1-MeIno and 1-MeAdo were significantly higher in patients hospitalized in the medical rather than surgical ward, reflecting more advanced disease, and also among patients who died within 5 years of follow-up as compared to those still alive. These results suggest an unfavourable prognostic significance of high urinary excretion of 1-MeIno and 1-MeAdo in breast cancer patients.

International audience; The main purpose of this study is to determine, via a three dimensions Finite Element analysis (FE), the stress and strain fields at the inner surface of a tubular specimen submitted to thermo-mechanical fatigue. To investigate the surface finish effect on fatigue behaviour at this inner surface, mechanical tests were carried out on real size tubular specimens under various thermal loadings. X ray measurements, Transmission Electron Microscopy observations and micro-hardness tests performed at and under the inner surface of the specimen before testing, revealed residual internal stresses and a large dislocation microstructure gradient in correlation with hardening gradients due to machining. A memory effect, bound to the pre-hardening gradient, was introduced into an elasto-visco-plastic model in order to determine the stress and strain fields at the inner surface. The temperature evolution on the inner surface of the tubular specimen was first computed via a thermo-elastic model and then used for our thermo-mechanical simulations. Identification of the thermo-mechanical model parameters was based on the experimental stabilized cyclic tension-compression tests performed at 20°C and 300°C. A good agreement was obtained between numerical stabilized traction-compression cycle curves (with and without pre-straining) and experimental ones. This 3 dimensional simulation gave access to the evolution of the axial and tangential internal stresses and local strains during the tests. Numerical results showed: a decreasing of the tangential stress and stabilization after 40 cycles, whereas the axial stress showed weaker decreasing with the number of cycles. The results also pointed out a ratcheting and a slightly non proportional loading at the inner surface. The computed mean stress and strain values of the stabilized cycle being far from the initial ones, they could be used to get the safety margins of standard design related to fatigue, as well as to get accurate loading conditions needed for the use of more advanced fatigue analysis and criteria.

International audience; The 304L stainless steel is a major component of residual heat removal circuits of pressurized water reactors (PWR).The main purpose of this study is to understand the risk of thermal fatigue damage resulting from the machining of the 304L steel pipes inner surface (pre-hardening gradient, residual stresses and scratches), at the scale of the microstructure. This work is based on previous results obtained for pipe specimens thanks to a macroscopic elasto-visco-plastic model. Applied to the pipe specimens, this modelling showed that a thermal loading with temperature gradient, induced a cyclic non linear biaxial loading at the inner surface of the pipe. In this paper, a polycrystal plasticity model, implemented in a Finite Element (FE) code, is adapted to cyclic loading. An elementary volume (3D aggregate), representing the inner surface and sub-surface of the 304L steel tube, is built from successive polishings and orientation mappings thanks to an Electron Back Scattering Diffraction method. At the grain scale, the polycrystal model is used as a "numerical microscope" to compute the local mechanical fields. Different fatigue criteria are tested to determine their sensitivity to surface properties (roughness, residual stress and pre-hardening) and to the microstructure of the material (crystallographic orientation and grain size). Pre-hardening leads to a lower and more homogeneous distribution of local strain amplitudes in the aggregate, but slightly higher stresses when compared to initial material without hardening. By contrast, surface roughness leads to large localized strain and stress fields in grains located at the bottom of scratches. To determine the surface micro-structural "hot spots" features and to test the sensitivity of different surface conditions, three different fatigue criteria (Manson-Coffin, Fatemi-Socie and Dissipated Energy criteria) have been computed. We point out that the pre-hardening may have a complex effect on fatigue resistance, since it reduces local plastic strain amplitudes, but increases local stresses. Moreover, the pre-hardening has a positive effect on fatigue since it delays damage initiation. By contrast, the surface roughness leads to a negative effect. However, we have shown that the three different fatigue criteria do not deliver similar quantitative predictions. Relevant criteria for high cycle fatigue, such as stress based criteria, are not considered in this paper, since the thermal loading used for computation is large enough to reduce cyclic plastic strain straining within all grains of 304L pipe inner surface for midlife of experiments.

Summary Background Docetaxel, a semisynthetic analog of paclitaxel, made for the needles of the European yew, Taxus baccata, is a potentially important chemotherapeutic agent for the treatment of cancer. Patients and methods In a phase II study patients with advanced and/or metastatic breast cancer and bidimensionally measurable disease, were treated with docetaxel 100 mg/ m2 every 3 weeks as a 1 hour infusion without any premedication. Treatment was evaluated after 2 courses and every 2 subsequent courses. Results Thirty-nine patients were entered, 32 were eligible. The eligible patients had a median age of 51 years (range 30–73) and a performance status WHO 1 median, (range 0–2). Twenty-eight patients had been treated with surgery, 24 with radiation. Hormonal treatment was previously given in 23, chemotherapy in 32. Of 24 patients treated as second line strategy, 13 achieved a partial remission, 1 a complete remission (overall response rate 58% (95% CI 37%-78%)). Eight patients treated as first line: 2 PR's, 1 CR. The median overall response duration was 38 weeks. The main toxicity consisted of transient grade 4 neutropenia in 149 of 167 evaluable courses (89%). However, the related infection rate was low. Re-treatment at 3 weeks, as scheduled, was nearly always possible. Other toxicities consisted of skin reactions (81%) and nail changes (41%), neurosensory toxicity (59%) and occasionally hypersensitivity reactions (16%). Fluid retention was a toxicity of major concern, observed in 59% of patients. Conclusion Docetaxel is a very active drug against breast cancer. Further studies are required to alleviate the non-hematological toxicities.

The antiemetic efficacy and safety of granisetron (40 μg/kg), a selective and potent 5-hydroxytryptamine (serotonin) antagonist, was compared with that of metoclopramide (7 mg/kg) plus dexamethasone (12 mg) in patients receiving fractionated chemotherapy. Patients receiving cisplatin at doses of at least 15 mg/m2 or etoposide at least 120 mg/m2 or ifosfamide at least 1.2 g/m2 on each of 5 consecutive days were eligible. A total of 143 patients received granisetron and 141 received the comparator regimen. The 5-day complete response rate (no vomiting, no worse than mild nausea) for granisetron (46.8%) was equivalent to that for metoclopramide plus dexamethasone (43.9%). The overall 5-day response profile was superior for granisetron (P=0.013) because of fewer failures in this group. The overall incidence of adverse experiences was significantly lower in the granisetron group (60.8% versus 77.3%,P=0.003). Headache and constipation, more prevalent in the granisetron group, are recognized side-effects of serotonin antagonists. Extrapyramidal syndrome, not seen in any granisetron patients, occurred in 20.6% of comparator patients (P

Summary Background The observed activity of cisplatin in breast cancer and its unattractive toxicity profile in palliative treatment warranted further study of platinum analogues in this disease. Patients and methods Sixty-two patients with recurrent or metastatic breast cancer, 61 of whom had been previously treated with chemotherapy, were randomly assigned to therapy with either iproplatin (n = 32) or carboplatin (n = 30). Both platinum analogues were administered intravenously, iproplatin at a dose of 240 mg/m2 every 4 weeks and carboplatin at a dose of 450 mg/m2 every 5 weeks. Results Only two patients responded to iproplatin (7%) for durations of 21 and 61 weeks, and one patient responded to carboplatin (3%) for a duration of 64 weeks. All responses were complete. At the given dose schedules carboplatin was more myelosuppressive than iproplatin. Non-hematologic toxicities included nausea and vomiting (93% vs. 90%), diarrhea (20% vs. 10%) and hemorrhage (16% vs. 10%) for iproplatin and carboplatin, respectively. Two patients developed alopecia with carboplatin. No renal toxicity was observed. Conclusions Both iproplatin and carboplatin have limited activity in previously treated women with advanced breast cancer when given in conventional dosages.

International audience; In the scope of cermet development for structural pieces of future nuclear reactors (1000-1650 degrees C), Mo-TiC(25at.%) was processed by hot isostatic pressure (HIP) and characterized in term of microstructure and chemical composition. The fabrication resulted in a three-phase material so called core/shell microstructure. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses, both coupled with X-ray detection (EDX), allowed to highlight the formation of TiC-Mo(15at.%) phase at the TiC/Mo interface, in agreement with the phase diagram. The formation mechanisms of this phase are discussed. (C) 2009 Elsevier B.V. All rights reserved.

International audience; Simulations of the elastic-viscoplastic behaviour of ceramic-metal composite, over the temperature range 298-993 K, \are performed on realistic aggregates built up from electron back scatter diffraction methods. Physical based constitutive models are developed in order to characterize the deformation behaviour of body centered cubic (bcc) metal and face centered cubic (fcc) ceramic under various temperatures. While the ceramic keeps elastic, the viscoplastic behaviour of the metal part is described with a dislocation - based model, implemented in the finite element code ABAQUS, in order to compute local strain and stress fields during compressive tests. It is shown that the adopted constitutive laws are able to give back local complex experimental evidence on weak points of the microstructure. (C) 2008 Elsevier Ltd. All rights reserved.

International audience; A crystalline modelling of deformation implemented in a finite element code coupled to a recrystallization Cellular Automaton code is proposed and applied to forging processes of superalloys. The coupled modelling is used in order to obtain a better understanding of the microstructural evolution of superalloys during high temperature forging at different strain rates and temperatures. The framework of the modelling is large plastic deformation and large lattice rotation. The used internal variables are dislocations densities on slip systems of the different phases. Modelling is based on viscoplatic constitutive and hardening laws at the scale of the slip systems and describes local strain and stress fields as well as the stored energy and the rotation of the lattice in the grains of the microstructure. At different steps of deformation, formation of subgrains, annihilation of dislocations, nucleation, growth and new orientation of grains are computed. The 3D aggregates representing the superalloy, are built up from Electron Back Scattered Diffraction method (EBSD) by means of a high resolution Scanning Electron Microscope. The phases are identified by means of EBSD, chemical analysis (EDS) and observations with a Scanning Electron Microscope. In this paper the studied aggregate is realised from a semi product of Udimet 720. Such technique is able to give us, a realistic description of the crystalline orientation, morphology and position of grains in the aggregate. The Finite Element meshing is deduced from the EBSD analysis. At high temperature, the Udimet 720 is constituted by a γ matrix with a Face Centred Cubic structure (FCC) and γ' precipitates (Ni3(Ti,Al)) with a Simple Cubic structure (SC). The various material parameters used for the coupled modelling are previously determined from compression tests performed at several strain rate and temperature; The dislocation densities are measured from Transmission Electronic Microscope.

A new methotrexate analog, 10-ethyl-10-deaza-aminopterin (10-EdAM), was found to induce a particular form of skin toxicity different than the skin rash reported to result from methotrexate. At histologic examination, it was found to be a toxic dermatitis that clinically most often first appears on the lower legs but can occur anywhere in the body, especially if treatment is continued. Nine cases are reported. A specific risk factor could not yet be identified. Discontinuation of 10-EdAM administration leads to complete healing; concomitant corticosteroid treatment also induces healing.

The aim of this study is to characterise the mechanical behaviour of composite material: CERamic‐METal. This material is composed of molybdenum‐titanium carbide. A numerical mesoscopic approach is built, which consists in creating a 3D‐ finite element layer by integrating the results produced by the EBSD acquisition performed on the undeformed material. The parameters used for this simulation were identified using a polycrystalline model and an inverse method from experimental results.

Cold drawing steel wires lead to an increase of their mechanical strength and to a drop of their ductility. The increase of their mechanical strength has long been related to the reduction of the various material scales by plastic deformation, but the mechanisms controlling their elongation to failure have received relatively little attention. It is usually found that heavily deformed materials show a tendency to plastic strain localization and necking. However, in this paper it is shown that, though the steel wires are plastically deformed up to strain levels as high as 3.5, a significant capability of plastic deformation is preserved in as-drawn wires. This apparent contradiction is resolved by the existence of residual stresses inside the wire. Finite element analyses have been conducted in order to show that residual stresses, inherited from the drawing process, are sufficient to produce a significant hardening effect during a post-drawing tensile test, without introducing any hardening in the local material behaviour. The main conclusion of this paper is that once the material has lost its hardening capabilities, residual stresses, inherited from the process, control the elongation of cold drawn wires. The finite element method allowed also the determination of the residual stress field that would lead to the best agreement between the simulated and the experimental stress strain curve of as-drawn wires.

International audience; Cold drawing of steel wires leads to an increase of their mechanical strength and to a drop in their ductility. The increase of their mechanical strength has long been related to the reduction of the various material scales by an intense plastic deformation. Besides, it was discussed in the companion paper that large plastic deformation leads to the loss of the material hardening capabilities and that, in such a case, residual stresses preserve the elongation to failure of wires. Experimental measurements of residual stresses inside the wire have therefore been undertaken. In this paper, lattice parameters as measured using synchrotron diffraction are compared with those calculated using the residual stress fields as determined by the finite-element method. There is a major disagreement between experimental and numerical results that is too large to be attributed to the errors of the finite-element analyses. Therefore, neutron diffraction experiments have also been performed. These measurements show that there is a significant variation of the lattice parameter with the drawing level, which is not inherited from residual stresses, and that variation is very sensitive to the cooling rate after processing. It is therefore proposed that cold drawing would induce a phase transformation of the steel, possibly a martensitic transformation.

Heavily drawn eutectoid steel wires are mainly used by the cable industry for applications such as tyre reinforcement, suspension cables or springs. Cables are made by a torsion assembly of wires, which have very high tensile strengths up to 4000 MPa and a level of ductility that has to be sufficient to undergo the torsion assembly process. Needless to say that theses mechanical properties are exceptional, as shows the comparison in figure 1 with those of carbon fibres, well known for their structural reinforcement properties.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m2 plus cyclophosphamide 600 mg/m2, with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P = .44), DDFS (P = .67), or OS (P = .99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P = .01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P < .001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m2 with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

A total of 91 eligible patients with metastatic cancer have been treated in a series of phase II trials of the novel pentacyclic pyrroloquinone, fosquidone. Tumour types were breast (24), ovary (25), head and neck (21) and melanoma (21). All patients, except those with melanoma had received prior chemotherapy. The drug was given intravenously as a 20 min infusion, at the dose of 120 mg/m2 on days 1 to 5 of a 3 week cycle. Treatment was well tolerated; the only significant side-effects being mild headaches and generalised musculo-skeletal pains. Response was assessed after 2 cycles of therapy. Only one patient (with head and neck cancer) achieved an objective partial response, lasting 6 weeks. A total of 12 patients demonstrated stable disease for a median duration of 15 to 20 weeks. Using this schedule of administration, fosquidone has no significant antitumour activity in this group of tumours.

Purpose: The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs. Methods: A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24 h for S9788 determination. Results: The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 ± 23 h and the last plasma sampling time was 48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 × 10–3μM ) before each drug administration. S9788 plasma levels of up to 3.7 μM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced by S9788 coadministration. Conclusion: The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity was observed.

Anaxirone, a rationally synthesised triepoxide derivative, was given to 46 patients with metastatic colorectal cancer. Good risk patients received 800 mg/m(2) as a rapid intravenous injection every 4 weeks, whereas poor risk patients received 650 mg/m(2). Of 46 patients, 45 were evaulable for toxicity and 42 for efficacy analysis. There were 37/45 patients with poor risk, showing no difference in toxicity as compared to good risk patients. The major toxic effect was myelosuppression with 34% of all patients experiencing grade 3 or 4 leucopenia; thrombocytopenia was less frequent. Locoregional phlebitis occurred in 66% of the patients. There was no objective tumour response to anaxirone in 42 evaluable patients. Only 4 patients achieved stabilisation of the disease lasting maximally up to 248 days. Anaxirone is inactive in metastatic colorectal cancer.

Phase II trials of flavone acetic acid have been performed in a total of 87 patients including 17 with advanced breast cancer, 23 with advanced colorectal cancer, 25 with advanced malignant melanoma and 22 with advanced head and neck cancer. Patients with colorectal cancer and melanoma had received no prior chemotherapy; in breast and head and neck cancer patients prior chemotherapy had been given with a median of 5 and 2 drugs respectively. The schedule used was a once-weekly regime, with a dose of 4.8 gms/m2 given as a 1 hour infusion, together with alkalinization (with i.v. sodium bicarbonate) given before and after FAA. Reassessment was performed after 6 weekly doses, although in 23 patients fewer than 6 doses were given, because of early disease progression in 15, and undue toxicity in 5. An additional 3 patients died within 72 hours of having received FAA and, although the precise cause of death in each case was not established, FAA toxicity could not be excluded. Treatment was generally manageable, the major manifestations of toxicity comprising uncomfortable warmth and flushes, nausea, diarrhoea, and visual complaints. Hypotension was also documented in 8 patients. No objective responses were seen in any of the patient sub-groups, although disease-stabilization was seen in 3 patients with breast cancer, 1 patient with advanced colorectal cancer, 2 patients with advanced melanoma and 4 patients with head and neck cancer. Further Phase II studies, using a higher dose of 8.6 gm/m2 over 6 hours once weekly, are currently in progress in Europe.(ABSTRACT TRUNCATED AT 250 WORDS)

PRIMARY CUTANEOUS 33 cell lymphomas (CBCL) are rare, and closely resemble those described in 195 1 by Crosti as reticulohistiocytoma [l]. Patients usually present with localised indolent nodular skin lesions with slow progression and low propensity for extracutaneous spread [2, 31. Because of this favourable prognosis, CBCL have been considered “skin-associated lymphoid tissue” (SALT)-derived lymphoma by a parallel with the lymphomas of “mucosa-associated lymphoid tissue” (MALT) [ 1, 31. Conventional therapy includes surgical excision, electron beam radiation therapy (EBRT) and systemic chemotherapy. All of these are effective, but remissions are mostly transient. To date, the optimum management for localised cutaneous lymphoma still remains controversial. A 53-year-old man presented in 1976 with nodular skin lesions on the left side of the thorax, progressing slowly for 6 years. Histological diagnosis was not certain (lymphocytoma cutis? malignant lymphoma?). One year later, he noticed a rapid increase in the size of the nodules. Histological examination revealed findings compatible with Crosti’s reticulohistiocytoma. He was treated with systemic combination chemotherapy (cyclophosphamide, doxorubicin, VM-26, prednisone) from May 1977 to December 1977, with complete response (CR). A first relapse occurred in May 1978, close to the site of onset. EBRT (32 Gy) led to prompt disappearance of lesions. Radiotherapy was followed by consolidation systemic chemotherapy (cyclophosphamide, vincristine, prednisone) from May 1978 to May 1980. Three years later, the patient developed nodules confined to a circumscribed area of the back. Histological features were compatible with Jessner and Kanof’s lymphocytic infiltration. EBRT (32 Gy) was performed, with clinical CR. He relapsed in the skin outside the initial site involved (but always on the trunk), and outside the previous radiotherapy fields, in 1985, 1986 and 1989. He was re-irradiated and showed good response. He was re-admitted to the hospital in October 1991 because of papulonodular lesions, ranging in diameter from 2 to 6 cm, on the left side of the thorax and abdomen (Fig. 1). Histological examination revealed a diffuse neoplastic dermal infiltrate without epidermotropism. Electron microscope examination confirmed lymphoid cells. Referring to the working formulation for clinical usage, the lymphoma was classified as diffuse small cleaved cells (centrocytic type), intermediategrade. Immunohistochemical data confirmed the B cell nature of the Fig. 1. Clinical presentation in October 1991, showing cutaneous nodules on the left side of the thorax and abdomen.

Sixty-one evaluable patients with measurable advanced malignant melanoma received 4-week courses of a combination of cisplatin 100 mg/m 2 as a 24-hr i.v. infusion on day 1 and vindesine 3 mg/m 2 as an i.v. bolus on days 1, 8, 15 for two courses and every other week thereafter. Two patients achieved complete response for 46 and 81+ weeks respectively, eleven patients achieved partial response for a median of 17 weeks (range 8–26) and three patients had no change for 24 weeks or more. The overall response rate of 21% did not seem to be affected by prior chemotherapy or site of indicator lesions, soft tissue vs visceral. Myelosuppression, consisting essentially of leucopenia, required dose schedule modifications in 41% of the first two courses and 12% of the remaining courses, but never produced major complications. Non-hematologic toxic effects were prominent, especially nausea and vomiting, which were universal. Alopecia was seen in 71% of the patients, neuromuscular manifestations in 39%, diarrhea in 30%, renal impairment in 25%, mucositis in 12%, ototoxicity in 7% and phlebitis in 3%. These results do not suggest striking additive or synergistic antitumor activity of cisplatin and vindesine in advanced malignant melanoma, at least with the method of drug administration selected for this trial.

The single agent activity of chlorozotocin was evaluated in advanced colorectal cancer not previously treated with chemotherapy. The drug was given at a dosage of 200 mg/m 2 i.v. repeated every 6 wk . Of 23 evaluable patients, 2 achieved a partial response lasting 4 and 5 months respectively. With this dosage regimen, chlorozotocin produced essentially nausea and vomiting in one-half of the patients as well as myelosuppression that varied with performance status. Our findings suggest that the therapeutic index of chlorozotocin is similar to that of other conventional nitrosourea derivatives in this disease. However, additional experience is needed to definitely assess how cumulative is their respective bone marrow toxicity.

A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were randomized into two groups; the cisplatin, methotrexate, bleomycin, and vincristine (CABO) group received cisplatin (50 mg/m2; day 4), methotrexate (40 mg/m2; days 1, 15), bleomycin (10 mg; days 1, 8, and 15), and vincristine (2 mg; days 1, 8, and 15) and the ABO group received methotrexate, bleomycin and vincristine in the same doses on days 1, 8, and 15. After three courses, patients in both arms received weekly methotrexate as maintenance therapy; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy +/- surgery. The complete response rate was 16% in patients receiving CABO, compared with 5% among patients given ABO. The corresponding overall response rates were 50% and 28%, respectively (P = 0.003). Among patients with recurrent or metastatic disease, progression was delayed in patients receiving CABO (median, 18 weeks) compared to those receiving ABO (median, 14 weeks) (P = 0.07), but there was no difference in survival time. Myelosuppression consisted mostly of leukopenia, which was seen in 67% of the CABO patients versus 47% in the other arm. Myelosuppression-associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group. Nausea and vomiting, mostly of grades 1 or 2, occurred in 93% of the patients given CABO and 44% of those receiving ABO. Other toxic effects--neuropathy, alopecia, stomatitis, constipation, fever/chills, diarrhea, cutaneous alterations, and renal impairment--occurred equally in the two treatment groups. This study underlines the role of cisplatin in head and neck cancer, although no impact on survival could be demonstrated. It also supports indirectly the superiority of combination chemotherapy over single-agent treatment for this disease.

A combination of cisplatin, methotrexate, bleomycin, and vincristine (CABO) was assessed in advanced epidermoid head and neck cancer. Among 72 patients with recurrent or metastatic disease and measurable lesions, there were 9 complete and 27 partial responses for an overall response rate of 50%. These results were adversely affected by prior surgery plus prior radiotherapy. The median response duration was 28 weeks (16‐l00+) in complete responders and 16 weeks (6‐84) in partial responders. CABO was also administered to 56 patients with measurable, previously untreated, locoregional disease. In these patients, complete and partial response rates were 18% and 46%, respectively. Toxic effects were generally mild to moderate. In spite of its encouraging therapeutic efficacy, CABO is unlikely to be clearly superior to single‐agent chemotherapy, at least in recurrent or disseminated disease. Increased effectiveness of CABO given as initial treatment suggests that chemotherapy might play an effective adjuvant role in carefully selected patients. Copyright © 1984 American Cancer Society

In 1977, the authors described the grid method, a topographic technique for mapping the microscopic spread of breast cancer. The current report describes the relapse-free survival of a series of 203 patients with T2 N- mammary cancer (T2 N0 N1 ab N-) who were treated by mastectomy and regional lymph node dissection and have been followed since 1974. A good prognosis did not prevent relapse in 15% to 20% of patients within the first 5 years. To determine whether the grid method can identify patients at high risk within this group, disease-free survival and survival were compared in two subsets, a "limited" group (L) and a "diffuse" group (D). The difference between the two groups was statistically significant for both parameters (88%) versus 77% and 93% versus 85% after 5 years) (P less than 0.01 and P less than 0.02). Other prognostic measures were uniformative. Thus, the grid method has a good prognostic score when compared with the factors usually measured--menopausal status, estrogen receptors, histologic type--and could be used to select appropriate adjuvant therapy in breast cancer.

A phase II study of iproplatin was conducted in advanced squamous cell carcinoma of the head and neck both in patients previously treated with chemotherapy or not. Iproplatin was given intravenously every 4 weeks at the dose of 240–300 mg/m 2 without hydration. A total of 101 4-week courses was given to 50 eligible patients. No antitumor activity was detected. Drug-induced toxicity consisted in moderate myelosuppression, frequent but mild nausea and vomiting, and occasionally diarrhea and stomatitis. This study demonstrates that iproplatin given in this dose and schedule is devoid of activity in advanced squamous cell carcinoma of the head and neck.

Spirogermanium was given as a 90 minute infusion to 47 eligible patients with refractory Hodgkin's (9 patients) or non-Hodgkin's lymphoma (38 patients). The schedule was 80 mg/m2 three times a week for the first two weeks and 100 mg/m2, 3 times a week, for the two subsequent weeks. In case of response or stable disease, the treatment was continued with biweekly infusions of 100 mg/m2 until tumor progression. In 64% of cases, three or more combinations had been previously administered; 66% of patients presented an extra-lymphatic spread of disease. Two patients with Hodgkin's disease showed a partial response of 11 and 23 weeks and two patients with non-Hodgkin's lymphoma achieved a complete response of 12 and 24 weeks. Overall, 14 patients showed a tumor progression within the first month of treatment. The main toxicity was neurological, with dizziness and lethargy during the infusion in 50% of cases. Hematologic toxicity was almost absent. Spirogermanium is ineffective in heavily pretreated patients with non-Hodgkin's lymphoma. The confirmed lack of activity in patients with refractory malignant lymphoma and the need of repeated and prolonged infusions definitely discourage the clinical use of the drug.

Forty-two patients with malignant melanoma were treated with doxifluridine, 4000 mg/m2 daily X 5, repeated every 3 weeks. The daily dose was reduced to 3000 mg/m2 in patients who had experienced severe myelosuppression with prior chemotherapy. A total of 35 patients were evaluable for response, and 25 of these received two or more courses. Two responses were observed. Toxicity mainly took the form of nausea, vomiting, stomatitis, dizziness, ataxia, and fatigue. Mild leukopenia was frequent (43%). Nadir counts less than 1.5 X 10(9)/l leukocytes or 50 X 10(9)/l platelets were seen in 7% and 2% of the courses respectively. Doxifluridine has no useful activity against malignant melanoma.

Twenty evaluable patients with advanced measurable colorectal cancer received 3-week courses of a combination of IV dacarbazine 300 mg/m2/day from day 1 to day 5 and IV mitomycin 2 mg/m2/day from day 1 to day 5. Fourteen of these patients had had no prior chemotherapy and received two or more courses of this two-drug regimen. None of the patients achieved complete or partial response. Severe to life-threatening myelosuppression, was encountered in patients with prior radiotherapy and or prior chemotherapy, and/or in patients with a Karnofsky score less than or equal to 70. Hematologic toxicity was mild in the other patients. Nonhematologic toxic effects were generally mild to moderate and consisted essentially in nausea and vomiting. It is concluded that in our hands the regimen selected for this trial has no significant antitumor activity in advanced colorectal cancer.

Twenty-two patients with advanced testicular cancer received iproplatin at a dose of 180–240 mg/m 2 every 4 weeks. All the patients progressed or recurred after chemotherapy including cisplatin. The most severe toxicity was thrombocytopenia with two toxic deaths after a first cycle of 240 and 180 mg/m 2 respectively. Nausea and vomiting were almost universal but mild in intensity. One renal failure occurred 6 weeks after the first cycle while the tumor was progressing. No antitumor activity was observed in this heavily pretreated population of patients.

Thirty-four patients with measurable metastatic gastric adenocarcinoma refractory to prior chemotherapy were treated with cis-platinum 100 mg/m2 in a 6-hr infusion at 3-week intervals. Thirty-one patients were evaluable for response. There were three complete and three partial responses. Median duration of response was 4 months. Toxicity consisted mainly of nausea and vomiting and was severe in 12 patients. One patient had a severe but reversible renal failure. These results confirm other data reported in the literature. Cis-platinum has activity in gastric adenocarcinoma and should now be further investigated in first-line chemotherapy.