An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

An EORTC phase I study of epirubicin in combination with fixed doses of cyclophosphamide and infusional 5-fu (CEF-infu) as primary treatment of large operable or locally advanced/inflammatory breast cancer.

PURPOSE: The association of continuous infusion 5-fluorouracil, epirubicin (50 mg/m2 q 3 weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50 mg/m2 [ 1, 2, 3] or 60 mg/m2/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. PATIENTS AND METHODS: Eligible patients had LO or LA/I BC, a performance status 0-1, adequate organ function and were <65 years old. Cyclophosphamide was administered at the dose of 400 mg/m2 day 1 and 8, q 4 weeks and infusional 5-fluorouracil 200 mg/m2/day was given day 1-28, q 4 weeks. Epirubicin was escalated from 30 to 45 and to 60 mg/m2 day 1 and 8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for >7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade > or =3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). RESULTS: A total of 21 patients, median age 44 years (range 29-63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4-6). DLTs on cycles I and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. CONCLUSIONS: This study establishes that epirubicin 60mg/m2 day 1 and 8, cyclophosphamide 400mg/m2 day 1 and 8 and infusional 5-fluorouracil 200 mg/m2/day day 1-21. q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study.

The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, 'Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.

Long- incubation time- interferon-gamma release assays in response to PPD-, ESAT-6- and/or CFP-10 for the diagnosis of Mycobacterium tuberculosis infection in children.

Background:Diagnosis of childhood active tuberculosis (aTB) or latent Mycobacterium tuberculosis (Mtb) infection (LTBI) remains a challenge, and replacement of tuberculin skin tests (TST) by commercialized interferon-gamma release assays (IGRA) is not currently recommended.Methods:266 children between 1 month and 15 years of age, 214 being at risk of recent Mtb infection and 51 being included as controls, were prospectively enrolled. According results of clinical evaluation, TST, chest X-Ray and microbiology, children were classified as non-infected, LTBI or aTB. Long-incubation time PPD-, ESAT-6-, and CFP-10-IGRA were performed and evaluated for their accuracy to correctly classify the children.Results:Whereas both TST and PPD-IGRA were suboptimal to detect aTB, combining CFP-10-IGRA with TST or with PPD-IGRA allowed us to detect all the children with aTB, with 96% specificity for children who were positive for CFP-10-IGRA. Moreover, combination of CFP-10- and PPD-IGRA also detected 96% of children classified as LTBI, but a strong IFN-γ response to CFP-10 (>500 pg/ml) was highly suggestive of aTB at least among children less than 3 years old.Conclusions:Long-incubation time CFP-10- and PPD-IGRA should help the clinicians to identify quickly aTB or LTBI in young children.

The effect of prenatal or early postnatal irradiation on the production of anti-arsonate antibodies and Cross-reactive idiotypes

Preliminary studies on the long-term effects of prenatal and early postnatal irradiation on the immune response to arsonate were performed using A/J mice. Pregnant mice were irradiated (0·5 Gy, X-rays) or sham-irradiated on a single occasion during gestation (between day 5 and 18 post-conception). Alternatively, newborn mice received the same treatment between day 2 and 7 after birth. Mice were immunized with keyhole limpet haemocyanin-arsonate (KLH-Ars) in adjuvant from 2 months after birth. The levels of specific antibodies to arsonate (anti-Ars) were measured by radioimmunoassay. In addition, the Ars-related cross-reactive idiotype (CRIA) was measured by the haemagglutination technique. In the primary response the titre of anti-Ars was reduced in animals that had been irradiated between day 12 and 15 of gestation. In the second response, in contrast, they had increased levels of anti-Ars. After immunization with KLH-Ars, high levels of CRIA were observed in all groups. However, in mice irradiated 18-20 days after conception the level of CRIA was often much higher than the level of anti-Ars, indicating that a large proportion of the CRIA-positive molecules were not specific for Ars. Thus, in this particular case, some specificity of the immune response was lost after irradiation. The expression of recurrent idiotypes may be a sensitive indicator of immunological perturbations after irradiation. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Interactions spatiales et auto-organisation des végétations semi-arides

Les recherches récapitulées dans cette thèse de doctorat ont porté sur les causes de l’organisation spatiale des végétations périodiques. Ces structures paysagères aux motifs réguliers, tachetés, tigrés ou labyrinthiques, d’échelle décamétrique à hectométrique, couvrant des étendues considérables sur au moins trois continents, constituent un cas d’école dans l’étude des processus endogènes présidant à l’hétérogénéité du couvert végétal. Ces structures prennent place sur un substrat homogène, mis à part la rétroaction du couvert lui-même, et sont marquées par des écotones abrupts et la persistance d’une proportion considérable de sol nu. Plusieurs modèles ont mis en avant l’existence possible d’un phénomène d’auto-organisation du couvert, qui verrait une structure d’ensemble émerger des interactions locales entre individus. Ces modèles se basent sur le jeu simultané de la consommation de la ressource (compétition) et de l’amélioration de l’un ou l’autre des éléments du bilan de la même ressource par le couvert (facilitation). La condition à l’existence d’une structure d’ensemble spatialement périodique et stable réside dans une différence entre la portée de la compétition (plus grande) et celle de la facilitation. L’apparition de ces structures est modulée par le taux de croissance biologique, qui est le reflet des contraintes extérieures telles que l’aridité, le pâturage ou la coupe de bois. Le modus operandi des interactions spatiales supposées entre individus reste largement à préciser.

Nos recherches ont été menées au sud-ouest de la République du Niger, à l’intérieur et dans les environs du parc Régional du W. Trois axes ont été explorés :(i) Une étude de la dépendance spatiale entre la structure de la végétation (biovolumes cartographiés) et les paramètres du milieu abiotique (relief, sol), sur base d’analyses spectrales et cross-spectrales par transformée de Fourier (1D et 2D). (ii) Une étude diachronique (1956, 1975 et 1996) à large échelle (3000 km²) de l’influence de l’aridité et des pressions d’origine anthropique sur l’auto-organisation des végétations périodiques, basée sur la caractérisation de la structure spatiale des paysages sur photos aériennes via la transformée de Fourier en 2D. (iii) Trois études portant sur les interactions spatiales entre individus :En premier lieu, via l’excavation des systèmes racinaires (air pulsé) ;Ensuite, par un suivi spatio-temporel du bilan hydrique du sol (blocs de gypse) ;Enfin, via le marquage de la ressource par du deutérium.

Nous avons ainsi pu établir que les végétations périodiques constituent bien un mode d’auto-organisation pouvant survenir sur substrat homogène et modulé par les contraintes climatiques et anthropiques. Un ajustement rapide entre l’organisation des végétations périodiques et le climat a pu être montrée en zone protégée. La superficie et l’organisation des végétations périodiques y ont tour à tour progressé et régressé en fonction d’épisodes secs ou humides. Par contre, en dehors de l’aire protégée, la possibilité d’une restauration du couvert semble fortement liée au taux d’exploitation des ressources végétales. Ces résultats ont d’importantes implications quant à la compréhension des interactions entre climat et écosystèmes et à l’évaluation de leurs capacités de charge. La caractérisation de la structure spatiale des végétations arides, notamment par la transformée de Fourier d’images HR, devrait être généralisée comme outil de monitoring de l’état de ces écosystèmes. Nos études portant sur les modes d’interactions spatiales ont permis de confirmer l’existence d’une facilitation à courte portée du couvert végétal sur la ressource. Cependant, cette facilitation ne semble pas s’exercer sur le terme du bilan hydrique traditionnellement avancé, à savoir l’infiltration, mais plutôt sur le taux d’évaporation (deux fois moindre à l’ombre des canopées). Ce mécanisme exclut l’existence de transferts diffusifs souterrains entre sols nu et fourrés. Des transferts inverses semblent d’ailleurs montrés par le marquage isotopique. L’étude du bilan hydrique et la cartographie du micro-relief, ainsi que la profondeur fortement réduite de la zone d’exploitation racinaire, jettent de sérieux doutes quant au rôle communément admis des transferts d’eau par ruissellement/diffusion de surface en tant que processus clé dans la compétition à distance entre les plantes. L’alternative réside dans l’existence d’une compétition racinaire de portée supérieure aux canopées. Cette hypothèse trouve une confirmation tant par les rhizosphères excavées, superficielles et étendues, que dans le marquage isotopique, montrant des contaminations d’arbustes situés à plus de 15 m de la zone d’apport. De même, l’étude du bilan hydrique met en évidence les influences simultanées et contradictoires (facilitation/compétition) des ligneux sur l’évapotranspiration.

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This PhD thesis gathers results of a research dealing with the causes of the spatial organisation of periodic vegetations. These landscape structures, featuring regular spotted, labyrinthine or banded patterns of decametric to hectometric scale, and extending over considerable areas on at least three continents, constitute a perfect study case to approach endogenous processes leading to vegetation heterogeneities. These patterns occur over homogeneous substratum, except for vegetation’s own feedbacks, and are marked by sharp ecotones and the persistence of a considerable amount of bare soil. A number of models suggested a possible case of self-organized patterning, in which the general structure would emerge from local interactions between individuals. Those models rest on the interplay of competitive and facilitative effects, relating to soil water consumption and to soil water budget enhancement by vegetation. A general necessary condition for pattern formation to occur is that negative interactions (competition) have a larger range than positive interactions (facilitation). Moreover, all models agree with the idea that patterning occurs when vegetation growth decreases, for instance as a result of reduced water availability, domestic grazing or wood cutting, therefore viewing patterns as a self-organised response to environmental constraints. However the modus operandi of the spatial interactions between individual plants remains largely to be specified.

We carried out a field research in South-West Niger, within and around the W Regional Park. Three research lines were explored: (i) The study of the spatial dependency between the vegetation pattern (mapped biovolumes) and the factors of the abiotic environment (soil, relief), on the basis of spectral and cross-spectral analyses with Fourier transform (1D and 2D). (ii) A broad scale diachronic study (1956, 1975, 1996) of the influence of aridity and human induced pressures on the vegetation self-patterning, based on the characterisation of patterns on high resolution remote sensing data via 2D Fourier transform. (iii) Three different approaches of the spatial interactions between individuals: via root systems excavation with pulsed air; via the monitoring in space and time of the soil water budget (gypsum blocks method); and via water resource labelling with deuterated water.

We could establish that periodic vegetations are indeed the result of a self-organisation process, occurring in homogeneous substratum conditions and modulated by climate and human constraints. A rapid adjustment between vegetation patterning and climate could be observed in protected zones. The area and patterning of the periodic vegetations successively progressed and regressed, following drier or wetter climate conditions. On the other hand, outside protected areas, the restoration ability of vegetation appeared to depend on the degree of vegetation resource exploitation. These results have important implications regarding the study of vegetation-climate interactions and the evaluation of ecosystems’ carrying capacities. Spatial pattern characterisation in arid vegetations using Fourier transform of HR remote sensing data should be generalised for the monitoring of those ecosystems. Our studies dealing with spatial interaction mechanisms confirmed the existence of a short range facilitation of the cover on water resource. However, this facilitation does not seem to act through the commonly accepted infiltration component, but rather on the evaporative rate (twice less within thickets). This mechanism excludes underground diffusive transfers between bare ground and vegetation. Inverse transfers were even shown by deuterium labelling. Water budget study and micro-elevation mapping, along with consistent soil shallowness, together cast serious doubts on the traditional mechanism of run-off/diffusion of surface water as a key process of the long range competition between plants. An alternative explanation lies in long range root competition. This hypothesis find support as well in the excavated root systems, shallow and wide, as in isotopic labelling, showing contaminations of shrubs located up to 15 m of the irrigated area. Water budget study also evidenced simultaneous contradictory effects (facilitation/competition) of shrubs on evapotranspiration.