M.D Odysseas Kargiotis
email: kargiody@mycosmos.gr

Sofia Markoula

Athanasios P Kyritsis

Epilepsy in the cancer patient

Keywords: cancer, antiepileptics, chemotherapy, valproic acid, levetiracetam

Purpose: Epileptic seizures in patients with malignancies usually occur as a consequence of brain metastases from systemic cancer or the presence of a primary brain tumor. Other less frequent causes include metabolic disorders such as electrolyte abnormalities, hypoglycemia, hypoxia and liver failure, paraneoplastic encephalitis, leptomeningeal carcinomatosis, side effects of certain chemotherapeutic agents, central nervous system infections and pre-existing epilepsy.

Methods: We reviewed all published literature in the English language regarding use of antiepileptic drugs in patients with cancer.

Results: In patients with brain metastases or primary brain tumors that had never experienced seizures, prophylactic anticonvulsant treatment is justified only for a period up to six months postoperatively after surgical excision of a cerebral tumor, since approximately half of the patients will never develop seizures and the anti-epileptic drugs may cause toxicity and interactions with antineoplastic therapies. For brief prophylaxis, newer antiepileptic drugs such as levetiracetam and oxcarbazepine are superior to older agents like phenytoin. In patients with a malignancy and seizures, certain antiepileptic drugs that express tumor inhibitory properties should be used such as valproic acid and levetiracetam, followed by oxcarbazepine and topiramate that exhibit good tolerance, efficient seizure control and absence of significant interactions with the chemotherapy.

Conclusions: Future clinical trials in patients with cancer and epilepsy should focus on combinations of chemotherapeutic interventions with antiepileptic drugs that demonstrate antineoplastic activities.

Introduction

Epileptic seizures may occur in patients with systemic cancer for a variety of reasons [START_REF] Grewal | Seizures and epilepsy in cancer: etiologies, evaluation, and management[END_REF]. Primary and metastatic brain tumors are frequently complicated by symptomatic epilepsy, defined as recurrent unprovoked seizures or single isolated seizure episode, both associated to the brain lesion. Brain tumor patients with seizures account for the 4% of epilepsy patients [START_REF] Herman | Epilepsy after brain insult: targeting epileptogenesis[END_REF]. In some cases, seizures might be the presenting symptom that will lead to the detection of the tumor, whereas alternatively seizures may represent a later manifestation following initial diagnosis or tumor recurrence. Epilepsy accompanies primary intracranial neoplasms in more than 30% of the cases; however a great variety in frequency exists among different tumor types. Similar incidence rates are reported for brain metastases, ranging from 25 to 40% [START_REF] Van Breemen | Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management[END_REF].

In this review we discuss the various causes of seizures in cancer patients and we briefly discuss the possible epileptogenic mechanisms. Moreover, we analyze the efficacy of the available antiepileptic pharmaceutical agents and the possible interactions with chemotherapeutic drugs. Finally, we focus on another aspect of antiepileptic treatment, which involves the potential antitumoral effects of certain agents and their potency to enhance current or future cytotoxic therapies.

Incidence and causes of seizures in cancer patients

In patients with cancer, epileptic seizures are mainly triggered by brain metastases or other focal cerebral abnormality and rarely by metabolic disorders such as electrolyte abnormalities, hypoglycemia, hypoxia and liver failure [START_REF] Bromfi | Epilepsy in patients with brain tumors and other cancers[END_REF]. Other conditions predisposing to epilepsy include paraneoplastic encephalitis [START_REF] Sioka | Paraneoplastic neurological syndromes and the role of PET imaging[END_REF] and leptomeningeal carcinomatosis [START_REF] Villanueva | Management of epilepsy in oncological patients[END_REF]. Chemotherapeutic agents, such as methotrexare, vincristine, ifosfamide, cyclosporine, fludarabine, cytarabine and cisplatin may also induce an encephalopathy with seizures [START_REF] Sioka | Central and peripheral nervous system toxicity of common chemotherapeutic agents[END_REF]. Radionecrosis in brain areas and opportunistic central nervous system (CNS) infections are other causes of seizures [START_REF] Van Breemen | Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management[END_REF].

Regarding primary brain tumors, epileptic seizures will lead to the initial detection of the intracranial lesion in 30 to 50% of the patients [START_REF] Wen | Medical management of patients with brain tumors[END_REF]. In primary brain tumors, epileptogenesis is dependent upon histological type, location, grade, as well as upon the individual's genetic susceptibility. Less aggressive tumor types are proven to be more epileptogenic. It has been suggested that slow growth rates allow for the tumor to gradually infiltrate adjacent areas and induce an epileptic foci by creating abnormal circuits and by preventing normal brain tissue's self-regulation and inhibition locally [START_REF] Samji | Brain tumors and epilepsy: pathophysiology of peritumoral changes[END_REF]. In addition, survival rates are higher, resulting in more patients developing seizures at some point of the disease progression, since they are exposed for a longer period to the irritating effects of the lesion. This is particularly evident in gliomas, where 60 to 85% of the patients with low grade astrocytomas and oligodendrogliomas suffer from epilepsy, whereas in glioblastoma multiforme the percentage is significantly lower, ranging from 30 to 50% [START_REF] Moots | The course of seizure disorders in patients with malignant gliomas[END_REF]. In a previous study of 119 patients with supratentorial gliomas, half of them presented with seizures, whereas preoperative incidence of epilepsy was 83% in patients with low-grade astrocytoma, 46% in anaplastic astrocytoma and 36% in glioblastoma [START_REF] Pace | Epilepsy and gliomas: incidence and treatment in 119 patients[END_REF]. In addition, dysembryoblastic neuroepithelial tumors and gangliogliomas represent the most epileptogenic brain tumors with a seizure incidence of 100% and 80-90% respectively [START_REF] Villemure | Epilepsy in patients with central nervous system tumors[END_REF]. Epilepsy is less frequent in meningiomas, ranging from 22 to 60%, although surgical resection may provoke post-treatment seizures in 20% of the patients without such manifestations before surgical intervention [START_REF] Lieu | Intracranial meningiomas and epilepsy: incidence, prognosis and influencing factors[END_REF].

Irrespective of the tumor type and despite the antiepileptic treatment, when seizures are the presenting symptom of a tumor the patient is at increased risk of developing recurrent seizures [START_REF] Glantz | Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumours. Reported of the Quality Standard Subcommittee of the American Academy of Neurology[END_REF]. Regarding location, tumors developing within the brain cortex are typically more epileptogenic, especially those detected at the frontal, temporal and parietal lobes. On the other hand, sellar neoplasms and those located in the posterior fossa do not usually cause seizures [START_REF] Liigant | Seizure disorders in patients with brain tumors[END_REF].

Provoking mechanisms

Several pathophysiological mechanisms are proposed as capable of triggering epileptic seizures in patients with brain tumors. These include the disruption of neuronal connections and inhibition of local network regulation, the impaired glial cell activity, the increased vascular permeability and the abnormal function of the blood brain barrier. In addition, rapidly growing tumors deregulate adjacent areas and result in peritumoral edema and inflammation, necrosis and hemosiderin deposition. These events might initialize abnormal circuits leading to seizure activity in the brain [START_REF] Rajneesh | Tumor-associated epilepsy[END_REF][START_REF] Beaumont | The pathogenesis of tumour associated epilepsy[END_REF].

In low grade gliomas, partial deafferentiation of adjacent cortical areas is believed to provoke seizures [START_REF] Kurzwelly | Seizures in patients with low-grade gliomas--incidence, pathogenesis, surgical management, and pharmacotherapy[END_REF]. Malignant brain tumors demonstrate increased metabolic rates and rapid cell growth leading to hypoxia and acidosis within and around the tumor mass as well as central necrosis, factors that contribute to neuronal excitability [START_REF] Schaller | Influences of brain tumor-associated pH changes and hypoxia on epileptogenesis[END_REF].

Moreover, adjacent brain cortex tissue is exposed to higher levels of several enzymes, such as lactate, enolase and adenosine 3′,5′-cyclic monophosphate (cAMP) phosphodiesterase, creating a metabolic imbalance and predisposing to generation of abnormal electrical events [START_REF] Kim | Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice[END_REF]. The enhancement of intercellular signaling exchange between neurons is believed to occur as a consequence of the increased expression of the transmembrane gap junction molecules connexins that is frequently observed in epileptogenic brain tumors [START_REF] Aronica | Expression of connexin 43 and connexin 32 gapjunction proteins in epilepsyassociated brain tumors and in the perilesional epileptic cortex[END_REF].

Perhaps the most extensively studied mechanism involves the role of the altered neurotransmitter receptor expression in brain tumors. Gliomas display increased expression of glutamate receptors, enhanced glutamate activity and decreased expression of GABA receptors in the adjacent brain tissue [START_REF] Bateman | Amino acid neurotransmitter levels in gliomas and their relationship to the incidence of epilepsy[END_REF]. The up-regulation of molecules such as the kainite and the N-methyl-D-aspartic acid (NMDA) receptors suppresses inhibitory signals and allows for the generation of potent epileptogenic foci [START_REF] Maas | Underediting of glutamate receptor GluR-B mRNA in malignant gliomas[END_REF][START_REF] Mody | NMDA receptors of dentate gyrus granule cells participate in synaptic transmission following kindling[END_REF].

Indications of antiepileptic drug treatment

Therapeutic strategies in patients with cancer and epilepsy must integrate an optimal antiepileptic medication. However, many physicians tend to prescribe antiepileptic agents in newly-diagnosed patients with primary or metastatic brain tumors, even in the absence of seizures, based on the fact that epilepsy may occur later during the course of the disease [START_REF] Siomin | Results of a survey of neurosurgical practice patterns regarding the prophylactic use of anti-epilepsy drugs in patients with brain tumors[END_REF]. Two recent meta-analyses failed to provide with sufficient evidence favoring prophylactic anticonvulsant medication in brain tumors. The first by [START_REF] Glantz | Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumours. Reported of the Quality Standard Subcommittee of the American Academy of Neurology[END_REF], analyzed 12 studies with 4 of them providing with level I evidence [START_REF] Glantz | Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumours. Reported of the Quality Standard Subcommittee of the American Academy of Neurology[END_REF]. The study by [START_REF] Sirven | Seizure prophylaxis in patients with brain tumors: a metanalysis[END_REF] examined five clinical trials that included patients with primary glial tumors, cerebral metastases or meningiomas and no history of seizures.

The antiepileptics used were phenobarbital, phenytoin and valproic acid and patient evaluation lasted up to six months. Lack of antiepileptic prophylactic effect was documented, irrespective of tumor type or pathology [START_REF] Sirven | Seizure prophylaxis in patients with brain tumors: a metanalysis[END_REF].

In the study by [START_REF] Rosati | Epilepsy in cerebral glioma: timing of appearance and histological correlations[END_REF] patients with brain tumors were considered epileptics and subsequently anticonvulsant treatment was administered if they have had a single convulsive seizure attack with evidence of interictal epileptiform abnormalities in the EEG; had stereotypic symptoms suggestive of focal seizures with or without interictal epileptiform abnormalities; or had experienced a single epileptic seizure episode associated with stereotypic symptoms suggestive of focal seizure with or without interictal epileptiform abnormalities. The authors introduced the term of remote symptomatic seizure in cases of a single seizure and no interictal epileptiform abnormalities or stereotypic symptoms suggestive of focal seizure and distinguished it from symptomatic epilepsy that requires treatment. Among the 35 patients who did not fulfill the criteria to receive antiepileptic treatment none developed seizures during the follow-up period or until death [START_REF] Rosati | Epilepsy in cerebral glioma: timing of appearance and histological correlations[END_REF].

A more recent meta-analysis that included all articles from 1966 to 2007 referring to prophylactic treatment with phenytoin, phenobarbital, and valproic sodium, found no difference between treated and control groups in terms of the prevention of the first seizure episode in patients with brain tumors. Additionally, the risk of an adverse event was higher for patients on antiepileptic drugs than for controls [START_REF] Tremont-Lukats | Antiepileptic drugs for preventing seizures in people with brain tumors[END_REF]. Regarding brain metastases, a study by [START_REF] Forsyth | Prophylactic anticonvulsants in patients with brain tumour[END_REF] including 60 patients found no significant prophylactic benefit from antiepileptic drugs [START_REF] Forsyth | Prophylactic anticonvulsants in patients with brain tumour[END_REF]. Similarly, a recent meta-analysis did not support routine prophylactic anticonvulsant treatment in patients without seizures [START_REF] Mikkelsen | The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline[END_REF].

Questionable remains the efficacy of postoperative administration of antiepileptics after brain tumor resection in patients without epileptic manifestations prior to surgery [START_REF] Shaw | Post-operative epilepsy and the efficacy of anticonvulsant therapy[END_REF]. However, Franceschetti et al (1990) studied 128 patients with surgically treated brain tumors and reported a significant benefit from short-term antiepileptic drug prophylaxis in patients without preoperative seizures, but again did not observe longterm prophylactic effectiveness [START_REF] Franceschetti | Influence of surgery and antiepileptic drugs on seizures symptomatic of cerebral tumours[END_REF]. Similarly, [START_REF] Pace | Epilepsy and gliomas: incidence and treatment in 119 patients[END_REF], by investigating 119 glioma patients that received prophylactic treatment with phenobarbital, carbamazepine or vigabatrin postoperatively found a high incidence of adverse reactions, 33.8, 14.3 and 12% respectively, and concluded that long-term prophylactic anticonvulsants are not indicated [START_REF] Pace | Epilepsy and gliomas: incidence and treatment in 119 patients[END_REF]. On the other hand, a study that evaluated the early postoperative prophylaxis with oxcarbazepine in 150 glioma patients, showed significant benefit, since seizure incidence was reduced to 2.7% within the first week [START_REF] Mauro | Prevention of early postoperative seizures in patients with primary brain tumors: preliminary experience with oxcarbazepine[END_REF]. Furthermore, a very recent study reported significant pre and postoperative prophylaxis, along with minimal toxicity with levetiracetam in patients with primary or metastatic brain tumors. Since 38% had experienced preoperative seizures and 97.5% of all patients remained seizure-free at the end of observation, this study clearly favors levetiracetam's use as a prophylactic antiepileptic in surgically treated brain tumors [START_REF] Zachenhofer | Perioperative levetiracetam for prevention of seizures in supratentorial brain tumor surgery[END_REF].

Thus, antiepileptic drug prophylaxis is not indicated in patients with primary or metastatic brain tumors and without a definite history of seizures. However, short term anticonvulsant prophylaxis after surgical excision of the tumor mass could represent an acceptable clinical practice, since up to 13% of the patients may experience seizures within the first postoperative week, irrespective of the presence of preoperative seizure history or not [START_REF] Santis | Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study[END_REF].

Efficacy of antiepileptic medications

The management of symptomatic epilepsy in patients with cancer consists mainly of the selection of the appropriate antiepileptic drug. Several older agents, such as carbamazepine, phenytoin, phenobarbital, valproic acid and newer ones, like levetiracetam, lamotrigine, gabapentin and topiramate are included within a list of drugs indicated for epilepsy. Currently, there are no guidelines how to treat patients with secondary, brain tumor-induced epilepsy. Thus, the clinician is expected to select the most appropriate medication, sometimes for each patient individually, by taking into consideration efficacy, tolerability, adverse effects, interactions with co-administrated pharmaceutical agents and perhaps the possible influence on tumor growth and progression.

An important aspect of an optimal antiepileptic drug therapy is its efficacy to control seizures in conjunction with limited adverse effects. Several clinical studies have documented superior effectiveness and /or tolerability of levetiracetam that exerts its effects through binding to synaptic vesicle protein SV2A [START_REF] Lynch | The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam[END_REF]. A study of levetiracetam in 18 patients with primary brain tumors and refractory epilepsy showed significant response in all patients, 89% of which remained seizure-free with minimal adverse reactions [START_REF] Dinapoli | Quality of life and seizure control in patients with brain tumor-related epilepsy treated with levetiracetam monotherapy: preliminary data of an open-label study[END_REF]. Similarly, superior results were obtained from the use of levetiracetam compared to phenytoin in a cohort of post craniotomy glioma patients [START_REF] Lim | Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II study[END_REF][START_REF] Usery | A prospective evaluation and literature review of levetiracetam use in patients with brain tumors and seizures[END_REF]. Regarding metastatic tumors, levetiracetam reduced seizure frequency to more than 50% in all 13 patients followed, leaving the majority of them seizure free (77%), while the most common complaints included headaches and somnolence [START_REF] Newton | Retrospective analysis of the efficacy and tolerability of levetiracetam in patients with metastatic brain tumors[END_REF]. The same authors studied a mixed patient population with primary and metastatic brain tumors treated with levetiracetam -primarily as monotherapy-and observed significant antiepileptic efficacy in 90% of the patients [START_REF] Newton | Retrospective analysis of the efficacy and tolerability of levetiracetam in brain tumor patients[END_REF]. As add on therapy, levetiracetam was evaluated in 19 glioma patients suffering from refractory epilepsy. The authors reported a significant response in 14 patients with no remarkable adverse reactions [START_REF] Maschio | Levetiracetam therapy in patients with brain tumour and epilepsy[END_REF]. The most frequent side effects of levetiracetam include psychomotor disturbances, insomnia and somnolence. On the other hand, the drug exerts antiemetic properties of unknown mechanism, which may prove useful in patients receiving chemotherapy [START_REF] Lee | Antiemetic properties of the antiepileptic drug levetiracetam[END_REF].

Satisfactory seizure control in brain tumor patients may also be achieved by valproic acid. Van Breemen et al (2009) investigated 99 glioma patients with secondary epilepsy and reported response rates of 79.3% with valproic acid as monotherapy and 81.5% with the combination of valproic acid and levetiracetam, while 52% and 59% remained entirely seizure free [START_REF] Van Breemen | Efficacy of anti-epileptic drugs in patients with gliomas and seizures[END_REF]. The administration of topiramate was also associated with efficient seizure control in patients with secondary epilepsy due to brain tumors. The response rate was 75.6% and along with the mild side effects offered an adequate antiepileptic intervention [START_REF] Maschio | Outcome and tolerability of topiramate in brain tumor associated epilepsy[END_REF]. Similar results were obtained from the use of oxcarbazepine, reporting fewer adverse reactions and at least equal with the older medications antiepileptic effect [START_REF] Maschio | The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine[END_REF].

Based on clinical studies and pharmacological profiles, [START_REF] Vecht | Seizures in low-and high-grade gliomas: current management and future outlook[END_REF] suggested initializing the anticonvulsant treatment with levetiracetam and in case of inadequate response, the co-administration of valproic acid due to the possible synergistic effects. Topiramate and lamotrigine could be used instead of valproic acid to assist levetiracetam's activity [START_REF] Vecht | Seizures in low-and high-grade gliomas: current management and future outlook[END_REF]. Another anticonvulsant as add on medication could be gabapentin, reported to decrease seizure frequency to 50% in a small group of brain tumor patients, leaving half of them seizure free [START_REF] Perry | Add-on gabapentin for refractory seizures in patients with brain tumours[END_REF]. [START_REF] Van Breemen | Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management[END_REF] considered as first-line agents lamotrigine, valproic acid and topiramate, whereas levetiracetam or gabapentin could be used as add on agents in refractory cases [START_REF] Van Breemen | Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management[END_REF].

In 12 patients with refractory brain tumor epilepsy, tiagabine as add on therapy was well tolerated and augmented seizure control in 7 of them [START_REF] Striano | Tiagabine in glial tumors[END_REF]. Pregabalin, either as monotherapy or in conjunction with other antiepileptics, produced an excellent response in all nine patients applied, but was accompanied by an increased rate of adverse affects [START_REF] Novy | Pregabalin in patients with primary brain tumors and seizures: a preliminary observation[END_REF]. [START_REF] Villanueva | Management of epilepsy in oncological patients[END_REF] argued that hepatic enzyme inducing antiepileptics and valproic acid should be avoided since these drugs either reduce activity or enhance toxicity of chemotherapy. They recommend the newer antiepileptics like vigabatrin, levetiracetam, gabapentin and pregabalin followed by lamotrigine, oxacarbazepine, topiramate and zonisamide which do not influence the pharmacologic profile of chemotherapeutics [START_REF] Villanueva | Management of epilepsy in oncological patients[END_REF]. Maschio et al (2010) followed 30 patients with secondary epilepsy due to brain metastatic disease and concluded that levetiracetam, oxcarbazepine and topiramate may be preferable for this group of patients, since they are well-tolerated, have minimal interactions with other drugs and reduce significantly the seizure frequency [START_REF] Maschio | Antiepileptics in brain metastases: safety, efficacy and impact on life expectancy[END_REF].

Limitations and complications of antiepileptic medications

Serious side effects of anticonvulsant medications, such as skin reactions, hematological complications and cognitive impairment seem to occur more frequently in cancer patients [START_REF] Maschio | The role side effects play in the choice of antiepileptic therapy in brain tumor-related epilepsy: a comparative study on traditional antiepileptic drugs versus oxcarbazepine[END_REF][START_REF] Cohen | Should prophylactic anticonvulsants be administered to patients with newly-diagnosed cerebral metastases? A retrospective analysis[END_REF][START_REF] Drane | Cognitive and behavioral effects of antiepileptic drugs[END_REF]. Concomitant therapeutic interventions could result in increased toxicity by the antiepileptic drugs. Thus, phenytoin may cause erythema multiforme and Steven-Johnson's syndrome when simultaneously administrated with cranial irradiation, a complication reported also by the use of carbamazepine [START_REF] Delattre | Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin[END_REF][START_REF] Khe | Stevens-Johnson syndrome in a patient receiving cranial irradiation and carbamazepine[END_REF][START_REF] Mamon | Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy[END_REF][START_REF] Aguiar | Toxic epidermal necrolysis in patients receiving anticonvulsants and cranial irradiation: A risk to consider[END_REF].

Antiepileptics in conjunction with radiotherapy for low-grade gliomas have been associated with poor performance in various cognitive domains, such as attention and executive function [START_REF] Klein | Effect of radiotherapy and other treatment-related factors on mid-term to longterm cognitive sequelae in low-grade gliomas: a comparative study[END_REF]. In addition, valproic acid, as well as carbamazepine, phenobarbital and phenytoin may cause severe hematologic complications, such as platelet and neutrophil depletion and are also associated with a common incidence of encephalopathy [START_REF] Moots | The course of seizure disorders in patients with malignant gliomas[END_REF][START_REF] Sirven | Seizure prophylaxis in patients with brain tumors: a metanalysis[END_REF]. Furthermore, some antiepileptic agents interfere with the activity of enzymes crucial for metabolizing common chemotherapeutic agents resulting in either reduction of chemotherapeutic drug clearance and subsequent increased toxicity or in accelerated clearance and reduced chemotherapeutic efficacy (Table 1). On the other hand, the metabolism of the antiepileptic drug itself is related to the co-administrated chemotherapy and it could be either enhanced or suppressed. Since antiepileptic drugs exert narrow therapeutic index, their pharmacokinetic profile may be easily altered [START_REF] Perucca | Clinically relevant drug interactions with antiepileptic drugs[END_REF].

Cytochrome P450 (CYP) is a family of enzymes implicated in the metabolism of various endogenous and exogenous molecules. Carbamazepine, phenytoin, phenobarbital, primidone and to a much lesser extend oxcarbazepine and topiramate are potent inducers of CYP and possibly of glucuronyl transferases and epoxide hydrolase, whereas valproic acid exerts inhibitory effects upon CYP isoenzymes. Levetiracetam, gabapentin, lamotrigine and vigabatrin do not significantly influence CYP activity. The three isoenzymes CYP3A4, CYP2C9 and CYP2C19 have the greatest affinity for both antiepileptic and anticancer drugs [START_REF] Yap | Drug interactions between chemotherapeutic regimens and antiepileptics[END_REF][START_REF] Vecht | Interactions between antiepileptic and chemotherapeutic drugs[END_REF]. Examples of antineoplastic drugs that are eliminated rapidly from circulation due to the induction of hepatic enzymes include busulfan, methotrexate, irinotecan, tamoxifen, etoposide, paclitaxel, vincristine, procarbazine, cisplatin and topotecan [START_REF] Ruggiero | Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: is it time to change treatment?[END_REF]. Valproic acid though, by exerting inhibitory enzyme activity, may increase concentrations of nitrosureas, cisplatin and etoposide leading to subsequent toxicity and imposing the reduction of the antineoplastic agent's dose [START_REF] Vecht | Interactions between antiepileptic and chemotherapeutic drugs[END_REF].

Since anticonvulsant medications are frequently introduced in patients with cancer, clinical trials testing novel therapeutic strategies might benefit from taking into account the possible drug interactions. Imatinib mesylate, an agent used to treat certain types of cancer, is primarily metabolized by the CYP3A4 isoenzyme and anticonvulsants up-regulating CYP3A4 result in a 2.9 fold reduction of imatinib's levels [START_REF] Pursche | Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients[END_REF]. The maximal tolerated dose of erlotinib in patients with recurrent glioblastoma or meningioma is significantly higher when co-administrated with enzyme inducing antiepileptics [START_REF] Raizer | A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas[END_REF]. Such interactions are crucial in determining the dosage of anticancer drugs in different groups of patients.

On the other hand, chemotherapeutic agents, such as methotrexate, doxorubicin and cisplatin, through an enzyme induction mechanism, can decrease efficacy of valproic acid, carbamazepine and phenytoin [START_REF] Avila | Seizures and epilepsy in cancer patients[END_REF]. Doxifluridine, fluorouracil and tamoxifen may reduce the metabolism rate of antiepileptic drugs (phenytoin) and increase susceptibility to toxicity [START_REF] Perucca | Clinically relevant drug interactions with antiepileptic drugs[END_REF]. Moreover, the interactions between anticancer and antiepileptic agents are also determined by their protein bounding capacity. In this way, phenytoin, phenobarbital and valproic acid compete with cisplatin, etoposide and teniposide for plasma protein bounding resulting in alterations of the unbound and active proportion of each drug. Furthermore, phenytoin, carbamazepine and phenobarbital minimize the activity of corticosteroids which are irreplaceable agents in most patients with brain tumors [START_REF] Avila | Seizures and epilepsy in cancer patients[END_REF].

Overexpression of molecules located on brain endothelial cells that function as modulators of drug transport through the blood brain barrier increase further resistance to antiepileptics. Expression of P-glycoprotein and multidrug resistance proteins 3 and 5 has been found up-regulated in glioma specimens and since these factors decrease the intracerebral access of antiepileptics such as carbamazepine, phenytoin, phenobarbital, lamotrigine and felbamate, it is argued that resistance to antiepileptic drug therapy in brain tumors is associated with altered transportation properties through the blood brain barrier [START_REF] Sisodiya | Mechanisms of antiepileptic drug resistance[END_REF][START_REF] Calatozzolo | Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma[END_REF]. To overcome this limitation, the use of drugs not susceptible to Pglycoptrotein dependence, such as levetiraceram, might prove beneficial to control seizures [START_REF] Ruggiero | Interactions between antiepileptic and chemotherapeutic drugs in children with brain tumors: is it time to change treatment?[END_REF].

Antitumoral effects of antiepileptic drugs

An ideal therapeutic approach against seizures in patients with cancer would include the administration of antiepileptic agents that have antitumor activity. However, among the wide range of anticonvulsants, only valproic acid has been associated with anticancer properties and representative studies are presented in table 2. Although in clinical use for decades, it was not until recently that valproic acid was recognized as a histone deacetylase inhibitor (HDACi), capable of inhibiting both class I and II histone deacetylases, resulting in hyperacetylation of histones H3 and H4 [START_REF] Gottlicher | Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells[END_REF][START_REF] Phiel | Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen[END_REF]. Alterations in the acetylation status of chromatin influence its structure, in a way that it is maintained in a more open conformation, allowing to previously silenced genes to be activated and to previously overexpressed genes to be inhibited. Several molecular pathways have been shown to be affected by valproic acid via gene expression regulation, such as those incorporating ribosomal proteins, oxidative phosphorylation pathways, mitogen activated protein kinase (MAPK) signaling, focal adhesion pathways, cell cycle regulation, antigen processing and presentation processes, proteasome and apoptosis pathways, phosphoinositide 3-kinase (PI3K) and Wnt signaling, calcium and transforming growth factor-beta (TGF-beta) signaling and ubiquitin-mediated proteolysis. For this reason, valproic acid could interfere with crucial cellular processes of carcinogenesis like cell differentiation, proliferation, apoptosis and migration [START_REF] Duenas-Gonzalez | Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors[END_REF].

Tested in C6 glioma cells, valproic acid induces neuronal differentiation, along with growth arrest and suppression of cell migration [START_REF] Benítez | Valproic acid induces polarization, neuronal-like differentiation of a subpopulation of C6 glioma cells and selectively regulates transgene expression[END_REF]. Similar effects were observed in malignant neuroblastoma cells, where morphological changes compatible with neuronal differentiation were accompanied by down-regulation of N-myc, induction of bcl-2 and neural cell adhesion molecule and up-regulation of the excreted antiangiogenic factors thrombospondin-1 and activin A. Moreover, valproic acid was shown to act in a synergistic manner towards these antitumoral effects with interferonalpha [START_REF] Cinatl | Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha[END_REF]. In combination with interferon-gamma, valproic acid increased caspase-8 promoter activity in medulloblastoma cells, rendering them vulnerable to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis and suppressed tumor growth in vivo [START_REF] Häcker | Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8[END_REF]. Regarding cell growth, most studies with valproic acid report reduced proliferation rates and/or apoptosis in different malignant cell types Several studies aimed to introduce simultaneous anticancer and antiepileptic therapeutic interventions by taking advantage of valproic acid's gene modulating properties. In this way, valproic acid enhanced the cytotoxicity of nitrosoureas and etoposide in glioma cells and synergized with interferon alpha and gamma to suppress neuroblastoma and medulloblastoma growth respectively [START_REF] Cinatl | Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha[END_REF][START_REF] Häcker | Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8[END_REF]75,80]. Valproic acid up-regulated melatonin MT1 receptor expression in C6 glioma and breast cancer cells and in combination with melatonin inhibited cell proliferation [START_REF] Jawed | Human melatonin MT1 receptor induction by valproic acid and its effects in combination with melatonin on MCF-7 breast cancer cell proliferation[END_REF]. In association with rapamycin, LY294002 and temozolomide, valproic acid triggered autophagic death in glioma cells [START_REF] Fu | Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines[END_REF]. Since valproic acid's anticancer activity has been documented in a number of solid tumors, including some that frequently invade the brain, its potent antitumoral effect against brain metastases remains to be clarified [START_REF] Duenas-Gonzalez | Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors[END_REF].

Interestingly, the valproic acid-induced hyperacetylation of histones may contribute to the enhancement of radiotoxicity in tumor cells. Thus, the growth of brain tumor xenografts in mice was further inhibited when irradiation was combined with valproic acid administration [START_REF] Camphausen | Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid[END_REF]. Similarly, [START_REF] Chinnaiyan | Postradiation sensitization of the histone deacetylase inhibitor valproic acid[END_REF] reported that radiosensitization of glioma cells by valproic acid was sustained up to 24 hours and involved the modulation of DNA repair processes associated with the histone gammaH2AX [START_REF] Chinnaiyan | Postradiation sensitization of the histone deacetylase inhibitor valproic acid[END_REF].

Recently, Bobustuc et al (2010) evaluated the effect of antiepileptics on O(6)methylguanine-DNA methyltransferase (MGMT) expression in gliomas [START_REF] Bobustuc | Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide[END_REF]. MGMT is a DNA repair enzyme that has been recognized to play a pivotal role in enhancing resistance to alkylating drugs, such as temozolomide. MGMT is frequently up-regulated in gliomas, rendering alkylating treatment insufficient [START_REF] Silber | Comparison of O6methylguanine-DNA methyltransferase activity in brain tumors and adjacent normal brain[END_REF]. In a clinical study, endogenous methylation and subsequent silencing of MGMT promoter proved to be an independent favorable prognostic factor in patients with glioblastoma. Moreover, only patients with tumors harboring a methylated MGMT promoter benefited from temozolomide treatment [START_REF] Hegi | MGMT gene silencing and benefit from temozolomide in glioblastoma[END_REF]. In the study by [START_REF] Bobustuc | Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide[END_REF], it was shown that levetiracetam is a potent inhibitor of MGMT that augments p53 binding on the MGMT promoter by recruiting the mSin3A/histone deacetylase 1 (HDAC1) co-repressor complex. Subsequently, levetiracetam sensitized glioma cells to temozolomide. Thus, it was suggested that in glioblastoma cases with MGMT over-expression, levetiracetam may enhance the cytotoxic effect of chemotherapy [START_REF] Bobustuc | Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide[END_REF].

Limited data in the literature is available regarding the influence of antiepileptic drugs on survival of patients with brain tumors. Non-enzyme inducers and particularly valproic acid which exerts tumor inhibitory effects, is shown to prolong survival of glioblastoma patients receiving CCNU chemotherapy compared to enzyme inducers (carbamazepine) [START_REF] Oberndorfer | P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy[END_REF]. On the contrary, a more recent study reported enhanced overall survival of glioblastoma patients receiving enzyme-inducing anticonvulsants, without proposing an explanation for the mechanism other than the possible increased toxicity by non-enzyme inducers [START_REF] Jaeckle | Correlation of enzymeinducing anticonvulsant use with outcome of patients with glioblastoma[END_REF]. The application of enzyme inducing antiepileptics in pediatric patients with acute lymphoblastic leukemia, receiving concomitant chemotherapy, was associated with increased hematological toxicity and CNS relapse as well as worse event-free survival. The authors documented accelerated clearance of teniposide and methotrexate but not of cytarabine and linked the unfavorable outcome to the lower efficacy of chemotherapy due to the up-regulation of catabolic enzymes [START_REF] Relling | Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia[END_REF].

Table 3 summarizes the results from some important clinical studies analyzed in this review. Large scale clinical studies are needed to investigate the possible antitumoral contribution of certain antiepileptics in humans with primary or metastatic brain tumors. There is preclinical evidence that molecular targeted combination of these agents with the available therapeutic interventions might offer survival benefit in patients with cancer. Although recent clinical studies evaluating seizure control reported conflicting results regarding overall survival by the use of valproic acid in patients receiving anticancer treatment, these studies were not designed to take advantage of the possible antitumoral and synergistic mechanisms of action of valproic acid according to preclinical data [START_REF] Van Breemen | Efficacy of anti-epileptic drugs in patients with gliomas and seizures[END_REF][START_REF] Oberndorfer | P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy[END_REF][START_REF] Jaeckle | Correlation of enzymeinducing anticonvulsant use with outcome of patients with glioblastoma[END_REF].

Conclusion

The management of cancer-related epilepsy is often challenging but also very substantial for the patients, the majority of which are associated with an unfavorable survival outcome. An algorithm for the proper selection of an antiepileptic drug in patients with cancer and epilepsy is depicted in figure 1. Although patients with primary or metastatic brain tumors are susceptible to epileptic seizures, prophylactic anticonvulsant treatment is not indicated, since many patients may never develop seizures and in addition it can increase unnecessary toxicity. However, the prophylactic use of anticonvulsants could be an acceptable decision postoperatively, after surgical excision of the tumor mass and for a limited time period, less than 6 months, provided that the patient has remained seizure free after surgery. For such antiepileptic prophylaxis newer agents, such as levetiracetam and oxcarbazepine are superior to older ones like phenytoin. In patients with brain tumor induced epilepsy, certain antiepileptics, such as levetiracetam and valproic acid, are beneficial. Alternative antiepileptic drugs include oxcarbazepine and topiramate because of their tolerance, efficient seizure control and absence of significant interactions with anticancer drugs.

Controlling the epileptic seizures and contributing to tumor suppression simultaneously would represent an attractive therapeutic approach against primary or metastatic brain tumors. * Some of the displayed interactions represent the predicted consequences from drug co-administration based on each drug metabolism, rather than experimentally proved ones. + These drug interactions are not exclusive neither unique between the co-administrated drugs. ** Referring to some of the tumors types that each chemotherapeutic agent is used or has been tested. ++ Numbers correspond to references in the reference list of the text

  [74]. Valproic acid treatment resulted in up-regulation of p21/WAF1, suppression of CDK4 and cell cycle arrest [75, 76, 77]. Besides causing growth arrest and apoptosis, valproic acid may also interfere with other fundamental processes of carcinogenesis. For instance, valproic acid decreased the invasive capacity of neural crest-derived human tumor cell lines via inhibition of matrix metalloproteinases-2 and -9 (MMPs) and induction of tissue inhibitor of metalloproteinases-1 [78]. In addition, in vivo medulloblastoma models treated with valproic acid display decreased growth rates and angiogenesis [79].

  74. Knüpfer MM, Pulzer F, Schindler I, Hernaíz Driever P, Knüpfer H, Keller E (2001) Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro. Anticancer Res. 21:347-351. 75. Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE, Gopalakrishnan V (2007) Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol. 85:159-170. 76. Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther. 4:1912-1922. 77. Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, Wirths O, Bayer TA (2010) Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 285:10678-10689. 78. Papi A, Ferreri AM, Rocchi P, Guerra F, Orlandi M (2010) Epigenetic modifiers as anticancer drugs: effectiveness of valproic acid in neural crest-derived tumor cells. Anticancer Res. 30:535-540. 79. Shu Q, Antalffy B, Su JM, Adesina A, Ou CN, Pietsch T, Blaney SM, Lau CC, Li XN (2006) Valproic Acid prolongs survival time of severe combined immunodeficient mice bearing intracerebellar orthotopic medulloblastoma xenografts. Clin Cancer Res. 12:4687-4694. 80. Ciusani E, Balzarotti M, Calatozzolo C, de Grazia U, Boiardi A, Salmaggi A, Croci D (2007) Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines. Oncol Res.16:453-463.

Figure legends Figure 1 .

 legends1 Figure legends

Table 1 : Common interactions between antiepileptic and chemotherapeutic drugs *, +

 1

	Chemotherape utic drug	Tumor type **	AED metabolism accelerating	AED metabolism inhibiting	Reduce AEDs levels of	Increase AEDs levels of	Others	Referen ces ++
	Carboplatin	Recurrent GBM,			Phenytoin			62
		neuroblastoma, brain
		metastasis, lung
	Cisplatin	Recurrent GBM,			Valproic			3, 62
		neuroblastoma, brain			acid,
		metastasis, lung,			phenytoin,
		lymphoma			carbamazep
					ine
	Cyclophospha	Neuroblastoma,	Carbamazepine,	Valproic				6, 59, 60
	mide	medulloblastoma,	phenobarbital,	acid
		malignant	phenytoin,
		meningioma, brain	primidone
		metastasis, breast,
		lymphoma
	Dacarbazine	Malignant			Phenytoin			62
		meningioma,
		melanoma,
		lymphoma
	Doxorubicin	Neuroblastoma,	Carbamazepine,		Valproic			3, 6, 60
		breast, lung,	phenobarbital,		acid,
		lymphoma	phenytoin		phenytoin,
					carbamazep
					ine
	Erlotinib	Lung, recurrent	Carbamazepine,					64
		GBM, malignant	phenobarbital,
		meningioma	phenytoin,
			primidone
	Etoposide	Recurrent GBM,	Carbamazepine,		Phenytoin			6, 59, 62
		neuroblastoma,	phenobarbital,
		medulloblastoma,	phenytoin,
		brain metastasis,	primidone
		lung
	Fluorouracil	Brain metastasis,				Phenytoin		3, 59, 60
		breast, colorectal
	Ifosfamide	Malignant	Carbamazepine,					6, 59, 62
		meningioma,	phenobarbital,
		neuroblastoma,	phenytoin,
		metastatic brain,	primidone
		breast, lymphoma,
		lung
	Imatinib	Recurrent GBM	Carbamazepine,					63
			phenobarbital,
			phenytoin,
			primidone
	Irinotecan	Recurrent GBM,	Phenytoin,					6, 59, 60
		colorectal, lung,	phenobarbital,
		brain metastasis	carbamazepine,
			primidone
	Ixabepilone	Breast	Phenytoin,					60
			phenobarbital,
			carbamazepine
	Methotrexate	Lymphoma	Carbamazepine,		Valproic			3, 6, 59,
			phenytoin,		acid,			60, 90
			phenobarbital		phenytoin
	Nitrosoureas	Recurrent GBM,	Carbamazepine,		Phenytoin			6, 59, 62

Table 1 : Common interactions between antiepileptic and chemotherapeutic drugs *, +

 1

	Chemotherape utic drug	Tumor type **	AED metabolism accelerating	AED metabolism inhibiting	Reduce AEDs levels of	Increase AEDs levels of	Others	Referen ces ++
	(carmustine,	medulloblastoma,	phenobarbital,
	lomustine)	brain metastasis	phenytoin,
			primidone
	Paclitaxel	Brain metastasis,	Carbamazepine,					6, 59, 60
		breast, lung	phenobarbital,
			phenytoin,
			primidone
	Procarbazine	Medulloblastoma,	Carbamazepine,				Contrain	59, 60,
		lymphoma	phenobarbital,				dicated	62
			phenytoin,				with
			primidone				carbama
							zepine
	Sunitinib	Renal	Carbamazepine,					60
			phenobarbital,
			phenytoin,
			primidone
	Tamoxifen	Breast	Phenobarbital	Valproic		Phenytoin		6, 59, 60
				acid
	Tegafur	Brain metastasis,				Phenytoin		3, 59
		colorectal
	Temozolomide GBM, low-grade	-	-				62
		glioma, brain
		metastasis
	Teniposide	Brain metastasis	Carbamazepine,					6, 59, 62,
			phenobarbital,					90
			phenytoin,
			primidone
	Thiotepa	Medulloblastoma,	Carbamazepine,					6, 59, 62
		metastatic brain,	phenobarbital,
		lymphoma, breast	phenytoin,
			primidone
	Topotecan	Neuroblastoma,	Carbamazepine,					6, 59, 62
		lymphoma, brain	phenobarbital,
		metastasis	phenytoin,
			primidone
	Vinblastine	Lymphoma, lung,	Carbamazepine,		Phenytoin			6, 59
		breast	phenobarbital,
			phenytoin,
			primidone
	Vincristine	Recurrent GBM,	Carbamazepine,		Phenytoin,			3, 6, 59,
		neuroblastoma,	phenobarbital,		carbamazep			60
		medulloblastoma,	phenytoin		ine
		malignant
		meningioma,
		lymphoma
	Vorinostat	Lymphoma,					Frequent	60, 62
		recurrent GBM					monitori
							ng with
							valproic
							acid

Table 1 : Common interactions between antiepileptic and chemotherapeutic drugs *, +

 1

	Chemotherape utic drug	Tumor type **	AED metabolism accelerating	AED metabolism inhibiting	Reduce AEDs levels of	Increase AEDs levels of	Others	Referen ces

++

GBM: glioblastoma multiforme; AED: antiepileptic drug.

Table 2 : Indicative pre-clinical studies of valproic acid's anticancer effect

 2

	Tumor type	Effect	Reference
	C6 glioma cell in vitro	Inhibition of proliferation, migration;	Benítez et al, 2008
		neuronal-like differentiation
	Malignant glioma cell	Inhibition of proliferation of 86HG39,	Knüpfer et al, 2001
	lines in vitro	A172, 85HG66 cell lines; inhibition of
		migration in T98G and 85HG66 cell
		lines
	Human glioma cell lines	Enhancement of radiosensitivity;	Chinnaiyan et al, 2008
	in vitro	accumulation in G(2)-M cell cycle phase
	Malignant glioma cell	Enhancement of radiosensitivity; in vivo	Camphausen et L, 2005
	lines in vitro and in vivo	tumor growth delay
	Malignant glioma cell	G(1) or G(2) phase accumulation;	Das et al, 2007
	lines in vitro	induction of p21/WAF1, topoisomerase-
		II and GFAP; enhancement of etoposide
		cytotoxicity
	Glioma cell lines in vitro	Induction of autophagy; synergistic	Fu et al, 2010
	and in vivo	effect with rapamycin, Ly294002 and
		temozolomide
	Human glioma cell lines	Synergistic effect with nitrosureas;	Ciusani et al, 2007
	in vitro	inhibition of cell proliferation
	human glioblastoma,	growth inhibition; apoptosis; down-	Papi et al, 2010
	melanoma and SKNMC	regulation of MMP-2 and MMP-9;
	tumor cell lines, in vitro	increase of TIMP1; inhibition of
		migration
	Medulloblastoma cell	Together with interferon-gamma restore	Häcker et al, 2009
	lines in vitro and in vivo	caspase-8 expression and sensitize to
		TRAIL-induced cell death
	Medulloblastoma cell	Prolongation of survival; inhibition of	Shu et al, 2006
	lines in vivo	proliferation and angiogenesis;
		apoptosis; differentiation
	Medulloblastoma cell	Cell cycle arrest; apoptosis; senescence;	Li et al, 2005
	lines in vitro and in vivo	differentiation; activation of p21;
		suppression of TP53, CDK4 and C-myc;
		inhibition of tumor growth in vivo
	Pancreatic and colon cell	Up-regulation of GRP78; inhibition of	Venkataramani et al, 2010
	lines in vitro	APP; inhibition of cell proliferation
	Neuroblastoma model	Synergistic effect with interferon-alpha;	Cinatl et al, 2002
		inhibition of cell growth; neuronal
		differentiation; down-regulation of N-
		myc, up-regulation of bcl-2 and neuronal
		adhesion molecule; up-regulation of
		thrombospondin-1 and activin A
	Human breast cancer cell	Up-regulation of MT1 receptor;	Jawed et al, 2007
	lines in vitro	inhibition of proliferation with
		melatonin
	GFAP: glial fibrillary acidic protein; MMP: matrix metalloproteinases; TIMP: tissue inhibitor of
	matrix metalloproteinases; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; CDK:
	cyclin-dependent kinase; TP53: tumor protein 53; GRP78: glucose regulate protein 78; APP: beta-
	amyloid precursor protein; MT1: melatonin.

Table 3 : Summary of important findings from clinical trials analyzed in the manuscript

 3

	Study	No of	Diagnosis	Anticonvulsant	Conclusions	Reference
		patients		agent
	Meta-analysis of 4 randomized clinical trials and 8 cohort studies to assess efficacy of prophylactic anticonvulsant patients medication in cancer	1017	Brain metastasis, glioma, sellar tumor meningioma,	Phenytoin, valproic acid, others phenobarbital,	Prophylactic administration of life-threatening occasionally AEDs is not indicated, AED-associated side common and especially effects are	Glantz et al, 2000
	Meta-analysis of five
	prospective				No evidence for
	randomized controlled trials to assess efficacy of prophylactic anticonvulsant	403	Brain metastasis, glioma, meningioma	Phenytoin, valproic acid, phenobarbital	AED no history of prophylaxis in patients with brain tumors and	Sirven et al, 2004
	medication in brain				seizures
	tumors
	Prospective study
	about seizure incidence and role of prophylactic	64	Glioma	Phenytoin, levetiracetam	Prophylactic AED treatment is not justified	Rosati et al, 2009
	anticonvulsants
	Prospective
	randomized study on the efficacy of prophylactic AEDs in	100	Metastatic and primary brain tumors	Phenytoin, phenobarbital	Prophylactic AED therapy is not justified	Forsyth et al, 2003
	brain tumor patients
	Prospective study on				Benefit of a
	the efficacy of				short term
	prophylactic AEDs in surgically treated	128	Supratentorial neoplasms	Phenytoin, phenobarbital	preventive treatment with	Franceschetti et al, 1990
	supratentorial				AEDs after
	neoplasms				surgery
	Retrospective analysis of the efficacy and tolerability of levetiracetam as perioperative seizure prophylaxis in supratentorial brain tumors	78	Glioma, meningioma, primary CNS lymphoma, brain necrosis radiation metastasis,	Levetiracetam	Low (2.5%) seizure frequency in the tolerated drug well levetiracetam; early postoperative period with	Zachenhofer et al, 2010
	Retrospective		Glioma,		Levetiracetam
	analysis of the effectiveness of levetiracetam in brain	41	primary CNS lymphoma, brain	Levetiracetam	proved very effective in brain tumor patients	Newton et al, 2006
	tumors		metastasis		with seizures
	Observational study on the efficacy of AEDs in patients with brain tumors and seizures	99	Glioma, ependymoma, meningioma, metastasis brain	Valproic acid, levetiracetam, lamotrigine carbamazepin,	The combination of valproic acid and efficient proved the most levetiracetam	van Breemen et al, 2009

CNS: central nervous system; AED: antiepileptic drug; GBM: glioblastoma multiforme


Antoine Beylot
email: antoine.beylot@cycleco.eu

Jérôme Payet

Clément Puech

Nadine Adra

Philippe Jacquin

Isabelle Blanc

Environmental impacts of large-scale grid-connected ground-mounted PV installations

Keywords: Environmental impacts, LCA, PV installations

This study characterizes the environmental performances of large-scale ground-mounted PV installations by considering a life-cycle approach. The methodology is based on the application of the existing international standards of Life Cycle Assessment (LCA). Four scenarios are compared, considering fixedmounting structures with (1) primary aluminum supports or (2) wood supports, and mobile structures with (3) single-axis trackers or (4) dual-axis trackers. Life cycle inventories are based on manufacturers' data combined with additional calculations and assumptions. Fixed-mounting installations with primary aluminum supports show the largest environmental impact potential with respect to human health, climate change and energy consumption. The climate change impact potential ranges between 37.5 and 53.5 gCO 2 eq/kWh depending on the scenario, assuming 1700 kWh/m².yr of irradiation on an inclined plane (30°), and multi-crystalline silicon modules with 14% of energy production performance. Mobile PV installations with dual-axis trackers show the largest impact potential on ecosystem quality, with more than a factor 2 of difference with other considered installations. Supports mass and composition, power density (in MW p /acre of land) and energy production performances appear as key design parameters with respect to large-scale ground mounted PV installations environmental performances, in addition to modules manufacturing process energy inputs.

Introduction

PV systems deployment and solar energy use are developing rapidly in Europe. In particular, Austria, Switzerland, Germany, France, Italy and the Netherlands experienced a two to fourfold increase in their annual installed photovoltaic power in 2009 [START_REF] Iea | Trends in photovoltaic applications: Survey report of selected[END_REF]. Large scale PV systems (> 500 kWp) represent a lower share of the photovoltaic power production compared to small scale systems (< 3 kWp). However, their market is showing a dramatic increase in number of installations. In France a 90% increase was observed between the 2 nd and 1 st trimesters 2010 for installations of power superior to 500 kWp, compared to a 38% increase for small scale installations [START_REF] Ser) | Syndicat des énergies renouvelables[END_REF].

In this context of rapid development, the issue of PV systems environmental impacts characterization has been intensively addressed and discussed. While several initial publications underlined the higher external environmental costs of PV compared to those of nuclear energy and natural-gas-fuel power plants [START_REF]Research results on socio-environmental damages due to electricity and transport. Office for Official Publications of the European Communities[END_REF]4], new LCA databases have been built to comply with the improvements in PV systems [START_REF] Fthenakis | Life Cycle Assessment of Photovoltaics: perceptions, needs and challenges[END_REF][START_REF] Jungbluth | Photovoltaics: ecoinvent report N° 6-XII[END_REF]. They highlighted the photovoltaic potential for a low carbon energy supply and the environmental benefits of PV as opposed to fossil-fuel based energy [START_REF] Alsema | Environmental impacts of PV electricity generation -A critical comparison of energy supply options[END_REF][START_REF] Iea | Analysis of PV system's values beyond energyby country and stakeholder[END_REF]. LCA data currently consider solar cells, panels and installation equipments production in the supply chain of different technologies. Up to now, most studies have focused on module technologies and small-scale installations. They exposed the key parameters for environmental performances of PV installations, when focusing on greenhouse gas emissions and primary energy use as environmental indicators: irradiation intensity received by PV installations, modules manufacturing electricity use and its corresponding fuel [START_REF] Pacca | Parameters affecting the life cycle performance of PV technologies and systems[END_REF][START_REF] Beloin-Saint-Pierre | Environmental impact of PV systems: effects of energy sources used in production of solar panels[END_REF]. However, only few evaluations of large-scale PV installations can be found in the literature [START_REF] Komoto | Estimation of Energy Payback Time and CO 2 Emission of Various Kinds of PV Systems[END_REF][START_REF] Mason | Energy Pay-Back and Life Cycle CO 2 Emissions of the BOS in an Optimized 3.5 MW PV Installation[END_REF].

This study aims at characterizing the environmental impacts of large-scale grid-connected ground-mounted PV installations (5MWp), considering one module technology (mc-Si) with different structures and types of supports (fixed-mounting or mobile). The results highlight key parameters related to large scale PV systems environmental performances on a life cycle perspective. Impacts on climate change and energy consumption are considered as indicators for the environmental assessment together with human health and ecosystem quality indicators. Recommendations are finally given to enable stakeholders in the field of large scale PV systems to minimize the environmental impacts of future installations.

Methodology

This Life Cycle Assessment (LCA) study was performed in compliance with the ISO standards 14040 and 14044 [START_REF]Environmental management -Life Cycle Assessmentprinciples and framework[END_REF]16] and followed the provisions of the ILCD handbook [17].

Scope of the study

The Functional Unit is defined as the kWh of electricity produced by a large-scale gridconnected ground-mounted PV installation (5MWp), considering 1700 kWh/m².yr of irradiation on an inclined plane (30°) and 30 years of life expectancy.

The system boundaries are described in Fig. 1. They include the manufacturing of core infrastructures (modules, mounting system, cabling, inverters, transformers), the manufacturing of complementary infrastructures (wire fences, control centers and road to access the plant), the plant installation (excavation and track construction), the use phase and the decommissioning (excavation, modules and structures end-of-life). Recycled waste material is assumed to substitute for primary produced material, without considering any correction factor.

Four grid-connected ground-mounted PV installations are compared in the study. Their differentiating key features are detailed in Tables 1 and2. The multi-crystalline silicon (mc-Si) PV technology is chosen for every scenario. Consequently, only the type of structure and its related system energy production differentiate the scenarios.

Life cycle impact assessment is performed with the use of the IMPACT 2002+ method (v2.04) [START_REF] Jolliet | Impact 2002+: A new life cycle impact assessment methodology[END_REF]. The results focus on four damage impact categories: climate change, resources, human health and ecosystem quality. The temporary carbon storage in bio-based goods (wood supports in one scenario) is taken into account in compliance with ILCD provisions, i.e. by considering "-0.01 kg CO 2 -equivalents" per 1 kg carbon dioxide and 1 year of storage/delayed emissions.

Inventory

The inventory distinguishes between:  foreground processes, corresponding to PV systems parameters, land occupation and electricity use and generation, for which specific data have been used.  upstream and downstream processes, corresponding to materials extraction and transformation, PV modules fabrication, materials and products transport, electricity production mix, infrastructures end-of-life, for which semi-specific or generic data have been used. Ecoinvent v2.0 [START_REF]The life cycle inventory data version 2.0[END_REF] was used as the reference database for semi-specific data.

PV installations electricity production

Energy efficiency of the PV modules is set at 14%, with an average performance ratio of 0.855 for the system. The increase in production thanks to mobility is respectively set to 5% for Scenario 3 considering single-axis trackers and to 32.5% for Scenario 4 considering dualaxis trackers, based on average manufacturers' data. The corresponding electricity generated over the 30 years installation life-time is given in Table 2 for the 4 scenarios. 218.0 218.0 228.9 288.9

Infrastructures

Data on infrastructures of large-scale PV installations have been either directly collected or calculated from manufacturers data, as detailed in Table 3. Ten 500 kW inverters are necessary for each PV installation, assuming 10 years of life expectancy (i.e. 30 inverters over each installation life-time), and five 1MW transformers, considering 30 years of life expectancy.

Key additional assumptions

In the absence of specific or semi-specific data for plant building operations (excavation, track construction), for engines composition (used in mobile installations) and for waste structures management (waste modules and supports), the model is based on hypothesis gathered in a Supporting information sheet. In particular, the necessary road to access the installation is assumed to be 3 km long. Moreover, multi-crystalline modules are assumed to be entirely recycled at the end of the installation life, by use of a thermal/chemical treatment.

The life cycle inventory corresponding to modules recycling is partly based on literature data [START_REF] Müller | Life Cycle Analysis of solar module recycling process[END_REF] completed with additional assumptions.

Transformers

Reference flows data compiled from a French manufacturer

Complementary infrastructures

Control center building made of steel reinforced concrete + steel wire fences -Reference flows data compiled from a German manufacturer for one installation (*) computed from the experience of the consulting and engineering partner (Transénergie)

Results

Scenarios comparison

The Life Cycle Impact Assessment results are shown in Figure 2 andTable 4. Negative values represent the environmental benefits of recycling. Those environmental benefits are not taken into account in the global results since they could be applied in another production chain where recycled aluminum is used. Scenario 1, considering fixed-mounting virgin aluminum supports, shows the largest environmental impacts in terms of human health, global warming and resources, while Scenario 4 (dual-axis tracker systems) generates the largest impacts on ecosystem quality. Scenarios 2 and 3 (fixed-mounting wood-based and single-axis trackers) globally show the best environmental performances, with gaps between their potential damage impacts ranging from 1 to 3% depending on the considered category.

Detailed environmental performances 3.2.1. Climate change

Modules manufacturing represents the largest share of climate change impact for all scenarios (38 -56% of the total impact). Moreover, virgin aluminum supports manufacturing stands for a large proportion of the total impact of scenario 1 (36%, if including environmental benefits due to aluminum recycling), contrarily to wood-based fixed-mounting supports (Scenario 2, 21% of the total impact) and galvanized steel mobile supports (Scenarios 3 and 4, respectively 5 and 12%). The climate change impact due to supports is 2 to 10 times larger in scenario 1 than in scenarios 2, 3 and 4. As a consequence, the total climate change impact is 28% larger in scenario 1 than in scenario 2, whereas the climate change impact due to modules is equal for both scenarios (21.4 g. CO 2 eq/kWh, a relatively low value to be related with the assumed use of the French electricity mix for modules manufacturing in scenarios).

Depending on the considered scenario, electric equipments (inverters, transformers and engines in case of mobile structures), complementary infrastructures (road, control centers) and foundations may represent a significant share of the total impact. For example, for World Renewable Energy Congress 2011 -Sweden Photovoltaic Technology (PV) 8-11 May 2011, Linköping, Sweden scenario 4, these elements represent up to 50% of the total climate change burden. This large share is partly due to the increase in electricity production, generating the decrease in environmental impacts of modules (16.1 g. CO 2 eq/kWh), combined with an increase of the impacts of these balance of system (BOS) components.

Human health

Impacts on human health show a similar trend with the impacts on climate change, both in terms of overall impact comparison and predominant Life Cycle phases. Modules manufacturing generates the largest environmental burden for scenarios 2, 3 and 4 (from 29 to 41% of the total impact depending on the scenario), while virgin aluminum supports manufacturing represents the largest share for scenario 1 (33% if including benefits due to

World Renewable Energy Congress 2011 -Sweden Photovoltaic Technology (PV) 8-11 May 2011, Linköping, Sweden recycling). Small particulates, NO x and SO 2 air emissions related to aluminum production (due in particular to electricity requirements and mostly emitted in the aluminum country of origin) represent 22% of the total impact on human health for scenario 1. On the other hand, the human health impact of wood (scenario 2) and galvanized steel supports (scenarios 3 and 4) is lower in absolute value and also stands for a lower share of the total impact.

Resources

Modules manufacturing contribution to the total burden on resources amounts to 53 to 70% depending on the scenario. The environmental benefit gained from the increase in electricity production in case of mobile installations, which is directly reflected in terms of modules impacts, is counterbalanced by different requirements in infrastructures (e.g. electric equipments). As a consequence, whereas scenarios 3 and 4 consider larger electricity production from 5 to 32.5% compared to scenario 2, the gap in impacts on resources between these 3 scenarios is lower than 2%.

Impact on resources of virgin aluminum supports accounts for 24% of scenario 1 total impact (if including benefits from aluminum recycling). This impact is 2 to 6 times larger than impacts of wood-based and galvanized steel supports of scenarios 2, 3 and 4.

Ecosystem quality

The impact on ecosystem quality is mainly influenced by land occupation, which represents 44 to 47% of the impact in case of scenarios 1 to 3 and up to 72% of the impact in case of scenario 4. The difference in impacts on ecosystem quality amounts to a factor 2.1-2.2 between mobile scenario 4 (dual-axis trackers) and scenarios 1 to 3, to compare with a 4.5 ratio between scenario 4 and scenarios 1-3 occupied surfaces. Indeed, power plants with dualaxes trackers require expanding the distances between each element of the PV field, because the shades induced by the moving PV planes are more important: the "power density" in terms of MWp/acre of land used is therefore much lower than for fixed-mounting systems.

Discussion

Key environmental parameters

Irradiation intensity received by PV installations, modules manufacturing electricity use and its corresponding fuel mix and solar radiation conversion efficiency were shown to be key environmental parameters of PV installations in several studies [START_REF] Pacca | Parameters affecting the life cycle performance of PV technologies and systems[END_REF][START_REF] Beloin-Saint-Pierre | Environmental impact of PV systems: effects of energy sources used in production of solar panels[END_REF]. Similarly, this study highlights the large influence of modules production, and to a lower extent of electricity production increase in mobile conditions, on the environmental performances of large-scale grid-connected ground-mounted PV installations. In addition, two other critical parameters arise: structure supports and occupied surfaces.

Metal/Wood supports

The environmental impact of supports production is predominant considering climate change, resources consumption and impacts on human health, and is responsible for the environmental gap between scenarios in several cases (e.g. between Scenarios 1 and 2). The impact of supports is firstly related with their weight: as observed by Mason et al. [START_REF]Environmental management -Life Cycle Assessmentprinciples and framework[END_REF], decreasing the quantity of metal supports in large-scale installations results in significant environmental improvements. However, materials nature appears as an even more critical environmental parameter. For example, the galvanized steel supports mass is 8% larger in scenario 4 than the primary aluminum supports mass in scenario 1 (considering mass per produced kWh), whereas the corresponding impact on e.g. climate change is 81% larger for supports of World Renewable Energy Congress 2011 -Sweden Photovoltaic Technology (PV) 8-11 May 2011, Linköping, Sweden scenario 1. Moreover, a sensitivity analysis has been conducted on aluminum supports, by considering secondary material (from old scrap) instead of virgin material. The use of secondary material generates significant decreases in environmental impacts of scenario 1: 42% for climate change, 39% for human health and 25% for resources, in compliance with the predominance of supports composition on the impacts of a large-scale PV installation.

Occupied surface

The occupied surface mainly determines the impact of large-scale PV installations on ecosystem quality. Consequently, land consuming alternatives such as mobile installations with dual-axis trackers will show relatively large impacts on ecosystem quality compared to fixed-mounting solutions, if considering the same modules technology.

Comparing large-scale grid-connected ground-mounted PV installations

The ranking of alternatives and their associated key parameters may differ from one environmental indicator to another, as observed when putting in perspective large-scale PV installations impacts on climate change and ecosystem quality. This study therefore enhances the need for a multi-criteria impact assessment method when comparing large-scale gridconnected ground-mounted PV installations. In addition, the results underline the multiplicity of parameters which may affect large-scale PV installations environmental performances. The environmental impacts of large-scale PV installations are the result of the interplay between a number of distinct parameters (e.g. energy production, supports mass and nature, electric equipments, etc.), whose related influence may counterbalance each other.

Conclusions, recommendations and perspectives

The impact assessment of large-scale ground mounted PV installations therefore gives a detailed picture of their related environmental performances. Key installations design parameters arise in an environmental perspective: supports mass and composition, power density (in MWp/acre of land) and energy production performances, in addition to key parameters related to modules manufacturing (in particular electricity consumption and electricity production mix).

The environmental performances of large-scale PV installations are not in linear correlation with a unique quantified plant parameter. In that sense, for example, increasing the electricity production thanks to mobile technologies does not necessarily bring environmental benefits if combined with an increase in requirements in materials. A multi-criteria perspective -with respect to environmental indicators and installations key design parameters -should be undertaken with a view to optimizing PV large-scale installations environmental performances in a near future.

Fig.

  Fig. 1. Scheme of system boundaries

Fig. 2 .

 2 Fig. 2. Detailed environmental impacts of the 4 scenarios (considering 1700 kWh/m².yr of irradiation on an inclined plane, mc-Si modules with 14% of energy production performance and IMPACT2002+ v2.04 damage indicators)

1. Scheme of system boundaries

	World Renewable Energy Congress 2011 -Sweden	Photovoltaic Technology (PV)
	8-11 May 2011, Linköping, Sweden

Table 1 .

 1 Scenarios key features

	Scenarios	1	2	3	4
	Module Technology	mc-Si	mc-Si	mc-Si	mc-Si
	Structure key features	Fixed mounting Primary aluminum supports	Fixed mounting Wood-based supports	Mobile Single-axis trackers	Mobile Dual-axis trackers

Table 2 .

 2 Energy production in scenarios

	Scenarios	1	2	3	4
	Increase in production due to mobility	-	-	5% (Average data from a Spanish supports manufacturer)	32.5% (Average data from an Italian supports manufacturer)
	Electricity production
	over 30 years (in GWh)

Table 3 .

 3 Data collection for infrastructures in scenarios

	World Renewable Energy Congress 2011 -Sweden	Photovoltaic Technology (PV)
	8-11 May 2011, Linköping, Sweden
		Scenario 1	Scenario 2	Scenario 3	Scenario 4
	Modules	35714 m² -value based on calculations from energy production performances
	Area	92 888 m²(*)	92 888 m²(*)	96 922 m²(*)	418 770 m²(*)
	Supports	Primary aluminum -Mass values from technical sheets from a German manufacturer	Wood, primary aluminum and iron -Mass values from data from a multi-MWp installation in France	Galvanized steel -Mass values from technical sheets from a Spanish manufacturer	Galvanized steel -Mass values from technical sheets from an Italian manufacturer
		Cast iron stakes -	Concrete -Mass values	Concrete -Mass	Concrete -Mass
	Foundations	approximation based on technical sheets from an	from data from a multi-MWp installation in	values from implementation	values from implementation
		Austrian manufacturer	France	schemes (*)	schemes (*)
	Cabling	Copper, aluminum and PVC -Mass values from implementation schemes (*)

Table 4 .

 4 Damage impact assessment results for the four scenarios(Impact 2002+method v2.04)

		Human health Ecosystem quality	Climate change	Resources
	Study case	(DALY/kWh)	(PDF.m².yr/kWh)	(g. CO 2 eq./kWh) (MJ primary/kWh)
	Scenario 1	4.65E-08	2.46E-02	53.5	1.10
	Scenario 2	3.24E-08	2.35E-02	38.0	0.88
	Scenario 3	3.34E-08	2.32E-02	37.5	0.90
	Scenario 4	4.12E-08	5.15E-02	42.8	0.88

Acknowledgements

ADEME is co-financing this project which brings together different French specialists from the PV industry and LCA fields.


N Legrand

N Labbe

D Weisz-Patrault
email: cdaniel.patrault@enpc.fr

A Ehrlacher
email: alain.ehrlacher@enpc.fr

T Luks
email: eluks@lptap.fme.vutbr.cz

J Horsky
email: fhorsky@fme.vutbr.cz

Analysis of roll gap heat transfers in hot steel strip rolling through roll temperature sensors and heat transfer models

Keywords: hot strip rolling, roll bite heat transfer, inverse thermal analysis, thermal fatigue

This paper presents an analysis of roll bite heat transfers during pilot hot steel strip rolling. Two types of temperature sensors (drilled and slot sensors) implemented near roll surface are used with heat transfer models to identify interfacial heat flux, roll surface temperature and Heat Transfer Coefficient HTC roll-bite in the roll bite. It is shown that: -the slot type sensor is more efficient than the drilled type sensor to capture correctly fast roll temperature changes and heat fluxes in the bite during hot rolling but its life's duration is shorter.

-average HTC roll-bite is within the range 15-26 kW/m 2 /K: the higher the strip reduction (e.g. contact pressure) is, the higher the HTC roll-bite is. -scale thickness at strip surface tends to decrease heat transfers in the bite from strip to roll.

-HTC roll-bite is not uniform along the roll-strip contact but seems proportional to contact pressure.

-this non uniform HTC roll-bite along the contact could contribute to decrease thermal shock (so roll thermal fatigue) when the work roll enters the roll bite, in comparison to a uniform HTC roll-bite . -Heat transfer in the roll bite is mainly controlled by heat conduction due to the huge roll-strip temperature difference, while heat dissipated by friction at roll-strip interface seems negligible on these heat transfers.

Introduction

In hot rolling, thermal sollicitations of rolls are characterized by cyclic thermal shocks in the roll bite due to the cyclic contact between a strip at ~1000°C and a roll at 50-100°C. This cyclic thermal loading, amplified with work roll water cooling, is responsible for roll degradation by thermal fatigue that strongly shorten rolls life. A decrease of roll thermal fatigue requires a better knowledge of real peaks of temperature and heat transfers in the roll bite that are the source of the roll thermal shock. Currently, these roll bite peaks are approximated with Heat Transfer Coefficients 'HTC' macroscopically tuned on measured mill data. This current way of identification is sufficient to optimize mill cooling capacity where only a knowledge of the average heat transfer within and from the roll is needed. However, to determine roll degradation by thermal fatigue, an accurate and local evaluation of these roll bite peaks of temperature and heat transfers is necessary: this is the first aim of this paper. Furthermore, a huge amount of literature work has been focused on HTC and heat flux identification by inverse models during hot rolling [START_REF] Kotrbacek | Experimental study of heat transfer and heat flux by inverse analysis during steel strip rolling[END_REF]. However, the long computing time associated to these models does not allow a real time interpretation of measurements necessary for on line control of rolling mills. The second aim of this paper is thus to show the applicability of fast models for heat transfers identification quasi in real time.

Hot pilot mill trials

Roll temperature sensors (fig. 1) Roll temperature sensors are manufactured with K-type thermocouples implemented in a cylindrical plug. The work roll is drilled with one axial hole and 4 radial holes, then the plugs are inserted and glued into the different radial holes (fig. 1a). The surface of the roll is finally regrinded to limit marks on the strip during rolling. The thermocouple is placed at a certain distance from roll surface (~0.5mm) to measure roll temperature at an inner roll radius. Moreover, the thermocouple wire is placed parallel to roll surface (and not perpendicular) to avoid perturbations of isotherms. Two different temperature sensors have been used: -slot temperature sensor (fig. 1b): the thermocouple is placed in a slot made by milling at the surface of the plug and brazed to the rest of the plug. A solder material (Nickel) covers the thermocouple. This sensor has a fast response time because the thermocouple is inserted in the continuum solder material (no empty and no air inside), but can be damaged easily during rolling. -drilled temperature sensor (fig. 1c) : the thermocouple is placed in a drilled hole remaining empty, e.g. containing air which is a strong thermal insulator. Consequently, the thermal response of that sensor is generally slower than the slot sensor but its mechanical resistance is generally higher. The roll was cooled by air outside the roll bite (no water cooling) and heated by the strip inside the roll bite. In comparison to a rolling configuration with water cooling, this rolling condition has the advantage to be simpler: only the heat transfer coefficient in the bite HTC roll-bite is unkown and must be tuned with experiments. Heat transfer with air is relatively well known: HTC air = 50 W/m2/K.

Pilot mill trials results. Rolling test results are reported in table 1 and roll temperature evolution measured with slot and drilled sensors during successive rotations are shown on Fig. 2. The response of the drilled sensor C1 is slower and smaller than the one of the slot sensor A, though both sensors are located at a similar distance from roll surface: ~0.5mm. This slower response comes from the air contained in the drilled sensor (fig. 1c) which acts as a strong thermal insulator, as confirmed by figure 5.

                       T t T D T r r T r r T 1 . 1 . 1 2 2 2 2 2 (1)
As the model is analytical, it considers thermal properties independent of temperature:  (thermal conductivity) = 17.3 W/m/K and D (thermal diffusivity) = 4.2 mm 2 /sec. These values correspond to average thermal properties of solder material used in the slot sensor. For the drilled sensor, lower values are used ( = 13 W/m/K, D = 2 mm 2 /sec.: fig. 5) because of air in the sensor.

-model n°2: a numerical finit difference roll gap heat transfer model for the strip coupled with a finit difference 1D roll temperature evolution model [START_REF]User's manual of Cylescale, roll and strip temperature evolution model -internal report ArcelorMittal[END_REF] is used in direct mode: the roll surface boundary condition HTC roll-bite is used as input of the roll temperature model to match predicted and measured temperatures at inner roll radius. The following 1D heat equation is solved for the roll:

              t T D r T r r T 1 . 1 2 2 (2)
The model can consider heat dissipation by friction in the bite and roll thermal properties dependent on temperature:  varies from 44 to 38 W/m/K and D varies from 11 to 8 mm 2 /sec. for temperature varying from 20 to 350°C. These values correspond to thermal properties of a normal steel grade which is the grade used for the work rolls. Model n°2 cannot consider the sensor in the work roll, in contrast to model n°1, however, it has been checked that the difference of roll thermal properties used in the two models has not a significant influence on results, except for the drilled sensor (fig. 5). Finally the difference of heat equations (2D: model n°1, 1D: model n°2) on results of the two models is discussed on fig. 7.

Evaluation of roll surface temperature and heat flux by inverse calculation (model n°1)

Influence of strip reduction. Fig. 3 shows for different strip reductions (5%, 10%, 15%, 20%) the evolution of roll temperature measured at the inner roll radius during rolling and the reconstructed interfacial heat flux and roll surface temperature at the outer roll radius with inverse model n°1: the higher the strip reduction is, the higher the surface temperature and heat flux from strip to roll in the bite are. This trend is due to the higher heat dissipated by plastic deformation corresponding to the higher strip reductions. Influence of strip surface scale. Fig. 4 shows the reconstruction by inverse model n°1 of temperature and heat flux at roll surface (using the measured temperature at inner roll radius, not shown here) for the two different furnace temperatures at which the strip has been heated prior to rolling: 1050°C (test n°6) and 1150°C (test n°10). The higher the heating furnace temperature is, the lower the roll bite heat flux is. A model has been used to determine the scale thickness formation for the two tests n°6 and n°10: -test n°6: strip pre-heated at 1050°C has produced a scale thickness of ~35 m at strip surface.

-test n°10: strip pre-heated at 1150°C has produced a scale thickness of ~60 m at strip surface.

As scale has a much lower thermal conductivity (2 W/m/K) than steel (15 W/m/K), the thicker scale thickness in test n°10 acts as a thermal insulator, decreasing roll-strip heat transfers.

Evaluation of roll surface temperature and heat flux using slot and drilled sensors. Fig. 5 shows heat flux and roll surface temperature reconstructed with drilled and slot sensors respectively using the inverse model n°1. For the reconstruction with the slot sensor, the thermal properties of the solder material were used:  = 17.3 W/m/K and D = 4.2 mm 2 /sec. For the reconstruction with the drilled sensor, the thermal properties and D have been adjusted to obtain a similar curve as for the slot sensor: = 13 W/m/K and D = 2 mm 2 /sec. were obtained. These lower values are consistent with the air contained in the drilled sensor that slows down heat exchanges with the sensor. Nevertheless due to these heat exchanges modified by air, the reconstruction at roll surface with the drilled sensor presents much more noise than the reconstruction with the slot sensor, especially for heat transfer reconstruction. The slot sensor is thus more efficient than the drilled sensor. Heat Transfer Coefficient evaluation (HTC). HTC roll-bite is adjusted by direct calculations to match measured and simulated roll temperatures at inner roll radius for test n°6, 1 st pass, 1 st revolution: HTC roll-bite was identified approximately to 20 kW/m 2 /K for test n°10 (fig. 6a shows the identification) and to 26 kW/m2/K for test n°6.

Evaluation of temperature response for slot and drilled sensors. For test n°10, fig. 6a and 6b compare at the inner roll radius the temperature measured with the two sensors with the temperature predicted by the model n°2 assuming an homogeneous material. The slot type sensor do not perturb the measured temperature field and can capture correctly the fast roll temperature change when passing through the roll bite (fig. 6a), but life's duration of the slot sensor is shorter than the drilled sensor. The drilled sensor perturb the measured temperature field when passing through the roll bite, this is due to the air contained in it that acts as thermal insulator but its life duration is longer (fig. 6b). These results are consistent with the ones of fig. 5.

HTC roll-bite as a function of strip surface scale. HTC roll-bite as a function of strip surface scale thickness can be identified by comparison of test n°6 (small scale thickness ~35 microns: HTC roll-bite = 26 kW/m 2 /°K) with test n° 10 (higher scale thickness ~60 microns: fig. 6a: HTC roll-bite = 20 kW/m 2 /°K ).

HTC roll-bite as a function of strip reduction. HTC roll-bite has been identified as a function of strip reduction using tests n°1 to 4 (Fig. 7a): the higher the strip reduction is, the higher the average HTC roll-bite is, with a saturation around 20%. Comparison of interfacial heat flux reconstructed with model n°2 and with inverse model n°1. For test n°6, fig. 7b shows a comparison of the interfacial heat flux determined by direct simulation with model n°2 using a uniform HTC roll-bite 26 kW/m 2 /K (value obtained as for fig. 6a) with the interfacial heat flux determined with the inverse model n°1 using directly temperature sensors. The bad agreement between the two interfacial heat fluxes can be due to HTC roll-bite assumed uniform in model n°2 while it seems not uniform but proportional to roll gap pressure according to model n°1. Moreover, the absence of peak of heat flux at bite entry obtained with model n°1 suggests that the real thermal fatigue submitted by the roll could be lower in comparison to the one determined with model n°2. Furthermore, fig. 7b shows that heat flux dissipated by friction is negligible compared to the conduction heat flux. Finally fig. 7b shows that at the exit of the roll bite, heat flux is reversed (change direction) with model n°1 while it remains strictly zero for model n°2: it is suspected that this difference is due the different heat equation used in the two models (2D heat equation for model n°1, 1D heat equation for model n°2). Additional work is needed to further investigate the above conclusions, it is scheduled in a future work.

Conclusions

Roll bite heat transfers and roll temperature distribution have been identified with roll temperature sensors combined with models. With this identification, it is now possible to evaluate precisely the corresponding roll thermal fatigue during rolling. It is scheduled in a future work.

  Fig. 1: temperature sensors

Table 1 :Fig. 2 :

 12 Fig.2: roll temperature evolution measured with slot sensor A and drilled sensor C1 (test n°10, 1 st pass)

Fig. 3 :

 3 Fig.3: strip reduction influence on heat flux and surface temperature (tests n°1 to 4 -1 st pass, 1 st revolution, sensor A)

Fig. 4 :

 4 Fig.4: influence of strip surface scale on roll surface temperature and surface heat flux for two different furnace temperatures: 1050°C and 1150°C (tests n°6 and 10 -1 st pass -2 1 st revolutions)

  Fig.5: roll surface temperature and heat flux reconstructed with slot and drilled sensors respectively (test n°10 -1 st pass, revolution n°1)

  Fig.6: comparison of simulated and measured temperature responses with slot sensor A and drilled sensor C1 (test n°10, 1 st pass, two 1 st revolutions, high scale thickness : ~ 60 microns)

Fig. 7 :

 7 Fig.7: HTC roll-bite identification as a function of strip reduction (left: tests n°1 to 4) and interfacial heat flux identified with models n°1 and n°2 (right: test n°6) (slot sensor A)