Dr Gerald Macklin
email: gm.macklin@ulster.ac.uk

MADNESS AND MODERNITY IN RIMBAUD"S UNE SAISON E N Enfer

Keywords:

This paper sets out to examine in detail the structure and internal development of Une Saison en enfer, Arthur Rimbaud"s diary composed in prose poetry. The paper argues that the collection articulates the experience of madness as an integral part of the author"s sojourn in a psychological Hades. At the same time it sees a journey towards a personal definition and sense of modernity as the means by which the victim ultimately extracts himself from his hell. Drawing on some of the key work on Une Saison en enfer by important Rimbaldians, the article seeks to illuminate and explain the central artistic tension in the collection between assertiveness and hesitation, certainty and doubt. Placing Rimbaud in the context of other writers who have explored alternative visions of Hell, the paper examines Rimbaud"s engagement with and rejection of traditional Western systems of belief and his fascination with oriental philosophies. The statement "Il faut être absolument moderne" thus represents a culmination, a point of arrival, an emergence from hell.

MADNESS AND MODERNITY IN RIMBAUD"S UNE SAISON EN ENFER

At the start of "Délires II" in Une Saison en enfer Rimbaud refers to "l"histoire d"une de mes folies".(1) While this clearly acts as a summary of the artistic period revisited and derided in that fifth section of the "carnet de damné", it is an expression which could be applied more widely to the collection as a whole. Running through Une Saison en enfer is a preoccupation with the state of madness which is seen as an integral part of the experience of the damned soul in its period in this emotional and psychological Hades. Yet this recurring evocation of insanity is conducted in close association with a stunning clarity and conviction which leads to a host of trenchant and apparently unchallengeable assertions from the first person narrator. That the "je" is therefore a focus for conflicting impulses, for a battle between certainty and confusion is a determining artistic principle which becomes quickly apparent to the reader. It is possible to go further and suggest that in Une Saison en enfer we find a multiplicity of competing voices and that this phenomenon is intimately related to the presentation of insanity in this tormented diary. There is a movement between calmness and agitation, clarity of thought and purpose and a contradictory voice which rejects all definitive thoughts and beliefs. The reader moves through a disturbing range of emphatic statements, disconcerting hesitations and outright negations and refutations. It is as if Une Saison en enfer is Rimbaud"s book of philosophy but a credo that only seems to find assurance and direction in its very final section "Adieu". In the preceding eight sections we find a tortured soul at odds with itself and working its way through a range of ideas, belief systems, religious doctrines, scientific trends and philosophical positions as it tries to move closer to a formulation of its own identity and stance. Paradox is the touchstone of this collection, reflected in its very title which posits a temporary stay in what has always been taken to be a permanent state.

The opening section of the work stands as a retrospective on a previous period of artistic and intellectual activity, a period from which the writer is now taking his distance. This is a defining feature of Rimbaud"s poetry for no poet is more apt to adopt a position only to disown it, to espouse a style or thought process only to move rapidly forward to a new outlook and form of expression. (2) Often spoken of as the "impatient" genius, Rimbaud can be seen as a restless author in that he never seems to settle in one posture for very long. It would appear that this restlessness is key to an understanding of Une Saison en enfer. So it is that statements like "je me suis armé contre la justice", "Je me suis enfui" and "Je me suis allongé dans la boue" (3) in this opening section appear to establish a strong central identity for the first person narratorrebellious, solitary, recalcitrant. Yet this impulse towards revolt, individualism and exhibitionism does not fully satisfy him and neither does his immersion in "le crime" and "la folie". Indeed he talks of ending it all in dissatisfaction before being lured back to earlier ways only to find that they are still illusory in their promise of salvation through charity. The suicidal impulse emerges regularly in the course of the collection and is intimately related to Rimbaud"s engagement with insanity. With the intervention of the voice of the devil the narrator finds himself deflated and reduced to pleading with Satan for a more indulgent attitude in return for "ces quelques hideux feuillets de mon carnet de damné". (4) It is interesting that the section ends with a reference to the absence of "facultés descriptives ou instructives" (5), this suggesting a lack of confidence on the part of the author in any knowledge or wisdom he may have or in any philosophical position he may adopt. Une Saison en enfer is all about uncertainty, contradiction and paradox as the stumbling narrative voice moves erratically towards some kind of coherence and resolution. Rimbaud"s livre paien or livre nègre presents "all the antitheses, antinomies and dualisms which are inherent in the condition of Western man." (Hackett 1981) (6) The tension between affirmativeness and tentativeness established in this introductory statement sets the tone for what follows. "Mauvais sang" represents a sustained endeavour on the part of the poet to understand himself through an exploration of his unconventional lineage. The second section in the whole, "Mauvais sang" is vital to the overall structure of the work. Its opening lines evoke ancestry in almost exclusively pejorative terms -"maladresse", "barbare", "ineptes", "tous les vices" and so on. One would be tempted to say that Rimbaud is depicting himself as the prisoner of a contaminated family line were it not for the fact that so many apparent negatives are often for him positive qualities. Vices can be redefined as virtuesthe Vierge folle talks of the Epoux infernal doing this in "Délires I" (7)so that one is left poised ambiguously between an acceptance and a rejection of this past. He may well revel in being of "mauvais sang" but one senses that this iconoclast who can state trenchantly "J"ai horreur de tous les métiers" ( 8) is not at all sure of who he really is. A striking feature of this second section and of Une Saison as a whole is its historical orientation as the poet attempts to evaluate periods in history, developments in human thought, industrial and scientific revolutions and other comparable movements. One agrees in this sense that « Une Saison en enfer qui est la relation d"un combat spirituel, est aussi l"histoire de l"homme occidental moderne qui, se libérant de Dieu, essaie, en surmontant la peur, la nostalgie et l"angoisse, de se créer une nouvelle foi centrée dans l"homme même. « (Davies 1975) [START_REF] Davies | [END_REF] He casts himself as a ubiquitous spirit capable of unending metamorphoses ("manant", "lépreux", "reître") but never settling into one role for any length of time. He recognizes his isolation, his lack of a familial niche and his ability to emerge recreated every time but this brings him no closer to an understanding of himself. This lack of a fixed identity must surely run counter to the apparent assurance of statements such as "c"est oracle, ce que je dis", "Je suis de race inférieure de toute éternité" and "je suis maudit, j"ai horreur de la patrie". [START_REF] Bernard/Guyaux | [END_REF] All of this turmoil is conveyed in a frenetic and agitated style, liberally sprinkled with exclamatory moments and full of unanswered questions. Wrestling with concepts of science and religion, Rimbaud imagines departures, returns, renewals and reincarnations in a desperate attempt to establish coherence and certainty. Alas, the outcome in "Mauvais sang" is a vertiginous play of fragments, of splinters of "certainty" immediately offset by expressions of doubt:

A qui me louer? Quelle bête faut-il adorer ? Quelle sainte image attaque-t-on ? Quels coeurs briserai-je ? Quel mensonge dois-je tenir ? -Dans quel sang marcher ? [START_REF] Bernard/Guyaux | [END_REF] This sequence illustrates excellently how the apparently assured narrative voice is undercut by competing voices with unanswerable questions, doubts, issues of allegiance, an iconoclastic impulse and an inability to define truth. It is also striking how intimations of violence run through this sequence ("attaque", "briserai", "sang") and it is certainly the case that Une Saison en enfer as a collection is characterized by constant suggestions of both physical and psychological violence. "Le rythme de la Saison en enfer est celui d"un trépignement immobile, d"une frénésie ressassante et toujours en lutte contre elle-même. » [START_REF][END_REF] [START_REF][END_REF] The Latin expression "De profundis Domine" (13) which appears in the middle of "Mauvais sang" is very revelatory in a number of ways. It suggests a speaking in tongues redolent of Babel and again indicative of insanity; it shows how the narrator is torn between pleas to Satan and prayers to God; it underlines his sense of being in the pit of Hell whence he cries for succour; and it illustrates how tones, registers and idioms can change at any moment in this diary of the damned. These mutations are defined by spaces in the manuscript which show that a lengthy section like "Mauvais sang" is a tapestry of subsections so that after the agitation of "de profundis" we have a more measured sequence where the poet documents his affection for "le forçat intraitable" and revealingly places him above the saint in a characteristically Rimbaldian inversion of normal hierarchies. The words "tu ne sais ni où tu vas ni pourquoi tu vas" [START_REF] Bernard/Guyaux | [END_REF] seem to epitomize the directionless nature of the collection as a whole and this is allied to an underscoring of the narrator"s isolation as a prophet not understood by the "foule exaspérée" who attend his execution. In the midst of this nightmarish image of being burned like Joan of Arc, he can still trot out more of the assertions that are such a feature of Une Saison -"Je n"ai jamais été de ce peuple-ci; je n"ai jamais été chrétien"; je suis de la race qui chantait dans le supplice". [START_REF] Bernard/Guyaux | [END_REF] The crisis of self-knowledge ("me connaisje?") is then projected through the remarkable sequence where he talks of the "nègre" which presents him as the only true negro and leads to thoughts of himself as a negro in Africa who will be subjected to the missionary zeal of the disembarking white colonists. The "fausse conversion" follows where, in a manner utterly typical of the collection as a whole, Rimbaud seems to accept a belief system only to reject it outright. This paragraph near the end of "Mauvais sang" seem to parody the clarity, calmness and happiness of the Christian convert who appears to be delivered from all pain and confusion: La raison m"est née. Le monde est bon. Je bénirai la vie. J"aimerai mes frères. Ce ne sont plus des promesses d"enfance. Ni l"espoir d"échapper à la vieillesse et à la mort. Dieu fait ma force, et je loue Dieu. [START_REF] Bernard/Guyaux | [END_REF] This is clearly a moment of deceptive calm since Rimbaud"s anti-Christian stance could never permit him to adopt religious orthodoxy except for the briefest instant or as a form of parody. It is also the case that the insanity which is evoked in the collection is evinced not just in phases of delirium and agitation but in these contrasting periods of apparent serenity and lucidity which will inevitably break down quite quickly. And so the concluding phases of "Mauvais sang" see a return to rebellion as evidenced by the sardonic comment "Je ne me crois pas embarqué pour une noce avec Jésus-Christ pour beau-père." [START_REF] Bernard/Guyaux | [END_REF] That such a sarcastic remark should follow so quickly upon the apparent serenity of religious acceptance is indicative of how Une Saison en enfer is composed of such contrasting tones and such divergent lines of thought. It is made up of all sorts of assertions and refutations, positive statements and almost immediate negation of those statements. Such conflict, sustained as it is, might well lead to a form of madness and it can be no coincidence that the closing lines of "Mauvais sang" seem to capture the descent into this mental hell as, in a storm of punctuation and fragmentation, Rimbaud yearns for calm yet finds only disturbance and is reduced to seeing life as a "farce éternelle". He experiences the bodily torments of burning lungs and searing temples, these being the physical counterpart to that mental disintegration which leads to ideas of death and suicide: Feu! feu sur moi! Là! ou je me rends. -Lâches ! -Je me tue ! Je me jette aux pieds des chevaux ! [START_REF] Bernard/Guyaux | [END_REF] The contrast between this delirium and the contrived serenity of the previous acceptance of Christian belief is a measure of how the narrator in Une Saison is torn between scenarios, identities and voices. Once again here we have a vision of suicide, the self-destructive impulse being a leitmotif in the work of Rimbaud and often seen in the Poésies, the Derniers Vers, Une Saison en enfer and the Illuminations. In Une Saison en enfer, "to plunge into the whirling drift of Rimbaud"s peripeties is to know the giddy experience of truth." (Cohn, 1999) [START_REF] Cohn | [END_REF] It was Claudel, of course, who saw Une Saison en enfer as a kind of culmination in French poetry. [START_REF] Murat | [END_REF] Yet Rimbaud also takes his place in a long line of writers who have evoked their own version of Hell -Dante, Sartre and Beckett are only three of those who come to mind. [START_REF]One thinks of Dante"s rings of hell, of Sartre"s psychological Hades in Huis clos and of Beckett"s hellish afterlife of the mind in Comédie[END_REF] Many critics see the third section, "Nuit de l"enfer", as the final stage in the poet"s descent into hell. Certainly the opening paragraph with its reference to the effects of a poisoned potion would seem to confirm that the poet now occupies his personal hell conceived of in terms of fire, burning and thirst but obviously a venue for psychological rather than physical torment. He mockingly recalls his chimera of conversion, salvation and happiness through religious belief but the mordant tone of "les nobles ambitions!" puts paid to such notions. Now the debate turns to the duration of this hellis it inferno or purgatorio? Yet one notes how the deceptively assertive "je" still produces those assertions seen throughout this collection such as the parody of Cartesian thought -"je me crois en enfer, donc j"y suis". ( 22) So much of this work involves unremitting efforts to escape from outmoded credos and philosophies and the statement "je suis esclave de mon baptême" [START_REF] Bernard/Guyaux | [END_REF] underscores the need to shake off the debilitating faith handed down by the family. All the time he is haunted by the voice of Satan whispering in his head. How to distinguish between error and truth is the central question here but such is the level of crisis in "Nuit de l"enfer" that conviction rapidly turns to pleas for mercy with God, Satan and the Holy Virgin all being invoked. There is a degree of unimaginable wretchedness at this point compounded by the ongoing desire for companionship from a position of impregnable isolation -"jamais personne ne pense à autrui." [START_REF] Bernard/Guyaux | [END_REF] Appropriately, this delirium leads to references to hallucinatory experience but interspersed with this mental disturbance one still encounters assertions of superiority and confidence -"Je suis mille fois le plus riche." [START_REF] Bernard/Guyaux | [END_REF] We have more than enough evidence now to question the consistency, integrity and continuity of the "je". One thinks of another comment in asubtle study of the collection that "the evolving subject in Une Saison en enfer endorses poesis over mimesis." (Paliyenko, 1997) [START_REF] Paliyenko | [END_REF] Surely, rather than a single entity, we find in the narrator in Une Saison a multiplicity of identities scattered through numerous fragments, moods and inclinations to create an impression of insanity rather than wholeness and stability? In fact, the collection seems to articulate a range of competing voices in the mind of the speaker and one senses that this is an exercise in the use of language to reflect intense mental disturbance. The splintered self craves unity, lucidity, serenity. Yet in this very process, a magical poeticization of language occursthe beautiful aesthetic by-product of the tortured mind.

There is a very real sense here of a soul trying to make sense of its predicament and one of the salient features is the endeavour to transcend traditional dualities and binary oppositionsheaven/hell, God/Satan, up-above /down-below. A redefinition and personalization of Hell is being undertaken in "Nuit de l"enfer" ("l"enfer est certainement en baset le ciel en haut") [START_REF] Bernard/Guyaux | [END_REF]. One feels a certain delirium at work here, as if the speaker is undergoing a nightmare or going through the hallucinations induced by a fever. Thus a phrase like "Extase, cauchemar, sommeil dans un nid de flammes" (28) both evokes the traditional notion of eternal hellfire and links it to supreme pleasure and to the possibility of hell as a state of rest. Rimbaud is thus muddling and inverting the conventional opposition between good and evil and this forms part of his ongoing campaign to release himself from the debilitating shackles of this old thinking. The reference to the biblical tale of Christ walking on the waters again suggests that Rimbaud is struggling to leave behind the teachings of Christianity and to find a new spiritual niche which will be more congenial for him. So it is that in Une Saison en enfer we are left poised between the old and the new, traditional doctrine and a new spirituality and thus it is far from surprising that we should find the collection to be brimful of assertions that are then qualified by counterstatements or negations. It is through this process that the author will finally reach a clearer, more settled affirmation of his new direction in the final subsection of the collection. The reference to Jesus seems to inspire the poet to set himself up as a new, alternative messiah and this leads in "Nuit de l"enfer" to a flurry of assertions in the first person: Je vais dévoiler tous les mystères… Je suis maître en fantasmagories.

J"ai tous les talents ! Je ferai de l"or, des remèdes. [START_REF] Bernard/Guyaux | [END_REF] These statements of self-confidence and special ability trigger a parody of Jesus himself where the poet sets himself up as a prophet asking all, including little children, to come to him and to have faith in him. Occupying this hell, he feels outside of time (as in "Barbare") and imagines "un concert d"enfers" for all his various vices as he maintains his dialogue with Satan and anticipates a return to life after his stay in Hades. Increasingly, one senses that this is a purgatory from which the sufferer will emerge cleansed and renewed but one should not oversimplify here as the concluding lines of "Nuit de l"enfer" are confusing, incoherent and contradictory with pleas to both God and Satan, a desire to be punished and a desire to be saved and the blatant contradiction of "je suis caché et je ne le suis pas." [START_REF] Bernard/Guyaux | [END_REF] Sections four and five share the title "Délires" but are markedly different in content. One feels that Rimbaud is using these sections as retrospectives on his hell, the first detailing a bizarre friendship and the second reflecting on a period of artistic activity now seen as defunct. In "Délires I" we find Rimbaud casting himself as the Epoux infernal who is represented to us through the filter of the memory of the Vierge folle and this device has the effect of maintaining that parody of biblical wisdom which runs like a leitmotif through the entire collection. It also illustrates once more how the issue of first person (31) identity continues to be involved here as one senses that the author is striving to create the illusion of a strong unified self in the face of the reality of fragmentation and multiplication of identities. That the section should take the form of a confession highlights the guilt of the Vierge as she recalls the wild, unconventional lifestyle into which she has been seduced by her enigmatic mentor. The Vierge humiliates herself by admitting sin and pleading for forgiveness in a demonstration of the abjectly servile posture demanded by traditional religion and so reviled by Rimbaud. The Vierge has lost her goodness by becoming "esclave de l"Epoux infernal" but is now trying to return to the simple morality of her original beliefs and in so doing is clearly betraying the Epoux infernal and presenting herself as an innocent victim of his charms. It is interesting that her description of the doctrines of the Epoux involves yet again a list of strong assertive statements seemingly outlining a very assured philosophy -"la vraie vie est absente. Nous ne sommes pas au monde." [START_REF] Bernard/Guyaux | [END_REF] It has, of course, been frequently argued that the Vierge is Verlaine placed in relation to the much stronger Rimbaud but "Délires I" works equally well if we imagine her to be Rimbaud"s weaker self drawn to the security of traditional teaching and in opposition to the experimental, iconoclastic other self as seen in the Epoux. In this latter interpretation, we would thus again be coming close to that view of Une Saison en enfer which sees the collection as a clash between assertivenss and uncertainty, affirmation and negation, claim and qualification. "Je n"aime pas les femmes. L"amour est à réinventer" [START_REF] Bernard/Guyaux | [END_REF] are two of the most quotable lines from the observations of the Epoux infernal and they comply very strongly with that tendency towards brevity and that laconic expression of ideology seen so often elsewhere in the collection. The Vierge proceeds to give us an extended insight into how the Epoux inverts traditional values ("infamie" becomes "gloire", for example) and how he has created an image for himself which is very much that of the rebel, the outcast, the freak, the self-harmer and so on. This acutely dramatizes the opposition in Une Saison between the safety of well established morality and the dangerous attractions of a path that is much less travelled. Complicating matters even more is the Vierge"s insight into a man who can be so violent towards himself and others and yet can have the most sensitive tenderness towards social pariahs, down and outs, drunks and other victims. This represents a fascinating mixture of cruelty and love, itself an example of the oxymoronic nature of Rimbaldian ideology. A revealing reference point here is Verlaine"s own celebrated poem "Crimen amoris" where he offers his portrait of Rimbaud as a fallen angel full of charm and venom and articulating an alternative ideology and spiritual message. ( 34) "These violent, yet controlled, fluctuations are characteristic of the whole work." (Hackett, 1981)

(35)
What emerges more and more forcefully here is the Vierge"s inability to understand either the teaching or the personality of her bizarre companion. Bound by a compulsion to follow him as would a disciple follow her saviour, the Vierge realizes that the Epoux is beguiled by change, by a desire to topple reality and to create a new society. Contrasting with his strength and confidence she is "pauvre, sourde, muette, aveugle" so it is scarcely surprising that in the end she should take fright and decide to return to the fold of conventional believers to find comfort and sanctuary. Yet we should not forget the title "Délires" for there is indeed in this section and the following one an attempt to capture a state of delirium in the hope of emerging into some state of lucidity, conviction, direction and clarity of purpose. For the Vierge this will be the false certainty of traditional Christian belief but for the narrator of Une Saison, here presenting himself as the disturbed "Epoux infernal", this must involve a totally new credo and philosophy which transcends all previous doctrines. As she evokes the more tender dimensions of their relationship, the Vierge acknowledges both that the Epoux was always destined to leave her and that she never understood him at all. For someone who wishes to live "somnambule", the Epoux has a "charité" and "bonté" which the Vierge in her more optimistic moments hoped would lead them to so some form of terre promise: Ou je me réveillerai, et les lois et les moeurs auront changé, -grâce à son pouvoir magique. [START_REF] Bernard/Guyaux | [END_REF] This is typical of the alternating exaltation and depression in this relationship, a pattern that reflects the wider system of peaks and troughs, certainties and doubts in the collection as a whole. Expressions such as "j"ignore son idéal" and questions like "parlet-il à Dieu?" are indicative of how Une Saison is written in a language designed to capture confusion, aspiration, disappointment and mental disturbance. This "storm inside Rimbaud"s skull" (Hackett, 1981) [START_REF] Hackett | [END_REF] is central to this whole text, a text so vital that Rimbaud wrote "mon sort dépend de ce livre." Having destroyed the Vierge"s value system, the Epoux will not or cannot replace it with a transparent or comprehensible ethos leaving his confederate "au plus profond de l"abîme" and bewildered by a behavioural pattern where one moment she sees horrible laughter and the next the most gentle of approaches ("Puis, il reprenait ses manières de jeune mère, de soeur aimée".) [START_REF] Bernard/Guyaux | [END_REF] This "drôle de ménage" seems to encapsulate the central issue of failed communication in Une Saison, impressing upon us that this is a diary written for its author and not for a wider readership who will inevitably struggle to comprehend it.

It is fascinating that the fifth of the nine sections, and thus the one at the very heart of the diary, is so preoccupied with the matter of language and expression. This is another perspective on delirium as this "alchimie du verbe" seems to describe a period of intense artistic development which, while exciting at the time, is now seen with a disillusioned eye. The fact that "Délires II" is dedicated to the poet himself "à moi" has a wider significance for the collection, especially as the evocation of the period is described as "l"histoire d"une de mes folies". (39) `It is utterly typical of Rimbaud to be able to describe his own endeavours, pursued so recently with such enthusiasm, from the detached perspective of one who has outgrown them and moved to a new stage. Just as his previous self had rejected "la peinture et la poésie moderne", so the author of Une Saison can now dismiss the predilections with which he replaced contemporary tastes. His interest in the ancient rather than the modern ("la littérature démodéee", "latin d"église", "romans de nos aieules") was only a temporary satisfaction and there is an ironic and cynical evocation of the dreamer and visionary who imagined global upheaval as part of "tous les enchantements". [START_REF] Bernard/Guyaux | [END_REF] The recollection of giving colour to the vowels and shaping the consonants as part of a campaign to find a new "verbe poétique" shows how readily Rimbaud can slough skins and underlines on the same page that the language of Une Saison is utterly different from that used previously in the Derniers Vers where:

J"écrivais des silences, des nuits, je notais l"inexprimable. Je fixais des vertiges.

Thus when he quotes "Larme" and "Bonne Pensée du matin" immediately afterwards, one realizes that he is now juxtaposing two utterly different styles and thus showing that his philosophical development is now being paralleled with an artistic evolution. "La vieillerie poétique" was what attracted him at that point in the recent past and the taste for hallucination is very much part of his awareness now of the need to emerge from a period of willed mental disorder into something more coherent: Je m"habituai à l"hallucination simple : je voyais trèsfranchement une mosquée à la place d"une usine, une école de tambours faite par des anges, des calèches sur les routes du ciel, un salon au fond d"un lac ; les monstres, les mystères ; un titre de vaudeville dressait des épouvantes devant moi.

Puis j"expliquais mes sophismes magiques avec l"hallucination des mots ! Je finis par trouver sacré le désordre de mon esprit . [START_REF] Bernard/Guyaux | [END_REF] This defintion of mental disorder as an inviolable principle is very much in keeping with the ideas of the "Lettre du voyant" and the concept of "l"hallucination des mots" extends the theme of visionary adventure to a complementary experimentation with language itself. It is interesting that Rimbaud then immediately talks about falling victim to a "longue fièvre" for this idea of the fever and delirium of hell from which an escape must be effected runs throughout Une Saison. At this previous moment, however, it was an escape from the world itself which was pursued as seen in the insertion at this point of "Chanson de la plus haute tour". Yet, "everything in Une Saison en enfer is antithetical to something else." [START_REF] Oxenhandler | [END_REF] [START_REF] Oxenhandler | [END_REF] A quite remarkable sequence follows, brimful of references to fire, burning, sun, aridity and dust which acts as a prelude to "Faim", quoted as an illustration of a proclivity at that time for all things mineral and an avoidance of liquids. There is a self-destructive impulse here, a revelling in fire and heat which is at the very antithesis of the mood in Une Saison itself where the soul stranded in hell seeks a way out and some new direction. The poem "Le loup criait…" follows immediately, chosen for its power to illustrate how the poet was gravitating towards selfdestruction:

Que je dorme! Que je bouille Aux autels de Salomon. [START_REF] Bernard/Guyaux | [END_REF] So we have moved from a desire for fire to an abhorrence of it and from the poems of the Derniers vers with their quaint reference points and "refrains niais" to a prose style that is utterly different in appearance and lexicon. One critic correctly describes Une Saison en enfer as a "seuil" (Murat, 2002) [START_REF] Murat | [END_REF] beyond which Rimbaud"s style and thinking change definitively. This juxtaposition on the pages of "Délires II" of these conflicting languages vividly dramatizes for the reader the essential fluidity of the presiding intelligence which is forever straining towards new forms and some new definition of itself. The "expression bouffonne et égarée au possible" ( 45) is very much that of the disturbed self that Une Saison will eventually leave behind and the simple style of "L"Eternité" in its song-like lyricism and brevity could not be further removed from the chunks of prose poetry that surround it. It is worth adding that "Délires II" maintains that penchant for the assertive one-liner seen earlier. Expressions like "je devins un opéra fabuleux" and "je tiens le système" are once again redolent of a mind that is striving to summarize its knowledge and wisdom in the tersest of formulae. At this point Rimbaud joins another distinguished groupthose writers such as La Rochefoucauld, Pascal, Baudelaire, Montherlant and others who are renowned for their ability to compress nuggets of wisdom into memorable one-line affirmations. (46) Yet when he talks of the "sophismes de la folie" we realize that this is a writer taking his distance from earlier positions and seeing through the naivety of previous assumptions. Once again the pattern of assertion and negation is discernible as is the notion of incipient madness contained in the words "les enchantements assemblés sur mon cerveau." [START_REF] Bernard/Guyaux | [END_REF] With sleeping for many days and melancholy dreams, he became ill and suicidal but always with "la croix consolatrice" and the rainbow of Christian teaching as a possible "salvation". One feels that the writer of Une Saison has graduated beyond such weakness and is finally putting behind him the errors of established religions and philosophies. No longer seduced by "le bonheur" (his quoting of "O saisons, o châteaux" at the end of "Délires II" illustrates his abandonment of a pursuit of "happiness"), he can now make a major step forward. The section thus closes with a trenchant break with the past and a confident assertion of an artistic quest clearly defined and accomplished in the present. After appearing to abandon hope à la Dante, Rimbaud has now rediscovered it. The emergence from hell has begun -"Je sais aujourd"hui saluer la beauté. » [START_REF] Bernard/Guyaux | [END_REF].

Having turned the corner, as it were, at the end of "Délires II", we now move to the last four sections of the collection which seem to lead us from "le plus profond de l"abîme" to the finale with its formulation of a new philosophy after all the confusion and contradiction. In "L"Impossible" we appear to find the necessary rejection of traditional belief systems as the prelude to the distillation of a personal credo. The fact that he begins by describing his childhood as a "sottise" shows that he is still very much in the mood for the rejection of previous preferences. Yet this is a qualified rejection for he does not regret many of his iconoclastic and rebellious postures, for example his disdain for men as "parasites de la propreté et de la santé de nos femmes, aujourd"hui qu"elles sont si peu d"accord avec nous". [START_REF] Bernard/Guyaux | [END_REF] Here he justifies himself on the gender issue and on the way men have exploited women, an issue treated in the "Lettre du voyant". He even goes further to claim "j"ai eu raison dans tous mes dédains" before proceeding to assess how he had seen life as a hell for the "damnés" where charity was unattainable or not even known. Mockingly, he evokes polite relations with polite society and the "élus" and "faux élus" who inhabit it. This is very much the western society, the "marais occidentaux" which he instinctively despises and contrasts with the East which is seen now as a lost civilization. Interestingly, the author talks of having had "deux sous de raison", a brief interlude where rational thought was possible before more delirium. This is very representative of how Une Saison as a whole works but he can still draw a line between his rejection of the west and his affinity with the Orient: J"envoyais au diable les palmes des martyrs, les rayons de l"art, l"orgueil des inventeurs, l"ardeur des pillards ; je retournais à l"Orient et à la sagesse première et éternelle. -Il paraît que c"est un rêve de paresse grossière ! [START_REF] Bernard/Guyaux | [END_REF] Yet his situation was more complicated than a discarding of hated western ways and an embracing of « la sagesse batarde du Coran » for there has to be some engagement with modernity. This must lie outside Christianity with its arrogance and self-deception and there follows a total repudiation of the nineteenth century decadence that has grown from this self-satisfaction:

N"est-ce pas parce que nous cultivons la brume! Nous mangeons la fièvre avec nos légumes aqueux. Et l"ivrognerie ! et le tabac ! et l"ignorance ! et les dévouements ! -Tout cela est-il assez loin de la pensée de la sagesse de l"Orient, la patrie primitive ? Pourquoi un monde moderne, si de pareils poisons s"inventent ! [START_REF] Bernard/Guyaux | [END_REF] He sarcastically derides the Church voices who will try to steer him back to their Eden even though it is "la pureté des races antiques" that he desires. Equally, the sophistry of the philosophers and the tardiness of science are held up for contempt. These are all impossible systems and false persuaders in that they do not lead to the "pleine sagesse" that the author covets and the section closes with a disturbed evocation of the purity mentioned earlier and the sense of impossibility of ever attaining it. We thus have a triple refutation of religion, science and philosophy. In the closing lines of the section we find a frenzied and disturbed style as a volley of exclamations injects great emotional and subjective force into a chapter that has pretensions of logic, argument and rationality. This is a diarist still torn between reason and delirium.

Lawler neatly summarizes Une Saison en enfer as a collection where Rimbaud "interprets a Christian sensibility caught between the extremes of damnation and salvation." (Lawler, 1992) [START_REF] Lawler | [END_REF] and this helps us to come to terms with section seven, "L"Eclair". It contains more parody of the Bible in "Rien n"est vanité" but the title distinctly suggests that the poet is making progress in his emergence from the "abîme". A shaft of light now illuminates the stygian depths of this personal hell of competing thought processes. Modern religion"s embracing of science and its attempts to reconcile traditional belief with scientific discovery and experimentation is just another of the fausses pistes to be rejected. Neither science nor religion"s promise of bliss can satisfy the writer and we have a sudden and almost instantaneous rejection of the work ethic that had seemed to appeal at the start of "L"Eclair". The tone is again sarcastic, cynical, detached: Ma vie est usée. Allons! Feignons, fainéantons, ô pitié ! Et nous existerons en nous amusant, en rêvant amours monstres et univers fantastiques, en nous plaignant et en querellant les apparences du monde, saltimbanque, mendiant, artiste, banditprêtre! [START_REF] Bernard/Guyaux | [END_REF] One recognizes again here that tendency to change tack, to contradict himself, to backtrack that is a constant feature of the collection and one would say that "L"Eclair", like "L"Impossible" before it, represents a refutation of all existing paths and philosophies. In a reference to being on his hospital bed, the poet evokes the last rites, a death-bed conversion and a confession which curiously anticipates aspects of his real death. The spirit of revolt still reigns supreme ("j"attaquerais à droite, à gauche…") and the proclivity for reassessing the past is extended at the start of "Matin" into a wistful attempt to rewrite it. The very title "Matin" seems to herald a further emergence from the "nuit de l"enfer" via the "éclair" that we have just experienced. He bitterly acknowledges that he has never had "une jeunesse aimable, héroique, fabuleuse, à écrire sur des feuilles d"or" [START_REF] Bernard/Guyaux | [END_REF] and that his present state is one of weakness in the light of "ma chute et mon sommeil". The search for self-knowledge and the attempt at self-explanation are equally futile but at least we have come to the end of the account of the season in hell: Pourtant, aujourd"hui, je crois avoir fini la relation de mon enfer. C"était bien l"enfer : l"ancien, celui dont le fils de l"homme ouvrit les portes. [START_REF] Bernard/Guyaux | [END_REF] For the first time he here identifies the type of hell he has been in and the fact that he now feels that he has escaped from it and has completed his report on the experience suggests that the sheet is now clean for a new start and a new form of thinking. This is indeed a new dawn, a new beginning and one is very aware of the significance of the dawn and morning in the Rimbaldian imaginative process. Even in his lassitude he can appeal for a new order: Quand irons-nous, par-delà les grèves et les monts, saluer la naissance du travail nouveau, la sagesse nouvelle, la fuite des tyrans et des démons, la fin de la superstition, adorerles premiers ! -Noel sur la terre! [START_REF] Bernard/Guyaux | [END_REF] This is a rousing finale, evoking a collectivity and taking the much used terms « travail » and « sagesse » (57) into new definitions. This "Noel" will be unlike any Christian festival as the door is shut on the old ways and a truly modern way is envisioned. We have a glimpse of progress here as the poet stops lamenting the past and turns resolutely towards the future. The mood is close to that found in "Royauté" in the Illuminations where aspirant royals promise an end to suffering and a new dawn. However, the caveat must be entered in both cases that there is a precarious and tenuous sense to the adventure. So finally we come to "Adieu" with its metaphor of a voyage and of a ship setting forth from "le port de la misère" to travel to the "splendides villes". One might see last two sections of Une Saison en enfer as pages where Rimbaud « a essayé de tourner vers soi, vers l"acceptation de soide son espoir, mais aussi de ses sottises, de ses vices, de tout ce que le poème "Honte" dénonca un jour si cruellement. » (Bonnefoy, 1961) [START_REF] Bonnefoy | [END_REF] The seasonal progression of the collection has now taken us to the autumn but this is a journey that will take us beyond the normal conception of time ("loin des gens qui meurent sur les saisons"). Just as "Barbare" (Illuminations) moves beyond conventional time in its opening words "Bien après les jours et les saisons, et les êtres et les pays" (59), so "Adieu" frames its idea of a very modern outlook within a redefinition of time. Thus the traditional association of autumn with sadness and the loss of summer are not applicable here. The vessel is about to depart from the wretchedness, the poverty and the corruption of the old world with its outmoded beliefs -"cette goule reine de millions d"âmes et de corps morts et qui seront jugés!" (60) His self-projection as a down and out corrupted both physically and morally by this decadent western world is the prelude for a vision of what might be found as an alternative. Rimbaud refers to hosts of wretches sleeping rough and drunken in rags under the rain. Projecting himself as one of these pariahs is a piece of social realism: Je me revois la peau rongée par la boue et la peste, des vers pleins les cheveux et les aisselles et encore de plus gros vers dans le coeur, étendu parmi les inconnus sans âge, sans sentiment… [START_REF] Bernard/Guyaux | [END_REF] The next sequence of "Adieu" is arguably the most famous in the collection and one of the most famous in all Rimbaud"s work. It seems like an antidote to the pain just described but its excessive optimism is seen as naïve and misplaced as the poet sees himself as a fallen artist and story-teller who once again must face "la réalité rugueuse" after such glorious flights of fancy: Quelquefois je vois au ciel des plages sans fin couvertes de blanches nations en joie. Un grand vaisseau d"or, au-dessus de moi, agite ses pavillons multicolores sous les brises du matin. J"ai créé toutes les fêtes, tous les triomphes, tous les drames. J"ai essayé d"inventer de nouvelles fleurs, de nouveaux astres, de nouvelles chairs, de nouvelles langues. J"ai cru acquérir des pouvoirs surnaturels. [START_REF] Bernard/Guyaux | [END_REF] This glorious vision seems tempered by the realization that previous imaginative departures have led to disillusionment. So we then read the famous passage which talks about his past failure and characterizes him as a discredited "artiste" and "conteur".

Moi! moi qui me suis dit mage ou ange, dispensé de toute morale, je suis rendu au sol, avec un devoir à chercher, et la réalité rugueuse à étreindre ! Paysan ! [START_REF] Bernard/Guyaux | [END_REF] The poet is very much on his guard against further self-deception but the major effect of his stay in hell seems to be that he will not fall prey any longer to such illusions and so the attempt to create "de nouvelles fleurs, de nouveaux astres, de nouvelles chairs, de nouvelles langues" will not be repeated. Rather, as the last part of "Adieu" states, he will move into « l"heure nouvelle ». One notes here the lucidity and the clarity of purpose of the speaker and one feels that all the truisms and assertions of Une Saison have been building to one last supreme one-liner that will encapsulate the message behind the entire collection: Il faut être absolument moderne . [START_REF] Bernard/Guyaux | [END_REF] Here he is speaking of a new type of modernity. It is not the false modernity of science and it is not the prevailing Christian ethic seen as the "horrible arbrisseau" which the poet has left behind definitively. This is a form of victory but the new era will be something other than a blissful transcendence. Rather it will represent a personal accomplishment as the poet turns his back on false friends and couples. "Il me sera possible de posséder la vérité dans une âme et un corps" overturns a false duality while showing that the new spirituality will actually incorporate the physical. His new truth will be experienced in both body and soul and at the end of the "carnet de damné" the pattern of shifting backwards and forwards between past and present is now relinquished. Hope is restored and the journey through madness completed. Closing the gates of hell behind him, the poet moves towards a higher realm. His face is now resolutely turned towards the future offered by the "splendides villes".

NOTES 1 .

 1 Bernard et Guyaux (1981, p. 228).


Athanasios G Pallis

Vassilis Chandrinos

Georgia Pavlakou

Nikolaos Xenidis

Ioannis Varthalitis

Nikolaos Vardakis

Lambros Vamvakas

Emmanouel Kontopodis

Maria Rovithi

MD Vassilis Georgoulias

A multicenter phase I trial of metronomic oral Vinorelbine plus Cisplatin in patients with NSCLC

Keywords: metronomic, oral Vinorelbine, cipslatin, NSCLC, phase I, maximum tolerated doses, dose-limiting toxicities

The purpose of the present study was to determine the maximum tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40-70 mg p.o./trice per week) and cisplatin (70-85 mg/m 2 intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg trice/week p.o. for vinorelbine and 85 mg/m 2 for cisplatin. Grade 4 neutropenia, febrile neutropenia, grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC.

Introduction

Vinorelbine (VNB) is a semisynthetic analogue of vinblastine that exerts its cytotoxicity via microtubule assembly inhibion [START_REF] Goa | Vinorelbine. A review of its pharmacological properties and clinical use in cancer chemotherapy[END_REF][START_REF] Potier | The synthesis of Navelbine prototype of a new series of vinblastine derivatives[END_REF]. Vinorelbine is active against a broad range of solid tumors [START_REF] Goa | Vinorelbine. A review of its pharmacological properties and clinical use in cancer chemotherapy[END_REF]. A new oral form of VNR has been recently developed [START_REF] Marty | Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors[END_REF][START_REF] Gralla | Oral vinorelbine in the treatment of non-small cell lung cancer: rationale and implications for patient management[END_REF] with response and survival results similar to the intravenous agent. A dose of 80 mg/m 2 orally is the equivalent of 30 mg/m 2 intravenously, while the oral dose of 60 mg/m 2 is equivalent to 25 mg/m 2 iv [START_REF] Gralla | Oral vinorelbine in the treatment of non-small cell lung cancer: rationale and implications for patient management[END_REF]. Oral VNR has yielded significant activity in advanced non-small-cell lung cancer [START_REF] Gralla | Oral vinorelbine in the treatment of non-small cell lung cancer: rationale and implications for patient management[END_REF][START_REF] Jassem | A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients[END_REF]. When given at 60 mg/m 2 /week for the first three administrations and then at 80 mg/m 2 /week, it showed the same efficacy as IV VNR in terms of objective response rate, progression-free survival, and overall survival [START_REF] Jassem | A multicenter randomized phase II study of oral vs. intravenous vinorelbine in advanced non-small-cell lung cancer patients[END_REF]. The availability of an oral formulation of vinorelbine represents an important advantage in terms of easiness of administration, a very important issue for the treatment of a disease in which palliative intend and quality of life are highly significant issues.

Metronomic administration of cytotoxic drugs is a novel dosing strategy that refers to frequent administration of low doses of chemotherapy over long periods of time, even years, which enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration [START_REF] Hanahan | Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice[END_REF][START_REF] Kerbel | Continuous low-dose anti-angiogenic/ metronomic chemotherapy: from the research laboratory into the oncology clinic[END_REF][START_REF] Kerbel | The anti-angiogenic basis of metronomic chemotherapy[END_REF]. Among several classes of cytotoxic drugs, microtubulebinding drugs are thought to be one of the most proper for metronomic testing because of their clinically relevant antiangiogenic and vascular-disrupting properties. Furthermore, oral VNB is ideal for metronomic administration because of its convenience of administration. Metronomic administration of VNB has been tested and proved feasible with sustainable antitumor activity without overt toxicity [START_REF] Briasoulis | Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer[END_REF].

Cisplatin is a key drug in the treatment of NSCLC and cisplatin-based doublets represents the backbone chemotherapy regimen in the front-line treatment of advanced NSCLC. Cisplatin-based chemotherapy regimens are associated with a 27% reduction in the risk of death and a 10% absolute improvement in overall survival [START_REF]Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group[END_REF]. The American Society of Clinical Oncology (ASCO) recommends a two-drug combination regimen for first line treatment of advanced NSCLC and states that platinum-based regimens are preferred [START_REF] Azzoli | American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer[END_REF].

Although the combination of oral VNB and cisplatin has been tested in NSCLC [START_REF] Jassem | Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer[END_REF][START_REF] Chen | A phase II study of oral vinorelbine in combination with cisplatin conducted in Taiwan in patients with unresectable localized or metastatic non-small cell lung carcinoma[END_REF] there is a complete lack of experience concerning the combination of metronomic administration of vinorelbine with standard iv administration of cytotoxic drugs. Other platinum-based metronomic chemotherapy regimens have shown significant efficacy and a very favorable toxicity profile, even in NSCLC patients with poor prognosis [START_REF] Correale | A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients[END_REF]. Therefore, a dose-escalating phase I trial was considered to be of interest to confirm the maximum tolerated doses (MTDs) and the dose-limiting toxicities (DLTs) of the combination of metronomic VNB and cisplatin in patients with NSCLC.

Patients and methods

Patients

Eligible patients were, aged 18 years or older, with histologically or cytologically confirmed, inoperable locally advanced (stage IIIB with pleural or pericardial effusion) or metastatic (stage IV) NSCLC, with an Eastern Cooperative Oncology Group performance status of 0 -2 [START_REF] Oken | Toxicity and response criteria of the Eastern Cooperative Oncology Group[END_REF]. Patients had to have received at least two prior chemotherapy lines (or in the case they had received only one, the oVNB/CDDP should be considered as acceptable treatment by the responsible treating oncologist).

Prior surgery or radiotherapy (≤25% of marrow-containing bones) was allowed, but a treatment-free interval of at least 4 weeks was required before study entry. Patients had to have a life expectancy of more than 3 months and adequate organ function [serum bilirubin ≤ 1.5 times the upper normal limit (UNL); AST and ALT ≤ 2.5 UNL in the absence of perceptible liver metastases, or ≤ 5 UNL in the presence of liver metastases; serum creatinine ≤ 1.5 times the UNL; neutrophils ≥ 1.5x 10-9 /L, and platelets ≥ 100x 10-9 /L]. Other eligibility criteria were: absence of active infection, history of significant cardiac disease (unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, ventricular arrhythmias). All patients gave written informed consent to participate in the study and the trial was approved by the Ethics and Scientific Committees of the participating centers. The study was conducted according to the Helsinki Declaration and Good Clinical Practice guidelines [START_REF]Good Clinical Practice: Consolidated Guideline[END_REF].

Treatment

Metronomic VNB was administered per os three times per week (every other day), at escalating doses ranging from 40 gm to 70mg, continuously. Cisplatin was administered iv after adequate hydration, at escalating doses ranging from 70mg/m 2 to 85mg/m 2 on day one, in cycles of three weeks. Standard pre-medication with 16mg ondasetron iv and post-medication with 8 mg oral ondasetron three times daily for a further 3 days, was used to reduce the risk of nausea/vomiting that can be associated with cisplatin administration.

Treatment was administered on the scheduled days if the absolute neutrophil count was ≥1500/dl, platelets ≥100,000/dl and all the other toxicities had resolved to grade ≤1. Otherwise, treatment was postponed for up to seven days until resolution of all toxicities. If therapy had to be postponed for more than seven days then doses were reduced to the previous dose levels. Patients requiring a dose reduction due to toxicity (grade IV neutropenia or febrile neutropenia, grade IV thrombocytopenia, and grade IV non-hematological toxicity except alopecia) had the doses of both drugs reduced to the previous dose level. Patients received the reduced dose for the remainder of the study. Patients who had a dose reduction and who experienced toxicity requiring a second dose reduction were taken of study treatment. Prophylactic administration of hematopoietic growth factors was not allowed. Treatment was continued until disease progression, the appearance of unacceptable toxicity, or patient's withdrawal of consent, for a maximum of 6 cycles.

Hematological toxicity was followed weekly with a complete blood cell count including differential and platelet counts; in case of grade 3 or 4 neutropenia, thrombocytopenia or febrile neutropenia, daily blood cell counts were performed until recovery. Blood chemistry and a physical examination were done before each cycle.

Dose Escalation

The following dose levels have been evaluated for the oVNB/cisplatin combination: 40/70, 40/75, 50/75, 50/80, 60/80, 60/85 and 70/85 (Table 2). The maximum-tolerated dose (MTD) was defined as the highest dose at which less than two of six patients experienced a hematologic or non-hematologic treatment-related dose-limiting toxicity (DLT). DLT was defined as the occurrence of the following adverse events (AEs) within the first 21 days of treatment: grade 4 neutropenia lasting for more than 7 consecutive days, febrile neutropenia, or grade 4 thrombocytopenia, or grade 3 nonhematologic toxicity, except alopecia. Toxicity was evaluated before each chemotherapy administration and was reported according to the National Cancer Institute Common Toxicity Criteria, version 2 [START_REF]Common toxicity criteria[END_REF]. At least three patients in the first cohort were required to have completed one cycle for dose escalation to occur. In the absence of any DLT, three patients entered the next dose level. If one DLT was observed, then three additional patients had to be enrolled to a total of six patients. If two DLTs were observed in six patients, then dosing at the level was stopped, and the MTD was considered exceeded.

Patient evaluation

Baseline assessment comprised of a complete medical history, evaluation of performance status, physical examination and vital signs, 12-lead ECG, blood tests (complete blood cell count with differential and blood chemistry), chest X-rays and computed tomography (CT) scans of the chest, abdomen and brain and a whole-body radionuclide bone scan. Baseline evaluation had to be performed within two weeks prior to therapy initiation. A complete medical history and a detailed physical examination with complete blood cell count with differential and blood chemistry, ECG and a chest X-ray were performed before each treatment administration to assess the disease status and treatment toxicity. Full blood cell count with differential and platelet counts were performed daily until recovery in case of grade 3-4 hematological toxicity. Response assessment was evaluated every two chemotherapy cycles, and every one month after treatment completion. Objective tumor responses were evaluated according to RECIST criteria [START_REF] Therasse | New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada[END_REF]. Patients who received at least one cycle were evaluable for safety, while patients who were administered at least two treatment cycles and had bidimensionally measurable disease were evaluable for efficacy.

Results

Patient Characteristics

From 06/2008 to 08/2009, 26 patients with NSCLCs were enrolled into the study. Patient characteristics are presented in Table 1. The median age at enrollment was 64.5 years, most patients (88.5%) were male, and 92.3% had a performance status of 0-1. Only six patients (23.1%) had received prior radiotherapy. All patients received a platinum based doublet as first-line treatment [cisplatin/docetaxel n=18 (69%); cisplatin/gemcitabine n=8 (31%)], while 22 patients (84.6%) received second-line treatment [pemetrexed n=18 (82%); docetaxel n=4 (18%)]. All patients were evaluable for toxicity.

Dose escalation and MTD

The dose escalation levels, the number of patients enrolled in each level and the DLTs observed are presented in Table 2. The DLTs observed were grade IV neutropenia (n=1 patient), febrile neutropenia (n=2 patients) and grade IV neutropenia along with grade IV diarrhea (n=1 patient). At the 7th dose level, 3 out of 5 patients developed DLTs and therefore this level was considered as the DLT level. The MTDs, which correspond to the doses recommended for future phase II studies, were 60 mg p.o. for vinorelbine three days per week and 85 mg/m 2 for cisplatin administered every three weeks.

Dose modifications

A total of 101 chemotherapy cycles were administered. The median number of cycles per patient was three while the median duration of treatment was 93 days (range:21-169). Only 10 cycles (10%) were delayed due to toxicity. Delayed hematologic recovery was the most frequent reason for delaying treatment. In 16 (15.8%) cycles a dose reduction was required due to toxicity. Six (5.9%) cycles were given at a reduced dose due to hematological toxicity, three cycles (3.0%) due to non-hematological toxicity, and seven (7.0%) for both hematological and non-hematological toxicity.

Three patients (11.5%) discontinued treatment due to an adverse event and one patient (3.8%) withdrew consent.

Toxicity

Tables 3 and4 list the hematological and non-hematological toxicities (by dose level and by grade) that were at least possibly related to treatment occurring in more than 10% of total cycles. The most frequent grade III-IV hematological toxicity was neutropenia which occurred in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly grade I or II.

Antitumor activity

Among the 24 patients who were evaluable for response, no patient had a complete response, while five patients achieved a partial response as their best response, for an overall response rate of 20.8% (95% CI: 4.59%-37.08%). Ten patients (41.7%) achieved stable disease and nine (37.5%) progressive disease. Responses were observed at the 2 nd (n=1 patient), 3 rd (n=1 patient), 4 th (n=1 patient), 5 th (n=1 patient), and 6 th (n=1 patient) dose levels.

Discussion

Metronomic chemotherapy is the continuous low-dose and dense administration of cytotoxic drugs aiming to avoid dose-limiting toxicities [START_REF] Bocci | Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs[END_REF]. This treatment strategy exerts its antitumor activity by inhibiting endothelial cell proliferation which, subsequently, results to decreased angiogenesis [START_REF] Hirata | Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by lowdose methotrexate[END_REF]. This therapeutic strategy may have several advantages in clinical practice, such as a favorable toxicity profile and treatment response regardless of the resistance profile of the cancer cell [START_REF] Hermans | Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model[END_REF][START_REF] Glode | Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma[END_REF]. Indeed, several clinical studies have provided evidence supporting the feasibility and activity of the metronomic treatment [START_REF] Kerbel | The anti-angiogenic basis of metronomic chemotherapy[END_REF][START_REF] Colleoni | Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects[END_REF][START_REF] Bottini | Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients[END_REF]. Since antimitotics are thought to be the most appropriate drugs for metronomic use [START_REF] Schwartz | Antivascular actions of microtubule-binding drugs[END_REF][START_REF] Kruczynski | Anti-angiogenic, vascular-disrupting and antimetastatic activities of vinflunine, the latest vinca alkaloid in clinical development[END_REF], vinorelbine is an ideal candidate for metronomic therapy; in addition, vinorelbine is available in oral formulation, which is very convenient for chronic metronomic administration. A recent report clearly demonstrated that oral vinorelbine serves very well the concept of metronomic therapy with a very favorable toxicity profile and significant antitumor activity [START_REF] Briasoulis | Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer[END_REF]. The results of the current phase I study demonstrated that metronomic vinorelbine in combination with cisplatin is feasible and active against NSCLC; in addition, the study defined that the recommended doses for a future phase II study are 60mg for oral vinorelbine, thrice/week (every other day) and 85mg/m 2 for cisplatin, on day 1, in cycles of three weeks.

The cisplatin/vinorelbine doublet is a well studied and active doublet in the treatment of NSCLC either in the adjuvant [START_REF] Douillard | Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial[END_REF][START_REF] Arriagada | Cisplatin-based adjuvant chemotherapy in patients with completely resected nonsmall-cell lung cancer[END_REF] or in the advanced disease setting [START_REF] Georgoulias | Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial[END_REF][START_REF] Pirker | Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial[END_REF][START_REF] Tan | Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer[END_REF]. On the other hand, this combination is very toxic with severe neutropenia occurring in more than 40%-80% of the patients [START_REF] Douillard | Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial[END_REF][START_REF] Georgoulias | Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial[END_REF][START_REF] Tan | Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer[END_REF]. Thus, we considered of interest a study evaluating the combination of metronomic administration of vinorelbine with cisplatin, a strategy which is likely to have a more favorable toxicity profile. Indeed, the results of the current study demonstrated that the metronomic oral vinorelbine-cisplatin doublet was very well tolerated with only 27% of patients developing grade III-IV neutropenia. Moreover, the fact that only 16 (15.8%) cycles required a dose reduction further proves the very favorable toxicity profile of this combination. A similar observation was reported by Briasoulis et al [START_REF] Briasoulis | Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer[END_REF] who yielded that metronomic administration of oral vinorelbine is feasible without overt toxicity.

The fact that a similar toxicity profile was observed between the current study and the study by Briasoulis et al [START_REF] Briasoulis | Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer[END_REF] suggests that cisplatin addition to vinorelbine did not alter significantly the toxicity profile of metronomic vinorelbine, at least in the population studied.

Another important issue is the efficacy of this combination. The response rate was 20.8% with another 41.7% of the patients experiencing a stable disease for a disease control rate of 62.5%, which is encouraging for this group of patients. Thus, this combination merits further assessment in the context of a phase II trial.

In conclusion the findings of this phase I study can be added to the growing bank of evidence for the usefulness of metronomic treatment in combination with standard drug administration. The combination of metronomic oral vinorelbine with cisplatin is feasible, well tolerated and active in the treatment of NSCLC, and merits further investigation in the context of a phase II trial.

Table 1

 1 Patients' characteristics

	No Pts (n=26)	%

Table 2

 2 Dose levels and DLTs observed at each dose level

	Dose Level	n	Vinorelbine	Cisplatin
			(mg per os; 3	(mg/m 2 , d1,
			days per	q21days)
			week)
	I	3	40	70	-
	II	3	40	75	-
	III	3	50	75	-
	IV	3	50	80	-
	V	3	60	80	-
	VI	6	60	85	Febrile neutropenia n=1
	VII	5	70	85	Febrile neutropenia n=1
					Grade IV neutropenia n=1
					Grade IV neutropenia and
					grade IV diarrhea n=1

This work was finically supported by the Cretan Association for Biomedical Research (CABR).

Conflict of interest

The authors declare that they do not have any conflict of interest


Donato Rigante
email: drigante@gmail.com

Giulia Bersani

Adele Compagnone

Anna Zampetti

Alessia De Nisco

Emanuela Sacco

Raffaella Marrocco

Exercise-induced rhabdomyolysis and transient loss of deambulation as outset of partial carnitine palmityl transferase II deficiency

Keywords:

We report the case of a 13-year-old boy with an abrupt onset of leg pain and muscle weakness, incapability of deambulation and a laboratory picture of exercise-induced acute rhabdomyolysis. Intravenous hyperhydration and forced diuresis were adopted to avoid renal complications. No evidence of articular or residual muscular damage were appreciated in the short-term. The recurrence of rhabdomyolysis required a muscular biopsy showing a disturbance of fatty acid -oxydation pathway.

Introduction

Rhabdomyolysis is a systemic disorder characterized by skeletal muscle necrosis resulting in the release of muscle cell contents into the blood as creatine kinase (CK) and myoglobin [START_REF] Luck | Rhabdomyolysis. A review of clinical presentation, etiology, diagnosis and management[END_REF]. Diagnosis is based on more than fivefold increase above normal in serum muscle enzymes and specifically on elevated CK levels (usually more than 1000 U/L, whilst lower levels may define more appropriately a state of myositis) with pathologic evidence of myoglobin in blood and urine [START_REF] Dekeyser | Severe rhabdomyolysis after recreational training[END_REF]. Multiple etiologies have been described (Table 1) and the various forms of rhabdomyolysis can present without symptoms or as life-threatening conditions with electrolyte imbalance, disseminated intravascular coagulation and acute renal failure, which are the most serious complications [START_REF] Zager | Rhabdomyolysis and myohemoglobinuric acute renal failure[END_REF]. A progressive fatigue with diffuse joint pain and reduced articular range of motion may be present especially in the drug-associated forms of rhabdomyolysis [START_REF] Baxter | Diagnosis and treatment of acute exertional rhabdomyolysis[END_REF]. The possibility that a state of rhabdomyolysis might hide an underlying metabolic disease is often taken into consideration with retardation.

Case report

A previously healthy 13-year-old boy was brought to the pediatric emergency room due to debilitating bilateral myalgias and hypostenia at the lower limbs, manifested after a football match, which forbade him from walking. Physical examination revealed an alert and cooperative boy, afebrile, with normal vital signs. No tenderness, swelling or deformity were noted in his lower extremities. Osteo-tendinous reflexes were symmetrically elicitable, while blood analysis revealed leukopenia (white blood cell count 2740/mm 3 , neutrophil granulocytes 770/mm 3 , with normal platelet count and normal hemoglobin), massive myoglobinemia (5917 ng/ml, n.v. 10-95), myoglobinuria (7580 mg/L) and increased levels of myo-specific enzymes (CK 12012 IU/l, n.v. 10-70; lactate dehydrogenase 1010 IU/l, n.v. 340-450; glutamic oxaloacetic transaminase 344 IU/l, n.v. 5-45; aldolase 50 IU/l, n.v. 1.3-8.2). His electrolytes were normal, while urine was brown-coloured and urinalysis negative for red blood cells. His past medical history was otherwise unremarkable with the exception of recurrent upper airway infections in the foregoing years. In addition, the boy had been adopted in his first infancy (his origins were Moroccan) by two Italian parents. Since the 3 days prior to his muscle complaints he received full-dosage amoxicillin/clavulanate for a febrile tonsillopharyngitis. Intravenous hyperhydration (3 L/day) and forced diuresis with furosemide were the only therapeutic interventions.

His white blood cell count decreased to 2290/mm 3 (neutrophil granulocytes 390/mm 3 ) on the 2 nd day, so that ceftriaxone was started empirically. Autoimmune screen (enclosed anti-Jo1 antibodies) and serology for common (viral, bacterial and rickettsial) pathogens were negative. Doppler ultrasonography ruled out venous thrombosis and abdominal echography was normal. He remained hemodynamically stable. All the cultural, cardiologic, metabolic and immunologic examinations gave negative results. Hyperhydration was maintained for a total of 4 days. Muscle enzymes showed a progressive normalization (CPK 14400 on the 3 rd day, 6338 on the 7 th , 113 on the 14 th ; LDH 1608 on the 5 th day, 781 on the 14 th ; SGOT 546 on the 3 rd day, 30 on the 14 th ) and so myoglobinemia (1906 on the 3 rd day, 209 on the 5 th , 69 on the 14 th ) with myoglobinuria (24 mg/L on the 2 nd day). Only an isolated hyperphosphoremia was recorded on the 5 th day (5.7 mg/dl, n.v. 3-4,5), while white blood cell count raised to 4260/mm 3 (neutrophil granulocytes 1430/mm 3 ) on the 10 th day. Blood urea nitrogen, creatinine, cystatin C, parathormon and blood gas analysis were constantly normal.

During the hospital stay, myalgia completely resolved and the possibility of deambulation became normal, but these signs recurred acutely 2 weeks after the first admission. On this occasion all blood and urinary investigation resulted negative, except for myoglobinemia and myoglobinuria. The severity and the recurrence of the myopathic presentation justified the recourse to muscle biopsy: the hystochemical/enzymatic analysis and the dosage of glycolytic enzymes resulted negative; the evaluation of mitochondrial enzymes showed a partial deficiency of carnitine palmityl transferase II (CPT II, 35.72 nm/min/g, n.v. 75.69± 18.28). The boy attended for review one month later: his muscle complaints had resolved, he was able to walk and there was no evidence of generalized muscle weakness on manual muscle test with blood parameters completely normalized.

Discussion

The CPT II enzyme is a ubiquitous enzyme localized at the internal mitochondrial membrane and is responsible for the mitochondrial oxidation of long chain fatty acids bound to carnitine, following transport across the intermithocondrial membrane [START_REF] Mcgarry | The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis[END_REF]. CPT II deficiency (OMIM 600650) is the most common, though rare, autosomal recessive inherited disorder of the fatty acid β-oxydation cycle with a widely heterogeneous phenotype and different clinical pictures: the result is the accumulation of long chain acylcarnitine in the mitochondrial matrix [START_REF] Angelini | Clinical varieties of carnitine and carnitine palmitoyltransferase deficiency[END_REF]. This enzyme deficiency has also resulted the most frequent associated disorder in a series of 36 patients with idiopathic myoglobinuria [START_REF] Tonin | Metabolic causes of myoglobinuria[END_REF]. Two clinical phenotypes of CPT II deficiency have been reported: an adult muscular form characterized by exercise intolerance and myoglobinuria and a more severe, infantile hepatocardiomuscular form. In the latter, a neonatal presentation leads invariably to early infantile death [START_REF] Mauro | Muscle carnitine palmitoyltransferase deficiency and myoglobinuria[END_REF]. Episodic muscle necrosis and paroxysmal myoglobinuria after prolonged exercise with prolonged muscular weakness might be modalities of presentation of CPT II deficiency in young adults, especially in cases of partial deficiency, when additional external triggers increasing the requirement for fatty acid oxydation, such as low-carbohydrate and highfat diet, fasting, exposure to excessive cold and prolonged major exercise, are required before the predominantly myopathic symptoms are elicited [START_REF] Smelt | Very long chain acyl-coenzyme A dehydrogenase deficiency with adult onset[END_REF].

Our case report highlights that the presenting symptom of late-onset CPT II deficiency might be exercise-induced rhabdomyolysis through the appearance of leg pain, severe weakness and transient loss of deambulation. In our patient leukopenia has been interpreted as a post-infectious effect, as it is not expected in CPT II deficiency.

In patients with rhabdomyolysis the risk of acute renal failure, prevention or treatment of which is a major factor in determining management of these patients, has been estimated to be between 17 and 35% in the adult series; two small series in children indicated a risk of 42% and 50% [START_REF] Zepeda-Orozco | Factors associated with acute renal failure in children with rhabdomyolysis[END_REF]. It is not known the rate of myoglobinuric acute renal failure occurring in rhabdomyolysis associated with CPT II deficiency. In these cases a vigorous fluid resuscitation (in isotonic saline boluses) should be started early in the management of these patients, even before a definitive etiology of rhabdomyolysis is known: this fluid therapy increases renal perfusion, inhibits cast formation and prevents further ischemic damage to the kidney [START_REF] Better | Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis[END_REF]. Once rhabdomyolysis is established, high uric acid concentration and low urinary pH must be prevented to avoid the precipitation of myoglobin and diuresis should be monitored until plasma CK levels are less than 1000 U/L. Furthermore patients with adult-onset form of CPT II deficiency need to modify their lifestyle, avoiding prolonged fasting and refraining from demanding exercises.

Conclusive aim of this report is alerting the clinician to the need for prompt medical management of patients displaying signs of rhabdomyolysis and emphasizing that individuals who have recurrent episodes of muscle necrosis or those with a personal or family history of exercise intolerance should be evaluated for underlying myopathies as CPT II deficiency.

Table 1 .

 1 Causes of acute rhabdomyolysis.

	TRAUMAS
	-Crush and electrical injuries
	-Physical abuse
	-Compression from prolonged immobilization
	PROLONGED EXERCISE (in military recruits, trained athletes or daily runners)
	NEUROMUSCULAR and METABOLIC DISEASES
	-Glycogen storage disease type V (McArdle disease)
	-Glycogen storage disease type VII (Tarui disease)
	-Muscular dystrophies (dystrophinopathies)
	-Mitochondrial myopathies
	-Polymyositis/dermatomyositis
	-Short-chain acyl-coenzyme A dehydrogenase deficiency
	-Medium-chain acyl-coenzyme A dehydrogenase deficiency
	-Long-chain acyl-coenzyme A dehydrogenase deficiency
	-Phosphorylase kinase deficiency
	-Phosphofructokinase deficiency
	-Phosphoglycerate mutase deficiency


ABSTRACT

We describe the case of a 23 year old gentleman who developed a severe generalised necrotising myopathy. Initially presenting with features of a viral induced polymyositis, both symptomatic and biochemical improvement was initially achieved with glucocorticoid based immunosuppression. Subsequently he represented with evidence of severe generalised rhabdomyolysis (creatinine kinase peaking at 210,000). Rendered anuric from the myogloburic assault, he required intensive care support from the development of multi-organ failure. Subsequent investigations failed to demonstrate an infective, inflammatory, metabolic or inherited aetiology. Muscle biopsy demonstrated severe generalised necrotising myopathy in the notable absence of inflammation. Confidential discussion with the patient and relatives confirmed a suspicion of anabolic androgenic steroid (AAS) abuse. There is limited literature as to the toxic effect of AAS compounds on muscle tissue, and these tend to focus on localised disease. Indeed AAS have consistently been shown in animal models to produce a generalised myotrophic state. Apart from the social uses of such compounds, it has been established since the 1960's the scope for their supervised use in various medical conditions. TEXT A 23 year old gentleman, with an unremarkable medical history presented with a one week history of coryzal symptoms and generalised myalgia. A reduced quantity of dark urine production was also noted; and there were no features of autoimmune disease. Born in Sri Lanka there was no recent history of foreign travel; and no significant family history. He denied the use of recreational drugs, and only occasionally used alcohol modestly. On physical examination he was a well muscle gentleman, with a painful proximal myopathy of both the upper and lower limbs; otherwise the examination was grossly unremarkable.

Creatinine kinase (CK) on admission was 28519 U/L (table 1). With a preceding history of an upper respiratory tract infection, a clinical diagnosis of polymyositis and rhabdomyolysis was made. Supportive therapy was directed. Immunosuppression was introduced with prednisolone 80 mg od. Admission investigations failed to demonstrate an infective or inflammatory aetiology (table 1). Intravenous methylprednisolone (1 g/ 5 days) was introduced to which he symptomatically improved, as did his markers of rhabdomyolysis. An in-patient Electromyelogram and muscle biopsy was performed (detailed later); and he was subsequently discharged on prednisolone 60 mg od. CK upon discharge was 13652 U/L. Three days later he represented with a recurrence of severe generlised myalgia and weakness. CK on representation was 52459 U/L. Intravenous methylprednisolone was again utilised. He subsequently developed a progressive weakness affecting the larynx, and was transferred to the intensive care unit (ICU) due to a concern over his airway patency. A CT scan of the chest revealed no neck or mediastinal mass. Due to a worsening metabolic acidosis secondary to renal failure, and fatiguing of the respiratory muscles he was electively intubated and ventilated.

This gentleman had a protracted admission to the ICU for 37 days. Supportive cardiovascular, respiratory, renal and gastrointestinal care was required. He remained dependent on dialysis due to renal failure secondary to rhabdomyolysis. CK continued to rise to a maximum of 210,000 U/L (table 1). Methylprednisolone was stopped, and hydrocortisone introduced to avoid further myelotoxicity. His ICU admission was associated with several line and chest associated septic episodes; as well as the development of the acute respiratory distress syndrome (ARDS). He developed several episodes of large bowel obstruction which required decompression with sigmoidoscopy and/or rectal tube insertion. There was no obvious lesion or volvulus seen upon endoscopy, or electrolyte inbalance to explain these repeated episodes. Of interest, his serum was noted to be hypertriglcerdiaemic several times; this was repeated off propofol which is known to have a high triglyceride content.

On Day 37 of his ICU admission he developed signs of recurrent obstruction with an increasingly distended abdomen. This compromised his ventilation, and was associated with a worsening metabolic acidosis. With the suspicion of an ischaemic event to the bowel he underwent an emergency laparotomy. A perforated gastric ulcer with peritoneal faecal soiling was seen, in addition to small bowel ischaemia. Mr C suffered a cardiac arrest which was unresponsive to advanced cardio-pulmonary resuscitation intra-operatively.

We propose that this gentleman's extreme rhabdomyolysis is secondary to anabolic androgenic steroid (AAS) use. Throughout the course of this case an aetiological factor was sought. His initial presentation was clinically consistent with a viral polymyositis, with a history of a preceding upper respiratory tract infection. Admission investigations did not support the diagnosis of an infective or inflammatory process (table 1). He did however improve clinically and biochemically to the introduction of steroids and supportive treatment. A bacterial or viral aetiology was excluded (table 1), as was an inflammatory/ auto-immune disease (table 1). Metabolic markers were not consistent with an underlying pathology to account for this gentleman's extreme rhabdomyolysis (table 1).

Nerve conduction studies demonstrated normal sensory and motor conduction from both the upper and lower limbs. The electromyelogram however, showed myopathic changes in all the muscles sampled with evidence of an acute inflammatory process. Subsequent muscle biopsy revealed no evidence of inflammatory myositis, inclusion body myositis, dermatomyositis, metabolic or mitochondrial myositis; only muscle fibre necrosis in the notable absence of inflammation (figure 1).

Standard urinary drug screen was negative including MDMA (table 1). A urinary anabolic screen was considered too late in the diagnostic process. A transthoraic echocardiogram was performed to delineate the cause of a raised troponin (likely due to renal failure); this demonstrated left ventricular hypertrophy, which in a young individual may represent anabolic androgenic steroid use. Confidential discussions with both the patient's family and friends confirmed the suspicion of anabolic steroid use. It would appear he had become interested in the social applications of anabolic steroid use, and his physique had significantly changed in the last year. Direct questioning of the patient prior to his death produced a severe stress response.

Muscle is an exceptionally sensitive tissue to toxins and drugs due to its high metabolic rate and various points of interaction [START_REF] Walsh | Toxic Myopathies[END_REF]. The wide spectrum of disease caused by drugs and toxins include myalgia and myopathy to myositis, rhabdomyolysis and acute renal failure. Drug induced myopathies represent a distinct subgroup of myopathies that differ in terms of their pathological mechanisms [START_REF] Coquet | Drug-induced and toxic myopathies[END_REF]. This group of disorders is of great interest to the clinician as the disease progress may be limited or reversed by treatment of the underlying cause [START_REF] Sieb | Iatrogenic and toxic myopathies[END_REF]. Toxic myopathies also serve as excellent experimental models in relation to muscle research. Toxic myopathies may be divided into six groups [START_REF] Coquet | Drug-induced and toxic myopathies[END_REF]. These are necrotizing myopathy, vaculoar myopathy inflammatory myopathy, mitochondrial myopathy, steroid myopathy and hypokalaemic myopathy (2). Body-builders, athletes and other sporting professions have used anabolic steroids for several decades as an aid to build muscle mass and strength (4). Anabolic-androgenic steroids (AAS) achieve a supra-physiological testosterone state, prolonging its action in vivo [START_REF] Shahidi | A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids[END_REF]. AAS have a wide physiological range of action. AAS use is associated with numerous side effects which are in general a dose related phenomenon; therefore it is the groups which use these in large doses that are most susceptible. These include masculination in women and children, hepatic and lipid impairment and behavioural changes such as aggression [START_REF] Shahidi | A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids[END_REF]. Anabolic steroid use is well associated with the development of left ventricular hypertrophy [START_REF] Goubier | Exertion induced rhabdomyolysis of the long head of the triceps[END_REF].

The beneficial use of anabolic steroids in medicine is a developing area of clinical interest [START_REF] Kicman | Pharmacology of anabolic steroids[END_REF]. These include HIVrelated muscle wasting, as well as other catabolic disease states such as chronic obstructive airway disease [START_REF] Shahidi | A review of the chemistry, biological action, and clinical applications of anabolic-androgenic steroids[END_REF] and the prevention glucocorticoid induced myopathy. Other conditions of note include hereditary angioedema, and certain growth failure syndromes in children. The use of AAS should be undertaken with extreme care by medical professionals, with vigilance to the development of side-effects.

In regards to muscle disease, AAS is associated with a myotrophic state. The published literature suggests an association between localised rhabdomyloysis such as the tricep and deltoid muscles, and the use of AAS [START_REF] Goubier | Exertion induced rhabdomyolysis of the long head of the triceps[END_REF][START_REF] Farkash | Rhabdomyolysis of the Deltoid Muscle in a Bodybuilder Using Anabolic-Androgenic Steroids: A Case Report[END_REF]. In these cases muscle pain was associated with rhabdomyolysis, however the development of renal failure was averted with supportive measures including optimisation of fluid balance and forced alkaline diuresis. Research using animal models has demonstrated that anabolic steroids induce apoptosis on differentiated skeletal model [START_REF] Abu-Shakra | Anabolic steroids induce injury and apoptosis of differentiated skeletal muscle[END_REF].

The muscle biopsy in this patient demonstrated evidence of extensive necrotising myositis. This is usually associated with drug therapy such as fibrates and statins (2), however as described anabolic steroids may cause both local and generalised muscle disease.

Therefore in conclusion we propose by the exclusion of other potential aetiological causes, this gentleman's extensive necrotising myositis, and resulting severe rhabdomylosis is a manifestation of anabolic-androgenic steroid toxicity. There is limited literature as to the potential toxic effect of androgenic anabolic steroids on differentiated skeletal muscle; apart from a few case reports which describe localised myopathy. Animal models have indeed demonstrated the ability of such agents to induce a generalised myopathic state. The potentially beneficial effects of androgenic anabolic steroids in a medical setting have been well recognised since the 1960's. There appears to be an increasing amount of published literature in regards to emerging areas to which these compounds may be suitable. This case also serves to highlight the toxic effects of such agents, and why these should be prescribed and monitored by a medical practioner.

  ACKNOWNLEDGEMENTSDr DG O'Donovan& KM Kurian-Consultant Neuropathologist's for providing muscle biopsy photograph