10.1007/s00280-009-0926-8</TITLE= > <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18372"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Cancer Chemotherapy and Pharmacology</TD></TR> <TR> <TD>=A9 Springer-Verlag 2009</TD></TR> <TR> <TD>10.1007/s00280-009-0926-8</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Original Article</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Fotemustine as second-line = treatment for=20 recurrent or progressive glioblastoma after concomitant and/or adjuvant=20 temozolomide: a phase II trial of Gruppo Italiano Cooperativo di = Neuro-Oncologia=20 (GICNO) </DIV> <P class=3DAuthorGroup>Alba A. Brandes<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/08667430516x2324/contact.gif">= </A></SUP>,=20 A. Tosoni<SUP>1</SUP>, E. Franceschi<SUP>1</SUP>,=20 V. Blatt<SUP>2</SUP>, A. Santoro<SUP>3</SUP>,=20 M. Faedi<SUP>4</SUP>, P. Amist=E0<SUP>5</SUP>,=20 M. Gardiman<SUP>6</SUP>, R. Labianca<SUP>7</SUP>,=20 C. Bianchini<SUP>8</SUP>, M. Ermani<SUP>9</SUP> and=20 M. Reni<SUP>10</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedale=20 Bellaria-Maggiore, Via Altura 3, 40139 Bologna,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Research and Development Unit, Azienda = Ospedale-Universit=E0 di Padova, Padova, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Istituto=20 Clinico Humanitas, Rozzano, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedale=20 Bufalini, Cesena, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neuroradiology, Ospedale = Santa=20 Maria della Misericordia, Rovigo, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Pathology, Azienda=20 Ospedale-Universit=E0 di Padova, Padova, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedali=20 Riuniti, Bergamo, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Scientific Department, Italfarmaco, = Milan,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosciences, = Statistics and IT=20 Unit, Azienda Ospedale-Universit=E0 di Padova, Padova,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Oncology, San Raffaele=20 Scientific Institute, Milan, = Italy</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/contact.gif">= </TD> = <TD><STRONG>Alba </STRONG><STRONG>A. </STRONG><STRONG>Brandes</= STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:alba.brandes@yahoo.it">alba.brandes@yahoo.it</A></TD></TR>= </TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>24 October 2008 <STRONG>Accepted:=20 </STRONG>5 January 2009 <STRONG>Published online:=20 </STRONG>24 January 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A>Background </SPAN>Standardized salvage = treatment has=20 not yet proved effective in glioblastoma multiforme (GBM) patients who = receive=20 prior standard radiotherapy plus concomitant and adjuvant temozolomide.=20 </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec2></A>Methods </SPAN>Patients with progressive GBM = after=20 radiotherapy plus concomitant and/or adjuvant temozolomide received = three-weekly=20 doses (100=9675 mg m<SUP>2</SUP>) of fotemustine followed, = after a=20 5-week rest, by fotemustine (100 mg m<SUP>2</SUP>) every = 3 weeks=20 for ≤1 year. </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec3></A>Results </SPAN>Forty-three patients (29 M, = 14 F;=20 median age 51 years, range 34=9668; median KPS 90) were enrolled.=20 Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: = 9=9633%);=20 three patients (7.1%) had partial response (PR); 15 (34.9%), disease=20 stabilization (SD). The median survival was 6 months (95% CI: = 5=967).=20 <I>MGMT</I> promoter status was methylated in 8 (18.6%) and unmethylated = in 26=20 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease = control=20 was 75% versus 34.6% in methylated and unmethylated <I>MGMT</I> patients = (<I>P</I> =3D 0.044); no significant difference was found = between groups=20 for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia = were=20 observed in 20.9 and 16.3% of patients, during the induction phase, and = in 0 and=20 9.5% patients during the maintenance phase, respectively. </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec4></A>Conclusions </SPAN>The findings of the = present trial,=20 that evaluate fotemustine in a homogeneous population, may represent a = new=20 benchmark for nitrosourea activity. Moreover, this is the first study to = evaluate correlation between <I>MGMT</I> promoter status and outcome of=20 fotemustine for relapsing GBM previously treated with radiotherapy and=20 temozolomide. </DIV></DIV></DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioblastoma=20 multiforme - Second-line=20 chemotherapy - Recurrence - Fotemustine - = <I>MGMT</I> - Clinical trial </P> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Worldwide, glioblastoma multiforme (GBM) is the most frequent primary = brain=20 tumor in adults, accounting for 15=9620% of intracranial tumors and 50% = of gliomas=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR6">6</A></CITE>].=20 The standard treatment for newly diagnosed GBM with temozolomide (TMZ),=20 concomitant, and adjuvant to radiotherapy provides a significant = increase in=20 overall survival with respect to radiotherapy alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR27">27</A></CITE>].=20 However, nearly all patients treated for GBM faced recurrence. None of = the=20 several drug regimens reported in literature substantially delays = disease=20 progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR2">2</A></CITE>].=20 However, promising results have recently been obtained using novel = agents, and=20 new schedules or synergic combinations [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR30">30</A></CITE>].=20 However, the findings reported following these new approaches require = further=20 confirmation based on results obtained in patients who have a longer = follow-up.=20 </P> <P>Nitrosoureas, used alone or in combination with other agents, are = still used=20 as standard second-line chemotherapy, and are considered the standard = arm in=20 randomized phase II studies for experimental therapy. Moreover, it has = not been=20 demonstrated that nitrosourea-based polychemotherapy is anymore = effective=20 against GBM than single agent chemotherapy. Fotemustine (FTMS), a third=20 generation chloroethylnitrosourea containing a phosphoalanine carrier = group, is=20 grafted to the nitrosourea radical. Thanks to the phosphoalanine group=20 contained, the drug is highly lipophilic; its octanol/water partition=20 coefficient being within a range that is more satisfactory than the = ranges=20 obtained with other nitrosoureas, such as carmustine (BCNU) and = lomustine=20 (CCNU). FTMS is able to cross the blood-brain barrier [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR18">18</A></CITE>];=20 in vitro and in vivo studies have shown that FTMS has a marked = anti-neoplastic=20 activity on human GBM and medulloblastoma cell lines [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR9">9</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR10">10</A></CITE>].=20 In their phase I study on 22 GBM patients, Khayat et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR14">14</A></CITE>]=20 specified the dose of FTMS to be used in clinical practice:=20 100 mg m<SUP>2</SUP> for 1-h infusions, conducted on days 1, = 8, and 15=20 (induction), to be repeated after 4=965 weeks (hematological = recovery) every=20 21 days (maintenance). However, in the literature, there is little=20 information on activity and toxicity of this regimen. </P> <P>The aim of the present phase II study on patients with recurrent or=20 progressive GBM, who were uniformly treated with prior radiotherapy and = TMZ, was=20 to evaluate the effect of FTMS on progression-free survival at = 6 months=20 (PFS-6), response, toxicity and any correlation with = O6-methylguanine=96DNA=20 methyltransferase (<I>MGMT</I>) gene promoter methylation status. = </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV><A name=3DSec3></A> <DIV class=3DHeading3>Eligibility</DIV> <P>The criteria for eligibility were GBM recurrent or progressive after = surgery=20 and TMZ concomitant with and/or adjuvant to radiotherapy, proven by MRI = or CT=20 scans at least 3 months following the radiotherapy end or by two=20 consecutive tests. Measurable disease with contrast enhancement using = MRI or CT=20 scans, tested within 2 weeks before study treatment start. In case = of=20 re-surgery before chemotherapy start, residual measurable disease with = contrast=20 enhancement must be proven by MRI or CT scans, performed within = 3 days=20 after surgery. At least one unidimensionally measurable lesion of = ≥2 cm in=20 diameter by MRI. Stable or decreasing dose of corticosteroids for at = least=20 2 weeks before patient=92s enrollment. At least 4 weeks = following=20 chemotherapy with TMZ. Other inclusion criteria were age ≥18 and = ≤70 years;=20 Karnofsky performance status ≥60; adequate bone marrow reserve = (absolute=20 neutrophils count = >1.5 =D7 10<SUP>9</SUP> L<SUP>−1</SUP>;=20 platelets = >100 =D7 10<SUP>9</SUP> L<SUP>−1</SUP>; = hemoglobin=20 >10 g dL<SUP>−1</SUP>); normal renal and liver = function (serum=20 creatinine <1.25=D7, upper limit of the normal range (ULN); BUN=20 <25 mg dL<SUP>−1</SUP>; serum bilirubin = ≤1.25=D7 ULN; AST and=20 ALT ≤ 1.5=D7 ULN; alkaline phosphatase ≤2=D7 ULN; = remaining life=20 expectancy ≥3 months. Patients with active infections or = other uncontrolled=20 diseases, psychiatric disturbances and/or a previous history of cancer = (except=20 for resected non-melanoma skin cancer or carcinoma=97in situ of the = uterine=20 cervix), were considered ineligible. </P> <P>All the histological specimens obtained at first diagnosis were = reviewed by=20 the coordinating center of Azienda Ospedaliera of Padova (M.G. = Department of=20 Pathology) and the diagnosis of GBM was confirmed according to the = criteria=20 specified in 2007 WHO central nervous tumor classification. </P> <P>The study, approved by the Institutional Ethics Committees of all=20 participating centers, was conducted according to the principles of the=20 declaration of Helsinki and the rules of good clinical practice. </P> <P>All patients signed a form giving their fully informed consent to = participate=20 in the study.</P></DIV> <DIV><A name=3DSec4></A> <DIV class=3DHeading3>Treatment schedule</DIV> <P>In line with phase I study protocol and with licensing instructions = of the=20 drug, FTMS 100 mg m<SUP>2</SUP> was administered i.v. over = 1 h=20 weekly for three consecutive weeks (induction therapy), followed after=20 5 weeks by one infusion of FTMS 100 mg m<SUP>2</SUP> = every=20 3 weeks (maintenance therapy) for up to 1 year, unless disease = progression or unacceptable toxicity was observed. If, due to toxicity,=20 treatment suspension was prolonged by more than 2 weeks beyond the = next=20 scheduled cycle of treatment planned, the patient was permanently = withdrawn from=20 the study. Based on the most severe toxicity experienced since the last = cycle,=20 the subsequent dose was reduced to 75% in the presence of grade 3 or 4 = platelet=20 toxicity, grade 4 neutrophils or white blood cells or hemoglobin = toxicity. In=20 cases of non-hematologic toxicity, chemotherapy was delayed until = recovery to=20 grade 1, for a maximum of 2 weeks (after which the patient was = withdrawn=20 from the study). In cases of recovery to grade 1 after grade 3 or 4 = toxicity, a=20 dose of 75% the treatment dose was administered. </P> <P>After the inclusion of the first three patients who experienced grade = 4=20 thrombocytopenia following induction therapy, the protocol was amended = to reduce=20 FTMS dosage during induction therapy to 75 mg m<SUP>2</SUP>. = In fact,=20 this life-threatening toxicity was considered unacceptable in the = palliative=20 setting of salvage therapy of GBM patients. </P></DIV> <DIV><A name=3DSec5></A> <DIV class=3DHeading3>Efficacy measures and toxicity monitoring</DIV> <P>Progression-free survival (PFS) was measured as from the initiation = of FTMS=20 to progression or death due to any cause or last follow-up assessment, = whichever=20 comes first. Overall survival (OS) was measured as from the start of = FTMS to=20 death for any reason, or last follow-up assessment. In this intent to = treat=20 study, data on all registered patients who met the main inclusion = criteria were=20 included in the statistical analysis. </P> <P>Evaluation of response, conducted in all patients, included clinical = and=20 neurological examinations and MRI or CT neuro-imaging according to = Macdonald=92s=20 criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR17">17</A></CITE>].=20 The first evaluation was made after the induction phase (7 weeks = after the=20 first study drug administration); thereafter evaluations were made every = two=20 cycles during the study treatment (6 weeks) and every 3 months = during=20 the follow-up period, or earlier if indicated. Neurological status was = assessed=20 by considering signs and symptoms possibly correlated with progression, = as=20 compared to the previous examination; each variation in daily = corticosteroids=20 dosage was recorded. </P> <P>Responses were confirmed as complete (CR), partial (PR) and stable = (SD) if=20 they were constant at subsequent scans obtained at least 4 weeks = apart from=20 each other. An independent central review of CT and MRI scans was made = for all=20 patients. </P> <P>All adverse events were recorded and graded according to the common = toxicity=20 criteria of the National Cancer Institute, version 3.0. (<A=20 href=3D"http://ctep.cancer.gov/forms/CTCAEv3.pdf">http://ctep.cancer.gov/= forms/CTCAEv3.pdf</A>).=20 </P></DIV> <DIV><A name=3DSec6></A> <DIV class=3DHeading3>DNA extraction and methylation-specific polymerase = chain=20 reaction</DIV> <P><I>MGMT</I> promoter methylation analysis was performed on tissue = taken from=20 the primary surgery specimen before radiotherapy and TMZ. </P> <P>DNA from 10 μm paraffin sections of cerebral lesion was = modified by=20 sodium bisulfite, which converts unmethylated cytosine to uracil, = according to=20 the procedure of Herman et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR13">13</A></CITE>].=20 Modified DNA was submitted for methylation-specific PCR (MSP) following = a=20 nested-PCR protocol [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR21">21</A></CITE>].=20 Since the quality of DNA obtained from formalin-fixed paraffin-embedded = tumor=20 tissue affects the success rate of MSP, in some cases <I>MGMT</I> = methylation=20 status was determined by a different nested-MSP approach, with a first = pair of=20 primers to obtain smaller amplicons (129 bp), for which forward and = reverse=20 primers have been described [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR21">21</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR28">28</A></CITE>].=20 </P></DIV> <DIV><A name=3DSec7></A> <DIV class=3DHeading3>End points and statistical analysis</DIV> <P>Data from all patients, who received at least one drug delivery and = for whom=20 at least one tumoral evaluation was performed, were included in the = response=20 analysis. </P> <P>The primary efficacy endpoint of the study was the percentage of = patients=20 free from disease progression at 6 months (PFS-6). Drug activity = was=20 evaluated following a one-stage Fleming study design for determination = of=20 response rates based on a single-treatment group. A sample size of 40 = patients=20 was estimated using exact binomial method and assuming: one-tailed = α equal to=20 0.1, (1-β) equal to 0.9 and π<0.1 (null hypothesis) versus = π ≥ 0.25=20 (alternative hypothesis), where π was the observed 6-month disease=20 progression-free probability. If seven or more patients were evaluated = as PFS-6,=20 it was assumed that the drug was active. </P> <P>Secondary objectives were the rate of best observed response, defined = as the=20 best response during the treatment and evaluated with Macdonald=92s = criteria=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR17">17</A></CITE>];=20 duration of objective response and stabilization; duration of complete = response;=20 time to disease progression, overall survival, toxicity, and evaluation = of=20 <I>MGMT</I> methylation and the correlation with clinical outcome. All = patients=20 receiving the study drug were included in the safety analysis. Median = time to=20 progression (mTTP) and median survival were also estimated with = associated 95%=20 CI. PFS-6 and OS were calculated using the Kaplan=96Meier method; = differences in=20 PFS-6 and OS were compared using the log rank test for statistical = significance.=20 </P></DIV></DIV> <DIV><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV><A name=3DSec9></A> <DIV class=3DHeading3>Patients=92 characteristics</DIV> <DIV class=3DPara> <DIV>From April 2005 to May 2006, 43 patients (29 males; median age:=20 51 years, range: 34=9668 years; median: KPS 90) were enrolled = in the=20 study. The demographic and clinical characteristics of patients are = outlined in=20 Table <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#Tab1">1</A>.=20 Each patient had completed external-beam radiation therapy = (60 Gy/30 F)=20 concurrent and/or followed by adjuvant TMZ. Median number of TMZ cycles = was 5=20 (range 1=9623). No patient underwent a second surgical procedure at the = time of=20 progression following TMZ administration. Median time between TMZ = treatment=20 completion and FTMS start was 1.5 months (range 1=9643). Thirty = patients=20 (69.8%) started FTMS within 3 months from TMZ last administration. = At time=20 of FTMS initiation 26 patients (60.5%) were on enzyme-inducing = antiepileptic=20 drugs (EIAEDs), while 11 patients (25.6%) were on non-EIAEDs and 6 = patients=20 (13.9%) were not on antiepileptic drugs. The median duration of = follow-up was=20 7.4 months (range 1.2=9622.7). In 39 of the 43 patients enrolled in = the=20 trial, enough histological material was obtained for evaluation of MSP. = MSP was=20 assessable on 34 of these 39 patients. <I>MGMT</I> promoter status was=20 methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not = assessable in 9=20 (20.9%) patients, respectively.<A name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Patients=92=20 characteristics </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft char=3D"."> </TH> <TH align=3Dleft> <P>Number of patients</P></TH> <TH align=3Dleft char=3D"."> <P>%</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Sex</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Male</P></TD> <TD align=3Dleft> <P>29</P></TD> <TD align=3Dchar char=3D"."> <P>67</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Female</P></TD> <TD align=3Dleft> <P>14</P></TD> <TD align=3Dchar char=3D"."> <P>33</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Age</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Median years (range)</P></TD> <TD align=3Dleft> <P>51 (34=9668)</P></TD> <TD align=3Dchar char=3D"."> </TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Karnofsky performance status (KPS)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Median (range)</P></TD> <TD align=3Dleft> <P>90 (70=96100)</P></TD> <TD align=3Dchar char=3D"."> </TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Extent of resection</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Macroscopically radical</P></TD> <TD align=3Dleft> <P>28</P></TD> <TD align=3Dchar char=3D"."> <P>65</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Partial</P></TD> <TD align=3Dleft> <P>12</P></TD> <TD align=3Dchar char=3D"."> <P>28</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Biopsy</P></TD> <TD align=3Dleft> <P>3</P></TD> <TD align=3Dchar char=3D"."> <P>7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P>Radiotherapy/TMZ</P></TD> <TD align=3Dleft> <P>43</P></TD> <TD align=3Dchar char=3D"."> <P>100</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P><I>MGMT</I> status </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Methylated</P></TD> <TD align=3Dleft> <P>8</P></TD> <TD align=3Dchar char=3D"."> <P>18.6</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Unmethylated</P></TD> <TD align=3Dleft> <P>26</P></TD> <TD align=3Dchar char=3D"."> <P>60.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Unknown</P></TD> <TD align=3Dleft> <P>9</P></TD> <TD align=3Dchar char=3D"."> <P>20.9</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>FTMS initiation and time to TMZ treatment = completion</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Within 3 months</P></TD> <TD align=3Dleft> <P>30</P></TD> <TD align=3Dchar char=3D"."> <P>69.8</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Beyond 3 months</P></TD> <TD align=3Dleft> <P>13</P></TD> <TD align=3Dchar char=3D"."> <P>30.2</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV><A name=3DSec10></A> <DIV class=3DHeading3>Progression-free survival</DIV> <P>Nine patients (20.9%; 95% CI: 9=9633%) were PFS-6 and the median PFS = was=20 1.7 months.</P> <P>The percentages of PFS-6 with <I>MGMT</I> promoter methylated or = unmethylated=20 status were 25% (95% CI: 7.5=9683%) and 19.2% (95% CI: 8.7=9642.3%), = respectively.=20 PFS-6 in the population (<I>n</I> =3D 40) treated after the = amendment=20 was 22.5%, not significantly different with the entire population of 43 = pts.=20 </P> <P>No significant differences were found between median PFS, evaluated = using the=20 log rank test, in relation to age (<I>P</I> =3D 0.89), KPS=20 (<I>P</I> =3D 0.33), and <I>MGMT</I> promoter methylated or = unmethylated=20 status (<I>P</I> =3D 0.15). No significant influence of type = of=20 antiepileptic drug was seen, being PFS-6 26.9% and 11.7% in patients on = EIAEDS=20 and on non-EIAEDS plus not on antiepileptic drugs, respectively=20 (<I>P</I> =3D 0.28). </P> <P>Patients that initiated FMTS at least 3 months after TMZ = completion=20 showed a significantly higher PFS-6, (30.7 vs. 16.7%) than patients who=20 initiated FTMS immediately after TMZ completion = (<I>P</I> =3D 0.034).=20 </P></DIV> <DIV><A name=3DSec11></A> <DIV class=3DHeading3>Response</DIV> <P>Among the 43 assessable patients, 3 had partial responses (7.1%, 95% = CI:=20 0=9615%), and 15 stable disease (34.9%, 95% CI: 21=9649%). Disease = control rate=20 (SD+PR) in the population treated after the amendment was 42.5%, not=20 significantly different with the entire population. All responses were = confirmed=20 by an independent centralized review, and stable or decreased steroid = dosage was=20 confirmed in all patients at the time of recording response. Median = duration of=20 response was 9.1 months (95% CI: 1.7=9616.4), and median duration = of disease=20 stabilization was 5 months (95% CI: 1.2=968.9). Disease control = rate was=20 significantly greater in methylated and unmethylated <I>MGMT</I> = patients, 75=20 and 34.6% (<I>P</I> =3D 0.044), respectively; and in patients = who=20 started FTMS at least 3 months after TMZ administration had been = concluded=20 (76.9 vs. 26.7%, <I>P</I> =3D 0.002). </P> <P>No significant influence of type of antiepileptic drug was seen, = being=20 disease control rate 42.3 and 41.2% in patients on EIAEDS and on = non-EIAEDS plus=20 non on antiepileptic drugs, respectively (<I>P</I> =3D 0.98). = </P></DIV> <DIV><A name=3DSec12></A> <DIV class=3DHeading3>Overall survival</DIV> <P>The median overall survival was 6 months (95% CI: 5=967). The = median=20 overall survival of the population treated after the amendment was=20 6 months. No statistical difference has been found between patients = with=20 methylated and those with unmethylated <I>MGMT</I> promoter status: = being=20 6 months (95% CI: 0=9614.2) versus 5.5 months (95% CI: = 4.2=966.8). </P> <P>The median overall survival for patients who started FTMS at least=20 3 months after TMZ administration had been concluded was = 8.4 months=20 (95% CI: 2.6=9614) versus 5.4 months (95% CI: 4.2=966.5) for = patients who=20 initiated FTMS immediately after TMZ completion = (<I>P</I> =3D 0.022).=20 </P> <P>The percentage of patients alive at 6 months was 51% (95% CI: = 38=9668%),=20 without difference between patients with methylated or unmethylated = <I>MGMT</I>=20 promoter status 62.5% (95% CI: 36.5=96100%) versus 46% (95% CI: = 30.5=9670%). Only=20 disease control rate obtained with FTMS was significantly correlated = with=20 survival (<I>P</I> =3D 0.002). </P></DIV> <DIV><A name=3DSec13></A> <DIV class=3DHeading3>Treatment and toxicity</DIV> <P>All 43 patients completed the induction phase as planned. After = induction=20 phase grade 3=964 thrombocytopenia and neutropenia were documented in 9 = (20.9%)=20 and 7 out 43 patients (16.3%), respectively; grade 3=964 lymphopenia was = found in=20 four patients (9.3%). The study was emended after the first three = patients by=20 decreasing the FTMS induction dose from 100 mg m<SUP>2</SUP> = once a=20 week for 3 weeks to 75 mg m<SUP>2</SUP>. Of note, the = first three=20 patients that received induction therapy at the dosage of=20 100 mg m<SUP>2</SUP> aged 48, 51, and 62 years, had a KPS = of 100,=20 100, and 80, started FTMS 30, 40, and 95 days after TMZ completion, = respectively, and did not have significant comorbidities to justify = increased=20 toxicities. </P> <P>The grade 3=964 thrombocytopenia reported for the induction phase in = the 40=20 patients treated after this amendment was 15%.</P> <DIV class=3DPara> <DIV>Twenty-one (49%) patients started maintenance chemotherapy and = received a=20 median of two cycles (range 1=9614). The main reason for not beginning = maintenance=20 therapy after the induction part was disease progression. Only one = patient, with=20 prolonged grade 2 neutropenia, discontinued therapy due to toxicity = after the=20 induction phase. The toxicity of the maintenance phase was grade 3 = leukopenia=20 and grade 4 neutropenia in 14 and 9.5% of the patients, respectively; no = patient=20 experienced grade 3=964 thrombocytopenia (Table <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#Tab2">2</A>).=20 The most commonly reported grade 3=964 non-hematological toxicity were = nausea and=20 vomiting in two (4.6%) patients and transaminase elevation in four = patients=20 (9.3%). Pneumonia was reported in one patient (2.3%).<A name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Hematological=20 toxicities during and after induction and during the maintenance phase = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P>Adverse Event</P></TH> <TH align=3Dleft> <P>Induction (<I>n</I> =3D 43) [% (Pts/Total)] </P></TH> <TH align=3Dleft> <P>Induction after amendment (<I>n</I> =3D 40) [% = (Pts/Total)]=20 </P></TH> <TH align=3Dleft> <P>Maintenance (<I>n</I> =3D 21) [% (Pts/Total)]=20 </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Thrombocytopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>11.6 (5/43)</P></TD> <TD align=3Dleft> <P>12.5 (5/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>9.3 (4/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Leukopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>5.0 (2/40)</P></TD> <TD align=3Dleft> <P>14.3 (3/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>2.3 (1/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Neutropenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>9.3 (4/43)</P></TD> <TD align=3Dleft> <P>10.0 (4/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>5.0 (2/40)</P></TD> <TD align=3Dleft> <P>9.5 (2/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Lymphopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>7.5 (3/40)</P></TD> <TD align=3Dleft> <P>14.3 (3/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>2.3 (1/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 = (0/21)</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV></DIV> <DIV><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>TMZ concomitant and adjuvant to radiotherapy, which has become the = standard=20 treatment for newly diagnosed GBM patients, prolongs overall and=20 progression-free survival more effectively than radiotherapy alone = [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR27">27</A></CITE>].=20 Consequently, first-line chemotherapy has become more homogeneous than = it was in=20 the past. However, while the outcome of patients with newly diagnosed = GBM has=20 improved worldwide, recurrence continues to be virtually inevitable. The = choice=20 of second-line chemotherapy is therefore of utmost importance in the = large=20 number of patients who continue to have a satisfactory PS and are = willing to=20 receive further treatment, nitrosourea being the most widely used = therapeutic=20 option. However, the real impact of this salvage chemotherapy in terms = of=20 activity, disease control, and toxicity after TMZ failure is still = largely=20 unknown. The present study is the first trial to evaluate correlation = between=20 <I>MGMT</I> methylation status (assessable in 79% of patients) and = outcome of=20 nitrosourea-based chemotherapy for progressing/relapsing glioblastoma = previously=20 treated with radiotherapy and TMZ in the adjuvant setting. Data on the = outcome=20 of fotemustine administration, used as second-line treatment in GBM = patients=20 were reported by Scoccianti et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR26">26</A></CITE>],=20 and Fabrini et al.[<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR8">8</A></CITE>];=20 the authors reported a similar PFS-6 rates (48 and 52%, respectively), = disease=20 control rate (48 and 62%, respectively), grade 3=964 hematological = toxicities=20 (14.8 and 10%, respectively). </P> <P>The results from these series seem to be better than ours both in = terms of=20 outcome and of toxicity. However, comparison across trials is always=20 challenging. Moreover, the lack of <I>MGMT</I> methylation status data = in the=20 other FTMS studies and the small number of patients included in these = three=20 studies might justify the differences, and highlight the relevance of = performing=20 larger prospective trials in this patient population. </P> <P>We decided to modify the fotemustine dose recommended in a prior = phase I=20 trial [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR14">14</A></CITE>]=20 and in other studies on glioma or melanoma patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR19">19</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR20">20</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR25">25</A></CITE>],=20 as grade 4 thrombocytopenia was observed after induction therapy in the = first=20 three patients and this life-threatening toxicity was considered = unacceptable in=20 the palliative setting of salvage therapy of GBM patients. This is = consistent=20 with the previous observation that hematological toxicity is increased = by prior=20 chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR24">24</A></CITE>].=20 Moreover, the following 40 patients, treated with the reduced dosage of = FTMS=20 during induction phase, experienced a 15% of grade 3=964 = thrombocytopenia and=20 neutropenia. </P> <P>Maintenance fotemustine showed hematological toxicities similar to = those=20 showed by BCNU delivered at first-relapse (grade 3=964 neutropenia and=20 thrombocytopenia in 10 and 8% of patients, respectively) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR3">3</A></CITE>].=20 However, no cumulative dose limit for fotemustine was found by us, = whereas the=20 use of BCNU is complicated by pulmonary toxicity (G4 toxicities = occurring in 5%=20 of cases [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR3">3</A></CITE>]),=20 which severely compromises quality of life, and life expectancy and = leads to=20 discontinuation of therapy (10%). </P> <P>Fotemustine administration was found to be more feasible and = tolerable than=20 PCV treatment, incurring fewer cases of discontinuation due to toxicity = (2.3 vs.=20 43%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR5">5</A></CITE>].=20 In terms of disease control, fotemustine yielded a PFS-6 of 21%, which = met the=20 primary efficacy end point of the study by confirming the drug activity. = </P> <P>Apparently promising results (response rate, 57%; PFS-6, 46%; 6-month = overall=20 survival, 77%) were recently reported following the use of combined = irinotecan=20 and bevacizumab [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>].=20 However, these drugs have not yet been registered by FDA or EMEA and nor = are=20 they available worldwide, nitrosoureas continuing to be the most = commonly used=20 second-line standard therapy. </P> <P>Other interesting approaches include TMZ re-challenge, which was = recently=20 investigated by Perry et al. In their retrospective analysis, the = authors showed=20 that TMZ re-challenge with a continuous = 50 mg m<SUP>−2</SUP> daily=20 schedule is an intriguing approach, especially for patients with = recurrence=20 after completion of TMZ administration concurrent with and adjuvant to=20 radiotherapy: GBM patients failing during the first 3=966 months of = adjuvant=20 therapy (B1); GBM patients failing after more than 6 months of = therapy=20 (B2); GBM patients who recurred after stopping treatment (B3). PFS-6 = rates were=20 28.6% (B1), 9.5% (B2), 30.4% (B3) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR22">22</A></CITE>].=20 Our findings are in line with these observations: patients in our series = who=20 initiated FMTS at least 3 months after completion of TMZ = administration had=20 a significantly higher PFS-6, (30.7 vs. 16.7%) than patients who = initiated FTMS=20 while still on TMZ, <I>P</I> =3D 0.034). </P> <P><I>MGMT</I> promoter methylation was found to be an independent = favorable=20 prognostic factor, irrespective of treatment, in newly diagnosed GBM = patients=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 Conversely, little information is available on the trend of <I>MGMT</I>=20 expression during tumoral progression, and after different = chemotherapeutic=20 treatments. In the present study, an analysis was made of the = correlation=20 between clinical outcome after fotemustine and <I>MGMT</I> promoter = methylation=20 status; to our knowledge, ours is the first study to analyze the = correlation=20 between <I>MGMT</I> promoter methylation status and second-line = treatment.=20 Adequate paraffin embedded tumor tissue was available in a higher = percentage of=20 patients than in other MSP studies (79 vs. 59=9667%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 The percentage of methylated patients found in our study was clearly = smaller=20 than those reported in other series given upfront and/or salvage therapy = (24 vs.=20 40=9647%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 Moreover, we found that disease control rate was 75 and 34.6% in = methylated and=20 unmethylated patients (<I>P</I> =3D 0.044). On the other hand, = no=20 significant difference was found between groups for PFS-6 and survival; = this=20 finding, which is in line with that reported in other series of = heterogeneously=20 pre-treated patients who underwent salvage therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR4">4</A></CITE>],=20 may reflect or a different pattern of resistance at progression, or a = change in=20 <I>MGMT</I> status at progression. A trend toward prolonged PFS-6 was = observed,=20 the lack statistical significance probably reflecting limited = statistical power=20 due to the relatively small number of cases in the present study, which=20 precluded the demonstration of this secondary endpoint. It is important = to bear=20 in mind that <I>MGMT</I> methylation analysis was not made in trials = that=20 reported more favorable results [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>].=20 For a reliable assessment of the role of this variable at the time of = salvage, a=20 prospective report should be undertaken to evaluate <I>MGMT</I> = methylation=20 status and, hopefully, to stratify patients enrolled in second-line = treatment=20 future trials. The findings made in the present trial may thus represent = a new=20 benchmark of nitrosourea activity in a homogeneously pre-treated = population that=20 failed to respond to the new standard treatment. </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr = P,=20 Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem = Porta V,=20 Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, = Sufliarsky J,=20 Gonzalez Larriba JL, Scherrer A, Menu Y (2004) Fotemustine = compared with=20 dacarbazine in patients with disseminated malignant melanoma: a = phase III=20 study. J Clin Oncol 22:1118=961125<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15020614"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2004.04.165" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXptlCku7Y%253D&md5=3Ddb0ab23b3c0518cf91d11377310f5bf8"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Brandes AA, Basso U, Pasetto LM, Ermani M = (2001) New=20 strategy developments in brain tumor therapy. Curr Pharm Des=20 7:1553=961580<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11562299"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.2174/1381612013397221" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3MXnslKjsbY%253D&md5=3D8280b84c3dffd676d0f4eeafbfc19290"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Brandes AA, Tosoni A, Amista P, Nicolardi L, = Grosso D,=20 Berti F, Ermani M (2004) How effective is BCNU in recurrent = glioblastoma=20 in the modern era? A phase II trial. Neurology = 63:1281=961284<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15477552"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADC%252BD2crgvVWntg%253D%253D&md5=3D15e051ac3e80690515dd32370523c7e9"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>4.</TD> <TD><A name=3DCR4></A>Brandes AA, Tosoni A, Cavallo G, Bertorelle R, = Gioia=20 V, Franceschi E, Biscuola M, Blatt V, Crino L, Ermani M (2006)=20 Temozolomide 3 weeks on and 1 week off as first-line = therapy for=20 recurrent glioblastoma: phase II study from gruppo italiano = cooperativo di=20 neuro-oncologia (GICNO). Br J Cancer 95:1155=961160<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17024124"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1038/sj.bjc.6603376"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD28XhtFChs73O&md5=3Dec2bfb8e494e50da4f5f6690f7e36300"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>5.</TD> <TD><A name=3DCR5></A>Brandes AA, Tosoni A, Vastola F, Pasetto LM, = Coria B,=20 Danieli D, Iuzzolino P, Gardiman M, Talacchi A, Ermani M (2004) = Efficacy=20 and feasibility of standard procarbazine, lomustine, and = vincristine=20 chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma=20 recurrent after radiotherapy. A Phase II study. Cancer = 101:2079=962085<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15372474"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1002/cncr.20611"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXhtVShtb7I&md5=3D98d70aa5b01a80353c52b2180bbb7c8a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>6.</TD> <TD><A name=3DCR6></A>CBTRUS CBtrotUS (2004) Primary brain tumors in = the=20 United States. Statistical report 1997=962001 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>7.</TD> <TD><A name=3DCR7></A>Esteller M, Garcia-Foncillas J, Andion E, = Goodman SN,=20 Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation = of the=20 DNA-repair gene MGMT and the clinical response of gliomas to = alkylating=20 agents. N Engl J Med 343:1350=961354<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11070098"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1056/NEJM200011093431901" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3cXosFOltLg%253D&md5=3D74554f013805644bc94de04a4ef0dabb"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>8.</TD> <TD><A name=3DCR8></A>Fabrini MG, Silvano G, Lolli I, Perrone F, = Marsella A,=20 Scotti V, Cionini L (2008) A multi-institutional phase II study on = second-line Fotemustine chemotherapy in recurrent glioblastoma. J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-008-9739-6">10.1007/s11060-008-9= 739-6</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>9.</TD> <TD><A name=3DCR9></A>Filippeschi S, Colombo T, Bassani D, De = Francesco L,=20 Arioli P, D=92Incalci M, Bartosek I, Guaitani A (1988) Antitumor = activity of=20 the novel nitrosourea S10036 in rodent tumors. Anticancer Res=20 8:1351=961354<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D3064716"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaL1MXhs1GltLY%253D&md5=3D8a51048c567c897ca87b1ac1ac62cd0a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>10.</TD> <TD><A name=3DCR10></A>Fischel JL, Formento P, Etienne MC, Gioanni = J, Frenay=20 M, Deloffre P, Bizzari JP, Milano G (1990) In vitro = chemosensitivity=20 testing of Fotemustine (S 10036), a new antitumor nitrosourea. = Cancer=20 Chemother Pharmacol 25:337=96341<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2306793"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1007/BF00686233"=20 target=3D_blank><IMG border=3D0 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/springer_link= .gif"=20 width=3D108 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK3cXhvFWmsr8%253D&md5=3Dd496ca9f87912ea618f88e5fa3b7d6d4"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>11.</TD> <TD><A name=3DCR11></A>Hegi ME, Diserens AC, Godard S, Dietrich PY, = Regli L,=20 Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) = Clinical=20 trial substantiates the predictive value of = <I>O</I>-6-methylguanine=96DNA=20 methyltransferase promoter methylation in glioblastoma patients = treated=20 with temozolomide. Clin Cancer Res 10:1871=961874<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15041700"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1158/1078-0432.CCR-03-0384" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXisVGltbY%253D&md5=3Dc19dd1eaab54b101bc8c08d60ddbf666"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>12.</TD> <TD><A name=3DCR12></A>Hegi ME, Diserens AC, Gorlia T, Hamou MF, de = Tribolet=20 N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg = JE, Hau=20 P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT = gene=20 silencing and benefit from temozolomide in glioblastoma. N Engl J = Med=20 352:997=961003<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15758010"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1056/NEJMoa043331"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2MXit1Wktro%253D&md5=3D097ea7d825247855e7d377cd24edf419"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>13.</TD> <TD><A name=3DCR13></A>Herman JG, Graff JR, Myohanen S, Nelkin BD, = Baylin SB=20 (1996) Methylation-specific PCR: a novel PCR assay for methylation = status=20 of CpG islands. Proc Natl Acad Sci USA 93:9821=969826<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8790415"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1073/pnas.93.18.9821" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK28XlsFeht7Y%253D&md5=3Dfa8271ce59e484e18be9c16750638fa7"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>14.</TD> <TD><A name=3DCR14></A>Khayat D, Lokiec F, Bizzari JP, Weil M, Meeus = L,=20 Sellami M, Rouesse J, Banzet P, Jacquillat C (1987) Phase I = clinical study=20 of the new amino acid-linked nitrosourea, S 10036, administered on = a=20 weekly schedule. Cancer Res 47:6782=966785<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D3677107"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABieD2M3mslA%253D&md5=3D83ff87f754c7e5510820933f38b04e4f"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>15.</TD> <TD><A name=3DCR15></A>Kleeberg UR, Engel E, Israels P, Brocker EB, = Tilgen=20 W, Kennes C, Gerard B, Lejeune F, Glabbeke MV, Lentz MA (1995) = Palliative=20 therapy of melanoma patients with fotemustine. Inverse = relationship=20 between tumour load and treatment effectiveness. A multicentre = phase II=20 trial of the EORTC-melanoma cooperative group (MCG). Melanoma Res=20 5:195=96200<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D7543785"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/00008390-199506000-00009"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= AByqA28josFY%253D&md5=3De016348fe8b00d81c8a978dcdeb5e364"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>16.</TD> <TD><A name=3DCR16></A>Levin VA (1980) Relationship of octanol/water = partition coefficient and molecular weight to rat brain capillary=20 permeability. J Med Chem 23:682=96684<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D7392035"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1021/jm00180a022"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaL3cXktFyrtro%253D&md5=3Dbfc654d2f08575e44dd0ab547905857b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>17.</TD> <TD><A name=3DCR17></A>Macdonald DR, Cascino TL, Schold SC Jr, = Cairncross JG=20 (1990) Response criteria for phase II studies of supratentorial = malignant=20 glioma. J Clin Oncol 8:1277=961280<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2358840"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABy%252BB1MzotFM%253D&md5=3D4c41b68c4cc650045b7113de40d08ab1"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>18.</TD> <TD><A name=3DCR18></A>Meulemans A, Giroux B, Hannoun P, Robine D, = Henzel D=20 (1991) Comparative diffusion study of two nitrosoureas: carmustine = and=20 fotemustine in normal rat brain, human, and rat brain biopsies.=20 Chemotherapy 37:86=9692<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2032474"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK3MXhsFKmt7s%253D&md5=3D66ef993adf6f9d2ce1de540dd377774f"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>19.</TD> <TD><A name=3DCR19></A>Mornex F, Thomas L, Mohr P, Hauschild A, = Delaunay MM,=20 Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, = Mousseau M,=20 Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M = (2003) A=20 prospective randomized multicentre phase III trial of fotemustine = plus=20 whole brain irradiation versus fotemustine alone in cerebral = metastases of=20 malignant melanoma. Melanoma Res 13:97=96103<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D12569292"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/00008390-200302000-00016"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3sXptFOgsw%253D%253D&md5=3Ded965f91ef46afbaa490d1a3db3879ca"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>20.</TD> <TD><A name=3DCR20></A>Ozkan M, Altinbas M, Er O, Kaplan B, Coskun = HS,=20 Karahacioglu E, Menku A, Cihan Y, Kontas O, Akdemir H (2004)=20 Post-operative sequential chemo-radiotherapy in high-grade = cerebral=20 gliomas with fotemustine. J Chemother 16:298=96302<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15330329"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXnt1Omt78%253D&md5=3De5c77beeeed11166592c52e189fed95a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>21.</TD> <TD><A name=3DCR21></A>Palmisano WA, Divine KK, Saccomanno G, = Gilliland FD,=20 Baylin SB, Herman JG, Belinsky SA (2000) Predicting lung cancer by = detecting aberrant promoter methylation in sputum. Cancer Res=20 60:5954=965958<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11085511"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3cXotV2lsrk%253D&md5=3Da3bade6555634ceb41d481d36b5fdb6b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>22.</TD> <TD><A name=3DCR22></A>Perry J, Mason W, Belanger K, Kavan P, Fulton = D,=20 Easaw J, Kirby S, Macdonald D, Shields C, JFP (2008) The = Temozolomide=20 RESCUE study: a Phase II trial of continuous (28/28) dose-intense=20 temozolomide (TMZ) after progression on conventional 5/28 day = TMZ in=20 patients with recurrent malignant glioma. In: 8th Congress of = European=20 Association of Neurooncology </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>23.</TD> <TD><A name=3DCR23></A>Perry JR, Rizek P, Cashman R, Morrison M, = Morrison T=20 (2008) Temozolomide rechallenge in recurrent malignant glioma by = using a=20 continuous temozolomide schedule: the =93rescue=94 approach. = Cancer=20 113:2152=962157<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D18756530"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1002/cncr.23813"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD1cXht12lu77J&md5=3Db537c90fb55700a06704536f9ceee7fd"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>24.</TD> <TD><A name=3DCR24></A>Raymond E, Haon C, Boaziz C, Coste M (1996) = Logistic=20 regression model of fotemustine toxicity combining independent = phase II=20 studies. Cancer 78:1980=961987<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8909320"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://dx.doi.org/10.1002/(SICI)1097-0142(19961101)78:9%3C1980::A= ID-CNCR20%3E3.0.CO;2-T"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK28XmvFylt7o%253D&md5=3D0491cc451a64e6cae5fa301558f915c2"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>25.</TD> <TD><A name=3DCR25></A>Schallreuter KU, Wenzel E, Brassow FW, Berger = J,=20 Breitbart EW, Teichmann W (1991) Positive phase II study in the = treatment=20 of advanced malignant melanoma with fotemustine. Cancer Chemother=20 Pharmacol 29:85=9687<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D1742855"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1007/BF00686343"=20 target=3D_blank><IMG border=3D0 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/springer_link= .gif"=20 width=3D108 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABy2D2snlsVE%253D&md5=3D45e9374741f0b89c606254622ffecf9b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>26.</TD> <TD><A name=3DCR26></A>Scoccianti S, Detti B, Sardaro A, Iannalfi A, = Meattini I, Leonulli BG, Borghesi S, Martinelli F, Bordi L, = Ammannati F,=20 Biti G (2008) Second-line chemotherapy with fotemustine in=20 temozolomide-pretreated patients with relapsing glioblastoma: a = single=20 institution experience. Anticancer Drugs 19:613=96620<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D18525321"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/CAD.0b013e3283005075" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD1cXms1yru7g%253D&md5=3D818e7376028122068ec04fc4d5c55c6b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>27.</TD> <TD><A name=3DCR27></A>Stupp R, Mason WP, van den Bent MJ, Weller M, = Fisher=20 B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, = Curschmann J,=20 Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross = JG,=20 Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant = and=20 adjuvant temozolomide for glioblastoma. N Engl J Med = 352:987=96996<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15758009"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1056/NEJMoa043330"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2MXit1Wksbk%253D&md5=3D6af2ec3ad875f64092ed3ea48d240b4d"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>28.</TD> <TD><A name=3DCR28></A>van Engeland M, Weijenberg MP, Roemen GM, = Brink M, de=20 Bruine AP, Goldbohm RA, van den Brandt PA, Baylin SB, de Goeij AF, = Herman=20 JG (2003) Effects of dietary folate and alcohol intake on promoter = methylation in sporadic colorectal cancer: the Netherlands cohort = study on=20 diet and cancer. Cancer Res 63:3133=963137<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D12810640"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>29.</TD> <TD><A name=3DCR29></A>Vredenburgh JJ, Desjardins A, Herndon JE 2nd, = Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, = Gururangan S,=20 Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS = (2007)=20 Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. = J Clin=20 Oncol 25:4722=964729<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17947719"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2007.12.2440" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2sXhtlCgsLjF&md5=3De1e036691b4b2589e8ddee519d352aed"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>30.</TD> <TD><A name=3DCR30></A>Wick A, Felsberg J, Steinbach JP, Herrlinger = U,=20 Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick = W=20 (2007) Efficacy and tolerability of temozolomide in an alternating = weekly=20 regimen in patients with recurrent glioma. J Clin Oncol = 25:3357=963361<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17664483"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2007.10.7722" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2sXhtVWqs7nO&md5=3Dc5cce80a0cb6336ec674c036910f4310"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR></TBODY></TABLE></BODY></HTML> ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/contact.gif R0lGODdhDgAKAKIAAP////r7v+rrl8TFDKOkAH1+AElKAAAAACwAAAAADgAKAAADLWi63AQwynEM KCLrXEgFAraFgmdxm2iCpdhla8mpZRUQo0aYw+7/u8phSCwSEwA7 ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/pubmed_link.gif R0lGODlhQQAUAPcAAAAAAAAICAgQEBAYGBAYIRghKSEpMSExOSExQik5SjlKWjlKY0JSa0pKSkpa c0pje0pjhFJSUlJSjFJrhFJzjFpaWlpalFp7lFp7nFqUlGNjnGOEnGOEpWOMrWOcnGOczmOl1muU tWuUvWul1nOUvXOcvXOcxnulzoSEhISt1oSt3oS154yMjIy13oy154y975SUlJTG95TG/5TO/5yc zpyl1pzO/62trbW1tff39/////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gA/0BhI kEaNgQcLKlzIsKHDhzQ+5BAYw0aMihVtaJyB0aLHjiA/Wrwo8iJIkiFJfshwg6LGlxlfjoQpU6TG mDJx1txZM8ZKFAI9Cr2ZAoHRAxQy4mTA4KaNogc22HhgtKPQjBgQXI25MoJLmDFLACiQYAAAqVdt IDggkwQAAA7UvuUp9AEAuj4zNAiqNKfYEhoJHHhRwsXTE2oRnHiQwobYAFoBCABQsQUFxhotb7C7 NePKvTRwktToNoTFAgj+qmWbYDKAASrEIiDwAgCCuzYMvIVto8DbALh35gWdFqbYBQ8SAJgg1rRR GwcApEgBV6wCAGIZUP7bQoCDEAAu/rwgcFfp6M9fbyoV+xbAAsfYV8tPLHaC++V37UKYQACBfY2c 8TQcX04ZF99NYpGQ2ILQJeCWWwccAAFldk3wwAMbTAhgeep5hF5oOcX0oFDN2SCYDa294MIACvw1 GXJ3bQAAYhOkICNiuvXkmV4EDmWRaje1IBkBA2h1wAAEkHfCg7c9YF8MKwrgGwcuCDBAAcAVZ9GH osWkQo1DcZBACBtgYEOZISBgWgsPtJBhCyU8oFEKCyBAwZwJTEDCBKK99GFxVgGKF01p9SVoWlwW GFNINhnqqKEz9TnUjqB9YOmlmFo6wqabfjDCpZ9y6umooXb6aaaopnopjx944OqrRrDGKuustNZq q6w8amDBrrz26uuvwAYr7LC/StBADjegUEEDzDbr7LPQRivttNQ+GwGyMChbwbbcduvtt+CGK+64 3aIQEAAAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/crossref_link.gif R0lGODlhQQAUAPcAAAAAAAgICAhrvQhzvRAQEBBzvRgYGBh7xiEhISF7xiGExikpKSmExjExMTk5 OTmMzkJCQkKMzkKUzkpKSkqMxkqUzlJSUlJSjFKczlpalFqUlFqc1mNjY2OcnGOczmOl1mtra2ul 3mut1nNzc3Ot3nt7e3u13oSEhIS93oyMjIycpYy11oy93pSUlJS93pS955ycnJyczpzG56WlpaW9 zqXO562tra3G3q3O57W1tbXW7729vb3W78bGxsbe787Ozs7e987n99bW1tbn997e3t7v9+fn5+fv 9+/v7+/3//f39/f///////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gA9eIhB sKDBgwgTKlzI8KAHJEoExmBCsaLFixeRQMTIsaPHix46/BAi8SNGJUJSGjFCJCURkzA9etBgI0fJ mExYWkyZ8keOHSpxMlHSIoWSjjNTwLgJUwgSikZSHrWIRIiSqkJiTgAA4CnHmSVaMP2YlUlVrx2J GBkqxEgDAhwITJhhgEADIT0CAAAxFSNYsQNhEjnaNmZVikgQcAVQIsCCGQEcQFiMFqSGsGM5rjws FCXFBQBG5LABwAAEAgSQ6LUh8zLgiWR1CqWIUgnoGSgBENix4wQTAgB2tMYc2KOQGyt0JPHBI4kM IEyAyMBxhCIPGTqWKMEhgwboHkSQ/pxYbOF38OGvP1IowH5IAgERCmAgUWDAgAM+XNgvIAODgAEF qNDDUysR0UNZPczwA3qZWeSDAAWw4MIRCtzHwAvsoVCBfCIU8EANQzAgwAc1HFGWWS9VpERLDBbH EQ8DMJBEEkokMEANS/BQwAFJvDDAA0V0WEANPlRwXxFMWEWbUxRldaJfrjVY0REH3FcADjbiMJSN 7BWAwgYfPFCACQyYcEABOlBERIo54bViX1ASB1tHPmCQwANBbFCBDxQNscGdLDBRQwQJSHAECQ8k EMISKvLkEpMtzjnbpJRa9JdAIXWg6aacdurpp6CGKuqmUXqQwamopqrqqqy26uqrOKpeEBYSP9iQ Qgm45qrrrrz26uuvwOp6Agwo5QBDC8gim0KyRTG7bLLPKuvstNBSK221yM6QQ0AAADs= ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/chemport_link.gif R0lGODlhQQAUAPcAAAAAvRAQxjExzkJC1lJSlFJS1lpanFpapWNjY2NjpWNjvWNj3mtra2trvXNz c3NzvXNz3nt7e3t7zoSEhISEzoyM55SUlJwY95ycnJyc56Up96Wlpa05962tra2t77VK97W1tb1a 971r9729vb2978Z798bGxs6M987Ozs7O996l/961/97e3ufG/+fn5+fn/+/W/+/v7+/v//fn//f3 9/f3///3//////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gBpUBhI sKDBgwgTKlxokAUNGjcExnDhgoXFixgzatzIsaNHCR1YuHhIgcWNkyhTqlzJsqXLlycVTADBIkYM CjdkyIDJs6dPlQoYYEDh4mbOnT+TKl3ZAIEFEzZx6kxJY8WJFTNOXFiak4TXFFxvNH1atOTUkyo0 nGihooRWriQALIAAwAPMuUydmijL4iyMCyVO0qjxtgUNGydbwFDZYieMnXEh3AAw4GQKsCnBApCs cuzem32Ral2MUqsIDhpmwNCgIsSJG6Y5fCjxIXXkFJtjCKgAYUCMuAMAZJD7orNevmdDbE2pVfWF FiU00HirtepzGs+BF5C8IMBJABUi6JOYPN44WdBnta5gvvx5CA4n4sPe2uL5jeybUQ6oPHlA3PIA lJeSAsehh9QMGnwA0Q2EtQeddKXRZx9+nN3Q3XfhBfidgCh5hhxSN8Dw3gluvXWfYSOeYENhE7YQ GUoxDMBbATf8d5IAAxSXkocGKkUDaWH5xKNZIAZppEtDOrTgkUzmdV5JJ7nQ5JQdFvhAAgYYcICW XG7pZZdgfilmmGSOaSYBesVAAwodTMAAAnAi8Gacc8oJ55x15knnnXz26WedcW5A1A0ujGBBBIg6 EIEDija6qKONRrroo5QyOqmkmFbqKE0xBAQAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/springer_link.gif R0lGODlhbAAUANUAAAAAAO/v76Kioo+Pj3BwcP8AAFBQUEBAQP9wcNbW1iAgIP8zM/+/v9/f38zM zJmZmf+Zmf///4ODg7+/vxAQEGZmZjMzM//f3//MzFpaWv9AQP+AgGZmZvX19X9/f5mZmf8QEK+v r//v7/9/f/+Zmf4BAgAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5BAUUACUALAAAAABsABQAAAb/wIdw SCwaj8ikcslsOh+JxiNCrVqrjNEIcu16v+CweEy9aEfkh0QwHW8KCwR5Tq+PMRpQIZ2RtMVvDHaD hGIBEw5XGntjD31/YYFUAQQeGR5kGSGFVwIGBwRWBAJeDRYHXYt8fmSSERWhAQekYgabnKIAV6Nf HqiKjGKOrG4FghEKFVQOiQ0BAQ1VDQ7REdTL01bZ0gHSEdUeulfM3+RUvtKJqo2PrcZUBAAG1RUA BBYAA6YH+BMUmP4MVKAQKgKBCuEOUAphQYAsAPUShbMyQcGBBvwIKKDQDZ0FA4kirBPWrtgxgwAA kJoAYEKEDABkUUiQIMIBTDYxTXTQMkJL/18TMlCIEM6BS6LiqhxA5cHCt56+GhSkMjLMMEhgXFEx BaABS5csHSxVivMm0qchAgAQe2ACorNVJloZi86ny6YKcFINZrUkoHdEqYT9GiGEApu/clIxK9eX AZdj4yaFG5juL6izeu5dhfWLKwWJBqBiOSCAhUT8qlgouPqsAwoI9Q2Q5yGUXCr1ug3ANFZjBLWb 7kUwQCFkVTBX3R2bEFswRH0RJnjwQErA9AnWPTSYTqrCqY2FKyjbPp1K9unapXvY7QH7de4Byovk i9xvpAIQMHghPKjipKG4jCECAwvQ90VyxRSgwX4A3GLHABSkNQAtAYbBQAEYckbGBQwwoEhfF+hV Y0d2IlYIxoAdamjiiiyaeNUTMMYo44w09vGNABLkqOOOPPbo449ABinkkEQSSUoHDdCk5JJMNunk k1BGKeWUVFbZQBAAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/config/css/A++_common.css .Keyword { BACKGROUND: white; FONT-SIZE: 12pt } BODY.for-print { MARGIN: 1.5em; BACKGROUND: white; FONT-SIZE: 12pt } DIV.Abstract { MARGIN-TOP: 1em } DIV.Acknowledgments { MARGIN-TOP: 1em } DIV.AbstractSection { MARGIN-TOP: 0.3em } P.AuthorGroup { FONT-WEIGHT: bold } .Contact { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } .Affiliation { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } .Citation { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } DIV.Capt { MARGIN-TOP: 1.5em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 1.5em; FONT-SIZE: 10pt } SPAN.CaptCont { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } TBODY.CaptCont { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } DIV.CaptCont { MARGIN-TOP: 0.3em; FONT-FAMILY: Arial, Helvetica, sans-serif; = FONT-SIZE: 10pt } .AbstractHeading { FONT-WEIGHT: bold } .KeywordHeading { FONT-WEIGHT: bold } .ArticleNoteHeading { FONT-WEIGHT: bold } .Acknowledgmentsheading { FONT-WEIGHT: bold } .CaptNr { FONT-WEIGHT: bold } DIV.SbLexicon { FONT-WEIGHT: bold } TABLE.Sidebar { FONT-FAMILY: Arial, Helvetica, sans-serif; BACKGROUND: #d6d6d6 } .Term { FONT-STYLE: italic } .AbstractSectionHeading { FONT-STYLE: italic } TABLE.OrderedList { PADDING-BOTTOM: 0.3em; MARGIN-TOP: 1em; PADDING-LEFT: 0.3em; = PADDING-RIGHT: 0.3em; MARGIN-BOTTOM: 1em; MARGIN-LEFT: 17pt; FONT-SIZE: = 12pt; PADDING-TOP: 0.3em } UNKNOWN { MARGIN-TOP: 0.3em } DIV.GlossaryDefSimplePara { MARGIN-TOP: 0.3em; MARGIN-LEFT: 1.5em } DIV.Para { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.FormalPara { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.ArticleNote { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.Motto { TEXT-ALIGN: right; MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.Figure { MARGIN-TOP: 1.5em; MARGIN-BOTTOM: 1em } .PCode { FONT-FAMILY: 'Courier New' } .Box { BORDER-BOTTOM: black 2px solid; BORDER-LEFT: black 2px solid; = PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = DISPLAY: block; BORDER-TOP: black 2px solid; BORDER-RIGHT: black 2px = solid; PADDING-TOP: 0.5em } .Important { BORDER-BOTTOM: black 2px solid; BORDER-LEFT: black 2px solid; = PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = DISPLAY: block; BACKGROUND: #d6d6d6; BORDER-TOP: black 2px solid; = BORDER-RIGHT: black 2px solid; PADDING-TOP: 0.5em } .Example { BORDER-LEFT: black 4px solid; PADDING-BOTTOM: 0.5em; PADDING-LEFT: = 0.5em; PADDING-RIGHT: 0.5em; DISPLAY: block; PADDING-TOP: 0.5em } .Trailer { PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = FONT-WEIGHT: bold; PADDING-TOP: 0.5em } DIV.GlossaryEntry { TEXT-INDENT: -1.5em; MARGIN-LEFT: 1.5em } TABLE.Stack { FONT-SIZE: 0.5em } ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/config/css/content_A++_SpringerLink.css BODY { BACKGROUND: white; FONT-SIZE: 12pt } DIV.Heading1 { MARGIN-TOP: 0.7em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.7em; COLOR: #444444; FONT-SIZE: 20pt; FONT-WEIGHT: bold } DIV.SubTitle { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #444444; FONT-SIZE: = 19pt; FONT-WEIGHT: bold } DIV.heading2 { MARGIN-TOP: 0.8em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.8em; FONT-SIZE: 19pt; FONT-WEIGHT: bold } DIV.SubHeading2 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 14pt } H2.rubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666; FONT-SIZE: = 16pt } .subrubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666; FONT-SIZE: = 14pt } DIV.heading3 { MARGIN-TOP: 0.8em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.8em; FONT-SIZE: 16pt; FONT-WEIGHT: bold } DIV.SubHeading3 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt; = FONT-WEIGHT: bold } H4.Section3 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 14pt } H5.Section4 { FONT-STYLE: italic; FONT-FAMILY: Arial, Helvetica, sans-serif; = FONT-SIZE: 14pt } H3.rubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666 } H5.Section5 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt } P.HeadSec6 { FONT-STYLE: italic; FONT-FAMILY: Arial, Helvetica, sans-serif } P.HeadSec7 { FONT-FAMILY: Arial, Helvetica, sans-serif; TEXT-DECORATION: underline } .HeadList { FONT-STYLE: italic; MARGIN-TOP: 1em } A:link { COLOR: #ff0000 } A:active { COLOR: #ff0000 } A:visited { COLOR: #5f5f5f } TR.header { BACKGROUND: #d6d6d6 } TR.BibSectionHeading { FONT-SIZE: 12pt } H1 { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #444444; FONT-SIZE: = 20pt } H2 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 16pt } H3 { FONT-FAMILY: Arial, Helvetica, sans-serif } H4 { FONT-FAMILY: Arial, Helvetica, sans-serif } H5 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt } ------=_NextPart_000_0000

From: Subject: 10.1007/s00280-009-0926-8 Date: Tue, 10 Feb 2009 20:53:12 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C98BC1.968EA6D0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/08667430516x2324/fulltext.html 10.1007/s00280-009-0926-8</TITLE= > <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18372"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Cancer Chemotherapy and Pharmacology</TD></TR> <TR> <TD>=A9 Springer-Verlag 2009</TD></TR> <TR> <TD>10.1007/s00280-009-0926-8</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Original Article</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Fotemustine as second-line = treatment for=20 recurrent or progressive glioblastoma after concomitant and/or adjuvant=20 temozolomide: a phase II trial of Gruppo Italiano Cooperativo di = Neuro-Oncologia=20 (GICNO) </DIV> <P class=3DAuthorGroup>Alba A. Brandes<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/08667430516x2324/contact.gif">= </A></SUP>,=20 A. Tosoni<SUP>1</SUP>, E. Franceschi<SUP>1</SUP>,=20 V. Blatt<SUP>2</SUP>, A. Santoro<SUP>3</SUP>,=20 M. Faedi<SUP>4</SUP>, P. Amist=E0<SUP>5</SUP>,=20 M. Gardiman<SUP>6</SUP>, R. Labianca<SUP>7</SUP>,=20 C. Bianchini<SUP>8</SUP>, M. Ermani<SUP>9</SUP> and=20 M. Reni<SUP>10</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedale=20 Bellaria-Maggiore, Via Altura 3, 40139 Bologna,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Research and Development Unit, Azienda = Ospedale-Universit=E0 di Padova, Padova, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Istituto=20 Clinico Humanitas, Rozzano, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedale=20 Bufalini, Cesena, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neuroradiology, Ospedale = Santa=20 Maria della Misericordia, Rovigo, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Pathology, Azienda=20 Ospedale-Universit=E0 di Padova, Padova, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Medical Oncology, = Ospedali=20 Riuniti, Bergamo, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Scientific Department, Italfarmaco, = Milan,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosciences, = Statistics and IT=20 Unit, Azienda Ospedale-Universit=E0 di Padova, Padova,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Oncology, San Raffaele=20 Scientific Institute, Milan, = Italy</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/contact.gif">= </TD> = <TD><STRONG>Alba </STRONG><STRONG>A. </STRONG><STRONG>Brandes</= STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:alba.brandes@yahoo.it">alba.brandes@yahoo.it</A></TD></TR>= </TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>24 October 2008 <STRONG>Accepted:=20 </STRONG>5 January 2009 <STRONG>Published online:=20 </STRONG>24 January 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A>Background </SPAN>Standardized salvage = treatment has=20 not yet proved effective in glioblastoma multiforme (GBM) patients who = receive=20 prior standard radiotherapy plus concomitant and adjuvant temozolomide.=20 </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec2></A>Methods </SPAN>Patients with progressive GBM = after=20 radiotherapy plus concomitant and/or adjuvant temozolomide received = three-weekly=20 doses (100=9675 mg m<SUP>2</SUP>) of fotemustine followed, = after a=20 5-week rest, by fotemustine (100 mg m<SUP>2</SUP>) every = 3 weeks=20 for ≤1 year. </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec3></A>Results </SPAN>Forty-three patients (29 M, = 14 F;=20 median age 51 years, range 34=9668; median KPS 90) were enrolled.=20 Progression-free survival at 6 months (PFS-6) was 20.9% (95% CI: = 9=9633%);=20 three patients (7.1%) had partial response (PR); 15 (34.9%), disease=20 stabilization (SD). The median survival was 6 months (95% CI: = 5=967).=20 <I>MGMT</I> promoter status was methylated in 8 (18.6%) and unmethylated = in 26=20 (60.5%) and not assessable in 9 (20.9%) patients, respectively. Disease = control=20 was 75% versus 34.6% in methylated and unmethylated <I>MGMT</I> patients = (<I>P</I> =3D 0.044); no significant difference was found = between groups=20 for PFS-6 and survival. Grade 3 and 4 thrombocytopenia and neutropenia = were=20 observed in 20.9 and 16.3% of patients, during the induction phase, and = in 0 and=20 9.5% patients during the maintenance phase, respectively. </DIV></DIV> <DIV class=3DAbstractSection> <DIV><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec4></A>Conclusions </SPAN>The findings of the = present trial,=20 that evaluate fotemustine in a homogeneous population, may represent a = new=20 benchmark for nitrosourea activity. Moreover, this is the first study to = evaluate correlation between <I>MGMT</I> promoter status and outcome of=20 fotemustine for relapsing GBM previously treated with radiotherapy and=20 temozolomide. </DIV></DIV></DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Glioblastoma=20 multiforme - Second-line=20 chemotherapy - Recurrence - Fotemustine - = <I>MGMT</I> - Clinical trial </P> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Worldwide, glioblastoma multiforme (GBM) is the most frequent primary = brain=20 tumor in adults, accounting for 15=9620% of intracranial tumors and 50% = of gliomas=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR6">6</A></CITE>].=20 The standard treatment for newly diagnosed GBM with temozolomide (TMZ),=20 concomitant, and adjuvant to radiotherapy provides a significant = increase in=20 overall survival with respect to radiotherapy alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR27">27</A></CITE>].=20 However, nearly all patients treated for GBM faced recurrence. None of = the=20 several drug regimens reported in literature substantially delays = disease=20 progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR2">2</A></CITE>].=20 However, promising results have recently been obtained using novel = agents, and=20 new schedules or synergic combinations [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR30">30</A></CITE>].=20 However, the findings reported following these new approaches require = further=20 confirmation based on results obtained in patients who have a longer = follow-up.=20 </P> <P>Nitrosoureas, used alone or in combination with other agents, are = still used=20 as standard second-line chemotherapy, and are considered the standard = arm in=20 randomized phase II studies for experimental therapy. Moreover, it has = not been=20 demonstrated that nitrosourea-based polychemotherapy is anymore = effective=20 against GBM than single agent chemotherapy. Fotemustine (FTMS), a third=20 generation chloroethylnitrosourea containing a phosphoalanine carrier = group, is=20 grafted to the nitrosourea radical. Thanks to the phosphoalanine group=20 contained, the drug is highly lipophilic; its octanol/water partition=20 coefficient being within a range that is more satisfactory than the = ranges=20 obtained with other nitrosoureas, such as carmustine (BCNU) and = lomustine=20 (CCNU). FTMS is able to cross the blood-brain barrier [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR18">18</A></CITE>];=20 in vitro and in vivo studies have shown that FTMS has a marked = anti-neoplastic=20 activity on human GBM and medulloblastoma cell lines [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR9">9</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR10">10</A></CITE>].=20 In their phase I study on 22 GBM patients, Khayat et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR14">14</A></CITE>]=20 specified the dose of FTMS to be used in clinical practice:=20 100 mg m<SUP>2</SUP> for 1-h infusions, conducted on days 1, = 8, and 15=20 (induction), to be repeated after 4=965 weeks (hematological = recovery) every=20 21 days (maintenance). However, in the literature, there is little=20 information on activity and toxicity of this regimen. </P> <P>The aim of the present phase II study on patients with recurrent or=20 progressive GBM, who were uniformly treated with prior radiotherapy and = TMZ, was=20 to evaluate the effect of FTMS on progression-free survival at = 6 months=20 (PFS-6), response, toxicity and any correlation with = O6-methylguanine=96DNA=20 methyltransferase (<I>MGMT</I>) gene promoter methylation status. = </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV><A name=3DSec3></A> <DIV class=3DHeading3>Eligibility</DIV> <P>The criteria for eligibility were GBM recurrent or progressive after = surgery=20 and TMZ concomitant with and/or adjuvant to radiotherapy, proven by MRI = or CT=20 scans at least 3 months following the radiotherapy end or by two=20 consecutive tests. Measurable disease with contrast enhancement using = MRI or CT=20 scans, tested within 2 weeks before study treatment start. In case = of=20 re-surgery before chemotherapy start, residual measurable disease with = contrast=20 enhancement must be proven by MRI or CT scans, performed within = 3 days=20 after surgery. At least one unidimensionally measurable lesion of = ≥2 cm in=20 diameter by MRI. Stable or decreasing dose of corticosteroids for at = least=20 2 weeks before patient=92s enrollment. At least 4 weeks = following=20 chemotherapy with TMZ. Other inclusion criteria were age ≥18 and = ≤70 years;=20 Karnofsky performance status ≥60; adequate bone marrow reserve = (absolute=20 neutrophils count = >1.5 =D7 10<SUP>9</SUP> L<SUP>−1</SUP>;=20 platelets = >100 =D7 10<SUP>9</SUP> L<SUP>−1</SUP>; = hemoglobin=20 >10 g dL<SUP>−1</SUP>); normal renal and liver = function (serum=20 creatinine <1.25=D7, upper limit of the normal range (ULN); BUN=20 <25 mg dL<SUP>−1</SUP>; serum bilirubin = ≤1.25=D7 ULN; AST and=20 ALT ≤ 1.5=D7 ULN; alkaline phosphatase ≤2=D7 ULN; = remaining life=20 expectancy ≥3 months. Patients with active infections or = other uncontrolled=20 diseases, psychiatric disturbances and/or a previous history of cancer = (except=20 for resected non-melanoma skin cancer or carcinoma=97in situ of the = uterine=20 cervix), were considered ineligible. </P> <P>All the histological specimens obtained at first diagnosis were = reviewed by=20 the coordinating center of Azienda Ospedaliera of Padova (M.G. = Department of=20 Pathology) and the diagnosis of GBM was confirmed according to the = criteria=20 specified in 2007 WHO central nervous tumor classification. </P> <P>The study, approved by the Institutional Ethics Committees of all=20 participating centers, was conducted according to the principles of the=20 declaration of Helsinki and the rules of good clinical practice. </P> <P>All patients signed a form giving their fully informed consent to = participate=20 in the study.</P></DIV> <DIV><A name=3DSec4></A> <DIV class=3DHeading3>Treatment schedule</DIV> <P>In line with phase I study protocol and with licensing instructions = of the=20 drug, FTMS 100 mg m<SUP>2</SUP> was administered i.v. over = 1 h=20 weekly for three consecutive weeks (induction therapy), followed after=20 5 weeks by one infusion of FTMS 100 mg m<SUP>2</SUP> = every=20 3 weeks (maintenance therapy) for up to 1 year, unless disease = progression or unacceptable toxicity was observed. If, due to toxicity,=20 treatment suspension was prolonged by more than 2 weeks beyond the = next=20 scheduled cycle of treatment planned, the patient was permanently = withdrawn from=20 the study. Based on the most severe toxicity experienced since the last = cycle,=20 the subsequent dose was reduced to 75% in the presence of grade 3 or 4 = platelet=20 toxicity, grade 4 neutrophils or white blood cells or hemoglobin = toxicity. In=20 cases of non-hematologic toxicity, chemotherapy was delayed until = recovery to=20 grade 1, for a maximum of 2 weeks (after which the patient was = withdrawn=20 from the study). In cases of recovery to grade 1 after grade 3 or 4 = toxicity, a=20 dose of 75% the treatment dose was administered. </P> <P>After the inclusion of the first three patients who experienced grade = 4=20 thrombocytopenia following induction therapy, the protocol was amended = to reduce=20 FTMS dosage during induction therapy to 75 mg m<SUP>2</SUP>. = In fact,=20 this life-threatening toxicity was considered unacceptable in the = palliative=20 setting of salvage therapy of GBM patients. </P></DIV> <DIV><A name=3DSec5></A> <DIV class=3DHeading3>Efficacy measures and toxicity monitoring</DIV> <P>Progression-free survival (PFS) was measured as from the initiation = of FTMS=20 to progression or death due to any cause or last follow-up assessment, = whichever=20 comes first. Overall survival (OS) was measured as from the start of = FTMS to=20 death for any reason, or last follow-up assessment. In this intent to = treat=20 study, data on all registered patients who met the main inclusion = criteria were=20 included in the statistical analysis. </P> <P>Evaluation of response, conducted in all patients, included clinical = and=20 neurological examinations and MRI or CT neuro-imaging according to = Macdonald=92s=20 criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR17">17</A></CITE>].=20 The first evaluation was made after the induction phase (7 weeks = after the=20 first study drug administration); thereafter evaluations were made every = two=20 cycles during the study treatment (6 weeks) and every 3 months = during=20 the follow-up period, or earlier if indicated. Neurological status was = assessed=20 by considering signs and symptoms possibly correlated with progression, = as=20 compared to the previous examination; each variation in daily = corticosteroids=20 dosage was recorded. </P> <P>Responses were confirmed as complete (CR), partial (PR) and stable = (SD) if=20 they were constant at subsequent scans obtained at least 4 weeks = apart from=20 each other. An independent central review of CT and MRI scans was made = for all=20 patients. </P> <P>All adverse events were recorded and graded according to the common = toxicity=20 criteria of the National Cancer Institute, version 3.0. (<A=20 href=3D"http://ctep.cancer.gov/forms/CTCAEv3.pdf">http://ctep.cancer.gov/= forms/CTCAEv3.pdf</A>).=20 </P></DIV> <DIV><A name=3DSec6></A> <DIV class=3DHeading3>DNA extraction and methylation-specific polymerase = chain=20 reaction</DIV> <P><I>MGMT</I> promoter methylation analysis was performed on tissue = taken from=20 the primary surgery specimen before radiotherapy and TMZ. </P> <P>DNA from 10 μm paraffin sections of cerebral lesion was = modified by=20 sodium bisulfite, which converts unmethylated cytosine to uracil, = according to=20 the procedure of Herman et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR13">13</A></CITE>].=20 Modified DNA was submitted for methylation-specific PCR (MSP) following = a=20 nested-PCR protocol [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR21">21</A></CITE>].=20 Since the quality of DNA obtained from formalin-fixed paraffin-embedded = tumor=20 tissue affects the success rate of MSP, in some cases <I>MGMT</I> = methylation=20 status was determined by a different nested-MSP approach, with a first = pair of=20 primers to obtain smaller amplicons (129 bp), for which forward and = reverse=20 primers have been described [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR21">21</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR28">28</A></CITE>].=20 </P></DIV> <DIV><A name=3DSec7></A> <DIV class=3DHeading3>End points and statistical analysis</DIV> <P>Data from all patients, who received at least one drug delivery and = for whom=20 at least one tumoral evaluation was performed, were included in the = response=20 analysis. </P> <P>The primary efficacy endpoint of the study was the percentage of = patients=20 free from disease progression at 6 months (PFS-6). Drug activity = was=20 evaluated following a one-stage Fleming study design for determination = of=20 response rates based on a single-treatment group. A sample size of 40 = patients=20 was estimated using exact binomial method and assuming: one-tailed = α equal to=20 0.1, (1-β) equal to 0.9 and π<0.1 (null hypothesis) versus = π ≥ 0.25=20 (alternative hypothesis), where π was the observed 6-month disease=20 progression-free probability. If seven or more patients were evaluated = as PFS-6,=20 it was assumed that the drug was active. </P> <P>Secondary objectives were the rate of best observed response, defined = as the=20 best response during the treatment and evaluated with Macdonald=92s = criteria=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR17">17</A></CITE>];=20 duration of objective response and stabilization; duration of complete = response;=20 time to disease progression, overall survival, toxicity, and evaluation = of=20 <I>MGMT</I> methylation and the correlation with clinical outcome. All = patients=20 receiving the study drug were included in the safety analysis. Median = time to=20 progression (mTTP) and median survival were also estimated with = associated 95%=20 CI. PFS-6 and OS were calculated using the Kaplan=96Meier method; = differences in=20 PFS-6 and OS were compared using the log rank test for statistical = significance.=20 </P></DIV></DIV> <DIV><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV><A name=3DSec9></A> <DIV class=3DHeading3>Patients=92 characteristics</DIV> <DIV class=3DPara> <DIV>From April 2005 to May 2006, 43 patients (29 males; median age:=20 51 years, range: 34=9668 years; median: KPS 90) were enrolled = in the=20 study. The demographic and clinical characteristics of patients are = outlined in=20 Table <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#Tab1">1</A>.=20 Each patient had completed external-beam radiation therapy = (60 Gy/30 F)=20 concurrent and/or followed by adjuvant TMZ. Median number of TMZ cycles = was 5=20 (range 1=9623). No patient underwent a second surgical procedure at the = time of=20 progression following TMZ administration. Median time between TMZ = treatment=20 completion and FTMS start was 1.5 months (range 1=9643). Thirty = patients=20 (69.8%) started FTMS within 3 months from TMZ last administration. = At time=20 of FTMS initiation 26 patients (60.5%) were on enzyme-inducing = antiepileptic=20 drugs (EIAEDs), while 11 patients (25.6%) were on non-EIAEDs and 6 = patients=20 (13.9%) were not on antiepileptic drugs. The median duration of = follow-up was=20 7.4 months (range 1.2=9622.7). In 39 of the 43 patients enrolled in = the=20 trial, enough histological material was obtained for evaluation of MSP. = MSP was=20 assessable on 34 of these 39 patients. <I>MGMT</I> promoter status was=20 methylated in 8 (18.6%) and unmethylated in 26 (60.5%) and not = assessable in 9=20 (20.9%) patients, respectively.<A name=3DTab1></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 1 </SPAN>Patients=92=20 characteristics </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft char=3D"."> </TH> <TH align=3Dleft> <P>Number of patients</P></TH> <TH align=3Dleft char=3D"."> <P>%</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Sex</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Male</P></TD> <TD align=3Dleft> <P>29</P></TD> <TD align=3Dchar char=3D"."> <P>67</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Female</P></TD> <TD align=3Dleft> <P>14</P></TD> <TD align=3Dchar char=3D"."> <P>33</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Age</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Median years (range)</P></TD> <TD align=3Dleft> <P>51 (34=9668)</P></TD> <TD align=3Dchar char=3D"."> </TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Karnofsky performance status (KPS)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Median (range)</P></TD> <TD align=3Dleft> <P>90 (70=96100)</P></TD> <TD align=3Dchar char=3D"."> </TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>Extent of resection</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Macroscopically radical</P></TD> <TD align=3Dleft> <P>28</P></TD> <TD align=3Dchar char=3D"."> <P>65</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Partial</P></TD> <TD align=3Dleft> <P>12</P></TD> <TD align=3Dchar char=3D"."> <P>28</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Biopsy</P></TD> <TD align=3Dleft> <P>3</P></TD> <TD align=3Dchar char=3D"."> <P>7</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P>Radiotherapy/TMZ</P></TD> <TD align=3Dleft> <P>43</P></TD> <TD align=3Dchar char=3D"."> <P>100</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P><I>MGMT</I> status </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Methylated</P></TD> <TD align=3Dleft> <P>8</P></TD> <TD align=3Dchar char=3D"."> <P>18.6</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Unmethylated</P></TD> <TD align=3Dleft> <P>26</P></TD> <TD align=3Dchar char=3D"."> <P>60.5</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Unknown</P></TD> <TD align=3Dleft> <P>9</P></TD> <TD align=3Dchar char=3D"."> <P>20.9</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D3 align=3Dleft char=3D"."> <P>FTMS initiation and time to TMZ treatment = completion</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Within 3 months</P></TD> <TD align=3Dleft> <P>30</P></TD> <TD align=3Dchar char=3D"."> <P>69.8</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft char=3D"."> <P> Beyond 3 months</P></TD> <TD align=3Dleft> <P>13</P></TD> <TD align=3Dchar char=3D"."> <P>30.2</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV><A name=3DSec10></A> <DIV class=3DHeading3>Progression-free survival</DIV> <P>Nine patients (20.9%; 95% CI: 9=9633%) were PFS-6 and the median PFS = was=20 1.7 months.</P> <P>The percentages of PFS-6 with <I>MGMT</I> promoter methylated or = unmethylated=20 status were 25% (95% CI: 7.5=9683%) and 19.2% (95% CI: 8.7=9642.3%), = respectively.=20 PFS-6 in the population (<I>n</I> =3D 40) treated after the = amendment=20 was 22.5%, not significantly different with the entire population of 43 = pts.=20 </P> <P>No significant differences were found between median PFS, evaluated = using the=20 log rank test, in relation to age (<I>P</I> =3D 0.89), KPS=20 (<I>P</I> =3D 0.33), and <I>MGMT</I> promoter methylated or = unmethylated=20 status (<I>P</I> =3D 0.15). No significant influence of type = of=20 antiepileptic drug was seen, being PFS-6 26.9% and 11.7% in patients on = EIAEDS=20 and on non-EIAEDS plus not on antiepileptic drugs, respectively=20 (<I>P</I> =3D 0.28). </P> <P>Patients that initiated FMTS at least 3 months after TMZ = completion=20 showed a significantly higher PFS-6, (30.7 vs. 16.7%) than patients who=20 initiated FTMS immediately after TMZ completion = (<I>P</I> =3D 0.034).=20 </P></DIV> <DIV><A name=3DSec11></A> <DIV class=3DHeading3>Response</DIV> <P>Among the 43 assessable patients, 3 had partial responses (7.1%, 95% = CI:=20 0=9615%), and 15 stable disease (34.9%, 95% CI: 21=9649%). Disease = control rate=20 (SD+PR) in the population treated after the amendment was 42.5%, not=20 significantly different with the entire population. All responses were = confirmed=20 by an independent centralized review, and stable or decreased steroid = dosage was=20 confirmed in all patients at the time of recording response. Median = duration of=20 response was 9.1 months (95% CI: 1.7=9616.4), and median duration = of disease=20 stabilization was 5 months (95% CI: 1.2=968.9). Disease control = rate was=20 significantly greater in methylated and unmethylated <I>MGMT</I> = patients, 75=20 and 34.6% (<I>P</I> =3D 0.044), respectively; and in patients = who=20 started FTMS at least 3 months after TMZ administration had been = concluded=20 (76.9 vs. 26.7%, <I>P</I> =3D 0.002). </P> <P>No significant influence of type of antiepileptic drug was seen, = being=20 disease control rate 42.3 and 41.2% in patients on EIAEDS and on = non-EIAEDS plus=20 non on antiepileptic drugs, respectively (<I>P</I> =3D 0.98). = </P></DIV> <DIV><A name=3DSec12></A> <DIV class=3DHeading3>Overall survival</DIV> <P>The median overall survival was 6 months (95% CI: 5=967). The = median=20 overall survival of the population treated after the amendment was=20 6 months. No statistical difference has been found between patients = with=20 methylated and those with unmethylated <I>MGMT</I> promoter status: = being=20 6 months (95% CI: 0=9614.2) versus 5.5 months (95% CI: = 4.2=966.8). </P> <P>The median overall survival for patients who started FTMS at least=20 3 months after TMZ administration had been concluded was = 8.4 months=20 (95% CI: 2.6=9614) versus 5.4 months (95% CI: 4.2=966.5) for = patients who=20 initiated FTMS immediately after TMZ completion = (<I>P</I> =3D 0.022).=20 </P> <P>The percentage of patients alive at 6 months was 51% (95% CI: = 38=9668%),=20 without difference between patients with methylated or unmethylated = <I>MGMT</I>=20 promoter status 62.5% (95% CI: 36.5=96100%) versus 46% (95% CI: = 30.5=9670%). Only=20 disease control rate obtained with FTMS was significantly correlated = with=20 survival (<I>P</I> =3D 0.002). </P></DIV> <DIV><A name=3DSec13></A> <DIV class=3DHeading3>Treatment and toxicity</DIV> <P>All 43 patients completed the induction phase as planned. After = induction=20 phase grade 3=964 thrombocytopenia and neutropenia were documented in 9 = (20.9%)=20 and 7 out 43 patients (16.3%), respectively; grade 3=964 lymphopenia was = found in=20 four patients (9.3%). The study was emended after the first three = patients by=20 decreasing the FTMS induction dose from 100 mg m<SUP>2</SUP> = once a=20 week for 3 weeks to 75 mg m<SUP>2</SUP>. Of note, the = first three=20 patients that received induction therapy at the dosage of=20 100 mg m<SUP>2</SUP> aged 48, 51, and 62 years, had a KPS = of 100,=20 100, and 80, started FTMS 30, 40, and 95 days after TMZ completion, = respectively, and did not have significant comorbidities to justify = increased=20 toxicities. </P> <P>The grade 3=964 thrombocytopenia reported for the induction phase in = the 40=20 patients treated after this amendment was 15%.</P> <DIV class=3DPara> <DIV>Twenty-one (49%) patients started maintenance chemotherapy and = received a=20 median of two cycles (range 1=9614). The main reason for not beginning = maintenance=20 therapy after the induction part was disease progression. Only one = patient, with=20 prolonged grade 2 neutropenia, discontinued therapy due to toxicity = after the=20 induction phase. The toxicity of the maintenance phase was grade 3 = leukopenia=20 and grade 4 neutropenia in 14 and 9.5% of the patients, respectively; no = patient=20 experienced grade 3=964 thrombocytopenia (Table <A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#Tab2">2</A>).=20 The most commonly reported grade 3=964 non-hematological toxicity were = nausea and=20 vomiting in two (4.6%) patients and transaminase elevation in four = patients=20 (9.3%). Pneumonia was reported in one patient (2.3%).<A name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Hematological=20 toxicities during and after induction and during the maintenance phase = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P>Adverse Event</P></TH> <TH align=3Dleft> <P>Induction (<I>n</I> =3D 43) [% (Pts/Total)] </P></TH> <TH align=3Dleft> <P>Induction after amendment (<I>n</I> =3D 40) [% = (Pts/Total)]=20 </P></TH> <TH align=3Dleft> <P>Maintenance (<I>n</I> =3D 21) [% (Pts/Total)]=20 </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Thrombocytopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>11.6 (5/43)</P></TD> <TD align=3Dleft> <P>12.5 (5/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>9.3 (4/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Leukopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>5.0 (2/40)</P></TD> <TD align=3Dleft> <P>14.3 (3/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>2.3 (1/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Neutropenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>9.3 (4/43)</P></TD> <TD align=3Dleft> <P>10.0 (4/40)</P></TD> <TD align=3Dleft> <P>0.0 (0/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>5.0 (2/40)</P></TD> <TD align=3Dleft> <P>9.5 (2/21)</P></TD></TR> <TR class=3Dnoclass> <TD colSpan=3D4 align=3Dleft> <P>Lymphopenia</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 3</P></TD> <TD align=3Dleft> <P>7.0 (3/43)</P></TD> <TD align=3Dleft> <P>7.5 (3/40)</P></TD> <TD align=3Dleft> <P>14.3 (3/21)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P> Grade 4</P></TD> <TD align=3Dleft> <P>2.3 (1/43)</P></TD> <TD align=3Dleft> <P>2.5 (1/40)</P></TD> <TD align=3Dleft> <P>0.0 = (0/21)</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV></DIV> <DIV><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>TMZ concomitant and adjuvant to radiotherapy, which has become the = standard=20 treatment for newly diagnosed GBM patients, prolongs overall and=20 progression-free survival more effectively than radiotherapy alone = [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR27">27</A></CITE>].=20 Consequently, first-line chemotherapy has become more homogeneous than = it was in=20 the past. However, while the outcome of patients with newly diagnosed = GBM has=20 improved worldwide, recurrence continues to be virtually inevitable. The = choice=20 of second-line chemotherapy is therefore of utmost importance in the = large=20 number of patients who continue to have a satisfactory PS and are = willing to=20 receive further treatment, nitrosourea being the most widely used = therapeutic=20 option. However, the real impact of this salvage chemotherapy in terms = of=20 activity, disease control, and toxicity after TMZ failure is still = largely=20 unknown. The present study is the first trial to evaluate correlation = between=20 <I>MGMT</I> methylation status (assessable in 79% of patients) and = outcome of=20 nitrosourea-based chemotherapy for progressing/relapsing glioblastoma = previously=20 treated with radiotherapy and TMZ in the adjuvant setting. Data on the = outcome=20 of fotemustine administration, used as second-line treatment in GBM = patients=20 were reported by Scoccianti et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR26">26</A></CITE>],=20 and Fabrini et al.[<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR8">8</A></CITE>];=20 the authors reported a similar PFS-6 rates (48 and 52%, respectively), = disease=20 control rate (48 and 62%, respectively), grade 3=964 hematological = toxicities=20 (14.8 and 10%, respectively). </P> <P>The results from these series seem to be better than ours both in = terms of=20 outcome and of toxicity. However, comparison across trials is always=20 challenging. Moreover, the lack of <I>MGMT</I> methylation status data = in the=20 other FTMS studies and the small number of patients included in these = three=20 studies might justify the differences, and highlight the relevance of = performing=20 larger prospective trials in this patient population. </P> <P>We decided to modify the fotemustine dose recommended in a prior = phase I=20 trial [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR14">14</A></CITE>]=20 and in other studies on glioma or melanoma patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR19">19</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR20">20</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR25">25</A></CITE>],=20 as grade 4 thrombocytopenia was observed after induction therapy in the = first=20 three patients and this life-threatening toxicity was considered = unacceptable in=20 the palliative setting of salvage therapy of GBM patients. This is = consistent=20 with the previous observation that hematological toxicity is increased = by prior=20 chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR24">24</A></CITE>].=20 Moreover, the following 40 patients, treated with the reduced dosage of = FTMS=20 during induction phase, experienced a 15% of grade 3=964 = thrombocytopenia and=20 neutropenia. </P> <P>Maintenance fotemustine showed hematological toxicities similar to = those=20 showed by BCNU delivered at first-relapse (grade 3=964 neutropenia and=20 thrombocytopenia in 10 and 8% of patients, respectively) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR3">3</A></CITE>].=20 However, no cumulative dose limit for fotemustine was found by us, = whereas the=20 use of BCNU is complicated by pulmonary toxicity (G4 toxicities = occurring in 5%=20 of cases [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR3">3</A></CITE>]),=20 which severely compromises quality of life, and life expectancy and = leads to=20 discontinuation of therapy (10%). </P> <P>Fotemustine administration was found to be more feasible and = tolerable than=20 PCV treatment, incurring fewer cases of discontinuation due to toxicity = (2.3 vs.=20 43%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR5">5</A></CITE>].=20 In terms of disease control, fotemustine yielded a PFS-6 of 21%, which = met the=20 primary efficacy end point of the study by confirming the drug activity. = </P> <P>Apparently promising results (response rate, 57%; PFS-6, 46%; 6-month = overall=20 survival, 77%) were recently reported following the use of combined = irinotecan=20 and bevacizumab [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>].=20 However, these drugs have not yet been registered by FDA or EMEA and nor = are=20 they available worldwide, nitrosoureas continuing to be the most = commonly used=20 second-line standard therapy. </P> <P>Other interesting approaches include TMZ re-challenge, which was = recently=20 investigated by Perry et al. In their retrospective analysis, the = authors showed=20 that TMZ re-challenge with a continuous = 50 mg m<SUP>−2</SUP> daily=20 schedule is an intriguing approach, especially for patients with = recurrence=20 after completion of TMZ administration concurrent with and adjuvant to=20 radiotherapy: GBM patients failing during the first 3=966 months of = adjuvant=20 therapy (B1); GBM patients failing after more than 6 months of = therapy=20 (B2); GBM patients who recurred after stopping treatment (B3). PFS-6 = rates were=20 28.6% (B1), 9.5% (B2), 30.4% (B3) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR22">22</A></CITE>].=20 Our findings are in line with these observations: patients in our series = who=20 initiated FMTS at least 3 months after completion of TMZ = administration had=20 a significantly higher PFS-6, (30.7 vs. 16.7%) than patients who = initiated FTMS=20 while still on TMZ, <I>P</I> =3D 0.034). </P> <P><I>MGMT</I> promoter methylation was found to be an independent = favorable=20 prognostic factor, irrespective of treatment, in newly diagnosed GBM = patients=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 Conversely, little information is available on the trend of <I>MGMT</I>=20 expression during tumoral progression, and after different = chemotherapeutic=20 treatments. In the present study, an analysis was made of the = correlation=20 between clinical outcome after fotemustine and <I>MGMT</I> promoter = methylation=20 status; to our knowledge, ours is the first study to analyze the = correlation=20 between <I>MGMT</I> promoter methylation status and second-line = treatment.=20 Adequate paraffin embedded tumor tissue was available in a higher = percentage of=20 patients than in other MSP studies (79 vs. 59=9667%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 The percentage of methylated patients found in our study was clearly = smaller=20 than those reported in other series given upfront and/or salvage therapy = (24 vs.=20 40=9647%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR12">12</A></CITE>].=20 Moreover, we found that disease control rate was 75 and 34.6% in = methylated and=20 unmethylated patients (<I>P</I> =3D 0.044). On the other hand, = no=20 significant difference was found between groups for PFS-6 and survival; = this=20 finding, which is in line with that reported in other series of = heterogeneously=20 pre-treated patients who underwent salvage therapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR4">4</A></CITE>],=20 may reflect or a different pattern of resistance at progression, or a = change in=20 <I>MGMT</I> status at progression. A trend toward prolonged PFS-6 was = observed,=20 the lack statistical significance probably reflecting limited = statistical power=20 due to the relatively small number of cases in the present study, which=20 precluded the demonstration of this secondary endpoint. It is important = to bear=20 in mind that <I>MGMT</I> methylation analysis was not made in trials = that=20 reported more favorable results [<CITE><A=20 href=3D"http://www.springerlink.com/content/08667430516x2324/fulltext.htm= l#CR29">29</A></CITE>].=20 For a reliable assessment of the role of this variable at the time of = salvage, a=20 prospective report should be undertaken to evaluate <I>MGMT</I> = methylation=20 status and, hopefully, to stratify patients enrolled in second-line = treatment=20 future trials. The findings made in the present trial may thus represent = a new=20 benchmark of nitrosourea activity in a homogeneously pre-treated = population that=20 failed to respond to the new standard treatment. </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr = P,=20 Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem = Porta V,=20 Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, = Sufliarsky J,=20 Gonzalez Larriba JL, Scherrer A, Menu Y (2004) Fotemustine = compared with=20 dacarbazine in patients with disseminated malignant melanoma: a = phase III=20 study. J Clin Oncol 22:1118=961125<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15020614"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2004.04.165" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXptlCku7Y%253D&md5=3Ddb0ab23b3c0518cf91d11377310f5bf8"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Brandes AA, Basso U, Pasetto LM, Ermani M = (2001) New=20 strategy developments in brain tumor therapy. Curr Pharm Des=20 7:1553=961580<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11562299"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.2174/1381612013397221" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3MXnslKjsbY%253D&md5=3D8280b84c3dffd676d0f4eeafbfc19290"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Brandes AA, Tosoni A, Amista P, Nicolardi L, = Grosso D,=20 Berti F, Ermani M (2004) How effective is BCNU in recurrent = glioblastoma=20 in the modern era? A phase II trial. Neurology = 63:1281=961284<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15477552"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADC%252BD2crgvVWntg%253D%253D&md5=3D15e051ac3e80690515dd32370523c7e9"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>4.</TD> <TD><A name=3DCR4></A>Brandes AA, Tosoni A, Cavallo G, Bertorelle R, = Gioia=20 V, Franceschi E, Biscuola M, Blatt V, Crino L, Ermani M (2006)=20 Temozolomide 3 weeks on and 1 week off as first-line = therapy for=20 recurrent glioblastoma: phase II study from gruppo italiano = cooperativo di=20 neuro-oncologia (GICNO). Br J Cancer 95:1155=961160<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17024124"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1038/sj.bjc.6603376"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD28XhtFChs73O&md5=3Dec2bfb8e494e50da4f5f6690f7e36300"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>5.</TD> <TD><A name=3DCR5></A>Brandes AA, Tosoni A, Vastola F, Pasetto LM, = Coria B,=20 Danieli D, Iuzzolino P, Gardiman M, Talacchi A, Ermani M (2004) = Efficacy=20 and feasibility of standard procarbazine, lomustine, and = vincristine=20 chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma=20 recurrent after radiotherapy. A Phase II study. Cancer = 101:2079=962085<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15372474"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1002/cncr.20611"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXhtVShtb7I&md5=3D98d70aa5b01a80353c52b2180bbb7c8a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>6.</TD> <TD><A name=3DCR6></A>CBTRUS CBtrotUS (2004) Primary brain tumors in = the=20 United States. Statistical report 1997=962001 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>7.</TD> <TD><A name=3DCR7></A>Esteller M, Garcia-Foncillas J, Andion E, = Goodman SN,=20 Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation = of the=20 DNA-repair gene MGMT and the clinical response of gliomas to = alkylating=20 agents. N Engl J Med 343:1350=961354<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11070098"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1056/NEJM200011093431901" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3cXosFOltLg%253D&md5=3D74554f013805644bc94de04a4ef0dabb"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>8.</TD> <TD><A name=3DCR8></A>Fabrini MG, Silvano G, Lolli I, Perrone F, = Marsella A,=20 Scotti V, Cionini L (2008) A multi-institutional phase II study on = second-line Fotemustine chemotherapy in recurrent glioblastoma. J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-008-9739-6">10.1007/s11060-008-9= 739-6</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>9.</TD> <TD><A name=3DCR9></A>Filippeschi S, Colombo T, Bassani D, De = Francesco L,=20 Arioli P, D=92Incalci M, Bartosek I, Guaitani A (1988) Antitumor = activity of=20 the novel nitrosourea S10036 in rodent tumors. Anticancer Res=20 8:1351=961354<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D3064716"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaL1MXhs1GltLY%253D&md5=3D8a51048c567c897ca87b1ac1ac62cd0a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>10.</TD> <TD><A name=3DCR10></A>Fischel JL, Formento P, Etienne MC, Gioanni = J, Frenay=20 M, Deloffre P, Bizzari JP, Milano G (1990) In vitro = chemosensitivity=20 testing of Fotemustine (S 10036), a new antitumor nitrosourea. = Cancer=20 Chemother Pharmacol 25:337=96341<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2306793"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1007/BF00686233"=20 target=3D_blank><IMG border=3D0 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/springer_link= .gif"=20 width=3D108 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK3cXhvFWmsr8%253D&md5=3Dd496ca9f87912ea618f88e5fa3b7d6d4"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>11.</TD> <TD><A name=3DCR11></A>Hegi ME, Diserens AC, Godard S, Dietrich PY, = Regli L,=20 Ostermann S, Otten P, Van Melle G, de Tribolet N, Stupp R (2004) = Clinical=20 trial substantiates the predictive value of = <I>O</I>-6-methylguanine=96DNA=20 methyltransferase promoter methylation in glioblastoma patients = treated=20 with temozolomide. Clin Cancer Res 10:1871=961874<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15041700"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1158/1078-0432.CCR-03-0384" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXisVGltbY%253D&md5=3Dc19dd1eaab54b101bc8c08d60ddbf666"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>12.</TD> <TD><A name=3DCR12></A>Hegi ME, Diserens AC, Gorlia T, Hamou MF, de = Tribolet=20 N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg = JE, Hau=20 P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT = gene=20 silencing and benefit from temozolomide in glioblastoma. N Engl J = Med=20 352:997=961003<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15758010"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1056/NEJMoa043331"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2MXit1Wktro%253D&md5=3D097ea7d825247855e7d377cd24edf419"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>13.</TD> <TD><A name=3DCR13></A>Herman JG, Graff JR, Myohanen S, Nelkin BD, = Baylin SB=20 (1996) Methylation-specific PCR: a novel PCR assay for methylation = status=20 of CpG islands. Proc Natl Acad Sci USA 93:9821=969826<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8790415"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1073/pnas.93.18.9821" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK28XlsFeht7Y%253D&md5=3Dfa8271ce59e484e18be9c16750638fa7"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>14.</TD> <TD><A name=3DCR14></A>Khayat D, Lokiec F, Bizzari JP, Weil M, Meeus = L,=20 Sellami M, Rouesse J, Banzet P, Jacquillat C (1987) Phase I = clinical study=20 of the new amino acid-linked nitrosourea, S 10036, administered on = a=20 weekly schedule. Cancer Res 47:6782=966785<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D3677107"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABieD2M3mslA%253D&md5=3D83ff87f754c7e5510820933f38b04e4f"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>15.</TD> <TD><A name=3DCR15></A>Kleeberg UR, Engel E, Israels P, Brocker EB, = Tilgen=20 W, Kennes C, Gerard B, Lejeune F, Glabbeke MV, Lentz MA (1995) = Palliative=20 therapy of melanoma patients with fotemustine. Inverse = relationship=20 between tumour load and treatment effectiveness. A multicentre = phase II=20 trial of the EORTC-melanoma cooperative group (MCG). Melanoma Res=20 5:195=96200<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D7543785"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/00008390-199506000-00009"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= AByqA28josFY%253D&md5=3De016348fe8b00d81c8a978dcdeb5e364"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>16.</TD> <TD><A name=3DCR16></A>Levin VA (1980) Relationship of octanol/water = partition coefficient and molecular weight to rat brain capillary=20 permeability. J Med Chem 23:682=96684<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D7392035"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1021/jm00180a022"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaL3cXktFyrtro%253D&md5=3Dbfc654d2f08575e44dd0ab547905857b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>17.</TD> <TD><A name=3DCR17></A>Macdonald DR, Cascino TL, Schold SC Jr, = Cairncross JG=20 (1990) Response criteria for phase II studies of supratentorial = malignant=20 glioma. J Clin Oncol 8:1277=961280<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2358840"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABy%252BB1MzotFM%253D&md5=3D4c41b68c4cc650045b7113de40d08ab1"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>18.</TD> <TD><A name=3DCR18></A>Meulemans A, Giroux B, Hannoun P, Robine D, = Henzel D=20 (1991) Comparative diffusion study of two nitrosoureas: carmustine = and=20 fotemustine in normal rat brain, human, and rat brain biopsies.=20 Chemotherapy 37:86=9692<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D2032474"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK3MXhsFKmt7s%253D&md5=3D66ef993adf6f9d2ce1de540dd377774f"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>19.</TD> <TD><A name=3DCR19></A>Mornex F, Thomas L, Mohr P, Hauschild A, = Delaunay MM,=20 Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, = Mousseau M,=20 Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M = (2003) A=20 prospective randomized multicentre phase III trial of fotemustine = plus=20 whole brain irradiation versus fotemustine alone in cerebral = metastases of=20 malignant melanoma. Melanoma Res 13:97=96103<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D12569292"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/00008390-200302000-00016"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3sXptFOgsw%253D%253D&md5=3Ded965f91ef46afbaa490d1a3db3879ca"= =20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>20.</TD> <TD><A name=3DCR20></A>Ozkan M, Altinbas M, Er O, Kaplan B, Coskun = HS,=20 Karahacioglu E, Menku A, Cihan Y, Kontas O, Akdemir H (2004)=20 Post-operative sequential chemo-radiotherapy in high-grade = cerebral=20 gliomas with fotemustine. J Chemother 16:298=96302<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15330329"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2cXnt1Omt78%253D&md5=3De5c77beeeed11166592c52e189fed95a"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>21.</TD> <TD><A name=3DCR21></A>Palmisano WA, Divine KK, Saccomanno G, = Gilliland FD,=20 Baylin SB, Herman JG, Belinsky SA (2000) Predicting lung cancer by = detecting aberrant promoter methylation in sputum. Cancer Res=20 60:5954=965958<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D11085511"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD3cXotV2lsrk%253D&md5=3Da3bade6555634ceb41d481d36b5fdb6b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>22.</TD> <TD><A name=3DCR22></A>Perry J, Mason W, Belanger K, Kavan P, Fulton = D,=20 Easaw J, Kirby S, Macdonald D, Shields C, JFP (2008) The = Temozolomide=20 RESCUE study: a Phase II trial of continuous (28/28) dose-intense=20 temozolomide (TMZ) after progression on conventional 5/28 day = TMZ in=20 patients with recurrent malignant glioma. In: 8th Congress of = European=20 Association of Neurooncology </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>23.</TD> <TD><A name=3DCR23></A>Perry JR, Rizek P, Cashman R, Morrison M, = Morrison T=20 (2008) Temozolomide rechallenge in recurrent malignant glioma by = using a=20 continuous temozolomide schedule: the =93rescue=94 approach. = Cancer=20 113:2152=962157<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D18756530"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1002/cncr.23813"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD1cXht12lu77J&md5=3Db537c90fb55700a06704536f9ceee7fd"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>24.</TD> <TD><A name=3DCR24></A>Raymond E, Haon C, Boaziz C, Coste M (1996) = Logistic=20 regression model of fotemustine toxicity combining independent = phase II=20 studies. Cancer 78:1980=961987<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D8909320"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://dx.doi.org/10.1002/(SICI)1097-0142(19961101)78:9%3C1980::A= ID-CNCR20%3E3.0.CO;2-T"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADyaK28XmvFylt7o%253D&md5=3D0491cc451a64e6cae5fa301558f915c2"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>25.</TD> <TD><A name=3DCR25></A>Schallreuter KU, Wenzel E, Brassow FW, Berger = J,=20 Breitbart EW, Teichmann W (1991) Positive phase II study in the = treatment=20 of advanced malignant melanoma with fotemustine. Cancer Chemother=20 Pharmacol 29:85=9687<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D1742855"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1007/BF00686343"=20 target=3D_blank><IMG border=3D0 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/springer_link= .gif"=20 width=3D108 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ABy2D2snlsVE%253D&md5=3D45e9374741f0b89c606254622ffecf9b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>26.</TD> <TD><A name=3DCR26></A>Scoccianti S, Detti B, Sardaro A, Iannalfi A, = Meattini I, Leonulli BG, Borghesi S, Martinelli F, Bordi L, = Ammannati F,=20 Biti G (2008) Second-line chemotherapy with fotemustine in=20 temozolomide-pretreated patients with relapsing glioblastoma: a = single=20 institution experience. Anticancer Drugs 19:613=96620<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D18525321"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1097/CAD.0b013e3283005075" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD1cXms1yru7g%253D&md5=3D818e7376028122068ec04fc4d5c55c6b"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>27.</TD> <TD><A name=3DCR27></A>Stupp R, Mason WP, van den Bent MJ, Weller M, = Fisher=20 B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, = Curschmann J,=20 Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross = JG,=20 Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant = and=20 adjuvant temozolomide for glioblastoma. N Engl J Med = 352:987=96996<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15758009"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A = href=3D"http://dx.doi.org/10.1056/NEJMoa043330"=20 target=3D_blank><IMG border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2MXit1Wksbk%253D&md5=3D6af2ec3ad875f64092ed3ea48d240b4d"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>28.</TD> <TD><A name=3DCR28></A>van Engeland M, Weijenberg MP, Roemen GM, = Brink M, de=20 Bruine AP, Goldbohm RA, van den Brandt PA, Baylin SB, de Goeij AF, = Herman=20 JG (2003) Effects of dietary folate and alcohol intake on promoter = methylation in sporadic colorectal cancer: the Netherlands cohort = study on=20 diet and cancer. Cancer Res 63:3133=963137<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D12810640"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>29.</TD> <TD><A name=3DCR29></A>Vredenburgh JJ, Desjardins A, Herndon JE 2nd, = Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, = Gururangan S,=20 Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS = (2007)=20 Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. = J Clin=20 Oncol 25:4722=964729<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17947719"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2007.12.2440" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2sXhtlCgsLjF&md5=3De1e036691b4b2589e8ddee519d352aed"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>30.</TD> <TD><A name=3DCR30></A>Wick A, Felsberg J, Steinbach JP, Herrlinger = U,=20 Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick = W=20 (2007) Efficacy and tolerability of temozolomide in an alternating = weekly=20 regimen in patients with recurrent glioma. J Clin Oncol = 25:3357=963361<BR><A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17664483"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/pubmed_link.g= if"=20 width=3D65 height=3D20></A> <A=20 href=3D"http://dx.doi.org/10.1200/JCO.2007.10.7722" = target=3D_blank><IMG=20 border=3D0 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/crossref_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2sXhtVWqs7nO&md5=3Dc5cce80a0cb6336ec674c036910f4310"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/08667430516x2324/chemport_link= .gif"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR></TBODY></TABLE></BODY></HTML> ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/contact.gif R0lGODdhDgAKAKIAAP////r7v+rrl8TFDKOkAH1+AElKAAAAACwAAAAADgAKAAADLWi63AQwynEM KCLrXEgFAraFgmdxm2iCpdhla8mpZRUQo0aYw+7/u8phSCwSEwA7 ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/pubmed_link.gif R0lGODlhQQAUAPcAAAAAAAAICAgQEBAYGBAYIRghKSEpMSExOSExQik5SjlKWjlKY0JSa0pKSkpa c0pje0pjhFJSUlJSjFJrhFJzjFpaWlpalFp7lFp7nFqUlGNjnGOEnGOEpWOMrWOcnGOczmOl1muU tWuUvWul1nOUvXOcvXOcxnulzoSEhISt1oSt3oS154yMjIy13oy154y975SUlJTG95TG/5TO/5yc zpyl1pzO/62trbW1tff39/////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gA/0BhI kEaNgQcLKlzIsKHDhzQ+5BAYw0aMihVtaJyB0aLHjiA/Wrwo8iJIkiFJfshwg6LGlxlfjoQpU6TG mDJx1txZM8ZKFAI9Cr2ZAoHRAxQy4mTA4KaNogc22HhgtKPQjBgQXI25MoJLmDFLACiQYAAAqVdt IDggkwQAAA7UvuUp9AEAuj4zNAiqNKfYEhoJHHhRwsXTE2oRnHiQwobYAFoBCABQsQUFxhotb7C7 NePKvTRwktToNoTFAgj+qmWbYDKAASrEIiDwAgCCuzYMvIVto8DbALh35gWdFqbYBQ8SAJgg1rRR GwcApEgBV6wCAGIZUP7bQoCDEAAu/rwgcFfp6M9fbyoV+xbAAsfYV8tPLHaC++V37UKYQACBfY2c 8TQcX04ZF99NYpGQ2ILQJeCWWwccAAFldk3wwAMbTAhgeep5hF5oOcX0oFDN2SCYDa294MIACvw1 GXJ3bQAAYhOkICNiuvXkmV4EDmWRaje1IBkBA2h1wAAEkHfCg7c9YF8MKwrgGwcuCDBAAcAVZ9GH osWkQo1DcZBACBtgYEOZISBgWgsPtJBhCyU8oFEKCyBAwZwJTEDCBKK99GFxVgGKF01p9SVoWlwW GFNINhnqqKEz9TnUjqB9YOmlmFo6wqabfjDCpZ9y6umooXb6aaaopnopjx944OqrRrDGKuustNZq q6w8amDBrrz26uuvwAYr7LC/StBADjegUEEDzDbr7LPQRivttNQ+GwGyMChbwbbcduvtt+CGK+64 3aIQEAAAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/crossref_link.gif R0lGODlhQQAUAPcAAAAAAAgICAhrvQhzvRAQEBBzvRgYGBh7xiEhISF7xiGExikpKSmExjExMTk5 OTmMzkJCQkKMzkKUzkpKSkqMxkqUzlJSUlJSjFKczlpalFqUlFqc1mNjY2OcnGOczmOl1mtra2ul 3mut1nNzc3Ot3nt7e3u13oSEhIS93oyMjIycpYy11oy93pSUlJS93pS955ycnJyczpzG56WlpaW9 zqXO562tra3G3q3O57W1tbXW7729vb3W78bGxsbe787Ozs7e987n99bW1tbn997e3t7v9+fn5+fv 9+/v7+/3//f39/f///////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gA9eIhB sKDBgwgTKlzI8KAHJEoExmBCsaLFixeRQMTIsaPHix46/BAi8SNGJUJSGjFCJCURkzA9etBgI0fJ mExYWkyZ8keOHSpxMlHSIoWSjjNTwLgJUwgSikZSHrWIRIiSqkJiTgAA4CnHmSVaMP2YlUlVrx2J GBkqxEgDAhwITJhhgEADIT0CAAAxFSNYsQNhEjnaNmZVikgQcAVQIsCCGQEcQFiMFqSGsGM5rjws FCXFBQBG5LABwAAEAgSQ6LUh8zLgiWR1CqWIUgnoGSgBENix4wQTAgB2tMYc2KOQGyt0JPHBI4kM IEyAyMBxhCIPGTqWKMEhgwboHkSQ/pxYbOF38OGvP1IowH5IAgERCmAgUWDAgAM+XNgvIAODgAEF qNDDUysR0UNZPczwA3qZWeSDAAWw4MIRCtzHwAvsoVCBfCIU8EANQzAgwAc1HFGWWS9VpERLDBbH EQ8DMJBEEkokMEANS/BQwAFJvDDAA0V0WEANPlRwXxFMWEWbUxRldaJfrjVY0REH3FcADjbiMJSN 7BWAwgYfPFCACQyYcEABOlBERIo54bViX1ASB1tHPmCQwANBbFCBDxQNscGdLDBRQwQJSHAECQ8k EMISKvLkEpMtzjnbpJRa9JdAIXWg6aacdurpp6CGKuqmUXqQwamopqrqqqy26uqrOKpeEBYSP9iQ Qgm45qrrrrz26uuvwOp6Agwo5QBDC8gim0KyRTG7bLLPKuvstNBSK221yM6QQ0AAADs= ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/chemport_link.gif R0lGODlhQQAUAPcAAAAAvRAQxjExzkJC1lJSlFJS1lpanFpapWNjY2NjpWNjvWNj3mtra2trvXNz c3NzvXNz3nt7e3t7zoSEhISEzoyM55SUlJwY95ycnJyc56Up96Wlpa05962tra2t77VK97W1tb1a 971r9729vb2978Z798bGxs6M987Ozs7O996l/961/97e3ufG/+fn5+fn/+/W/+/v7+/v//fn//f3 9/f3///3//////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// //////////////////////////////////////////////////////////////////////////// /////////////////////////////////////////////////////ywAAAAAQQAUAAAI/gBpUBhI sKDBgwgTKlxokAUNGjcExnDhgoXFixgzatzIsaNHCR1YuHhIgcWNkyhTqlzJsqXLlycVTADBIkYM CjdkyIDJs6dPlQoYYEDh4mbOnT+TKl3ZAIEFEzZx6kxJY8WJFTNOXFiak4TXFFxvNH1atOTUkyo0 nGihooRWriQALIAAwAPMuUydmijL4iyMCyVO0qjxtgUNGydbwFDZYieMnXEh3AAw4GQKsCnBApCs cuzem32Ral2MUqsIDhpmwNCgIsSJG6Y5fCjxIXXkFJtjCKgAYUCMuAMAZJD7orNevmdDbE2pVfWF FiU00HirtepzGs+BF5C8IMBJABUi6JOYPN44WdBnta5gvvx5CA4n4sPe2uL5jeybUQ6oPHlA3PIA lJeSAsehh9QMGnwA0Q2EtQeddKXRZx9+nN3Q3XfhBfidgCh5hhxSN8Dw3gluvXWfYSOeYENhE7YQ GUoxDMBbATf8d5IAAxSXkocGKkUDaWH5xKNZIAZppEtDOrTgkUzmdV5JJ7nQ5JQdFvhAAgYYcICW XG7pZZdgfilmmGSOaSYBesVAAwodTMAAAnAi8Gacc8oJ55x15knnnXz26WedcW5A1A0ujGBBBIg6 EIEDija6qKONRrroo5QyOqmkmFbqKE0xBAQAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: image/gif Content-Transfer-Encoding: base64 Content-Location: http://www.springerlink.com/content/08667430516x2324/springer_link.gif R0lGODlhbAAUANUAAAAAAO/v76Kioo+Pj3BwcP8AAFBQUEBAQP9wcNbW1iAgIP8zM/+/v9/f38zM zJmZmf+Zmf///4ODg7+/vxAQEGZmZjMzM//f3//MzFpaWv9AQP+AgGZmZvX19X9/f5mZmf8QEK+v r//v7/9/f/+Zmf4BAgAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAACH5BAUUACUALAAAAABsABQAAAb/wIdw SCwaj8ikcslsOh+JxiNCrVqrjNEIcu16v+CweEy9aEfkh0QwHW8KCwR5Tq+PMRpQIZ2RtMVvDHaD hGIBEw5XGntjD31/YYFUAQQeGR5kGSGFVwIGBwRWBAJeDRYHXYt8fmSSERWhAQekYgabnKIAV6Nf HqiKjGKOrG4FghEKFVQOiQ0BAQ1VDQ7REdTL01bZ0gHSEdUeulfM3+RUvtKJqo2PrcZUBAAG1RUA BBYAA6YH+BMUmP4MVKAQKgKBCuEOUAphQYAsAPUShbMyQcGBBvwIKKDQDZ0FA4kirBPWrtgxgwAA kJoAYEKEDABkUUiQIMIBTDYxTXTQMkJL/18TMlCIEM6BS6LiqhxA5cHCt56+GhSkMjLMMEhgXFEx BaABS5csHSxVivMm0qchAgAQe2ACorNVJloZi86ny6YKcFINZrUkoHdEqYT9GiGEApu/clIxK9eX AZdj4yaFG5juL6izeu5dhfWLKwWJBqBiOSCAhUT8qlgouPqsAwoI9Q2Q5yGUXCr1ug3ANFZjBLWb 7kUwQCFkVTBX3R2bEFswRH0RJnjwQErA9AnWPTSYTqrCqY2FKyjbPp1K9unapXvY7QH7de4Byovk i9xvpAIQMHghPKjipKG4jCECAwvQ90VyxRSgwX4A3GLHABSkNQAtAYbBQAEYckbGBQwwoEhfF+hV Y0d2IlYIxoAdamjiiiyaeNUTMMYo44w09vGNABLkqOOOPPbo449ABinkkEQSSUoHDdCk5JJMNunk k1BGKeWUVFbZQBAAOw== ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/config/css/A++_common.css .Keyword { BACKGROUND: white; FONT-SIZE: 12pt } BODY.for-print { MARGIN: 1.5em; BACKGROUND: white; FONT-SIZE: 12pt } DIV.Abstract { MARGIN-TOP: 1em } DIV.Acknowledgments { MARGIN-TOP: 1em } DIV.AbstractSection { MARGIN-TOP: 0.3em } P.AuthorGroup { FONT-WEIGHT: bold } .Contact { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } .Affiliation { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } .Citation { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } DIV.Capt { MARGIN-TOP: 1.5em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 1.5em; FONT-SIZE: 10pt } SPAN.CaptCont { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } TBODY.CaptCont { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 10pt } DIV.CaptCont { MARGIN-TOP: 0.3em; FONT-FAMILY: Arial, Helvetica, sans-serif; = FONT-SIZE: 10pt } .AbstractHeading { FONT-WEIGHT: bold } .KeywordHeading { FONT-WEIGHT: bold } .ArticleNoteHeading { FONT-WEIGHT: bold } .Acknowledgmentsheading { FONT-WEIGHT: bold } .CaptNr { FONT-WEIGHT: bold } DIV.SbLexicon { FONT-WEIGHT: bold } TABLE.Sidebar { FONT-FAMILY: Arial, Helvetica, sans-serif; BACKGROUND: #d6d6d6 } .Term { FONT-STYLE: italic } .AbstractSectionHeading { FONT-STYLE: italic } TABLE.OrderedList { PADDING-BOTTOM: 0.3em; MARGIN-TOP: 1em; PADDING-LEFT: 0.3em; = PADDING-RIGHT: 0.3em; MARGIN-BOTTOM: 1em; MARGIN-LEFT: 17pt; FONT-SIZE: = 12pt; PADDING-TOP: 0.3em } UNKNOWN { MARGIN-TOP: 0.3em } DIV.GlossaryDefSimplePara { MARGIN-TOP: 0.3em; MARGIN-LEFT: 1.5em } DIV.Para { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.FormalPara { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.ArticleNote { MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.Motto { TEXT-ALIGN: right; MARGIN-TOP: 1em; MARGIN-BOTTOM: 1em } DIV.Figure { MARGIN-TOP: 1.5em; MARGIN-BOTTOM: 1em } .PCode { FONT-FAMILY: 'Courier New' } .Box { BORDER-BOTTOM: black 2px solid; BORDER-LEFT: black 2px solid; = PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = DISPLAY: block; BORDER-TOP: black 2px solid; BORDER-RIGHT: black 2px = solid; PADDING-TOP: 0.5em } .Important { BORDER-BOTTOM: black 2px solid; BORDER-LEFT: black 2px solid; = PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = DISPLAY: block; BACKGROUND: #d6d6d6; BORDER-TOP: black 2px solid; = BORDER-RIGHT: black 2px solid; PADDING-TOP: 0.5em } .Example { BORDER-LEFT: black 4px solid; PADDING-BOTTOM: 0.5em; PADDING-LEFT: = 0.5em; PADDING-RIGHT: 0.5em; DISPLAY: block; PADDING-TOP: 0.5em } .Trailer { PADDING-BOTTOM: 0.5em; PADDING-LEFT: 0.5em; PADDING-RIGHT: 0.5em; = FONT-WEIGHT: bold; PADDING-TOP: 0.5em } DIV.GlossaryEntry { TEXT-INDENT: -1.5em; MARGIN-LEFT: 1.5em } TABLE.Stack { FONT-SIZE: 0.5em } ------=_NextPart_000_0000_01C98BC1.968EA6D0 Content-Type: text/css; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/config/css/content_A++_SpringerLink.css BODY { BACKGROUND: white; FONT-SIZE: 12pt } DIV.Heading1 { MARGIN-TOP: 0.7em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.7em; COLOR: #444444; FONT-SIZE: 20pt; FONT-WEIGHT: bold } DIV.SubTitle { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #444444; FONT-SIZE: = 19pt; FONT-WEIGHT: bold } DIV.heading2 { MARGIN-TOP: 0.8em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.8em; FONT-SIZE: 19pt; FONT-WEIGHT: bold } DIV.SubHeading2 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 14pt } H2.rubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666; FONT-SIZE: = 16pt } .subrubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666; FONT-SIZE: = 14pt } DIV.heading3 { MARGIN-TOP: 0.8em; FONT-FAMILY: Arial, Helvetica, sans-serif; = MARGIN-BOTTOM: 0.8em; FONT-SIZE: 16pt; FONT-WEIGHT: bold } DIV.SubHeading3 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt; = FONT-WEIGHT: bold } H4.Section3 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 14pt } H5.Section4 { FONT-STYLE: italic; FONT-FAMILY: Arial, Helvetica, sans-serif; = FONT-SIZE: 14pt } H3.rubric { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #666666 } H5.Section5 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt } P.HeadSec6 { FONT-STYLE: italic; FONT-FAMILY: Arial, Helvetica, sans-serif } P.HeadSec7 { FONT-FAMILY: Arial, Helvetica, sans-serif; TEXT-DECORATION: underline } .HeadList { FONT-STYLE: italic; MARGIN-TOP: 1em } A:link { COLOR: #ff0000 } A:active { COLOR: #ff0000 } A:visited { COLOR: #5f5f5f } TR.header { BACKGROUND: #d6d6d6 } TR.BibSectionHeading { FONT-SIZE: 12pt } H1 { FONT-FAMILY: Arial, Helvetica, sans-serif; COLOR: #444444; FONT-SIZE: = 20pt } H2 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 16pt } H3 { FONT-FAMILY: Arial, Helvetica, sans-serif } H4 { FONT-FAMILY: Arial, Helvetica, sans-serif } H5 { FONT-FAMILY: Arial, Helvetica, sans-serif; FONT-SIZE: 12pt } ------=_NextPart_000_0000_01C98BC1.968EA6D0--