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Resume Introduction Les carcinomes de la conjonctive sont des neoplasies rares a fort potentiel recidivant. L’obtention d’un bon controle tumoral necessite des traitements adjuvants tels que la cryotherapie, la chimiotherapie locale ou la radiotherapie. Nous presentons la technique et les resultats preliminaires de l’association chirurgie-protontherapie pour la prise en charge de ces carcinomes recidivants et/ou invasifs. Patients et methodes Depuis juin 2001 jusqu’a septembre 2008, quinze patients presentant des carcinomes invasifs ont eu une protontherapie adjuvante apres exerese chirurgicale. Un dispositif specifique de sculpture du faisceau d’irradiation permet une irradiation localisee du site tumoral en preservant au mieux les structures saines adjacentes. Resultats Le suivi moyen des patients etait de 39,1 mois. Selon la classification TNM, ils se repartissaient en 7 T4, 5 T3 et 3 T2 ; ils etaient tous N0M0. Treize patients ont ete controles sur le plan carcinologique. Deux patients ont presente des recidives. Ils presentaient des tumeurs recidivantes multi-operes de grande taille et la protontherapie avait ete realisee plus de 6 mois apres la prise en charge therapeutique initiale. Dans les effets secondaires, il a ete constate des syndromes secs, des cataractes, des dysplasies conjonctivales, des vaisseaux episcleraux dilates inesthetiques, des alopecies ciliaires, une stenose des voies lacrymales et un cas de glaucome unilateral. Conclusion Les traitements classiques ne permettent pas toujours le controle tumoral des carcinomes invasifs recidivants et le traitement final de ces neoplasies reste trop souvent l’enucleation, voire l’exenteration. La protontherapie, si son indication est posee precocement, semble etre un traitement adjuvant efficace qui expose a des effets secondaires acceptables.

PurposeTo evaluate the results of 15 years of experience with proton beam radiotherapy in the treatment of intraocular melanoma, and to determine univariate and multivariate risk factors for local failure, eye retention, and survival.MethodsA total of 368 cases of intraocular melanoma were treated with proton beam radiotherapy at Centre Lacassagne Cyclotron Biomedical of Nice, France, between 1991 and 2006. Actuarial methods were used to evaluate rate of local tumor control, eye retention, and survival after proton beam radiotherapy. Cox regression models were extracted to evaluate univariate risk factors, while regularized least squares algorithm was used to have a multivariate classification model to better discriminate risk factors.ResultsTumor relapse occurred in 8.4% of the eyes, with a median recurrence time of 46 months. Enucleation was performed on 11.7% of the eyes after a median time of 49 months following proton beam; out of these, 29 eyes were enucleated due to relapse and 16 due to other causes. The univariate regression analysis identified tumor height and diameter as primary risk factors for enucleation. Regularized least squares analysis demonstrated the higher effectiveness of a multivariate model of five risk factors (macula distance, optic disc distance, tumor height, maximum diameter, and age) in discriminating relapsed vs nonrelapsed patients.ConclusionsThis data set, which is the largest in Italy with relatively long-term follow-up, demonstrates that a high rate of tumor control, survival, and eye retention were achieved after proton beam irradiation, as in other series.

Nous rapportons le cas d’un homme, âge de 66 ans, monophtalme, avec un probable melanome choroidien de petite taille (epaisseur = 2,2 mm, grand diametre basal = 7,6 mm) concernant la totalite de l’aire maculaire. L’acuite visuelle initiale etait de 7/10e Pa2. Informe des benefices et des risques du traitement, le patient a neanmoins prefere ne pas etre traite et etre suivi regulierement. Au terme de 4 annees d’observation, le volume de la tumeur avait quadruple (epaisseur = 4,3 mm et LTD = 10,4 mm), et l’acuite visuelle etait effondree a 1/20e Pa14, ce qui a convaincu le patient d’accepter un traitement. Plus de deux ans apres une protontherapie, le patient ne presentait pas de metastases. Ce cas clinique souleve la question de la prise en charge du melanome choroidien de petite taille, notamment en cas de localisation retrofoveolaire, en cas d’atteinte d’un œil unique d’une personne d’âge moyen en bon etat general et en cas de conservation de la fonction visuelle : quand traiter, pourquoi traiter et comment traiter ?

Bei grosflachiger, diffuser oder multilokularer Ausdehnung des Bindehautmelanoms kann die Protonenbestrahlung bei bestimmten Indikationen eine mogliche Alternative zur Exenteratio darstellen. Bei ausgedehnten Tumoren kann es in der Folge zu Problemen der Augenoberflache und der Tranenproduktion kommen. In dieser Studie untersuchten wir die Beschaffenheit der Augenoberflache von 10 Patienten, die zwischen 1996 und 2002 mit Protonen behandelt worden waren. Die Patienten wurden im Rahmen der Nachbeobachtung untersucht. Dabei waren 8 der 10 durch Protonenbestrahlung behandelten Falle Melanomrezidive, die zuvor bereits adjuvant vorbehandelt worden waren. Neben der ophthalmologischen Grunduntersuchung wurde eine ausfuhrliche Tranenfilmdiagnostik und Analyse der okularen Oberflache durchgefuhrt. Der Nachbeobachtungszeitraum betrug 17 bis 87 Monate (Mittel 40,9±20,1). Bei 6 Patienten wurden mehr als 50% des Ober- und Unterlids in das Strahlenfeld eingeschlossen. Bei diesen lag in allen Fallen eine mittlere bis schwere Sicca-Symptomatik vor. Die Impressionszytologie der Bindehaut zeigte eine squamose Metaplasie in 9 von 10 Fallen. Die squamose Metaplasie der konjunktivalen Epithelien deutet auf eine radiogene, dauerhafte Differenzierungsstorung der konjunktivalen Zellverbande hin. Die Tranenfilminstabilitat korreliert mit dem Verlust von muzinbildenden Becherzellen und der Atrophie von Meibom’schen Drusen.

Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis. Following a previous phase II study, this phase III multicenter trial was conducted between November 1997 and March 2002.Nontreated, strictly unresectable cases were eligible. Twice-daily radiation: two fractions of 1.2 Gy/day, 5 days per week, with no split (D1--D46). Total tumor doses: 80.4 Gy/46 day (oropharynx), 75.6 Gy/44 day (hypopharynx). Chemotherapy (arm B): Cisplatin 100 mg/m2 (D1, D22, D43); 5FU, continuous infusion (D1--D5), 750 mg/m2/day cycle 1; 430 mg/m2/day cycles 2 and 3.A total of 163 evaluable patients. Grade 3-4 acute mucositis 82.6% arm B/69.5% arm A (NS); Grade 3-4 neutropenia 33.3% arm B/2.4% arm A (p0.05). Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months (p0.01). At 24 months, overall survival (OS), disease-free survival (DFS), and specific survival (SS) were significantly better in arm B. OS: 37.8% arm B vs. 20.1% arm A (p = 0.038); DFS: 48.2% vs. 25.2% (p = 0.002); SS: 44.5% vs. 30.2% (p = 0.021). No significant difference between the two arms in the amount of side effects at 1 and 2 years.For these unresectable cases, chemoradiation provides better outcome than radiation alone, even with an "aggressive" dose-intensity radiotherapy schedule.

But Notre etude a pour objectifs l’analyse de la survie a moyen terme des melanomes interessant le corps ciliaire et des principaux facteurs pronostiques de la mortalite specifique apres traitement. Materiel et methodes Cent six patients (27 localisations ciliaires et 79 localisations choroido-ciliaires), traites entre juin 1983 et avril 1998, ont ete inclus dans cette etude retrospective dont la date de point a ete fixee a janvier 2002. Deux periodes se succedent dans notre service. Avant 1991, tous les melanomes (72 patients) ont ete traites par beta-curietherapie au moyen d’applicateurs de ruthenium-106. A partir de 1991, les melanomes diagnostiques et suivis a Lyon (34 patients) ont ete traites par protontherapie au cyclotron biomedical de Nice. Certaines grosses tumeurs et les recidives ont beneficie d’un traitement additionnel. Resultats Les dimensions tumorales montrent qu’il s’agit essentiellement de grosses tumeurs. En effet, 67 melanomes (63 %) sont des stades T3 de l’UICC. L’epaisseur tumorale moyenne est de 6,6 mm et le diametre maximal moyen de 10,3 mm. Vingt-quatre tumeurs (23 %) depassent 13 mm de plus grand diametre et 48 (45,3 %) depassent 7 mm d’epaisseur. Soixante-onze pour cent des patients sont encore en vie 5 ans apres traitement. Trente-cinq pour cent des patients vont presenter des metastases au long de cette etude. On constate egalement 27,7 % de recidives en nette correlation avec les dimensions tumorales et le traitement par applicateur de ruthenium. Les facteurs de risque consideres comme significatifs sont l’existence d’un decollement de retine exsudatif ou d’une effraction macroscopique de la racine de l’iris au moment du diagnostic, le diametre tumoral superieur a 13 mm et la localisation choroido-ciliaire. Discussion et conclusion Avec 71 % de survie a 5 ans, les melanomes interessant le corps ciliaire semblent effectivement d’un pronostic legerement plus pejoratif que ceux epargnant cette structure. Le diametre tumoral superieur a 13 mm, l’existence d’un decollement de retine ou d’une effraction macroscopique de la racine de l’iris au moment du diagnostic grevent par contre le pronostic en analyse multivariee. Toutefois, on ne peut conclure a une difference de pronostic entre les localisations ciliaires et choroido-ciliaires, les deux populations n’etant pas comparables.

Contexte. - La Federation nationale des centres de lutte contre le cancer (FNCLCC) et les Centres regionaux de lutte contre le cancer (CRLCC), en collaboration avec des partenaires des secteurs public (CHU, CHG), prive et certaines societes savantes ont entrepris, depuis 1993, d'elaborer des recommandations pour la pratique clinique en cancerologie : les Standards, Options et Recommandations» (SOR). L'objectif de l'operation SOR est d'ameliorer la qualite et l'efficience des soins aux patients atteints de cancer en fournissant aux praticiens une aide a la decision facilement utilisable. Objectifs. - Actualiser les recommandations pour la prise en charge des patients atteints de tumeurs malignes des glandes salivaires (lymphomes, sarcomes et melanomes exclus) valides en 1997. Ces recommandations concernent le diagnostic, la classification, le traitement et la surveillance de ces tumeurs. Methodes. - La methodologie d'elaboration des SOR repose sur une revue et une analyse critique des donnees de la litterature scientifique par un groupe d'experts pluridisciplinaire, permettant de definir, sur la base du niveau de preuve scientifique et du jugement argumente des experts, des « Standards », des « Options » et des « Recommandations ». Avant publication, les SOR sont revus par des experts independants. Resultats. - Cet article presente une mise a jour des recommandations concernant la radiotherapie. Les principales recommandations sont les suivantes: ○ la technique d'irradiation peut etre une irradiation conformationnelle avec dosimetrie previsionnelle 3D (avec ou non modulation d'intensite) ou une irradiation 2D; ○ pour les patients ayant eu une chirurgie complete, la radiotherapie postoperatoire aux photons n'est pas indiquee pour les tumeurs de bas grade de stades I et II (standard, niveau de preuve B2); elle est indique pour les tumeurs de haut grade de stades II, III et IV et dans les tumeurs de bas grade de stades III et IV (standard, niveau de preuve B2). La neutrontherapie n'est pas indiquee (standard, niveau de preuve D); ○ pour les patients operes ayant eu une chirurgie macroscopiquement ou microscopiquement incomplete, la radiotherapie postoperatoire est indiquee (standard). La neutrontherapie ou la radiotherapie aux photons peuvent etre proposees (options); ○ pour les patients non operables, la radiotherapie aux photons et la neutrontherapie peuvent etre proposees (options, niveau de preuve B2); ○ pour les patients non resecables et/ou recidivants, la neutrontherapie exclusive ou une chirurgie de reduction tumorale suivie d'une radiotherapie aux photons peuvent etre proposees (options, niveau de preuve C).

Purpose: A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature. Material and Methods: Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together. Results: Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve. Discussion: The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma. Conclusion: The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.

To report the clinical features and outcomes of iris melanomas treated by proton beam therapy. A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon, Department of Ophthalmology, in 36 patients treated by proton beam therapy for presumed (n = 29) and confirmed (n = 7) iris melanomas between July 1997 and October 2010. Ciliary body melanomas with iris involvement were excluded. The patients’ mean age was 54.4 years (range, 22–82 years). The average tumor diameter was 3.8 mm (range, 2.5–8.0). The iridocorneal angle was invaded by the tumor in 47 % of cases (n = 17), the ciliary body in 17 % of cases (n = 6), and the sclera in 3 % (n = 1). Raised intraocular pressure was present before treatment in 11.1 % of cases (n = 4). Tumor biopsy was performed in 19 % of cases (n = 7). Four patients had undergone an initial incomplete surgical excision of tumor before radiotherapy. Surgical preparation of the eye with tantalum ring positioning had been performed in all cases 3–4 weeks before irradiation. The prescribed dose was 60 Cobalt Gray Equivalent (CGE) of proton beam radiotherapy delivered in four fractions on four consecutive days. The median follow-up was 50 months (mean 60.5, range 15–136). One patient (2.7 %) was lost to follow-up. None of the patients showed tumor progression, local recurrence, or metastasis. None of the patients required secondary enucleation. Cataract was developed in 62 % of patients, glaucoma in two cases (6 %) after irradiation, and hyphema with the aggravation of pre-existing glaucoma in one patient. No patients developed neovascular glaucoma. Proton beam therapy appears to be the treatment of choice for the conservative treatment of iris melanomas with excellent tumor control and an acceptable rate of complications. Longer follow-up studies on a larger series is necessary to consolidate these results.

Small choroidal melanomas have a better prognosis than large tumours. However, these small tumours can spread, often late in their course. The aim of the study was to analyse survival and tumour characteristics of six cases of late metastatic diseases after conservative treatment.A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon among 523 patients treated between 1991 and 2010 by proton beam therapy (508) or brachytherapy with 106 (Ru/Rh) (15) for uveal melanomas. We have selected patients with small choroidal melanoma (thickness≤3 mm and diameter≤9 mm) (59 patients), who have developed hepatic metastases (six of 59).At the time of diagnosis, median age was 57 years (range, 37-82 years). The mean tumour thickness was 2.9 mm (range 2.5-3 mm), and the mean diameter was 7 mm (5-8 mm). Orange pigment was observed in four cases, subretinal fluid was observed in two cases, and one tumour touched the optic disc. Five patients had proton beam therapy. One patient had beta brachytherapy (106 Ru/106 Rh). Average follow-up was 8.3 years (range 4.2-11.8 years). None of the six patients developed local tumour recurrence. The mean survival time after diagnosis of melanoma was 9.8 years (range, 4.9-14.6 years). The average time from treatment of primary tumour to detection of liver metastasis was 7 years (range 3.9-12 years). The mean survival time from the diagnosis of metastasis was 35.2 months (range 9-101 months). Small melanoma-related death was 0% at 3 years, 1.7% at 5 years, 5.1% at 10 years and 10.2% at 15 years in our series.Despite a small tumoral size and an early and effective local treatment, six of 59 small choroidal melanomas have developed metastasis after local treatment. Small tumours represent a significant risk of metastasis.

Resume Objectif de l’etude. – Les carcinomes epidermoides non resecables de l’oropharynx et de l’hypopharynx conservent un pronostic defavorable a court ou moyen terme. Plus de 70 % des patients decedent dans les cinq ans de part l’evolution locoregionale. Nous rapportons pour ces tumeurs l’experience du centre Antoine Lacassagne d'une association concomittante de radiotherapie bifractionnee non acceleree et chimiotherapie. L’observance, la toxicite, la reponse tumorale, la survie et la presence d’eventuels facteurs cliniques pronostiques associes a ce traitement ont ete evaluees. Patients et methodes. – Quatre-vingt douze patients consecutifs ont ete pris en charge par ce protocole de mai 1992 a fevrier 2000. Tous etaient atteints d’un carcinome epidermoide pharynge non resecable de stade IV. La radiotherapie de la tumeur primitive et des ganglions satellites a ete delivree par deux faisceaux paralleles opposes, par les photons d’un appareil de telecobaltherapie ou d’un accelerateur de 4 a 6 MV, a raison de deux fractions de 1,2 Gy/j, cinq jours par semaine, sans interruption en cours de traitement. Une dose totale de 80,4 Gy a ete delivree aux cancers de l’oropharynx en 46 jours et de 75,6 Gy en 44 jours a ceux de l’hypopharynx. La chimiotherapie a consiste en une administration de deux a trois cycles, tous les 21 jours, de cisplatine a la dose de 100 mg/m 2 , et de 5-fluoro-uracile en perfusion continue sur cinq jours a raison de 750 mg/m 2 /j (1 er cycle), 430 mg/m 2 /j (2 e et 3 e cycles). Une attention particuliere a ete accordee aux soins complementaires en cours de traitement, tels que la mise en place systematique d’une nutrition enterale et un traitement de la mucite par laser de basse energie. Resultats. – En dehors de deux deces precoces lies au traitement, la toxicite aigue, bien que significative (mucite de grades III et IV de l’OMS : 89 % dont 16 % de grades IV, epithelite de grade III de l’OMS : 72 %, neutropenie de grade III et IV : 61 %) n’a pas ete une cause d’interruption de traitement de plus d’une semaine, grâce notamment aux soins complementaires. Le taux de reponse complete a six mois etait de 74 %. Les taux actuariels de survie globale etaient respectivement a un et deux ans de 72 et 50 % avec un recul median de 17 mois. Les facteurs pronostiques de la survie globale etaient l’etat general (taux de survie globale a trois ans de 71 % si l’indice de Karnofsky du patient etait entre 90 et 100 %, 30 % s’il etait de 80 %, 0 % enfin s’il etait entre 60 et 70 %, p = 0,0001) et la localisation tumorale (taux de survie globale a trois ans de 28 % en cas de cancer de l’hypopharynx, 37 % en cas de cancer du panpharynx et 55 % en cas de cancer de l’oropharynx, p = 0,009). Conclusion. – L’analyse de ces resultats a confirme l’efficacite de la radiotherapie bifractionnee non acceleree concomitante a la chimiotherapie par cisplatine et 5-fluoro-uracile sur ce type de tumeur particulierement evoluee. Quant a l’etat general du patient avant traitement, seule une prise en charge nutritionnelle efficace peut conduire a une optimisation des conditions de realisation et de succes du protocole.

Resume Dans le traitement des tumeurs des glandes salivaires, si la radiotherapie par rayonnements a faible transfert d'energie lineique (photons, electrons) associee a une chirurgie microscopiquement complete fait passer le taux de controle local de 34 a 74%, des resultats interessants sont beaucoup plus difficiles a obtenir pour les tumeurs localement evoluees, et le plus souvent le traitement reste palliatif. Dans ce travail, toutes les analyses des series publiees sur les tumeurs des glandes salivaires inoperables ont ete revues. Dans ces situations, elles montrent globalement un taux de controle local persistant de 31 % avec les photons contre 64 % avec les neutrons rapides. Un essai prospectif randomise a ete mene par le Radiation Therapy Oncology Croup et le Medical Research Council. Cet essai a ete interrompu pour desraisons ethiques liees a l'evidente superiorite du bras neutron. Les resultats publies en 1988 et revus en 1993 indiquent des taux de controle local de 67 % avec les neutrons contre 17 % avec les photons ( p

Despite the fact that fast neutron irradiation of glioblastoma has shown on autopsies an ability to sterilize tumors, no therapeutic windows have been found for these particles due to their toxicity toward normal brain. Therefore, the Boron Neutron Capture Enhancement (BNCE) of fast neutron beam has been suggested. This paper addresses the problem of fast neutron beam collimation, which induces a dramatic decrease of the thermal neutron flux in the depth of the tissues when smaller irradiation fields are used. Thermoluminescent dosimeter TLD-600 and TLD-700 were used to determine the thermal neutron flux within a Plexiglas phantom irradiated under the Nice Biomedical Cyclotron p(60)+Be(32) fast neutron beam. A BNCE of 4.6% in physical dose was determined for a 10×10 cm2 field, and of 10.4% for a 20×20 cm2 one. A Dose Modification Factor of 1.19 was calculated for CAL 58 glioblastoma cells irradiated thanks to the larger field. In order to increase the thermal flux in depth while shaping the beam, heavy material collimation was studied with Monte Carlo simulations using coupled FLUKA and MCNP-4A codes. The use of 20 cm width lead blocks allowed a 2 fold thermal neutron flux increase in the depth of the phantom, while shielding the fast neutron beam with a fast neutron dose transmission of 23%. Using the DMF of 1.19, a BNCE of 40% was calculated in the beam axis. This enhancement might be sufficient to open, at least theoretically, a therapeutic window.

La reponse des cellules tumorales humaines a l'irradiation in vitro par des particules de TEL eleve depend de plusieurs facteurs. Pour les particules chargees, la radiosensibilite augmente avec le TEL jusqu'a des valeurs de TEL voisines de 200 KeV/μm, puis diminue pour des valeurs de TEL superieures. En clinique, l'augmentation du TEL moyen de la particule chargee en profondeur est responsable d'une efficacite biologique relative (EBR) croissante. La probabilite de mortalite de la cellule par une particule traversant le noyau est proche de 1 pour les particules de TEL tres eleve comme l'Ar de 7 MeV par nucleon (TEL = 1500 KeV/μm); elle n'est que de 0,02 pour les ions d'O de 400 MeV (TEL = 20 KeV/μm). L'EBR est plus elevee pour les petites doses, la relation EBR/dose etant plus marquee dans les cellules ayant un rapport α/β plus faible apres exposition aux photons, selon le modele lineaire-quadratique. Les particules moins efficaces que les photons en terme de mortalite cellulaire moyenne induisent des degâts individuels importants, reveles par la production de micronoyaux (MN) multiples. Concernant le lien entre l'EBR et la radiosensibilite intrinseque, les donnees recentes utilisant a la fois la technique des colonies et la methode des MN, montrent que l'EBR est d'autant plus elevee que les cellules sont radioresistantes aux photons.

Les tumeurs cerebrales de haut grade gardent un pronostic effroyable bien qu'elles ne metastasent pas. L'utilisation de neutrons rapides a permis des sterilisations, mais elle s'est heurtee a la grande radiosensibilite des tissus cerebraux sains. Une perspective nouvelle est representee par l'utilisation des captures de neutrons sur le Bore-10 ( 10 B), c'est-a-dire par la creation selectivement a l'interieur des cellules tumorales de reactions nucleaires avec emission de particules a en surdosage dans un faisceau de neutrons rapides. L'utilisation de ces reactions pourrait permettre une amelioration de l'index therapeutique des neutrons rapides, sous reserve que des teneurs superieures a 100 μg/g de 10 B puissent etre obtenues dans les cellules tumorales.

The aim of the present study was to check whether platinum (Pt) concentrations achieved in tumors with a daily low-dose schedule were close to those promoting radiosensitization. Fifteen previously untreated patients with histologically proven advanced uterine cervix tumors were studied. They received a daily irradiation 30 min after a short infusion of 5 mg cisplatin for 5 consecutive days every week. A biopsy was taken from the accessible tumor mass, 4 to 6 hr after the daily injection. Blood samples were obtained once a week, just before the daily injection (H0) and 30 min after (H30). Quantificative analysis of Pt concentrations was performed by atomic absorption spectrophotometry. Plasma and tumoral Pt concentrations exhibited a marked intersubject variability. The median tumoral Pt concentration was 1,710 mg/g. Median total and ultrafiltrable Pt concentrations in plasma taken at H0 and H30 were 231 and 360 ng/ml, and 7 and 90 ng/ml respectively. Tumoral and total plasma Pt concentrations significantly increased during the course of treatment. Present data show that tumoral Pt concentrations achieved with this CDDP schedule are in the range of tumoral Pt concentrations previously shown to promote radiosensitization (2,000 ng/g). These results suggest that this CDDP radiosensitization regimen might be started with higher CDDP doses in order to reach earlier radiosensitizing Pt tumoral concentrations.

In an effort to clarify the relationship between sensitivity of human tumour cells to low-LET and to fast neutron irradiation, 10 human tumour cell lines were exposed to cobalt gamma-rays and to 60 MeV (p -Be+) neutron beam. The data were pooled with results of 31 human tumour cell lines previously published. The analysis of date using the linear-quadratic model indicated that not only alpha values increased after neutron irradiation, but so did beta values too, although to a lesser extent. The mean inactivation dose (MID) was derived for each cell line from the linear-quadratic parameters after low-LET and high-LET exposure. MID values following neutron irradiation were closely correlated to those after gamma-ray irradiation. In these 41 cell lines, the extreme values of RBE derived by the ratio of MID varied by a factor of 3 among the cell lines. RBE was positively correlated to photon MID, meaning that intrinsically radiation resistant tumour cells have a higher neutron RBE, on average. Similar findings were observed if alpha ratios were used instead of MID ratios. In addition, the RBE/dose variations were more marked in cells with the higher RBE. Taken together, these data suggest that, although considerable variations exist among human tumour cell lines, intrinsically radioresistant cells are relatively more sensitized when exposed to high LET beams than radioresponsive tumours. An 'intrinsic gain factor' may thus be expected in irradiating radiation resistant tumours with fast neutrons, in addition to the hypoxic or kinetic gain factors. Because the quadratic component is still present after neutron irradiation, we suggest using MID ratio as a reference RBE when comparing survival curves of cells exposed to radiations of different qualities.

Summary The proton therapy facility of the Centre Antoine-Lacassagne in Nice began treatment of ocular tumors in June 1991. Up to October 1995, a total number of 600 patients were treated. An overview of the cases treated during the first 4 years of activity is given and the main problems encountered in the field, possibly interacting with the accuracy and reliability of the dose distribution, are listed.

The radiation protection calculations used to determine the wall thicknesses of the structure housing the accelerator, the proton and the neutron treatment areas at the Biomedical cyclotron of Nice are presented. The results were obtai­ ned from different equations and methods taken from the literature. The paper gives the characteristics of the entrance labyrinths to the treatment rooms. These labyrinths allowed the suppression of heavy motorized doors which tend to slow access and frighten patients. The problem of radioactivity of air caused mainly by interactions of neutrons with the different air compounds are discus­ sed. The necessary ventilation system for the cyclotron bunker, the beam line and the treatment rooms is described. This paper does not address all the aspects of radiation protection and safety precautions for cyclotrons.

Little is known about the action of charged particles of very high linear energy transfer (LET) on human cells and, in particular, the relationship between DNA damage and reproductive death. The aim of this study was to measure the biological efficiency of a low-energy argon beam (E = 7.1 MeV/nucleon, LET = 1590 keV/micron) produced at GSI, Darmstadt, on a human melanoma cell line (CAL4) established in our Institute. Two different methods were used: the micronucleus (MN) test and the colony-forming assay. The MN test, using the cytochalasin-block method, is a measure of genotoxic damage. MN are scored in binucleate cells (BNC) and are formed from acentric fragments or whole chromosomes that have not been incorporated into daughter nuclei at mitosis. The colony-forming assay quantifies reproductive death. Parallel experiments were run with cobalt gamma-rays for comparison. After Co irradiation, the MN-free BNC dose-response curve coincided with that of the loss of colony-forming ability, suggesting the potential of the former as a predictive test of cell killing. After Ar irradiation, there was a dissociation between the two effects, especially at high doses: cell death was greater than the frequency of BNC with MN. The inactivation cross-section was 74 microns2; it was 39 microns2 for MN yield. Therefore, the relative biological effectiveness (RBE) was higher for cell killing than for MN yield (0.8 and 0.5, respectively at a Co dose of 3 Gy). The total MN count in BNC followed the same pattern of response as the fraction of BNC with MN.(ABSTRACT TRUNCATED AT 250 WORDS)

Resume Le developpement de la protontherapie est conditionne par deux facteurs: la demonstration de son efficacite dans le traitement de tumeurs frequentes et surtout son cout. Actuellement le prix d'une installation neuve telle celle en cours de realisation a Boston est de l'ordre de 100 millions de francs. Le cout de l'accelerateur intervient pour le quart de cette somme, un autre quart est pour la ligne de faisceau, le reste va a la tete isocentrique et au bâtiment. Il existe d'autres options. Il faut un generateur moins cher et surtout plus compact pour diminuer les couts induits. Differents projets en developpement en France sont en cours d'evaluation.

Radiation therapy with positively charged particles implies that the Bragg peak be spread out to deliver a homogeneous dose to the tumour. The spread-out Bragg peak (SOBP) has a higher linear energy transfer (LET) than the entrance beam. In addition, there is an LET gradient from proximal to distal SOBP. The aim of this study is to find out whether these small LET variations lead to differences in radiation response. Human melanoma cells (CAL4) were exposed to 65 MeV proton beams produced by the cyclotron Medicyc at five different positions: 2 mm depth corresponding to the entrance, 15, 20, 25 and 26.8 mm depth corresponding to four different positions in the half-modulated SOBP. Survival curves were generated using the in vitro colony method and fitted with the linear-quadratic model. Survival differences were observed at high doses; they were statistically significant at a dose of 8 Gy. With respect to the entrance position (2 mm), the relative biological effectiveness (RBE) at 1% survival was 1.09, 1.12, 1.19 and 1.27 at 15, 20, 25 and 26.8 mm in the SOBP, respectively. Whereas RBE values in the SOBP greater than 1.0 relative to the entrance beam represent a small biological advantage to be added to the well-known physical advantage of high energy proton beams; the RBE gradient along the SOBP would imply that the distal end of the tumour would receive a higher biologically equivalent dose than the proximal end, despite a homogeneous physical dose, especially at the high doses per fraction given in ocular melanomas. Although the increase in effectiveness with depth is mild, it should be kept in mind during eye treatment planning, in case a critical target is present at the extreme end of the SOBP.

From September 1983 to September 1987, 238 patients with squamous cell carcinoma of the upper aerodigestive tract were given 3 cycles of chemotherapy [cisplatinum (cis-DDP), 100 mg/m2 on day 1; 5-fluorouracil (5-FU), 1,000 mg/m2 on days 2-6] before any local treatment. Eighty-one of these patients had pharyngolaryngeal cancer. Of the 45 of 50 laryngeal cancers and 26 of 31 hypopharyngeal cancers suitable for evaluation, complete responses (CR) were obtained in 51.1% and 53.8%, respectively. These response rates led to changes in the postchemotherapy protocols. For CRs, mutilating surgical protocols were replaced by definitive radiotherapy: one local recurrence has been observed among the 9 laryngeal cancers, and 3 of 10 hypopharyngeal cancer patients, who had an initial indication of total laryngectomy or total pharyngolaryngectomy replaced by radiotherapy. In the group of CR, survival rates at 2 years were 93% and 69%, respectively, for the larynx and hypopharynx vs 65.6% and 40% for non-CR patients. The possibility of conservative treatment sparing vocal function with a high degree of reliability would in itself appear to be justification for induction chemotherapy in pharyngolaryngeal cancers, even though its long-term effects remain controversial.

Summary The organization of a networking for patient recruitment is a main concern for a new facility using charged particles. The experience of choroidal melanoma in Nice demonstrates the possibility to create “de novo” a protontherapy center treating a sufficient number of patients. The influence of the opening of new facilities is analyzed.

Diffuse and multifocal patterns of conjunctival melanoma may not be treatable with standard eye-sparing methods. The purpose of this study was to evaluate the usefulness of proton beam radiation therapy as an alternative to exenteration. Twenty patients with extended conjunctival melanoma were treated by proton beam irradiation. Most cases were T3 tumours which were not accessible to brachytherapy due to their extension, localisation with fornical or caruncular involvement. Only 2 patients had a tumour limited to the bulbar conjunctiva. Both were recurrent tumours with multiple lesions. Sixteen cases were recurrences after various pre-treatments. The area of the conjunctiva which was suspected to have microscopic disease was treated by 31 Gy in 6 fractions. The “high risk” areas with a clinically detectable tumour (primary target volume) were treated by an additional boost using a smaller beam size and applying 2 fractions up to 45 Gy. An individually shaped compensator was brought into the beam to modify the range of the protons so that the eye was irradiated only at a depth of 2 mm. The mean follow-up time was 38.1±26.6 months (median 34 months). Recurrent disease occurred in 6 cases (30%); 2 of them outside the irradiated volume, 3 within the target volume treated by 31 Gy, and just one in the primary target volume treated by 45 Gy. An exenteration followed only in two patients (10%). 6 patients (30%) suffered from metastatic disease and 4 (20%) of them have died by now. During follow up we found no statistically significant association between the occurrence of local recurrence after proton radiotherapy and the development of metastases. Best corrected visual acuity remained stable in 12 cases (60%); in 14 patients the best corrected visual acuity was 0.25 or better. A sicca-syndrome developed in 19/20 patients. However, only 10/20 patients used artificial tears more than 5×/d. A focal cataract developed in 7 patients (35%). There was eyelash loss in the area of irradiated eyelids. In 4 cases a limbal stem cell deficiency occurred with the consequence of corneal vascularisation. Proton radiotherapy may serve as an alternative to exenteration in case of T3 and diffuse T1 or T2 conjunctival melanomas.

The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients.To update clinical practice guidelines for the management of patients with salivary gland malignant tumors previously validated in 1997. These recommendations cover diagnosis, classification, treatment and follow-up of patients with these tumors.The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPG s according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers.This article is a summary version of the full document presenting the updated clinical practice guidelines with algorithms. The main questions addressed by the expert group in this update concern the place of fine needle aspiration biopsy in preoperative diagnosis, the place of cervical lymph node area surgical treatment, the place of postoperative irradiation and neutron therapy in the treatment of unresectable tumors and also the place of medical imaging, especially RMI, for the diagnosis of these tumors.

A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature.Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together.Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve.The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma.The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.

International audience; Recently, radiotherapy possibilities have been dramatically increased by software and hardware developments. Improvements in medical imaging devices have increased the importance of three-dimensional (3D) images as the complete examination of these data by a physician is not possible. Computer techniques are needed to present only the pertinent information for clinical applications. We describe a technique for an automatic 3D reconstruction of the eye and CT scan merging with fundus photographs (retinography). The final result is a "virtual eye" to guide ocular tumor protontherapy. First, we make specific software to automatically detect the position of the eyeball, the optical nerve, and the lens in the CT scan. We obtain a 3D eye reconstruction using this automatic method. Second, we describe the retinography and demonstrate the projection of this modality. Then we combine retinography with a reconstructed eye, using a CT scan to get a virtual eye. The result is a computer 3D scene rendering a virtual eye into a skull reconstruction. The virtual eye can be useful for the simulation, the planning, and the control of ocular tumor protontherapy. It can be adapted to treatment planning to automatically detect eye and organs at risk position. It should be highlighted that all the image processing is fully automatic to allow the reproduction of results, this is a useful property to conduct a consistent clinical validation. The automatic localization of the organ at risk in a CT scan or an MRI by automatic software could be of great interest for radiotherapy in the future for comparison of one patient at different times, the comparison of different treatments centers, the possibility of pooling results of different treatments centers, the automatic generation of doses-volumes histograms, the comparison between different treatment planning for the same patient and the comparison between different patients at the same time. It will also be less time consuming.

AIMS To assess the cellular proliferation using the monoclonal antibody Ki-67, in paraffin embedded uveal melanomas irradiated by proton beam, as well as in non-irradiated uveal melanomas. METHODS 30 enucleated eyes were included for histopathological study and Ki-67 immunostaining. Patients were enucleated between 1991 and 1996 for uveal melanoma, 14 after proton beam irradiation and 16 without treatment (control group). The mean follow up period was 2.5 years after diagnosis and 1 year after enucleation. RESULTS A significant relation was found between Ki-67 score and mitotic index ( r = 0.56, p = 0.001), histological largest tumour diameter ( r = 0.38, p = 0.03), fibrosis ( r = −0.35, p = 0.05), absence of tumoral pigmentation (p = 0.05), and presence of vascular thrombosis (p = 0.03). The Ki-67 score was significantly higher in the non-irradiated group (p = 0.01) and in the group of patients whose cause of enucleation was tumoral evolution (p = 0.005) compared with the group of patients enucleated after neovascular glaucoma. The Ki-67 score was very high in a case of orbital recurrence of uveal melanoma and metastatic death. 70% of metastasised tumours showed a Ki-67 score higher than the median value. CONCLUSION Ki-67 labelling is a reliable method of estimating the proliferative activity in uveal melanomas after proton beam irradiation. The Ki-67 score is significantly correlated with prognostic variables (mitotic index and histological largest tumour diameter), and with radiation effects after proton beam irradiation.

From the theoretical point of view, the Faraday cup (FC) is an absolute instrument for fluence measurements of proton beams. As the FC is easily manufactured it can be considered an `in-house' calibration system. Moreover, at the moment no national standards for proton dosimetry are available. Up to now the experimental tests of these instruments show that much study still has to be done to better understand their use in reference dosimetry. To investigate the possibility of using an FC as a secondary standard, an FC was jointly designed by the `TERA Collaboration' and `Centre Antoine-Lacassagne' (Nice, France) to evaluate the main parameters of the instrument. A comparison between two FCs of different designs - the `TERA FC' and the `Nice FC' - and an ionization chamber (IC) used for routine proton dosimetry was carried out. Results show that the two FCs agree to within 1.5 - 3.6%. While the differences between FC and IC are larger - 6% for the `TERA FC' and 8.2% for the `Nice FC', the FC giving a lower dose evaluation - they follow the same trend shown by the calorimetric measurements. The data show that once the beam characteristics are defined, the fluence measurements are reproducible and show a good accuracy.

International audience; no abstract

Summary Neutron capture irradiation aims to selectively destroy tumor cells using 10 B(n,α) 7 Li nuclear reactions produced within themselves. Following the capture reaction, an α particle and a, 7 Li ion are emitted. Carrying an energy of 2.79 MeV, they destroy all molecular structures along their path close to 10 μ m. These captures, used exclusively with a ‘slow’ neutron irradiation, provide a neutron capture therapy (BNCT). If they are used in addition to a fast neutron beam irradiation, they provide a neutron capture potentiation (NCP). The Centre Antoine-Lacassagne in Nice is actively involved in the European Demonstration Project for BNCT of grade IV glioblastomas (GBM) after surgical excision and BSH administration. Taking into account the preliminary results obtained in Japan, work on an ‘epithermal’ neutron target compatible with various cyclotron beams is in progress to facilitate further developments of this technique. For NCP, thermalized neutron yield has been measured in phantoms irradiated in the fast neutron beam of the biomedical cyclotron in Nice. A thermal peak appears after 5 cm depth in the tissues, delayed after the fast neutron peak at 1.8 cm depth. Thus, a physical overdosage of 10% may be obtained if 100 ppm of 10 B are assumed in the tissues. Our results using CAL 58 GBM cell line demonstrate a dose modification factor (DMF) of 1.19 when 100 ppm of boric acid are added to the growth medium. Thus for the particles, issued from neutron capture, a biological efficiency at least twice that of fast neutrons can be derived. These results, compared with historical data on fast neutron irradiation of glioblastoma, suggest that a therapeutic window may be obtained for GBM.

Summary V79 cells were exposed to fast neutrons generated by 60 MeV p → Be produced by the cyclotron Medicyc at four different depths: 1.3, 25.8, 72.2 and 116.8 mm. Survival was assessed by the in vitro colony method. Mean inactivation doses ( MID ) were significantly different among the four points. The ratio of MID was used to determine the relative efficiency of the neutron beam at these points. Compared to 25.8 mm depth, a 40% increase in biological effect was observed at the superficial point versus a 14 to 16% decrease in effect for the deeper points. This is ascribed to absorption of low energy neutrons near the surface and to beam hardening with depth. Taking in consideration the relative physical dose delivered, these findings suggest that skin-sparing may be markedly reduced and that the lower effectiveness with depth should be kept in mind when dealing with deep tumours.

Neutron Capture Radiography (NCR) aims at imaging the 10B biodistribution in a slice of an organ or a tumor. In this paper, we would like to describe a method to get very bright and sharp images with the translucent CR 39 detector used as a light guide, and a photo-electronic method to get the local track density. The assumption of proportionality between track density and 10B concentration in the sample is revised to take into account of the track overlap which may lead to mistake as high as 50% in the concentration evaluation. Based on a binomial statistic law the following function has been derived to prevent this effect: $$\delta = BGN + \varepsilon .\left[ {1 - {{\left( {1 - \frac{1}{N}} \right)}^{a.\left[ {{}^{10}B} \right]}}} \right]$$ Where δ is the track density, BGN the background noise, e the detector efficiency, 1/N the probability to hit a site on the detector surface, a the factor of proportionality of the particles which hit the detector surface, and [10B] the boron-10 concentration in the sample.

A number of data measuring survival of animal or human cells to low LET ionizing radiation have demonstrated that these cells may be hypersensitive to doses below 1 Gy, possibly due to the absence of an inducible repair mechanism, which is observed at higher doses. The production of micronuclei (MN) in cells exposed to ionizing radiation reflects genotoxic damage. Moreover, the micronucleus assay is sensitive to low radiation doses. We have exposed 10 human tumour cell lines to doses ranging between 0.12 and 4 Gy. Using cytochalasin B to block the cells in a binucleate phase, we have scored the fraction of binucleate cells (BNC) expressing MN, as well as the number of MN per BNC, as a function of γ-ray dose. Experimental points were fitted with a binomial equation. Doses from 1 to 4 Gy were fitted separately from those below 1 Gy, and the initial slopes after both fits were compared. Taken together, the initial slopes of MN induction after low-dose (LD) irradiation were not different from those after high-dose (HD) irradiation. Only in one cell line was a significant increase in MN production detected after LD irradiation. This cell line had the shallowest linear term after HD irradiation. It appeared that the likeliness of expressing hypersensitivity at LD was correlated with the quadratic term of MN induction at HD, which does not contradict an inducible repair hypothesis. However, the failure of observation of a significant hypersensitivity at LD for nine cell lines, and the high variability of response at LD suggests that this occasional effect may be influenced by other factors as well.

Clinically Complete Response (CCR) occuring after induction chemotherapy has often been considered as a good prognosis indicator. The routine use of CDDP-5-FU giving a relatively large amount of CCR, the GETTEC, a francophone study group, promoted in 1985 a multicentric study (ERCCACI: Enregistrement des Regressions Cliniques Completes Apres Chimiotherapie d’Induction) recording all these CCR in order to assess its value, the endpoints being survival, local and regional control, metastasis and second primaries. Retrospective inclusions were allowed and a total number of 408 cases were included by 8 institutions from april 1981 to may 1991: almost a half of the patients has been included by the Centre Antoine-Lacassagne (215) in Nice, followed by the Centre Oscar-Lambret (55) in Lille, Institut Gustave-Roussy (36) in Villejuif, Fondation Bergonie (31) in Bordeaux, Hopital Michallon (23) in Grenoble, Institut Jules-Bordet (20) in Brussels, Institut Curie (18) in Paris, Hopital de Rangueil (10) in Toulouse.

Objectif Les melanomes malins de l’uvee sont les tumeurs intra-oculaires primitives les plus frequentes et justifient d’evaluer et de parfaire regulierement leur protocole de prise en charge et nos pratiques. Leur relative faible incidence incite a repertorier « tous » les melanomes afin d’y parvenir. L’objectif de notre travail est ainsi de participer a l’effort de creation des bases de donnees nationales qui serviront ce but. Materiels et Methodes Dans cette etude retrospective, 1 000 patients porteurs de melanomes de l’uvee posterieure ont ete admis entre juin 1991 et novembre 2007 afin, pour leur majeure partie, d’etre adresses a notre centre de radiotherapie pour une protontherapie en faisceaux qui reste, apres 17 ans d’usage, l’actuel traitement de reference. Pour chaque patient, nous repertorions son statut anatomique et fonctionnel, ses caracteristiques tumorales, ses particularites de traitement et son devenir avec un suivi de 17 ans a 3 mois. Discussion Nous appuierons notre presentation sur les resultats obtenus chez nos 1 000 patients en termes de survie, de survie sans complication de la maladie ou du traitement, de statut anatomique et fonctionnel des yeux conserves. Nous situerons nos resultats par rapport a nos etudes anterieures et aux donnees de la litterature. Nous degagerons les facteurs pronostiques pour la survenue de metastases ou de complications du traitement et pour le bon resultat fonctionnel d’un traitement conservateur. Conclusion Ce travail initiera la base de donnees de tous les melanomes de l’uvee posterieure deja traites, pour une meilleure lecture de l’enregistrement prospectif national des futurs patients.

Introduction Les tumeurs malignes de la conjonctive sont des tumeurs rares et potentiellement letales necessitant un traitement adjuvant a l’exerese chirurgicale. La protontherapie fait partie des outils therapeutiques a notre disposition. Objectifs et Methodes Nous nous proposons de presenter les specificites techniques imaginees et appliquees dans notre Centre de radiotherapie afin d’adapter la protontherapie, dont l’efficacite a deja ete etablie pour les melanomes choroidiens, au traitement des tumeurs conjonctivales. Le protocole mis en place demande une cooperation etroite entre ophtalmologiste et radiotherapeute. Un reperage par clips scleraux est realise en premier lieu par le chirurgien ; puis l’adaptation d’un compensateur personnalise et un schema d’irradiation fractionne permettent de traiter au mieux la conjonctive bulbaire et palpebrale ainsi que la sclere sur une epaisseur de 2 mm. Resultats Nous appuierons notre presentation sur les resultats obtenus chez les patients presentant un melanome malin – 33 patients dont 12 melanomes primitifs et 21 melanomes recidivant — ou un carcinome invasif – 11 patients dont 4 carcinomes primitifs et 7 carcinomes recidivants- et qui ont beneficie de cette strategie therapeutique depuis 1992. Discussion Notre protocole de protontherapie semble apporter une amelioration dans le traitement des tumeurs malignes de la conjonctive. Les resultats sont neanmoins dependants du type de tumeur et des possibilites d’intervention des la premiere exerese chirurgicale. Conclusion La protontherapie, deja utilisee pour de nombreuses tumeurs malignes oculaires, peut, grâce a notre technique, etre adaptee a la prise en charge des tumeurs malignes de la conjonctive avec une amelioration notable du pronostic, surtout lorsqu’elle est prescrite en premiere intention.

A total of 25 patients with inoperable cervical cancer were treated by daily radiotherapy (2 Gy); sensitisation was obtained by administration of 5 mg cisplatin 30 min before each irradiation session. The total cumulative dose of cisplatin varied between 50 and 150 mg. A complete kinetic profile (0-24 h) of platinum (Pt) was established after the first dose and at the end of treatment for 22 patients. Pt was quantified by atomic absorption spectrophotometry using Zeeman-effect background correction for trace analysis. The total Pt AUC0-24h increased from 1.53 +/- 0.77 to 7 +/- 3.55 micrograms.h.ml-1 between the start and the end of treatment (P less than 0.001). Ultrafilterable Pt (Pt UF) rose from 0.079 +/- 0.038 to 0.138 +/- 0.095 microgram.h.ml-1 (P less than 0.01). Elimination half-lives were unchanged for total Pt but rose for Pt UF; these kinetic modifications in Pt UF did not correlate with any significant change in individual serum creatinine levels. No clear correlation was found between the cumulative cisplatin dose and tumor levels measured in 13 patients, and the tumor cisplatin dose did not correlate with response to treatment. Patients with hematological toxicity were characterised by an increase in their residual Pt UF level during treatment. Overall, our findings strengthen the notion of Pt UF kinetic variability during repeated treatment.

Resume — La nostalgie designe a la fois la douleur de la separation, dont Freud montre les conditions de representabilite, et le desir ardent de retrouver la mere perdue. La parole nostalgique temoigne de la fixation a une relation maternelle archaique qui constitue un obstacle au processus analytique. On peut voir sous cet angle l’essai d’analyse de Dora et son echec, qui permet finalement un large developpement theorique.