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Subject: Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet Seyfried BT, Kiebish M, Marsh J, Mukherjee P - J Can Res Ther
Date: Fri, 2 Apr 2010 19:06:41 +0200
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<!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" =
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<HTML><HEAD><TITLE>Targeting energy metabolism in brain cancer through =
calorie restriction and the ketogenic diet Seyfried BT, Kiebish M, Marsh =
J, Mukherjee P - J Can Res Ther</TITLE>
<META http-equiv=3DContent-Type content=3D"text/html; =
charset=3Dwindows-1252">
<META=20
content=3D"Journal of Cancer Research and Therapeutics, full-text, =
online, electronic, e-journal, free access, open access, online =
submission"=20
name=3Dkeywords>
<META=20
content=3D"Official publication of Association of Radiation Oncology of =
India (AROI)"=20
name=3Ddescription><!--DC META DATA START-->
<META=20
content=3D"Targeting energy metabolism in brain cancer through calorie =
restriction and the ketogenic diet"=20
name=3DDC.Title><LINK =
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rel=3DSCHEMA.dc>
<META content=3DSeyfried name=3DDC.Creator><LINK=20
href=3D"http://purl.org/metadata/dublin_core_elements#creator" =
rel=3DSCHEMA.dc>
<META=20
content=3D"Angiogenesis, apoptosis, calorie restriction, glioma, =
inflammation, ketone bodies, metabolic control analysis, vascularity"=20
name=3DDC.Subject>
<META=20
content=3D"Malignant brain tumors are a significant health problem in =
children and adults and are largely unmanageable. As a metabolic =
disorder involving the dysregulation of glycolysis and respiration (the =
Warburg effect), malignant brain cancer can be managed through changes =
in metabolic environment. In contrast to malignant brain tumors that are =
mostly dependent on glycolysis for energy, normal neurons and glia =
readily transition to ketone bodies (&#946;-hydroxybutyrate) for energy =
in vivo when glucose levels are reduced. The transition from glucose to =
ketone bodies as a major energy source is an evolutionary conserved =
adaptation to food deprivation that permits the survival of normal cells =
during extreme shifts in nutritional environment. Only those cells with =
a flexible genome, honed through millions of years of environmental =
forcing and variability selection, can transition from one energy state =
to another. We propose a different approach to brain cancer management =
that exploits the metabolic flexibility of normal cells at the expense =
of the genetically defective and less metabolically flexible tumor =
cells. This approach to brain cancer management is supported from recent =
studies in orthotopic mouse brain tumor models and in human pediatric =
astrocytoma treated with calorie restriction and the ketogenic diet. =
Issues of implementation and use protocols are discussed."=20
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href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DSearch&amp;db=
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..&amp;entries=3D10&amp;journal=3DY&amp;but_search=3D++Go++&amp;type=3DA&=
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href=3D"http://www.cancerjournal.net/searchresult.asp?search=3Dinflammati=
on&amp;opt_type=3Dphrase&amp;field=3D*&amp;author=3D&amp;age_group=3D..&a=
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rom_month=3D..&amp;from_year=3D..&amp;to_month=3D..&amp;to_year=3D..&amp;=
sort=3D..&amp;entries=3D10&amp;journal=3DY&amp;but_search=3D++Go++&amp;ty=
pe=3DA&amp;pg=3D1"=20
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href=3D"http://www.cancerjournal.net/searchresult.asp?search=3Dketone =
bodies&amp;opt_type=3Dphrase&amp;field=3D*&amp;author=3D&amp;age_group=3D=
..&amp;speciality=3D..&amp;article_type=3D..&amp;article_realateto=3D..&a=
mp;from_month=3D..&amp;from_year=3D..&amp;to_month=3D..&amp;to_year=3D..&=
amp;sort=3D..&amp;entries=3D10&amp;journal=3DY&amp;but_search=3D++Go++&am=
p;type=3DA&amp;pg=3D1"=20
              target=3D_blank>ketone bodies</A>
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              =
href=3D"http://www.cancerjournal.net/searchresult.asp?search=3Dmetabolic =
control =
analysis&amp;opt_type=3Dphrase&amp;field=3D*&amp;author=3D&amp;age_group=3D=
..&amp;speciality=3D..&amp;article_type=3D..&amp;article_realateto=3D..&a=
mp;from_month=3D..&amp;from_year=3D..&amp;to_month=3D..&amp;to_year=3D..&=
amp;sort=3D..&amp;entries=3D10&amp;journal=3DY&amp;but_search=3D++Go++&am=
p;type=3DA&amp;pg=3D1"=20
              target=3D_blank>metabolic control analysis</A>
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href=3D"http://www.cancerjournal.net/searchresult.asp?search=3Dvascularit=
y&amp;opt_type=3Dphrase&amp;field=3D*&amp;author=3D&amp;age_group=3D..&am=
p;speciality=3D..&amp;article_type=3D..&amp;article_realateto=3D..&amp;fr=
om_month=3D..&amp;from_year=3D..&amp;to_month=3D..&amp;to_year=3D..&amp;s=
ort=3D..&amp;entries=3D10&amp;journal=3DY&amp;but_search=3D++Go++&amp;typ=
e=3DA&amp;pg=3D1"=20
              target=3D_blank>vascularity</A></LI></UL></TD></TR>
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            height=3D20><B>&nbsp;&gt;&nbsp;&nbsp;</B><A=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
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            height=3D20><B>&nbsp;&gt;&nbsp; </B><A=20
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href=3D"http://www.cancerjournal.net/citation.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried;aid=3DJC=
anResTher_2009_5_9_7_55134">Citation=20
            Manager</A> </TD></TR>
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            =
href=3D"http://www.cancerjournal.net/articleStatistics.asp?issn=3D0973-14=
82;year=3D2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfrie=
d;aid=3DJCanResTher_2009_5_9_7_55134">Access=20
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            height=3D20><B>&nbsp;&gt;&nbsp; </B><A=20
            =
href=3D"http://www.cancerjournal.net/readercomments.asp?issn=3D0973-1482;=
year=3D2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried;a=
id=3DJCanResTher_2009_5_9_7_55134">Reader=20
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          onmouseout=3DnavleftMouseOut(this); width=3D"100%"=20
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            =
href=3D"http://www.cancerjournal.net/notifyme.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried;aid=3DJC=
anResTher_2009_5_9_7_55134">Email=20
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          onmouseout=3DnavleftMouseOut(this); width=3D"100%"=20
            height=3D20><B>&nbsp;&gt;&nbsp; </B><A=20
            =
href=3D"http://www.cancerjournal.net/favorites.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried;aid=3DJC=
anResTher_2009_5_9_7_55134">Add=20
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        <TR>
          <TD class=3Dempty align=3Dright width=3D"100%" height=3D20>* =
Registration=20
            required (free)&nbsp;&nbsp; =
</TD></TR></TBODY></TABLE><BR>&nbsp;=20
      <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%" border=3D0>
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        <TR>
          <TD class=3DnavCell width=3D"100%" height=3D4>&nbsp;</TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#abstract=
">Abstract</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Brain Cancer Persists as a Major Disease of =
Mortality and Morbidity"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Brain =
Cancer Persists as a Major Disease of Mortality and Morbidity">Brain=20
            Cancer Per...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Metabolic Control Theory/Analysis"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Metaboli=
c Control Theory/Analysis">Metabolic=20
            Contro...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Adaptability and Variability Selection"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Adaptabi=
lity and Variability Selection">Adaptability=20
            and...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Energy Metabolism in Brain Tumors"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Energy =
Metabolism in Brain Tumors">Energy=20
            Metabolis...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Complicating Issues for Implementing Diet Therapy =
for Malignant Brain Cancer"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Complica=
ting Issues for Implementing Diet Therapy for Malignant Brain =
Cancer">Complicating=20
            Iss...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            title=3D"Guidelines for Implementing Dietary Management of =
Malignant Brain Cancer"=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Guidelin=
es for Implementing Dietary Management of Malignant Brain =
Cancer">Guidelines=20
            for I...</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A =
title=3DConclusions=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Conclusi=
ons">Conclusions</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A =
title=3DAcknowledgements=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Acknowle=
dgements">Acknowledgements</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#Referenc=
e">References</A></TD></TR>
        <TR>
          <TD class=3DnavCell colSpan=3D2 height=3D1></TD></TR>
        <TR>
          <TD class=3Dleftnavcell onmouseover=3DnavleftMouseOver(this);=20
          onmouseout=3DnavleftMouseOut(this); colSpan=3D2=20
            height=3D20>&nbsp;<B>&gt;</B>&nbsp;&nbsp;<A title=3Dafigs=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#afigs">A=
rticle=20
            Figures</A></TD></TR></TBODY></TABLE><BR>
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width=3D"100%">
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          <TD class=3DnavCell colSpan=3D2 height=3D4>&nbsp;</TD></TR>
        <TR>
          <TD class=3Dleftnavcell colSpan=3D2 =
height=3D25><B>&nbsp;Article Access=20
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                <TD width=3D"100%" colSpan=3D3><FONT =
class=3DtocAT><B>REVIEW=20
                  ARTICLE</B></FONT></TD></TR>
              <TR>
                <TD width=3D"33%" height=3D5></TD>
                <TD width=3D"33%" height=3D5></TD>
                <TD width=3D"34%" height=3D5></TD></TR>
              <TR>
                <TD class=3Dother width=3D"100%" colSpan=3D3><B>Year =
</B>:=20
                  2009&nbsp; |&nbsp; <B>Volume</B> : 5&nbsp; |&nbsp;=20
                  <B>Issue</B> : 9&nbsp; |&nbsp; <B>Page</B> : =
7-15</TD></TR>
              <TR>
                <TD class=3Dother width=3D"100%"=20
            colSpan=3D3>&nbsp;</TD></TR></TBODY></TABLE>
            <P><FONT class=3DsTitle>Targeting energy metabolism in brain =
cancer=20
            through calorie restriction and the ketogenic=20
            diet</FONT><BR><BR><FONT class=3DarticleAuthor>B Thomas N =
Seyfried,=20
            Michael Kiebish, Jeremy Marsh, Purna =
Mukherjee</FONT><BR><FONT=20
            class=3DAuthorAff>&nbsp;Department of Biology, Boston =
College,=20
            Chestnut Hill, MA 02467, USA<BR></FONT><BR>
            <TABLE class=3DPrePublication width=3D"40%" border=3D0>
              <TBODY>
              <TR>
                <TD height=3D1>Date of Web Publication</TD>
                <TD>21-Aug-2009</TD></TR></TBODY></TABLE></P>
            <P><FONT class=3DCorrsAdd><B>Correspondence =
Address</B>:<BR>B Thomas N=20
            Seyfried<BR>Department of Biology, Boston College, Chestnut =
Hill, MA=20
            02467 <BR>USA<BR><A=20
            =
href=3D"http://www.cancerjournal.net/login.asp?rd=3Darticle.asp?issn=3D09=
73-1482;year=3D2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSe=
yfried"><IMG=20
            alt=3D"Login to access the Email id"=20
            src=3D"http://www.medknow.com/images/email.gif" =
border=3D0></A>
            <P><B>Source of Support:</B> None, <B>Conflict of =
Interest:</B>=20
            None</P><B>DOI:</B>&nbsp;10.4103/0973-1482.55134<BR><BR><A=20
            =
href=3D"http://www.copyright.com/ccc/openurl.do?sid=3DMedknow&amp;issn=3D=
0973-1482&amp;servicename=3Dall&amp;WT.mc_id=3DMedknow"=20
            target=3D_blank><IMG alt=3D"Get Permissions"=20
            src=3D"http://www.medknow.com/journals/images/gp.gif"=20
            border=3D0></A></FONT>=20
            <P></P>
            <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
border=3D0>
              <TBODY>
              <TR>
                <TD class=3DinsideLine width=3D"100%"=20
            height=3D1></TD></TR></TBODY></TABLE>&nbsp;<BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub width=3D"85%" =
height=3D15>&nbsp;&gt;<A=20
                  name=3Dabstract></A>&nbsp;Abstract</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD width=3D"15%" height=3D15></TD></TR></TBODY></TABLE>
            <P class=3Dabst>Malignant brain tumors are a significant =
health=20
            problem in children and adults and are largely unmanageable. =
As a=20
            metabolic disorder involving the dysregulation of glycolysis =
and=20
            respiration (the Warburg effect), malignant brain cancer can =
be=20
            managed through changes in metabolic environment. In =
contrast to=20
            malignant brain tumors that are mostly dependent on =
glycolysis for=20
            energy, normal neurons and glia readily transition to ketone =
bodies=20
            (&#946;-hydroxybutyrate) for energy in vivo when glucose =
levels are=20
            reduced. The transition from glucose to ketone bodies as a =
major=20
            energy source is an evolutionary conserved adaptation to =
food=20
            deprivation that permits the survival of normal cells during =
extreme=20
            shifts in nutritional environment. Only those cells with a =
flexible=20
            genome, honed through millions of years of environmental =
forcing and=20
            variability selection, can transition from one energy state =
to=20
            another. We propose a different approach to brain cancer =
management=20
            that exploits the metabolic flexibility of normal cells at =
the=20
            expense of the genetically defective and less metabolically =
flexible=20
            tumor cells. This approach to brain cancer management is =
supported=20
            from recent studies in orthotopic mouse brain tumor models =
and in=20
            human pediatric astrocytoma treated with calorie restriction =
and the=20
            ketogenic diet. Issues of implementation and use protocols =
are=20
            discussed.</P><BR>
            <P class=3Dkyds><B>Keywords:</B>&nbsp;Angiogenesis, =
apoptosis, calorie=20
            restriction, glioma, inflammation, ketone bodies, metabolic =
control=20
            analysis, vascularity</P><BR>
            <TABLE class=3Dsitethis width=3D"100%" border=3D0>
              <TBODY>
              <TR>
                <TD class=3Dother><B>How to cite this =
article:</B><BR>Seyfried=20
                  BT, Kiebish M, Marsh J, Mukherjee P. Targeting energy=20
                  metabolism in brain cancer through calorie restriction =
and the=20
                  ketogenic diet. J Can Res Ther=20
            2009;5:7-15</TD></TR></TBODY></TABLE><BR>
            <TABLE class=3Dsitethis width=3D"100%" border=3D0>
              <TBODY>
              <TR>
                <TD class=3Dother><B>How to cite this =
URL:</B><BR>Seyfried BT,=20
                  Kiebish M, Marsh J, Mukherjee P. Targeting energy =
metabolism=20
                  in brain cancer through calorie restriction and the =
ketogenic=20
                  diet. J Can Res Ther [serial online] 2009 =
[cited&nbsp;2010 Apr=20
                  2];5:7-15. Available from:&nbsp;<A=20
                  =
href=3D"http://www.cancerjournal.net/text.asp?2009/5/9/7/55134">http://ww=
w.cancerjournal.net/text.asp?2009/5/9/7/55134</A></TD></TR></TBODY></TABL=
E><BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Brain Cancer Persists as a Major Disease of =
Mortality and Morbidity"></A>&nbsp;&gt;&nbsp;Brain=20
                  Cancer Persists as a Major Disease of Mortality and=20
                Morbidity</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  =
border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>Malignant brain=20
            cancer is a catastrophic disease of morbidity and mortality =
in=20
            adults and is the second leading cause of cancer death in =
children.=20
            <SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref1"=20
            name=3Dft1>[1]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref2"=20
            name=3Dft2>[2]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref3"=20
            name=3Dft3>[3]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref4"=20
            name=3Dft4>[4]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref5"=20
            name=3Dft5>[5]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref6"=20
            name=3Dft6>[6]</A></SUP> Despite advances in imaging =
technologies, the=20
            standard therapies for malignant gliomas today are basically =
the=20
            same as they have been for over five decades and generally =
involve=20
            surgical resection followed by chemotherapy with or without=20
            radiation therapy.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref2"=20
            name=3Dft2>[2]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref7"=20
            name=3Dft7>[7]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref8"=20
            name=3Dft8>[8]</A></SUP> While these therapies may manage =
glioma=20
            growth over a short term (weeks to months), they can =
facilitate=20
            glioma recurrence and enhance growth rate over the longer=20
            term.<SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A></SUP> Surgical resection induces =
wound-associated=20
            growth factor production, whereas radiation therapy produces =

            oxidative tissue damage creating a microenvironment that =
facilitates=20
            aggressive tumor recurrence and formation of =
macrophage/tumor cell=20
            fusion hybrids.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A></SUP> Fusion hybrids are destabilized and =
invasive=20
            tumor cells representing the pinnacle of biological =
chaos.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref10"=20
            name=3Dft10>[10]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref11"=20
            name=3Dft11>[11]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref12"=20
            name=3Dft12>[12]</A></SUP> In view of the adverse biological =

            consequences of conventional surgical and radiation =
therapies, it is=20
            remarkable that some glioblastoma patients can survive for =
as long=20
            as 2 years following these procedures. It is our opinion =
that the=20
            brain of glioma patients should rarely, be irradiated and =
that=20
            radiation therapy for brain cancer management does more harm =
than=20
            good. The calorically restricted ketogenic diet (CRKD, =
described=20
            below) will be more effective than radiation therapy for =
long-term=20
            brain cancer management and will not harm=20
            patients.<BR><BR>Conventional chemotherapy has faired little =
better=20
            than radiation therapy for the long-term management of =
malignant=20
            brain cancer. Brain tumor chemotherapy is often associated =
with=20
            severe adverse effects that diminish the length or quality =
of=20
            life.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref8"=20
            name=3Dft8>[8]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref13"=20
            name=3Dft13>[13]</A></SUP> Indeed, bevacizumab and =
irinotecan therapy=20
            for malignant brain cancer management killed 6% of those =
taking the=20
            drug, while an additional 38% of patients had to discontinue =
the use=20
            due to toxicity issues.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref13"=20
            name=3Dft13>[13]</A></SUP> Despite the severity of these =
adverse=20
            effects, the authors consider the response to this drug =
therapy=20
            superior to that of other available antiangiogenic drug =
therapies.=20
            Although temozolomide produced slight gains in glioblastoma =
patient=20
            survival, the absence of body weight controls in the =
original study=20
            makes it difficult to determine if these gains were primary =
effects=20
            of the drug or secondary effects of caloric restriction =
involving=20
            fatigue and weight loss.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref15"=20
            name=3Dft15>[15]</A></SUP> The therapeutic targeting of =
brain=20
            tumor-associated mutations, while conceptually appealing, =
may also=20
            be problematic as hundreds of mutations can be found in =
tumors and=20
            not all tumor cells express the same mutations. Targeted =
therapies=20
            suffer from the misconception that mutations cause cancer =
when, in=20
            fact, most tumor-associated mutations arise as epiphenomena =
of tumor=20
            progression, and their association with causality is far =
from=20
            clear.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref16"=20
            name=3Dft16>[16]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref17"=20
            name=3Dft17>[17]</A></SUP> Hence, new approaches are needed =
that can=20
            better manage malignant brain tumors while permitting a =
decent=20
            quality of life.<BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Metabolic Control =
Theory/Analysis"></A>&nbsp;&gt;&nbsp;Metabolic=20
                  Control Theory/Analysis</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  =
border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>Metabolic control=20
            analysis evaluates the degree of flux in metabolic pathways =
and can=20
            be used to analyze and treat complex diseases. <SUP><A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref18"=20
            name=3Dft18>[18]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref19"=20
            name=3Dft19>[19]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref20"=20
            name=3Dft20>[20]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref21"=20
            name=3Dft21>[21]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref22"=20
            name=3Dft22>[22]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref23"=20
            name=3Dft23>[23]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref24"=20
            name=3Dft24>[24]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref25"=20
            name=3Dft25>[25]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref26"=20
            name=3Dft26>[26]</A></SUP> The approach is based on findings =
that=20
            compensatory genetic and biochemical pathways regulate the=20
            bioenergetic potential of cells and ultimately the =
phenotype.<SUP>=20
            <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref27"=20
            name=3Dft27>[27]</A></SUP> As rate-controlling enzymatic =
steps in=20
            biochemical pathways are dependent on metabolic environment, =
the=20
            management of disease phenotype depends more on the flux of =
the=20
            entire system than on any specific metabolic step or =
metabolite. In=20
            other words, complex disease phenotypes can be managed =
through=20
            self-organizing networks that display system-wide dynamics =
involving=20
            glycolysis and respiration.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> Global manipulations of these =
metabolic=20
            networks can restore orderly adaptive behavior of widely =
disordered=20
            states involving complex gene-environmental =
interactions.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref30"=20
            name=3Dft30>[30]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref31"=20
            name=3Dft31>[31]</A></SUP> <BR><BR>Abnormal energy =
metabolism and=20
            biological chaos characterize brain tumors.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref32"=20
            name=3Dft32>[32]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref33"=20
            name=3Dft33>[33]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref34"=20
            name=3Dft34>[34]</A></SUP> Consequently, the general =
principles of=20
            metabolic control analysis can be effective for brain cancer =

            management. This hypothesis is based on differences in =
energy=20
            metabolism between normal cells and neoplastic brain cells. =
As long=20
            as brain tumors are provided a physiological environment =
conducive=20
            for their glycolytic energy needs, they will survive; when =
this=20
            environment is restricted or abruptly changed, they will be =
either=20
            growth arrested or perish.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> In this report, we describe how =
diet=20
            therapies, which lower circulating glucose and elevate =
ketone bodies=20
            (acetoacetate and &#946;-hydroxybutyrate, &#946;-OHB), can =
target brain tumors=20
            while enhancing the metabolic efficiency of normal neurons =
and glia.=20
            The success of this therapeutic strategy is also based on =
the=20
            principles of evolutionary biology involving adaptability =
and=20
            variability selection.<BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Adaptability and Variability =
Selection"></A>&nbsp;&gt;&nbsp;Adaptability=20
                  and Variability Selection</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  =
border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>According to Richard=20
            Potts, the evolutionary success of our species has been due =
largely=20
            to the inheritance of traits that bestowed adaptive=20
            versatility.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref35"=20
            name=3Dft35>[35]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref36"=20
            name=3Dft36>[36]</A></SUP> These traits were honed over =
millions of=20
            years and enabled humans to adapt rapidly to abrupt changes =
in the=20
            physical environment. The adaptability to abrupt =
environmental=20
            change is a property of the genome, which was selected for =
in order=20
            to ensure survival under environmental extremes. This =
hypothesis can=20
            be extended to the individual cells of the organism, which =
exist as=20
            an integrated society of cells. The success of the organism =
in=20
            dealing with environmental stress and disease is therefore =
dependent=20
            on the integrated action of all cells in the organism. =
Further, this=20
            integrated action depends on the flexibility of each cell's =
genome,=20
            which must respond to both internal and external signals.=20
            Environmental forcing has therefore selected for those =
genomes most=20
            capable of adapting to change in order to maintain =
homeostasis.<SUP>=20
            <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref35"=20
            name=3Dft35>[35]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref36"=20
            name=3Dft36>[36]</A></SUP> <BR><BR>In contrast to normal =
cells, which=20
            readily adapt to environmental stress through integrated =
genetic=20
            modifications, tumor cells have lost their adaptability due =
to=20
            accumulated genetic mutations and genomic rearrangements. =
These=20
            genetic defects generally involve the inactivation of tumor=20
            suppressor genes and activation of oncogenes or aneuploidy. =
The=20
            widely held notion that tumor cells are somehow hardy or =
tough and=20
            resistant to death (programmed or nonprogrammed) is a gross=20
            misconception.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> How can tumor cells that express =
multiple=20
            types and kinds of genetic mutations be more fit and hardy =
than=20
            normal cells that possess a flexible genome with adaptive=20
            versatility? Reduced genomic flexibility will increase=20
            susceptibility to environmental stress and the likelihood of =
cell=20
            death. Regardless of when or how genomic defects become =
involved in=20
            the initiation or progression of tumors, these defects can =
be=20
            exploited for the metabolic destruction or management of the =
tumor=20
            according to the principles of evolutionary biology and =
metabolic=20
            control analysis.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> Our recent findings using calorie =

            restricted diets, that produce energy stress, provide direct =
support=20
            for this hypothesis.<SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref37"=20
            name=3Dft37>[37]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref38"=20
            name=3Dft38>[38]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A></SUP> <BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Energy Metabolism in Brain =
Tumors"></A>&nbsp;&gt;&nbsp;Energy=20
                  Metabolism in Brain Tumors</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>While =
glucose is the=20
            preferred energy substrate of normal neurons and glia, these =
cells=20
            will metabolize ketone bodies (&#946;-hydroxybutyrate and =
acetoacetate)=20
            for energy under fasting-induced reductions of blood =
glucose. This=20
            is a conserved physiological adaptation to prolonged food=20
            restriction and evolved to enhance survival and maintain =
adequate=20
            brain function while sparing proteins.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref40"=20
            name=3Dft40>[40]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref41"=20
            name=3Dft41>[41]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref42"=20
            name=3Dft42>[42]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref43"=20
            name=3Dft43>[43]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref44"=20
            name=3Dft44>[44]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref45"=20
            name=3Dft45>[45]</A></SUP> In contrast to normal brain, =
which can=20
            oxidize either glucose or ketone bodies for energy, =
malignant brain=20
            tumors from either humans or animal models lack metabolic=20
            flexibility and are largely dependent on glucose for =
energy.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref33"=20
            name=3Dft33>[33]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref46"=20
            name=3Dft46>[46]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref47"=20
            name=3Dft47>[47]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref48"=20
            name=3Dft48>[48]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref49"=20
            name=3Dft49>[49]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref50"=20
            name=3Dft50>[50]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref51"=20
            name=3Dft51>[51]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref52"=20
            name=3Dft52>[52]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref53"=20
            name=3Dft53>[53]</A></SUP> Enhanced glycolysis produces =
excess lactic=20
            acid that can return to the tumor as glucose through the =
<FONT=20
            class=3Dspl>&nbsp;Cori cycle&nbsp;</FONT><A=20
            href=3D"javascript:openWin('speciallinks.asp?id=3D2741')" =
;><FONT=20
            class=3Dother><SUP>More Details</SUP></FONT></A>.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref54"=20
            name=3Dft54>[54]</A></SUP> Although some neural tumors =
metabolize=20
            ketone bodies, this metabolism is largely for lipid =
synthesis rather=20
            than for energy production.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref55"=20
            name=3Dft55>[55]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref56"=20
            name=3Dft56>[56]</A></SUP> Many brain tumors also have a =
reduced=20
            activity of succinyl-CoA: 3-ketoacid CoA transferase, the=20
            rate-controlling step for utilizing &#946;-OHB as a =
respiratory=20
            fuel.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref57"=20
            name=3Dft57>[57]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref58"=20
            name=3Dft58>[58]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref59"=20
            name=3Dft59>[59]</A></SUP> Although glutamine may provide =
energy to=20
            some nonneural tumors, glutamine stimulates glycolysis in C6 =
rat=20
            glioma cells and may not serve as a direct respiratory =
fuel.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref60"=20
            name=3Dft60>[60]</A></SUP> Considered together, these =
studies indicate=20
            that brain tumors either lack or have reduced capacity to =
metabolize=20
            &#946;-OHB for energy and, like most malignant tumors, =
depend heavily on=20
            glycolysis for their metabolic energy.<BR><BR>In addition to =

            glycolytic dependence, most tumors including brain tumors =
express=20
            abnormalities in the number and function of their =
mitochondria.<SUP>=20
            <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref50"=20
            name=3Dft50>[50]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref61"=20
            name=3Dft61>[61]</A></SUP> Such abnormalities would prevent =
the=20
            bioenergetic utilization of ketone bodies, which require =
functional=20
            mitochondria for oxidation.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref62"=20
            name=3Dft62>[62]</A></SUP> Warburg originally emphasized =
that the high=20
            glycolytic rate of tumors resulted from diminished or =
disturbed=20
            respiration.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref63"=20
            name=3Dft63>[63]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref64"=20
            name=3Dft64>[64]</A></SUP> While most cells die from damaged =

            respiration, those cells that can enhance and modify their =
anaerobic=20
            glycolysis in response to respiratory damage will survive =
and form=20
            tumors. Later studies in a variety of neural and nonneural =
tumor=20
            systems showed that these respiratory disturbances could =
involve=20
            abnormalities in TCA cycle components, alterations in =
electron=20
            transport, and deficiencies in oxidative =
phosphorylation.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref46"=20
            name=3Dft46>[46]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref65"=20
            name=3Dft65>[65]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref66"=20
            name=3Dft66>[66]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref67"=20
            name=3Dft67>[67]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref68"=20
            name=3Dft68>[68]</A></SUP> While mitochondrial DNA mutations =
might=20
            also diminish respiration, most described mutations are=20
            nonpathological and may result from methodological =
problems.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref69"=20
            name=3Dft69>[69]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref70"=20
            name=3Dft70>[70]</A></SUP> Structural defects of the inner=20
            mitochondrial membrane, that would alter the proton motive =
gradient,=20
            could also prevent normal ATP production despite the =
appearance of=20
            oxidative metabolism, i.e., oxygen consumption and CO<SUB> =
2</SUB>=20
            production.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref66"=20
            name=3Dft66>[66]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref71"=20
            name=3Dft71>[71]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref72"=20
            name=3Dft72>[72]</A></SUP> Uncoupled mitochondria could give =
the=20
            appearance of normal respiration. Considered together, these =

            findings indicate that brain tumors suffer from reduced =
respiratory=20
            capacity coupled to an increased glycolysis and lactic acid=20
            production, i.e., the Warburg effect.<BR><BR>Although =
aerobic=20
            glycolysis characterizes many tumors, Warburg considered =
these=20
            phenomena too labile or too dependent on environmental =
conditions to=20
            be reliable indicators of tumor metabolism.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref64"=20
            name=3Dft64>[64]</A></SUP> Rather, he emphasized the =
importance of=20
            defects in the coordination of glycolysis with respiration. =
The=20
            latency between tumor initiation and progression was =
considered the=20
            period necessary to disconnect respiration from glycolysis.=20
            Considerable effort is underway to explain the Warburg =
effect.=20
            <SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref73"=20
            name=3Dft73>[73]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref74"=20
            name=3Dft74>[74]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref75"=20
            name=3Dft75>[75]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref76"=20
            name=3Dft76>[76]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref77"=20
            name=3Dft77>[77]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref78"=20
            name=3Dft78>[78]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref79"=20
            name=3Dft79>[79]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref80"=20
            name=3Dft80>[80]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref81"=20
            name=3Dft81>[81]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref82"=20
            name=3Dft82>[82]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref83"=20
            name=3Dft83>[83]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref84"=20
            name=3Dft84>[84]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref85"=20
            name=3Dft85>[85]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref86"=20
            name=3Dft86>[86]</A></SUP> Regardless of how the Warburg =
effect=20
            becomes established in tumor cells, a dependence on glucose =
for=20
            survival together with multiple types of mutations and =
mitochondrial=20
            defects makes most tumors vulnerable to management through=20
            principles of evolutionary biology and metabolic control =
analysis as=20
            we recently described.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> Our recent studies with caloric =
restriction=20
            and the ketogenic diet provide support for this =
hypothesis.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A></SUP> <BR><BR><B>Dietary energy =
metabolism and=20
            brain cancer <BR><BR></B><I>The ketogenic diet<BR><BR></I>In =
1995,=20
            Nebeling and coworkers attempted the first nutritional =
metabolic=20
            therapy for human malignant brain cancer using the ketogenic =

            diet.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref87"=20
            name=3Dft87>[87]</A></SUP> The ketogenic diet (KD) is a =
high-fat=20
            low-carbohydrate diet that has been used for decades as an =
effective=20
            therapy for refractory seizures in children.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref88"=20
            name=3Dft88>[88]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref90"=20
            name=3Dft90>[90]</A></SUP> The objective of the study was to =
shift the=20
            prime substrate for energy metabolism from glucose to ketone =
bodies=20
            in order to disrupt tumor metabolism while maintaining the=20
            nutritional status of patients.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref87"=20
            name=3Dft87>[87]</A></SUP> The patients in this landmark =
clinical=20
            study included two female children with nonresectable =
advanced stage=20
            brain tumors (anaplastic astrocytoma stage IV and cerebellar =

            astrocytoma stage III). A measurable tumor remained in both =
subjects=20
            following extensive radiation and chemotherapy. Although =
severe=20
            life-threatening adverse effects occurred from the radiation =
and=20
            chemotherapy, both children responded remarkably well to the =
KD and=20
            experienced long-term tumor management without further =
chemo- or=20
            radiation therapy. Indeed, one of the patients was still =
alive at=20
            the time of this writing (Nebeling, personal communication). =

            Positron emission tomography with fluoro-deoxy-glucose =
(FDG-PET)=20
            also showed a 21.8% reduction in glucose uptake at the tumor =
site in=20
            both subjects on the KD.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref87"=20
            name=3Dft87>[87]</A></SUP> These findings indicated that the =

            calorically restricted diet, which lowered glucose and =
elevated=20
            ketone bodies, reduced glycolytic energy metabolism in these =
brain=20
            tumors. The KD is also most effective for seizure management =
when=20
            given in calorically restricted amounts.<SUP> <A class=3Dref =

            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref31"=20
            name=3Dft31>[31]</A></SUP> <BR><BR>Despite the efficacy of =
this=20
            therapeutic approach together with the absence of adverse =
side=20
            effects, no further human studies or clinical trials have =
been=20
            conducted on the therapeutic efficacy of the calorie =
restricted=20
            ketogenic diet (CRKD) for brain cancer in either children or =
adults.=20
            The reason for this is not clear but appears to reflect a =
preference=20
            by the North America Brain Tumor Collaborative for using=20
            "hand-me-down" drug therapies from other cancer studies =
rather than=20
            exploring less costly and more effective alternative=20
            approaches.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref8"=20
            name=3Dft8>[8]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref13"=20
            name=3Dft13>[13]</A></SUP> This is unfortunate as our recent =
findings=20
            in brain tumor animal models show that the therapeutic =
potential of=20
            the CRKD, involving reduced glucose and elevated b-OHB is =
likely to=20
            be greater than that for any current brain tumor =
therapy.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A></SUP> Moreover, the CRKD would =
eliminate or=20
            greatly reduce the need for adjuvant anticonvulsant and =
steroidal=20
            medications for brain tumor patients as the CRKD was =
designed as an=20
            antiepileptic therapy and, when administered in restricted =
amounts,=20
            will naturally elevate circulating glucocorticoid =
levels.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref88"=20
            name=3Dft88>[88]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref90"=20
            name=3Dft90>[90]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref91"=20
            name=3Dft91>[91]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref92"=20
            name=3Dft92>[92]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref93"=20
            name=3Dft93>[93]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref94"=20
            name=3Dft94>[94]</A></SUP> These findings indicate that the =
CRKD would=20
            be an effective multifactorial diet therapy for malignant =
brain=20
            cancer and should be considered seriously as a therapeutic=20
            option.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A></SUP> <BR><BR><B>Dietary energy=20
            restriction<BR><BR></B>We recently confirmed the findings of =
the=20
            Nebeling group in a series of orthotopic mouse brain tumor =
models=20
            treated with the CRKD and dietary energy restriction<SUP> <A =

            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref37"=20
            name=3Dft37>[37]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref38"=20
            name=3Dft38>[38]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A></SUP> <A class=3Dref=20
            =
href=3D"javascript:omovimg('viewimaget.asp?img=3DJCanResTher_2009_5_9_7_5=
5134_f1.jpg')">[Figure=20
            1]</A>. As with the KD, dietary restriction (DR) reduces =
glucose and=20
            elevates ketone bodies.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref30"=20
            name=3Dft30>[30]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref31"=20
            name=3Dft31>[31]</A></SUP> The DR-induced inhibition of =
brain tumor=20
            growth is directly correlated with reduced levels of glucose =
and=20
            elevated levels of ketone bodies.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A></SUP> The gradual transition from =
glucose to=20
            ketone bodies as an energy source is the key to the =
long-term=20
            management of brain tumors. DR is produced from a total =
restriction=20
            of dietary nutrients and differs from starvation in that DR =
reduces=20
            total caloric energy intake without causing anorexia or=20
            malnutrition.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref20"=20
            name=3Dft20>[20]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref95"=20
            name=3Dft95>[95]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref96"=20
            name=3Dft96>[96]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref97"=20
            name=3Dft97>[97]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref98"=20
            name=3Dft98>[98]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref99"=20
            name=3Dft99>[99]</A></SUP> As a natural dietary therapy, DR =
improves=20
            health, prevents tumor formation, and reduces =
inflammation.<SUP> <A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref20"=20
            name=3Dft20>[20]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref97"=20
            name=3Dft97>[97]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref100" =

            name=3Dft100>[100]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref101" =

            name=3Dft101>[101]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref102" =

            name=3Dft102>[102]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref103" =

            name=3Dft103>[103]</A></SUP> <BR><BR>Previous studies showed =
that the=20
            antitumor effects of DR result from caloric restriction =
<I>per=20
            se</I> and not from the restriction of any specific dietary=20
            component such as proteins, vitamins, minerals, fats, or=20
            carbohydrates.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref98"=20
            name=3Dft98>[98]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref99"=20
            name=3Dft99>[99]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref104" =

            name=3Dft104>[104]</A></SUP> Calorie restriction, that =
lowers glucose=20
            and elevates ketone bodies,<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref30"=20
            name=3Dft30>[30]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref31"=20
            name=3Dft31>[31]</A></SUP> improves the mitochondrial =
respiratory=20
            function and glutathione redox state in normal cells.<SUP> =
<A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref105" =

            name=3Dft105>[105]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref106" =

            name=3Dft106>[106]</A></SUP> Ketone bodies can also protect =
normal=20
            neurons and glia from damage associated with aggressive =
tumor growth=20
            through a variety of neuroprotective mechanisms.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref43"=20
            name=3Dft43>[43]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref62"=20
            name=3Dft62>[62]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref107" =

            name=3Dft107>[107]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref108" =

            name=3Dft108>[108]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref109" =

            name=3Dft109>[109]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref110" =

            name=3Dft110>[110]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref111" =

            name=3Dft111>[111]</A></SUP> Although elevated ketone bodies =
are often=20
            associated with diabetic states, ketone body elevation in =
people=20
            with normal physiology is considered "good medicine" and =
therapeutic=20
            for a broad range of neurological and neurodegenerative=20
            diseases.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref23"=20
            name=3Dft23>[23]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref41"=20
            name=3Dft41>[41]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref43"=20
            name=3Dft43>[43]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref112" =

            name=3Dft112>[112]</A></SUP> Thus, DR naturally inhibits =
glycolysis=20
            and tumor growth by lowering glucose while, at the same =
time,=20
            enhancing the health and vitality of normal cells and =
tissues=20
            through ketone body metabolism.<BR><BR><I>Dietary =
restriction is=20
            antiangiogenic and proapoptotic<BR><BR></I>Rous first =
suggested in=20
            1914 that DR might inhibit tumor growth by delaying tumor=20
            vascularity (angiogenesis) from the host.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref113" =

            name=3Dft113>[113]</A></SUP> Angiogenesis involves =
neovascularization=20
            or the formation of new capillaries from existing blood =
vessels and=20
            is associated with the processes of tissue inflammation, =
wound=20
            healing, and tumorigenesis.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref114" =

            name=3Dft114>[114]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref115" =

            name=3Dft115>[115]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref116" =

            name=3Dft116>[116]</A></SUP> A significant literature =
suggests that=20
            vascularity is rate limiting for the formation of solid =
tumors,=20
            including brain tumors.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref117" =

            name=3Dft117>[117]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref118" =

            name=3Dft118>[118]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref119" =

            name=3Dft119>[119]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref120" =

            name=3Dft120>[120]</A></SUP> The malignancy and invasiveness =
of brain=20
            tumors is also correlated with the degree of their =
vascularity since=20
            prognosis is generally better for tumors that are less =
vascular than=20
            for those that are more vascular.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref117" =

            name=3Dft117>[117]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref121" =

            name=3Dft121>[121]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref122" =

            name=3Dft122>[122]</A></SUP> The inhibition of vascularity =
is=20
            therefore considered an important therapeutic strategy for =
managing=20
            brain tumors.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref13"=20
            name=3Dft13>[13]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref123" =

            name=3Dft123>[123]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref124" =

            name=3Dft124>[124]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref125" =

            name=3Dft125>[125]</A></SUP> The challenge is to target =
tumor=20
            angiogenesis without harming patients or reducing the =
quality of=20
            life. <BR><BR>We recently corroborated the Rous hypothesis =
in our=20
            mouse and human brain tumor models by showing that DR is=20
            antiangiogenic <A class=3Dref=20
            =
href=3D"javascript:omovimg('viewimaget.asp?img=3DJCanResTher_2009_5_9_7_5=
5134_f2.jpg')">[Figure=20
            2]</A>. DR also reduces angiogenesis in prostate and breast=20
            cancer.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref104" =

            name=3Dft104>[104]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref126" =

            name=3Dft126>[126]</A></SUP> As DR targets brain tumor =
angiogenesis=20
            naturally, while also enhancing the health and vitality of =
normal=20
            brain cells, we suggest that the antiangiogenic effects of =
DR or=20
            CRKDs will be greater than that of any known antiangiogenic =
drug=20
            therapy for brain tumors including those involving =
metronomic=20
            applications.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref14"=20
            name=3Dft14>[14]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref38"=20
            name=3Dft38>[38]</A></SUP> Clinical trials with glioblastoma =
patients=20
            could support our hypothesis.<BR><BR>Our findings with mouse =
brain=20
            tumor models show that the antiangiogenic effects of DR =
arise from=20
            reduced tumor energy metabolism due to DR. This is important =
since=20
            the angiogenic properties of most human gliomas are closely =
linked=20
            to the metabolic activity.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref127" =

            name=3Dft127>[127]</A></SUP> DR or therapeutic fasting can =
also reduce=20
            cerebral blood flow and oxygen consumption that would =
further stress=20
            brain tumor cells already weakened from reduced glucose =
levels.<SUP>=20
            <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref41"=20
            name=3Dft41>[41]</A></SUP> Besides reducing angiogenesis, DR =
also=20
            significantly increases brain tumor apoptosis.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref37"=20
            name=3Dft37>[37]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref38"=20
            name=3Dft38>[38]</A></SUP> This was associated with enhanced =
caspase-3=20
            activation and poly(ADP-ribose) polymerase cleavage in mouse =
brain=20
            tumors. The proapoptotic effects of DR occur in large part =
from=20
            reduced glycolytic energy that most tumors rely upon for=20
            growth.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref52"=20
            name=3Dft52>[52]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref128" =

            name=3Dft128>[128]</A></SUP> This could kill tumor cells by =
depleting=20
            available energy or by creating oxidative stress through =
glucose=20
            deprivation.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref129" =

            name=3Dft129>[129]</A></SUP> <BR><BR>Reduced glycolytic =
energy would=20
            also reduce lactate levels. This is important since lactate =
can=20
            enhance tumor inflammation.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref130" =

            name=3Dft130>[130]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref131" =

            name=3Dft131>[131]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref132" =

            name=3Dft132>[132]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref133" =

            name=3Dft133>[133]</A></SUP> Previous studies show that DR =
also=20
            reduces inflammation and the inflammatory properties of =
macrophages,=20
            while enhancing their phagocytic activities.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref102" =

            name=3Dft102>[102]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref134" =

            name=3Dft134>[134]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref135" =

            name=3Dft135>[135]</A></SUP> An uncoupling of the =
detrimental=20
            inflammatory properties of tumor-associated macrophages from =
their=20
            beneficial phagocytic properties (to remove tumor cell =
corpses) is=20
            considered essential for the eventual management of brain=20
            cancer.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref9"=20
            name=3Dft9>[9]</A></SUP> Hence diet therapies, which lower =
glucose=20
            availability and elevate ketone bodies, can reduce brain =
tumor=20
            growth through integrated anti-inflammatory, antiangiogenic, =
and=20
            proapoptotic mechanisms. <BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Complicating Issues for Implementing Diet =
Therapy for Malignant Brain Cancer"></A>&nbsp;&gt;&nbsp;Complicating=20
                  Issues for Implementing Diet Therapy for Malignant =
Brain=20
                Cancer</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  =
border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>Several complicating=20
            issues can arise in attempting to implement calorically =
restricted=20
            diets for brain cancer management. The first issue is the=20
            nonconventional and nonpharmacological nature of the diet =
therapy.=20
            Modern medicine does not look favorably on diet therapies =
for=20
            complex diseases especially when well-established parameters =
for=20
            acceptable clinical practice are available, regardless of =
their poor=20
            efficacy. In the case of brain cancer management, these =
approved=20
            practices generally involve surgical resection followed a =
few weeks=20
            later by either radiation therapy or radiation and =
chemotherapy. The=20
            type of therapy will usually depend on the age and health =
status of=20
            the patient. However, the number of older GBM patients who =
are=20
            either offered no therapy or who choose no therapy appears =
to be=20
            increasing.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref3"=20
            name=3Dft3>[3]</A></SUP> On the other hand, a significant =
neurological=20
            damage often occurs in those children who survive malignant =
brain=20
            cancer.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref136" =

            name=3Dft136>[136]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref137" =

            name=3Dft137>[137]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref138" =

            name=3Dft138>[138]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref139" =

            name=3Dft139>[139]</A></SUP> These situations are =
unacceptable and=20
            highlight the inadequacies of conventional approaches to =
malignant=20
            brain cancer management in adults or children. Indeed, =
healthy=20
            long-term survivors of these conventional practices are =
generally=20
            the exception rather than the rule.<BR><BR>Despite this =
bleak=20
            situation, the brain tumor field continues with clinical =
trials=20
            using new combinations of radiation and toxic drug therapies =
in the=20
            hope of finding a therapeutic approach with an improved =
efficacy.=20
            More than 50 years of research, however, indicates that such =

            approaches are largely ineffective in extending survival or=20
            improving quality of life. It is our opinion that =
therapeutic=20
            approaches to brain cancer management, which produce adverse =
effects=20
            and reduce quality of life, should not be pursued, =
especially when=20
            more effective and less toxic alternative therapies are =
available.=20
            As most brain cancer therapies are highly toxic to cells and =

            tissues, toxicity has become the norm rather than the =
exception for=20
            new cancer therapies. The problem is in recognizing the =
existence=20
            and scientific basis for effective, nontoxic, alternative =
dietary=20
            approaches and whether these approaches can become part of =
the=20
            standard clinical practice in the field.<BR><BR>A second =
issue in=20
            implementing calorically restricted diets for brain cancer=20
            management is the simplicity of action. How can the process =
of=20
            simply lowering blood glucose while elevating ketone bodies =
through=20
            DR be so effective in managing malignant brain cancer? The=20
            simplicity of action is based on the Warburg effect, a=20
            well-established scientific fact which makes tumor cells =
dependent=20
            on glucose metabolism for their survival and reduces the =
tumor=20
            cell's ability to use ketone bodies as an alternative =
metabolic=20
            fuel.<SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A></SUP> How can a diet therapy, which =
reduces food=20
            intake and body weight, be recommended to patients who are =
already=20
            loosing body weight because of cancer cachexia? By killing=20
            glycolytically active tumor cells, the diet therapies will =
reduce=20
            tumor cachexia, which depends on the release of =
cachexia-enhancing=20
            molecules from the tumor cells.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref39"=20
            name=3Dft39>[39]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref54"=20
            name=3Dft54>[54]</A></SUP> In contrast to most conventional =
brain=20
            tumor therapies, which indiscriminately target both normal =
cells and=20
            tumor cells, DR and particularly CRKD are the only known =
therapies=20
            that can target brain tumor cells while enhancing the health =
and=20
            vitality of normal brain cells.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref87"=20
            name=3Dft87>[87]</A></SUP> In this regard, calorie =
restricted diet=20
            therapies are superior in concept and efficacy to all =
current=20
            conventional brain cancer therapies. Support for our =
position on=20
            this issue can be established through randomized controlled=20
            trials.<BR><BR>A third difficulty with calorically =
restricted diets=20
            for brain cancer management is the lack of a standardized =
use=20
            protocol. In other words, how is the diet implemented? This =
is a=20
            legitimate concern, which hinders applicability to a broad =
range of=20
            patients. Similar concerns are often raised for implementing =
the=20
            ketogenic diet as a therapy for epilepsy. Fortunately, =
several=20
            medical groups have established protocols and menus for =
implementing=20
            the ketogenic diet or low glycemic diets in children.<SUP> =
<A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref140" =

            name=3Dft140>[140]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref141" =

            name=3Dft141>[141]</A></SUP> Clinicians could adapt these =
protocols=20
            and menus for their brain cancer patients. Nebeling and =
Lerner also=20
            provided a protocol for using the medium-chain triglyceride=20
            ketogenic diet for brain cancer management.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref142" =

            name=3Dft142>[142]</A></SUP> Since most reasonably healthy =
adults can=20
            tolerate more DR than children, adults have greater =
flexibility than=20
            children in using calorically restricted diet therapies for =
brain=20
            cancer management.<BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  name=3D"Guidelines for Implementing Dietary Management =
of Malignant Brain Cancer"></A>&nbsp;&gt;&nbsp;Guidelines=20
                  for Implementing Dietary Management of Malignant Brain =

                Cancer</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>We =
suggest a=20
            sequential series of therapeutic phases for the dietary =
management=20
            of malignant brain cancer. Phase I would gradually lower =
circulating=20
            glucose levels and elevate circulating &#946;-OHB levels =
over several=20
            weeks using CRKDs or therapeutic fasting.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref29"=20
            name=3Dft29>[29]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref112" =

            name=3Dft112>[112]</A></SUP> Blood glucose ranges between =
3.0 and 3.5=20
            mM (55-65mg/dl) and &#946;-OHB ranges between 4 and7 mM =
should be=20
            effective for tumor management. These values are well within =
normal=20
            physiological ranges of glucose and ketones and will have=20
            antiangiogenic and proapoptotic effects causing metabolic =
isolation=20
            and a significant growth arrest. The importance of =
maintaining low=20
            blood glucose levels cannot be overemphasized. Caloric =
restriction=20
            provides an effective means to maintain low blood glucose =
levels.=20
            Consequently, the diet therapy will require considerable =
personal=20
            discipline, as water-only fasting will occasionally be =
required to=20
            lower glucose and elevate ketone bodies. The CRKD can reduce =
the=20
            feeling of hunger while maintaining low glucose and elevated =
ketone=20
            body levels. Glucose levels can be monitored several =
times/day with=20
            any standard glucose-meter, while blood ketone levels can be =

            monitored once/week with either a ketone-meter or with an =
enzyme=20
            assay as we described.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref30"=20
            name=3Dft30>[30]</A></SUP> A clinical chemistry laboratory =
would be=20
            needed to measure blood ketone levels using the enzyme =
assay. It is=20
            better to measure ketone levels in blood than in urine, as =
urine=20
            values may not reflect ketone body availability for energy. =
It is=20
            imperative that daily records be kept of the blood glucose =
levels=20
            and weekly records for ketone measurements. Brain tumor =
imaging=20
            analysis can be used to assess the efficacy of the diet =
therapy in=20
            tumor progression.<SUP><A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref143" =

            name=3Dft143>[143]</A></SUP> Tumor imaging using PET may be =
a problem,=20
            however, especially if the diet reduces glucose uptake. This =
would=20
            actually be a favorable outcome and suggestive of diet =
efficacy.=20
            Additionally, CRKDs would eliminate the need for =
antiepileptic drugs=20
            or steroidal medications for reasons described above. The =
use of=20
            steroids is not recommended during diet therapy as steroids =
can=20
            increase blood glucose values, which would contribute to =
tumor=20
            recurrence.<BR><BR>Phase II of the therapy would involve =
surgical=20
            resection. We suggest surgical resection as an option after =
first=20
            implementing the diet therapy. The diet should halt =
progression and=20
            more clearly delineate tumor tissue from surrounding normal =
brain=20
            tissue. Neurosurgeons should recognize that smaller brain =
tumors=20
            with reduced vascularity and clearly circumscribed =
boundaries should=20
            be easier to resect than larger brain tumors with poorly=20
            circumscribed boundaries and extensive vascularization. This =
would=20
            also insure greater debulking thereby increasing the =
likelihood=20
            long-term survival. The diet therapy could also be continued =

            following surgery to facilitate healing and to maintain =
metabolic=20
            pressure on any surviving tumor cells.<BR><BR>Finally, phase =
III=20
            could involve carefully executed weight cycling strategies =
to=20
            maintain metabolic pressure on surviving tumor cells.<SUP> =
<A=20
            class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref144" =

            name=3Dft144>[144]</A></SUP> Weight cycling for humans could =
include=20
            weekly transitions from ketogenic diets to nutritious low- =
calorie,=20
            low glycemic diets. While several investigators have =
suggested using=20
            glycolysis inhibitors to target tumor energy metabolism, =
these=20
            inhibitors will target glycolysis in both tumor cells and =
normal=20
            cells, thus potentially producing adverse effects.<SUP> <A =
class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref85"=20
            name=3Dft85>[85]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref145" =

            name=3Dft145>[145]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref146" =

            name=3Dft146>[146]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref147" =

            name=3Dft147>[147]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref148" =

            name=3Dft148>[148]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref149" =

            name=3Dft149>[149]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref150" =

            name=3Dft150>[150]</A></SUP> An interesting therapeutic =
strategy could=20
            also involve low doses of glycolysis inhibitors combined =
with the=20
            CRKD. With this approach, ketone bodies could protect normal =
cells=20
            from the adverse effects of low glucose while more =
effectively=20
            targeting the energy metabolism of the tumor cells. Studies =
are in=20
            progress to examine this possibility.<BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  =
name=3DConclusions></A>&nbsp;&gt;&nbsp;Conclusions</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>We =
provide=20
            information on a new, alternative approach to brain cancer=20
            management using calorically restricted diets. The objective =
of this=20
            new therapeutic approach is to change the metabolic =
environment of=20
            the tumor and the host. Only those cells with a normal =
flexible=20
            genome, honed through millions of years of environmental =
forcing and=20
            variability selection, are expected to survive extreme =
shifts in=20
            metabolic environment.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref28"=20
            name=3Dft28>[28]</A></SUP> Indeed, extreme conditions of =
survival and=20
            fitness will test the limits of a cell population's =
persistence in=20
            any given location over time.<SUP> <A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref35"=20
            name=3Dft35>[35]</A>,<A class=3Dref=20
            =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ref36"=20
            name=3Dft36>[36]</A></SUP> In other words, it is the theory =
of Potts=20
            applied with sustained pressure to the entire population of =
normal=20
            and neoplastic brain cells. This therapeutic approach, =
illustrated=20
            with calorically restricted diets, will be mosre efficacious =
than=20
            current approaches for brain cancer management because it is =
based=20
            on the principles of evolutionary biology and metabolic =
control=20
            theory.<BR><BR><BR>
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub><A=20
                  =
name=3DAcknowledgements></A>&nbsp;&gt;&nbsp;Acknowledgements</TD>
                <TD class=3Dinthis align=3Dright>&nbsp;</TD>
                <TD align=3Dright width=3D"15%"><A=20
                  =
href=3D"http://www.cancerjournal.net/article.asp?issn=3D0973-1482;year=3D=
2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#top"><IM=
G=20
                  alt=3DTop=20
                  =
src=3D"http://www.cancerjournal.net/images/arrow_top.gif"=20
                  border=3D0></A></TD></TR></TBODY></TABLE><BR><BR>This =
work was=20
            supported in part from NIH grants (HD39722) and (CA102135), =
a grant=20
            from the American Institute of Cancer Research, and the =
Boston=20
            College Expense Fund. The paper was presented at the =
Symposium on<B>=20
            </B>"Applications of 2-deoxy-d-glucose in the management of =
cancer,"=20
            Institute of Nuclear Medicine and Allied Sciences,<B> =
</B>New Delhi,=20
            India,<B> </B>November 8-10, 2006.<BR><BR>&nbsp;
            <TABLE class=3DleftNav cellSpacing=3D0 cellPadding=3D0 =
width=3D"100%"=20
            border=3D0>
              <TBODY>
              <TR>
                <TD class=3DpageSub height=3D15><A=20
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2009;volume=3D5;issue=3D9;spage=3D7;epage=3D15;aulast=3DSeyfried#ft25"=20
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MG=20
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MG=20
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href=3D'+SITE_URL +'reviewers.asp>Reviewers</a>&nbsp;</td><td =
width=3D"68%">&nbsp;</td></tr></table>';

link[1]=3D'<table border=3D0 cellpadding=3D0 cellspacing=3D0 =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"10%" =
height=3D"20px">&nbsp;</td>'
link[1]+=3D'<td width=3D"19%" class=3D"topBand1Sel" =
height=3D"20px">&nbsp;&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'currentissue.asp>Current Issue</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL +'aheadofprint.asp>Ahead of =
Print</a></td><td width=3D"65%" height=3D"20px"></td></tr></table>';

link[2]=3D'<table border=3D0 cellpadding=3D0 cellspacing=3D0 =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"23%" =
height=3D"20px">&nbsp;</td>'
link[2]+=3D'<td width=3D"57%" class=3D"topBand1Sel" =
height=3D"20px">&nbsp;&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'search.asp>Simple Search</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL +'advancesearch.asp>Advanced =
Search</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu"  =
href=3D'+SITE_URL +'imagesearch.asp>Image =
Search</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu" =
href=3D'+SITE_URL +'backissues.asp>Year wise =
Issues</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu" =
href=3D"backissuesxml.asp">Year wise Issues (XML)</a></td><td =
width=3D"20%" height=3D"20px"></td></tr></table>';

link[3]=3D'<table border=3D0 cellpadding=3D0 cellspacing=3D0 =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"27%" =
height=3D"20px">&nbsp;</td>'
link[3]+=3D'<td width=3D"16%" class=3D"topBand1Sel" =
height=3D"20px">&nbsp;&nbsp;<a  class=3D"topmenu" href=3D'+SITE_URL =
+'contributors.asp>Instructions</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL +'submitarticle.asp>Online =
Submission</a></td><td width=3D"32%">&nbsp;</td></tr></table>';

link[4]=3D'<table border=3D0 cellpadding=3D0 cellspacing=3D0 =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"47%" =
height=3D"20px">&nbsp;</td>'
link[4]+=3D'<td width=3D"19%" class=3D"topBand1Sel" =
height=3D"20px">&nbsp;&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'refereeResource.asp>For Reviewers</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL +'contributors.asp>For =
Contributors</a></td><td width=3D"23%" =
height=3D"20px">&nbsp;</td></tr></table>';

link[5]=3D'<table border=3D0 cellpadding=3D0 cellspacing=3D0 =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"55%" =
height=3D"20px">&nbsp;</td>'
link[5]+=3D'<td width=3D"24%" class=3D"topBand1Sel" =
height=3D"20px">&nbsp;&nbsp;<a class=3D"topmenu"  href=3D'+SITE_URL =
+'sections.asp?id=3D1;sid=3D>Images</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a  =
class=3D"topmenu" href=3D'+SITE_URL =
+'sections.asp?id=3D2;sid=3D>Reviews</a>&nbsp;&nbsp;|&nbsp;&nbsp;&nbsp;|&=
nbsp;&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'sections.asp?id=3D4;sid=3D>Clinical Series</a></td><td =
width=3D"4%">&nbsp;</td></tr></table>';

link[6]=3D'<table border=3D0 cellpadding=3D"0" cellspacing=3D"0" =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"38%" =
height=3D"20px">&nbsp;</td>'
link[6]+=3D'<td width=3D"44%" class=3D"topBand1Sel" align=3D"right"><a =
class=3D"topmenu" href=3D'+SITE_URL +'whatsnew.asp>What\'s =
New</a>&nbsp;&nbsp;|&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'alerts.asp>Table of Contents Alerts</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL =
+'links.asp>Links</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu" =
href=3D'+SITE_URL =
+'sitestatistics.asp>Hits</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL =
+'searchmeeting.asp>Conferences</a>&nbsp;&nbsp;</td>';
link[6]+=3D'<td width=3D"10%">&nbsp;</td></tr></table>';

link[7]=3D'<table border=3D0 cellpadding=3D"0" cellspacing=3D"0" =
class=3D"topBand2" width=3D"100%"><tr><td width=3D"51%" =
height=3D"20px">&nbsp;</td>';
link[7]+=3D'<td width=3D"35%" align=3D"right" class=3D"topBand1Sel" =
height=3D"20px"><a class=3D"topmenu" href=3D'+SITE_URL =
+'addresses.asp>Addresses</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a =
class=3D"topmenu" href=3D'+SITE_URL +'advertise.asp>Advertise with =
us</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu" href=3D'+SITE_URL =
+'feedback.asp>Feedback</a>&nbsp;&nbsp;|&nbsp;&nbsp;<a class=3D"topmenu" =
href=3D'+SITE_URL +'joinus.asp>Apply as Referee </a>&nbsp;&nbsp;</td>';
link[7]+=3D'<td width=3D"2%">&nbsp;</td></tr></table>';



function lib_bwcheck(){ //Browsercheck (needed)
	this.ver=3Dnavigator.appVersion
	this.agent=3Dnavigator.userAgent
	this.dom=3Ddocument.getElementById?1:0
	this.opera5=3Dthis.agent.indexOf("Opera 5")>-1
	this.ie5=3D(this.ver.indexOf("MSIE 5")>-1 && this.dom && =
!this.opera5)?1:0;=20
	this.ie6=3D(this.ver.indexOf("MSIE 6")>-1 && this.dom && =
!this.opera5)?1:0;
	this.ie4=3D(document.all && !this.dom && !this.opera5)?1:0;
	this.ie=3Dthis.ie4||this.ie5||this.ie6
	this.mac=3Dthis.agent.indexOf("Mac")>-1
	this.ns6=3D(this.dom && parseInt(this.ver) >=3D 5) ?1:0;=20
	this.ns4=3D(document.layers && !this.dom)?1:0;
	this.bw=3D(this.ie6 || this.ie5 || this.ie4 || this.ns4 || this.ns6 || =
this.opera5)
	return this;
}




function showHideLayer(obj,visible)
{							=09
	this.evnt=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	if(!this.evnt) return false
	this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09
   	this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09
	this.css.visibility =3D visible;
	this.css.top=3D'100px';
	this.css.left=3D'12px';
	if (bw.ie5 ||bw.ie4 || bw.ie6)
		this.css.width=3D'100%';=09
	else
		this.css.width=3D'98%';=09

	this.css.position=3D"absolute";

}


function writeSubmenu(obj,item)
{							=09
   	this.evnt=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	if(!this.evnt) return false
	this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09
   	this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09
	thecontent=3D(item=3D=3D-1)? "" : link[item]
	this.wref.innerHTML=3Dthecontent;

}


function navleftMouseOver(src)
{=20

	src.className=3D"leftnavcellover";
}=20



function navleftMouseOut(src)
{=20
	src.className=3D"";
}

function navtabMouseOver(src)
{=20
	src.className=3D"topBand1MO";
}=20



function navtabMouseOut(src)
{=20
	src.className=3D"topBand1";
}


function navMouseOver(src,item)
{=20
	if (item !=3D default_menu_item)
	src.className=3D"topBand1MO";=09

}=20



function navMouseOut(src,lyr)
{=20
	if (lyr!=3Ddefault_menu_item)
	src.className=3D"topBand1";=09
}

function onlpgld(item)
{
	default_menu_item=3Ditem;=09
	resetTDs(item);
	writeSubmenu("submenu",item);
	showHideLayer("submenu","visible");
}


function navMouseBotOut(src)
{
	src.className=3D"footer";
}


function navMouseBotOver(src)
{
	src.className=3D"pageSub";
}


function menu(src,item)
{=20

=09
	default_menu_item =3D item;
	writeSubmenu("submenu",item);
	showHideLayer("submenu","visible");=09
	resetTDs(item);

}=20

function resetTDs(item)
{
	var ob;
	for(x=3D0;x<8;x++)
	{
	obj=3D"m" + x;
 	ob=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	ob.className=3D"topBand1";
	if (x =3D=3D item)
		{
		ob.className=3D"topBand1Sel";
		}=09
	}
}


function writehDetail(obj,nm,cate,sing,dble,chkout,webadd)
	{			=09

   	this.evnt=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	if(!this.evnt) return false;
	this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09
   	this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09

	var det;
	if (sing=3D=3D0){
		sing=3D"N.A";}
	else{
		sing=3D sing + " INR";}

	if (dble=3D=3D"0")
		dble =3D"N.A"
	else
		dble=3D dble+ " INR";

	if (webadd !=3D '')
	{
		=
det=3D'Hotel&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;:=
 <b>'+nm + '</b><br>Category&nbsp;&nbsp;&nbsp;&nbsp;:<b> '+ cate =
+'</b><br>Singlebed&nbsp;&nbsp;&nbsp;:<b> '+ sing =
+'</b><br>Doublebed&nbsp;&nbsp;:<b> '+ dble + =
'</b><br>Checkout&nbsp;&nbsp;&nbsp;&nbsp;: <b>' + chkout + =
'</b>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;<a target=3D"_blank" =
href=3D"'+webadd+'">More Details >></a>';
	}
	else
	{
		=
det=3D'Hotel&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;:=
 <b>'+nm + '</b><br>Category&nbsp;&nbsp;&nbsp;&nbsp;:<b> '+ cate =
+'</b><br>Singlebed&nbsp;&nbsp;&nbsp;:<b> '+ sing =
+'</b><br>Doublebed&nbsp;&nbsp;:<b> '+ dble + =
'</b><br>Checkout&nbsp;&nbsp;&nbsp;&nbsp;: <b>' + chkout + '</b>';
	}=09

	this.wref.innerHTML=3Ddet;
}


function writetoObj(obj,curr, valu)
	{=09


   	this.evnt=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	if(!this.evnt) return false;
	this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09
   	this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09
	this.wref.innerHTML=3D"<b>"+ curr+ valu + "</b>";
}
function openLogo(ClientID)
{
var attributes =3D 'toolbar=3D0,location=3D0,directories=3D0,status=3D0, =
menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D550,height=3D600,left=3D=
0,top=3D0';
sealWin=3Dwindow.open('http://www.ccavenue.com/verifySeal.jsp?ClientID=3D=
'+ClientID ,'win',attributes);=20
self.name =3D 'mainWin';=20
}
function openWin(pg)
{

	if (pg.indexOf('special') >=3D 0 )
		{
		var attributes =3D =
'toolbar=3D0,location=3D0,directories=3D0,status=3D0, =
menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D800,height=3D600,left=3D=
0,top=3D0';
		}
	else
		{
		var attributes =3D =
'toolbar=3D0,location=3D0,directories=3D0,status=3D0, =
menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D600,height=3D400,left=3D=
0,top=3D0';
		}

	sealWin=3Dwindow.open(pg ,'',attributes);=20
	self.name =3D pg;=20
}

function chkgcform(frm)
{
	if (document.gc_form.gc_login.value=3D=3D'')
	{
		alert("Please enter your Gold Con username");
		return false;
	}
	if (document.gc_form.gc_pswd.value=3D=3D'')
	{
		alert("Please enter your Gold Con password");
		return false;
	}
	return true;
}
function writetCV(obj,cv,photo)
	{=09


   	this.evnt=3Dbw.dom? =
document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay=
ers[obj]:0;
	if(!this.evnt) return false;
	this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09
   	this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09
	this.wref.innerHTML=3D"<img src=3D'gc_images/" + photo + "'><br><br>" + =
cv;
}

function valfld(field)
{

	var valid =3D "0123456789"; // these are allowed values
	var ok =3D "yes";
	var temp;
	if (field.value.length =3D=3D 0 )
	{
		//alert("Invalid entry! please enter number");
		field.value =3D ""
		field.focus();
		field.select();
		return false;=09
	}
	for (var i=3D0; i<field.value.length; i++)
	{
		temp =3D "" + field.value.substring(i, i+1);
		if (valid.indexOf(temp) =3D=3D "-1")=20
		ok =3D "no";
	}
	if (ok =3D=3D "no")=20
	{
		alert("Invalid entry! Only numbers are allowed!");
		field.value =3D ""
		field.focus();
		field.select();

		return false;
	}
	else
		return true;
	}


function chkvldemail(email_address)
   {
         //Assumes that valid email addresses consist of =
user_name@domain.tld
         at =3D email_address.indexOf('@');
         dot =3D email_address.indexOf('.');
        =20
         if(at =3D=3D -1 ||=20
            dot =3D=3D -1 ||        =20
            dot =3D=3D 0 ||=20
            dot =3D=3D email_address.length - 1)
		{alert("Please enter valid email address.");
            return(false);
		}
           =20
         user_name =3D email_address.substr(0, at);
         domain_name =3D email_address.substr(at + 1, =
email_address.length);                 =20

         if(Validate_String(user_name) =3D=3D=3D false || =
Validate_String(domain_name) =3D=3D=3D false)
		{=09
			alert("Please enter valid email address.");
	            return(false);=20
                }
         else
		 return(true);
}

function Validate_String(string, return_invalid_chars)
         {
         valid_chars =3D =
'1234567890-_.^~abcdefghijklmnopqrstuvwxyzABCDEFGHIJKLMNOPQRSTUVWXYZ';
         invalid_chars =3D '';
        =20
         if(string =3D=3D null || string =3D=3D '')
            return(true);
        =20
         //For every character on the string.  =20
         for(index =3D 0; index < string.length; index++)
            {
            charx =3D string.substr(index, 1);                       =20
           =20
            //Is it a valid character?
            if(valid_chars.indexOf(charx) =3D=3D -1)
              {
              //If not, is it already on the list of invalid characters?
              if(invalid_chars.indexOf(charx) =3D=3D -1)
                {
                //If it's not, add it.
                if(invalid_chars =3D=3D '')
                   invalid_chars +=3D charx;
                else
                   invalid_chars +=3D ', ' + charx;
                }
              }
            }                    =20
           =20
         //If the string does not contain invalid characters, the =
function will return true.
         //If it does, it will either return false or a list of the =
invalid characters used
         //in the string, depending on the value of the second =
parameter.
         if(return_invalid_chars =3D=3D true && invalid_chars !=3D '')
           {
           last_comma =3D invalid_chars.lastIndexOf(',');
          =20
           if(last_comma !=3D -1)
              invalid_chars =3D invalid_chars.substr(0, $last_comma) +=20
              ' and ' + invalid_chars.substr(last_comma + 1, =
invalid_chars.length);
                     =20
           return(invalid_chars);
           }
         else
           return(invalid_chars =3D=3D '');=20
         }

function trimstr(par)
{

while (par.charAt(0)=3D=3D" "){
par=3Dpar.replace(" ","")
}
i=3Dpar.length-1
while(par.charAt(i)=3D=3D" "){
par=3Dpar.slice(0,i)
i=3Di-1
}
return par
}

// var xyz =3D createBar(
// total_width,
// total_height,
// background_color,
// border_width,
// border_color,
// block_color,
// scroll_speed,
// block_count,
// scroll_count,
// action_to_perform_after_scrolled_n_times
// )

var w3c=3D(document.getElementById)?true:false;
var ie=3D(document.all)?true:false;
var N=3D-1;
var back_color=3D'white';
var bar_color=3D'green';
function =
createBar(w,h,bgc,brdW,brdC,blkC,speed,blocks,count,action,flag){
if(ie||w3c){

	bgc=3Dback_color;
	blkC=3Dbar_color;

if (flag!=3D''){
	h=3D13;
	}
h=3D10
var t=3D'<div id=3D"_xpbar'+(++N)+'" style=3D"visibility:visible; =
position:relative; overflow:hidden; width:'+w+'px; height:'+h+'px; =
background-color:'+bgc+'; border-color:'+brdC+'; =
border-width:'+brdW+'px; border-style:solid; font-size:1px;">';
t+=3D'<span id=3D"blocks'+N+'" style=3D"left:-'+(h*2+1)+'px; =
position:absolute; font-size:1px">';
for(i=3D0;i<blocks;i++){
t+=3D'<span style=3D"background-color:'+blkC+'; left:-'+((h*i)+i)+'px; =
font-size:1px; position:absolute; width:'+h+'px; height:'+h+'px; '
t+=3D(ie)?'filter:alpha(opacity=3D'+(100-i*(100/blocks))+')':'-Moz-opacit=
y:'+((100-i*(100/blocks))/100);
t+=3D'"></span>';
}
t+=3D'</span></div>';
document.write(t);
var =
bA=3D(ie)?document.all['blocks'+N]:document.getElementById('blocks'+N);
bA.bar=3D(ie)?document.all['_xpbar'+N]:document.getElementById('_xpbar'+N=
);
bA.blocks=3Dblocks;
bA.N=3DN;
bA.w=3Dw;
bA.h=3Dh;
bA.speed=3Dspeed;
bA.ctr=3D0;
bA.count=3Dcount;
bA.action=3Daction;
bA.togglePause=3DtogglePause;
bA.showBar=3Dfunction(){
this.bar.style.visibility=3D"visible";
}
bA.hideBar=3Dfunction(){
this.bar.style.visibility=3D"hidden";
}
bA.tid=3DsetInterval('startBar('+N+')',speed);
return bA;
}}

function startBar(bn){
var =
t=3D(ie)?document.all['blocks'+bn]:document.getElementById('blocks'+bn);
if(parseInt(t.style.left)+t.h+1-(t.blocks*t.h+t.blocks)>t.w){
t.style.left=3D-(t.h*2+1)+'px';
t.ctr++;
if(t.ctr>=3Dt.count){
eval(t.action);
t.ctr=3D0;
}}else t.style.left=3D(parseInt(t.style.left)+t.h+1)+'px';
}

function togglePause(){
if(this.tid=3D=3D0){
this.tid=3DsetInterval('startBar('+this.N+')',this.speed);
}else{
clearInterval(this.tid);
this.tid=3D0;
}}

function togglePause(){
if(this.tid=3D=3D0){
this.tid=3DsetInterval('startBar('+this.N+')',this.speed);
}else{
clearInterval(this.tid);
this.tid=3D0;
}}
function showpp(el_id)

{

	if (document.getElementById(el_id).style.display=3D=3D"")
	{
	document.getElementById(el_id).style.display=3D"none";
	}
	else
	{
	document.getElementById(el_id).style.display=3D""
	var attributes =3D =
'toolbar=3D0,location=3D0,directories=3D0,status=3D0, =
menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D1,height=3D1,left=3D0,to=
p=3D0';


	=
sealWin=3Dwindow.open('http://www.jpgmonline.com/vans.asp','',attributes)=
;=20
	}=09
}


var ns =3D (navigator.appName.indexOf("Netscape") !=3D -1);
var d =3D document;
var px =3D document.layers ? "" : "px";

function JSFX_FloatDiv(id, sx, sy)
{
	var =
el=3Ddocument.getElementById?document.getElementById(id):document.all?doc=
ument.all[id]:document.layers[id];
	window[id + "_obj"] =3D el;
	if(document.layers)el.style=3Del;
	el.cx =3D el.sx =3D sx;el.cy =3D el.sy =3D sy;
	el.sP=3Dfunction(x,y){this.style.left=3Dx+px;this.style.top=3Dy+px;};
	el.flt=3Dfunction()
	{
		var pX, pY;
		pX =3D (this.sx >=3D 0) ? 0 : ns ? innerWidth :=20
		document.documentElement && document.documentElement.clientWidth ?=20
		document.documentElement.clientWidth : document.body.clientWidth;
		pY =3D ns ? pageYOffset : document.documentElement && =
document.documentElement.scrollTop ?=20
		document.documentElement.scrollTop : document.body.scrollTop;
		if(this.sy<0)=20
		pY +=3D ns ? innerHeight : document.documentElement && =
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